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

Abstract

This application provides compounds, pharmaceutical compositions and / or dosage forms, as well as their uses. Such uses include but not limited to, treat and / or prevent hair loss or hair depigmentation.

Description

PCT PATENT APPLICATIONCOMPOSITIONS AND METHODS FOR TREATING HAIR GRAYING AND LOSS ASSOCIATED WITH AGINGACKNOWLEDGEMENT OF GOVERNMENT SUPPORT

[0001] This invention was made with government support under Grant No. CA166593 awarded by the National Institutes of Health. The government has certain rights in this invention.CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority of the U.S. Provisional Patent Application No: 63 / 625,853, filed on January 26, 2024, and entitled "COMPOSITIONS AND METHODS FOR TREATING HAIR GRAYING AND LOSS ASSOCIATED WITH AGING", the entire contents of which are herein incorporated in their entireties.FIELD OF THE DISCLOSURE

[0003] The present application relates generally to compounds and their uses in hair loss and hair depigmentation.SUMMARY OF THE DISCLOSURE

[0004] One aspect of the present disclosure encompasses a compound of Formula (I), Formula (II), Formula (II’), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof.

[0005] In Formula (I), Ri is a substituted or unsubstituted cycloalkyl, R2 is an alkyl, and R3 is a substituted or unsubstituted aryl. In Formula (II), R4 is a substituted or unsubstituted heterocycloalkyl and Rs is a substituted or unsubstituted aryl. In Formula (II’), R4’ is a substituted or unsubstituted heterocycloalkyl and Rs’ is a substituted or unsubstituted aryl. In Formula (III), Re is a substituted or unsubstituted nitrogen containing heterocycloalkyl. In Formula (IV), R7 is -NH(C=O)-Ri7 or -O(C=O)- R17 wherein R17 is substituted or unsubstituted alkyl, alkenyl, or aryl, and Rs is hydrogen or hydroxy. In one aspect, the compound is a compound of Formula (I). In another aspect, the compound of Formula (I) is a compound wherein R1 is cyclohexane, R2 is methyl, and / or R3 is a phenyl substituted with at least one alkoxy 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 wherein R4 is a substituted pyrrolidine, including but not limiting to, a pyrrolidine substituted with an alkyl or a carbonyl. In another aspect, the compound of Formula (II) is a compound wherein Rs is a phenyl substituted with a carboxylic acid or an ester, including but not limiting to, a substituted or unsubstituted azepine or a substituted or unsubstituted piperidine. In another aspect, the compound of Formula (II’) is a compound wherein R4’ is a substituted pyrrolidine, including but not limiting to, a pyrrolidine substituted with an alkyl or a carbonyl. In another aspect, the compound of Formula (II’) is a compound wherein Rs is a phenyl substituted with a carboxylic acid or an ester, including but not limiting to, a substituted or unsubstituted azepine or a substituted or unsubstituted piperidine. In one aspect, the compound is a compound of Formula III. In yet another aspect, the compound of Formula (III) is a compound wherein Re is an unsubstituted azepine, or Re is 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 wherein R7 is -NH(C=O)-Ri7, Rs is hydrogen or an alkyl, and R17 is an aryl-substituted alkenyl. In yet another aspect, the compound of Formula (IV) is a compound wherein R7 is -O(C=O)-Ar and Rs is hydroxy.

[0006] Another aspect of the present disclosure encompasses a compound of the following, or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof:

[0007] Another aspect of the present disclosure encompasses a pharmaceutical composition comprising a compound of Formula (I), Formula (II), Formula (II’), Formula (III), and / or Formula (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (HB), (IIC), (IIIA), (IIIB), (NIC), (IVA), and (IVB)), a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof; and a pharmaceutically acceptable carrier or excipient. In one aspect, the composition is for systemic delivery or local delivery.

[0008] Another aspect of the present disclosure encompasses a pharmaceutical dosage form comprising a compound of Formula (I), Formula (II), Formula (II’), Formula (III), and / or Formula (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (HB), (IIC), (IIIA), (IIIB), (NIC), (IVA), and (IVB)), a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof; and a pharmaceutically acceptable carrier or excipient. In one aspect, the dosage form comprises an oral dosage form, a topical dosage form, or a hair follicle dosage form.

[0009] Another aspect of the present disclosure encompasses a compound having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof. In another aspect, the compound has the structure of cpd34, cpd 37, cpd 65, cpd 257, cpd557, cpd 1107, cpd1840, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof. In another aspect, the compound has the structure of cpd 571 , cpd 621 , cpd 644, cpd715, cpd758, cpd 2152, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof. In yet another aspect, the compound has the structure of cpd 256, cpd 755, cpd 795, cpd 2062, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof.

[0010] Another aspect of the present disclosure encompasses a pharmaceutical composition comprising a compound of Formula (I), Formula (II), Formula (II’), Formula (III), and / or Formula (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (I IB), (IIC), (I HA), (IIIB), (NIC), (IVA), and (IVB))), or having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, a prodrug thereof, or any combination thereof. In one aspect, the composition is for systemic delivery or local delivery.

[0011] Another aspect of the present disclosure encompasses a pharmaceutical dosage form comprising a compound of Formula (I), Formula (II), Formula (II’), Formula (III), and / or Formula (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (I IB), (IIC), (I HA), (IIIB), (NIC), (IVA), and (IVB))), or having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, a prodrug thereof, or any combination thereof. In one aspect, the dosage form comprises an oral dosage form, a topical dosage form, or a hair follicle dosage form.

[0012] Another aspect of the present disclosure encompasses a method of treating hair loss and / or hair depigmentation in a subject, the method comprising administering the compound, the pharmaceutical composition or the dosage form disclosed herein to the subject. In one aspect, the hair loss and / or hair depigmentation is associated with aging. In another aspect, the subject is human. In another aspect, the subject is an elder human.

[0013] Another aspect of the present disclosure encompasses a method of activating a stem cell factor (SCF) promoter in a cell, the method comprising contacting the cell with a compound of Formula (I), Formula (II), Formula (II’), Formula (III), and / or Formula (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (I IB), (IIC), (IIIA), (I IIB), (NIC), (IVA), and (IVB))), a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, a prodrug thereof, or any combination thereof. In one aspect, the method increases SCF expression in the cell. In another aspect, the cell is a keratinocyte.

[0014] Another aspect of the present disclosure encompasses a method of activating a stem cell factor (SCF) promoter in a cell, the method comprising contacting the cell with a compound having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, a prodrug thereof, or any combination thereof. In one aspect, the method increases SCF expression in the cell. In another aspect, the cell is a keratinocyte.

[0015] Yet another aspect of the present disclosure encompasses use of one or more compounds of Formula (I), (II), (II’), (III), (IV), or one or more compounds having thestructure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, a prodrug thereof, or any combination thereof, in a method of treating hair loss and / or hair depigmentation in a subject, comprising administering the compound(s) to a subject in need of such treatment. In yet another aspect, the disclosed pharmaceutical composition and / or dosage form also encompass such use.REFERENCE TO COLOR FIGURES

[0016] The application file contains at least one photograph or drawing executed in color. Copies of this patent application publication with color photographs or drawings will be provided by the Office upon request and payment of the necessary fee.BRIEF DESCRIPTION OF THE FIGURES

[0017] FIG. 1 depicts the strategy and workflow of screening small molecules that activate stem cell factor (SCF) promoter using Green Fluorescence Protein (GFP) as a readout.

[0018] FIG. 2 provides the flow chart for the High-Throughput Screening (HTS) steps.

[0019] FIG. 3 provides the flow chart of Cherry-Pick HTS Imaging and TaqMan PCR, respectively.

[0020] FIG. 4 provides the steps of HTS Cherry-Pick images screening.

[0021] FIG. 5 shows the heatmap of 109 compounds at 0.21 pM.

[0022] FIG. 6 shows the heatmap of 126 compounds at 0.83 pM.

[0023] FIG. 7 shows the heatmap of 195 compounds at 2.5 pM.

[0024] FIG. 8 shows the heatmap of 51 compounds overlapped at all three concentrations.

[0025] FIG. 9 shows the heatmap of 51 compounds overlapped at 0.21 pM.

[0026] FIG. 10 shows the heatmap of 51 compounds overlapped at 0.83 pM.

[0027] FIG. 11 shows the heatmap of 51 compounds overlapped at 2.5 pM.

[0028] FIG. 12 shows the compound selection overlap between the HTS and TaqMan RT-PCR.

[0029] FIG. 13 shows compounds selected through the overlap between the 126 compounds (at 0.83 pM) selected through HTS and the 298 compounds selected by TaqMan RT-PCR.

[0030] FIG. 14 shows 34 compounds selected through the overlap between the 161 compounds (at 2.5 pM) selected through HTS and the 298 compounds selected by TaqMan RT-PCR.

[0031] FIG. 15 shows 14 compounds selected through the overlap between the 51 compounds (at all three concentrations: 2.5 pM, 0.83 pM, and 0.27 pM) selected through HTS and the 298 compounds selected by TaqMan RT-PCR.

[0032] FIGs. 16A, 16B and 16C depict cluster analysis on compounds (cpds).

[0033] FIG. 17 shows the test and the test results of the screened compounds using an in vitro assay involving vinculin in human cell line K562.

[0034] FIG. 18 shows the test and the test results of the screened compounds in another in vivo assay by topical application of the compounds to mice tail skin.

[0035] FIG. 19 shows that some compounds increased SCF protein expression in the in vivo assay.

[0036] FIGs. 20A, 20B and 20C show IHC staining of SCF by DMSO, CPD755 and CPD 256, respectively.

[0037] FIG. 21 shows steps in SILA (stable isotope labeling by amino acids in cell culture).

[0038] FIG. 22 shows the steps of using photo-affinity chromatography for protein target identification.DETAILED DESCRIPTION

[0039] The present disclosure is based in part on screening and identifyingcompounds capable of activating a stem cell factor (SCF) promoter in a cell, such as a keratinocyte. Another aspect of the present disclosure is based on the discovery that a compound of Formula (I), Formula (II), Formula (II’), Formula (III), or Formula (IV) is useful in treating or preventing hair loss, hair thinning, hair depigmentation, or hair graying.or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof.

[0041] Another aspect of the present disclose is based upon the discovery that one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, is / are useful in treating or preventing hair loss, hair thinning, hair depigmentation, or hair graying.COMPOUNDS

[0042] The present disclosure encompasses a compound of Formula (I), Formula (II), Formula (II’), Formula (III), Formula (IV), or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof. In Formula (I), Ri is a substituted or unsubstituted cycloalkyl, R2 is an alkyl, and R3 is a substituted or unsubstituted aryl. In Formula (II), R4 is a substituted or unsubstituted heterocycloalkyl, and Rs is a substituted or unsubstituted aryl. In Formula (II’), R4’ is a substituted or unsubstituted heterocycloalkyl, and Rs’ is a substituted or unsubstituted aryl. In Formula (III), Re is a substituted or unsubstituted nitrogen containing heterocycloalkyl. In one aspect, the compound is a compound of Formula (I). In another aspect, the compound of Formula (I) is a compound wherein R1 is cyclohexane, R2 is methyl, and / or R3 is a phenyl substituted with at least one alkoxyand / 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 wherein R4 is a substituted pyrrolidine, including but not limiting to, a pyrrolidine substituted with an alkyl or a carbonyl. In another aspect, the compound of Formula (II) is a compound wherein Rs is a phenyl substituted with a carboxylic acid or an ester, including but not limiting to, a substituted or unsubstituted azepine or a substituted or unsubstituted piperidine. In one aspect, the compound is a compound of Formula (II’). In yet another aspect, the compound of Formula (II’) is a compound wherein R4’ is a substituted pyrrolidine, including but not limiting to, a pyrrolidine substituted with an alkyl or a carbonyl. In another aspect, the compound of Formula (II’) is a compound wherein Rs’ is a phenyl substituted with a carboxylic acid or an ester, including but not limiting to, a substituted or unsubstituted azepine or a substituted or unsubstituted piperidine. In one aspect, the compound is a compound of Formula III. In yet another aspect, the compound of Formula (III) is a compound wherein Re is an unsubstituted azepine, or Re is 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 wherein R7 is -NH(C=O)-Ri7, Rs is hydrogen, and R17 is an aryl-substituted alkenyl. In yet another aspect, the compound of Formula (IV) is a compound wherein R7 is - O(C=O)-Ar and Rs is hydroxy.

[0043] Another aspect of the present disclosure encompasses a compound of the following, or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof:

[0044] In one aspect, the compound(s) activates a stem cell factor (SCF) promoter in a cell, such as a keratinocyte. In another aspect of the present disclosure is based on the discovery that a compound of Formula (I), Formula (II), Formula (II’), Formula (III), and / or Formula (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB)), a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof is useful in treating or preventing hair loss, hair thinning, hair depigmentation, or hair graying.

[0045] In another aspect of the present disclosure is based on the discovery that a compound having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof, is / are useful in treating or preventing hair loss, hair thinning, hair depigmentation, or hair graying. . In one aspect, the compound has the structure of cpd34, cpd 37, cpd 65, cpd 257, cpd557, cpd 1107, cpd1840, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof. In another aspect, the compound has the structure of cpd 571 , cpd 621 , cpd 644, cpd715, cpd758, cpd 2152, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof. In yet another aspect, the compound has the structure of cpd 256, cpd 755, cpd 795, cpd 2062, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof. The structures of these compounds are shown in TABLE A below.TABLE AMETHODS OF USE

[0046] In one aspect, the compound of Formula (I), (II), (II’), (III), and / or (IV), or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate, a prodrug thereof, or any combination thereof, is used to activate a stem cell factor (SCF) promoter in a cell, such as in a keratinocyte. In one embodiment, the compound is selected from Formula (IA), (IB), (HA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB), or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof. In another aspect, one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof, is used to activate a stem cell factor (SCF) promoter in a cell, such as in a keratinocyte.SCF promoter refers to the 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 their surface. Several transcription factors bind to specific sites on the SCF promoter, allowing for fine-tuned control of SCF expression based on cellular signals and environmental cues. Different cell types may express different levels of SCF due to variations in the activity of the SCF promoter depending on the specific regulatory elements presented. SCF promoter is important for research on diseases related to hematopoiesis, such as leukemia, as well as for potential therapeutic applications involving manipulating stem cell populations. Additionally, SCF binds to the c-Kit receptor on stem cells within hair follicles, thus plays a crucial role in hair growth by regulating the activity of hair follicle stem cells, stimulating their proliferation and differentiation, which is necessary for hair growth during the anagen (active growth) phase of the hair cycle and when its function is impaired, it can contribute to hair loss. Low levels of SCF produced by the promoter can lead to decreased hair follicle proliferation and ultimately, thinning hair. When the SCF promoter is not functioning optimally, it can lead to reduced production of SCF, hindering hair follicle activity and causing hair thinning. Specifically for androgenetic alopecia, studies suggest that androgens like dihydrotestosterone (DHT) may negatively affect SCF production in the dermal papilla cells of the hair follicle, contributing to hair loss in conditions like male pattern baldness.

[0047] In another aspect, the compound of Formula (I), (II), (II’), (III), and / or (IV), or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof, such as the compound of Formula (IA), (IB), (HA), (I IB), (IIC), (I I IA), (IIIB), (IIIC), (IVA), and (IVB), or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof, is used to prevent or treat hair loss or hair depigmentation, either through SCF pathway or other mechanisms. In yet another aspect, one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, andcpd2152 as disclosed herein, or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof, is used to prevent or treat hair loss or hair depigmentation, either through SCF pathway or other mechanisms. There are many different types of hair loss, the most common by far being alopecia wherein human males begin losing scalp hair at the temples and on the crown of the head. While this type of hair loss is largely confined to males, hence its common name male pattern baldness, it is not unknown in women. Further, there are various types of hair, including, terminal hairs and vellus hairs and modified terminal hairs, such as seen in eye lashes and eyebrows. Terminal hairs are coarse, pigmented, long hairs in which the bulb of the hair follicle is seated deep in the dermis. Vellus hairs, on the other hand, are fine, thin, non-pigmented short hairs in which the hair bulb is located superficially in the dermis. As alopecia progresses, a transition takes place in the area of approaching baldness wherein the hairs themselves are changing from the terminal to the vellus type. Another factor that contributes to hair loss or thinning is a change in the cycle of hair growth. All hair, both human and animal, passes through a life cycle that includes three phases, namely, the anagen phase, the catagen phase and the telogen phase. The anagen phase is the period of active hair growth and, insofar as scalp hair is concerned, this general lasts for 3-5 years. The catagen phase is a short transitional phase between the anagen and telogen phases which, in the case of scalp hair, lasts only 1 -2 weeks. The final phase is the telogen phase which, for all practical purposes, can be denominated a resting phase where all growth ceases and the hair eventually is shed preparatory to the follicle commencing to grow a new one. Scalp hair in the telogen phase is also relatively short-lived, some 3-4 months elapsing before the hair is shed and a new one begins to grow. Under normal hair growth conditions on the scalp, approximately 88% of the hairs are in the anagen phase, only 1 % in catagen and the remainder in telogen. With the onset of male pattern baldness, a successively greater proportion of the hairs are in the telogen phase with correspondingly fewer in the active growth anagen phase.

[0048] Alopecia is associated with the severe diminution of hair follicles. A bald human subject will average only about 306 follicles per square centimeter, whereas a non-bald human in the same age group will have an average of 460 follicles per square centimeter. This amounts to a one-third reduction in hair follicles which, when added to the increased proportion of vellus hair follicles and the increased number of hairfollicles in the telogen phase, is both significant and noticeable. Approximately 50% of the hairs must be shed to produce visible thinning of scalp hair. It is thus a combination of these factors: transition of hairs from terminal to vellus, increased number of telogen hairs-some of which have been shed, and diminution and loss of hair follicles that produces baldness.COMPOSITIONS AND DOSAGE FORMS

[0049] One aspect of the disclosure encompasses a pharmaceutical composition or a dosage form for delivery of the compounds of Formula (I), (II), (II’), (III), and / or (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIIA), (I I IB), (IIC), (IIIC), (IVA), and (IVB)), or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof.

[0050] Another aspect of the disclosure encompasses a pharmaceutical composition or a dosage form for delivery of one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt thereof, a polymorph, a stereoisomer, a solvate or a prodrug thereof.

[0051] A pharmaceutical composition or dosage form may comprise an effective amount of the compounds of Formula (I), (II), (II’), (III), and / or (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB)), a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, a prodrug thereof, or a combination thereof.

[0052] A pharmaceutical composition or dosage form may comprise an effective amount of one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt thereof, a polymorph, astereoisomer, a solvate, a prodrug thereof, or a combination thereof.

[0053] Pharmaceutically acceptable salts of may include, without limitation, acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methylbromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate, and the like.

[0054] The amount of compounds of Formula (I), (II), (II’), (III), and / or (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIC), (I I IA), (IIIB), (I I IC), (IVA), and (IVB)) in the composition may be a therapeutically effective amount.

[0055] The amount of compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, in the composition may be a therapeutically effective amount.

[0056] As used herein “therapeutically effective amount” or “therapeutically effective dosage” refers to an amount that is effective to achieve a desired therapeutic result. In some embodiments, the desired therapeutic result includes SCF activation, and / or preventing / treating hair loss, hair thinning and / or hair depigmentation. For example, the therapeutically effective amount may be an amount that increases 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. The therapeutically effective amount may be an amount that induces 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.

[0057] In some cases, the amount of compound of Formula (I), (II), (II’), (III), and / or(IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (I IB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB)), or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof; presented in the composition is more than about 1 pg. For example, the composition may comprise an amount of compounds of Formula (I), (II), (III), and / or (IV) of about 2 pg or more, about 5 pg or more, about 10 pg or more, about 100 pg or more, about 500 pg or more, about 1000 pg or more, about 1500 pg or more, about 2000 pg or more, about 2500 pg or more, about 3000 pg or more, about 3500 pg or more, about 4000 pg or more, about 4500 pg or more, about 5000 pg or more, about 5500 pg or more, about 6000 pg or more, about 6500 pg or more, about 7000 pg or more, about 7500 pg or more, about 8000 pg or more, about 8500 pg or more, about 9000 pg or more, about 9500 pg 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.

[0058] In some cases, the amount of one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof; presented in the composition is more than about 1 pg. For example, the composition may comprise an amount of one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof; of about 2 pg or more,about 5 g or more, about 10 pg or more, about 100 pg or more, about 500 pg or more, about 1000 pg or more, about 1500 pg or more, about 2000 pg or more, about 2500 pg or more, about 3000 pg or more, about 3500 pg or more, about 4000 pg or more, about 4500 pg or more, about 5000 pg or more, about 5500 pg or more, about 6000 pg or more, about 6500 pg or more, about 7000 pg or more, about 7500 pg or more, about 8000 pg or more, about 8500 pg or more, about 9000 pg or more, about 9500 pg 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.

[0059] Additionally or alternatively, the amount of the compound of Formula (I), (II), (III), and / or (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (I IB), (I I IA), (I I IB), (IIIC), (IVA), and (IVB)) in the composition may be 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 wt.% to about 75 wt.%, about 30 wt.% to about 75 wt.%, about 40 wt.% to about 75 wt.%, about 50 wt.% to about 75 wt.%, about 60 wt.% to about 75 wt.%; about 0.01 wt.% to about 65 wt.%, about 0.1 wt.% to about 65 wt.%, about 1 wt.% to about 65 wt.%, about 5 wt.% to about 65 wt.%, about 10 wt.% to about 65 wt.%, about 15 wt.% to about 65 wt.%, about 20 wt.% to about 65 wt.%, about 30 wt.% to about 65wt.%, about 40 wt.% to about 65 wt.%, about 50 wt.% 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 0.01 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 ranges and subranges thereof, based on the total weight of the composition.

[0060] Additionally or alternatively, the amount of one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, in the composition may be 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 0.01wt.% 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 wt.% to about 75 wt.%, about 30 wt.% to about 75 wt.%, about 40 wt.% to about 75 wt.%, about 50 wt.% to about 75 wt.%, about 60 wt.% to about 75 wt.%; about 0.01 wt.% to about 65 wt.%, about 0.1 wt.% to about 65 wt.%, about 1 wt.% to about 65 wt.%, about 5 wt.% to about 65 wt.%, about 10 wt.% to about 65 wt.%, about 15 wt.% to about 65 wt.%, about 20 wt.% to about 65 wt.%, about 30 wt.% to about 65 wt.%, about 40 wt.% to about 65 wt.%, about 50 wt.% 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 0.01 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 ranges and subranges thereof, based on the total weight of the composition.

[0061] Alternatively or additionally, the composition may include other hair growth actives, or any combination thereof in an amount 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 85wt.%, 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 wt.% to about 75 wt.%, about 30 wt.% to about 75 wt.%, about 40 wt.% to about 75 wt.%, about 50 wt.% to about 75 wt.%, about 60 wt.% to about 75 wt.%; about 0.01 wt.% to about 65 wt.% about 0.1 wt.% to about 65 wt.%, about 1 wt.% to about 65 wt.%, about 5 wt.% to about 65 wt.%, about 10 wt.% to about 65 wt.%, about 15 wt.% to about 65 wt.%, about 20 wt.% to about 65 wt.%, about 30 wt.% to about 65 wt.%, about 40 wt.% to about 65 wt.%, about 50 wt.% 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 0.01 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 ranges and subranges thereof, based on the total weight of the composition.

[0062] Additionally or alternatively, the compositions may comprise a mixture of a compound of Formula (I), (II), (II’), (III), and / or (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIC), (IIIA), (I I IB), (NIC), (IVA), and (IVB)), and / or in combination with another active. The different actives in the formulation may have a weight ratio ranges 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 ,T11:2 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 ranges and subranges thereof. In one instance, the weight ratio of the compounds of Formula (I), Formula (II), or Formula (III) to another active is 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 ranges and subranges thereof.

[0063] Additionally or alternatively, the compositions may comprise a mixture of one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, and / or in combination with another active. The different actives in the formulation may have a weight ratio ranges from 1 :100 to 100:1 , 1 :50 to 50:1 , 1 :20 to 20:11 :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 ranges and subranges thereof. In one instance, the weight ratio of the compounds of Formula (I), Formula (II), or Formula (III) to another active is 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 ranges and subranges thereof.

[0064] The pharmaceutical composition or dosage form can be formulated and administered to a subject by several different routes and means. For instance, a composition may be administered and / or delivered systemically or locally. Local delivery comprises, among others, topical, transdermal, epidermal, scalp or hair follicle delivery. The pharmaceutical composition or dosage form comprise conventional nontoxic pharmaceutically acceptable adjuvants, carriers, excipients, and vehicles as desired. In one aspect, therapeutically effective amount of the compound may range from 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 range from about 0.5 mcg / day to about 100 mg / day, from about 1 mcg to about60 mg / day, from about 20 mcg to about 50 mg / day, from about 20 mcg to about 30 mg / day, or from about 15 mcg to about 25 mg / day. Administering of the composition or dosage form may result a blood level of at or about 1 ng / ml, at or about 2 ng / ml, at or about 4 ng / ml, at or about 5 ng / ml, at or about 6 ng / ml, at or about 8 ng / ml, at or about 10 ng / ml, at or about 12 ng / ml, at or about 15 ng / ml, at or about 20 ng / ml, at or about 22 ng / ml, at or about 24 ng / ml, at or about 26 ng / ml, at or about 28 ng / ml, at or about 30 ng / ml, at or about 32 ng / ml, at or about 34 ng / ml, at or about 36 ng / ml, at or about 38 ng / ml, at or about 40 ng / ml, at or about 42 ng / ml, at or about 44 ng / ml, 46 ng / ml, at or about 48 ng / ml, at or about 50 ng / ml.

[0065] In another aspect, the pharmaceutical composition or dosage form can be administered to the subject daily or more than once daily. For example, the composition can be used administered once, twice or three times per day. The duration of each administration can be as short as few seconds. Further, the composition or dosage form can be administered every 2, 3, 4, 5, 6, 7, 14, or every 30 days. Such treatment regimen is subject to alter and adjust based on subject’s individual needs and response sensitivity. The composition can be administered over a period ranging from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months. The composition can also be administered over a period of about 1 day, about 7 days, about 30 days, about 60 days, about 120 days, or about 180 days or more. In some aspects, the composition may be administered over a long period, such as about 24 weeks, about 48 week, about 60 weeks, about 148 weeks, about 208 weeks, indefinitely, or until resolution of the condition being treated.

[0066] A pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients. Non-limiting examples of excipients include chemical enhancers, humectants, pressure sensitive adhesives, antioxidants, solubilizers, thickening agents, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combinations thereof. One or more excipients can be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, by inhalation spray, rectal, or intrapulmonary administration.

[0067] Extended-release formulations could be used for substantially continuous delivery of drug at a preselected rate. For example, the compound of Formula (I), (II),(II’), (III), and / or (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB)), can be delivered at a rate of from about 1 mg to about 100 mg / day, from about 40 to about 60 mg / day, or from about 10 to about 30 gm / day. By way of another example, compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, can be delivered at a rate of from about 1 mg to about 100 mg / day, from about 40 to about 60 mg / day, or from about 10 to about 30 gm / day. Appropriate amounts of the composition can be readily determined by the ordinarily skilled artisan based upon, for example, the intended duration of administration of the active by the extended release formulation, the delivery mechanism, the particular formulation, and the relative potency of the drug among other factors.Binders

[0068] Non-limiting examples of binders suitable for the formulations of various aspects include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. The polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.

[0069] The binder can be introduced into the mixture to be granulated in a solid form, including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art. Alternatively, the binder can be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.Diluents

[0070] Non-limiting examples of diluents (also referred to as “fillers” or “thinners”) include carbohydrates, inorganic compounds, and biocompatible polymers, such as polyvinylpyrrolidone (PVP). Other non-limiting examples of diluents include dibasiccalcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, saccharides such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols; starches; pre-manufactured direct compression diluents; and mixtures of any of the foregoing.Disintegrants

[0071] Disintegrants can be effervescent or non-effervescent. Non-limiting examples of non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.Preservatives

[0072] 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, o-aminobenzoic acid, p-aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-caraotene, beta-apo- carotenoic acid, camosol, carvacrol, catechins, cetyl 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), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetic acid, ellagic acid, erythorbic acid, sodium erythorbate, esculetin, esculin, 6- ethoxy-1 ,2-dihydro-2,2,4-trimethylquinoline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechin, epicatechin, epicatechin gallate, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g., datiscetin, myricetin, daemfero), flavanones, fraxetin, fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, gum guaiacum, hesperetin, alpha-hydroxybenzyl phosphinic acid, hydroxycinammicacid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytryrosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, lecithin citrate; R- alpha-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxy tryptamine, methyl gallate, monoglyceride citrate; monoisopropyl citrate; morin, beta-naphthoflavone, nordihydroguaiaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphates, phytic acid, phytylubichromel, pimento extract, propyl gallate, polyphosphates, quercetin, transresveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol, tocopherols (i.e., alpha-, beta-, gamma- and delta-tocopherol), tocotrienols (i.e., alpha- , beta-, gamma- and delta-tocotrienols), tyrosol, vanilic acid, 2,6-di-tert-butyl-4- hydroxymethylphenol (i.e., lonox 100), 2,4-(tris-3',5'-bi-tert-butyl-4'-hydroxybenzyl)- mesitylene (i.e., lonox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiary butyl hydroquinone (TBHQ), thiodipropionic acid, trihydroxy butyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivates, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof.Flavor-modifying agents

[0073] Suitable flavor-modifying agents include flavorants, taste-masking agents, sweeteners, and the like. Flavorants include, but are not limited to, synthetic flavor oils and flavoring aromatics and / or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. Other non-limiting examples of flavors include cinnamon oils, oil of Wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0074] Taste-masking agents include but are not limited to cellulose hydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFlo HP22; low-substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel® and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461 , Ethocel®, Aqualon®-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts ofcarboxymethylcelluloses (CMC) such as Aualon®-CMC; polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, 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; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials. In other aspects, additional taste-masking agents contemplated are those described in U.S. Pat. Nos. 4,851 ,226; 5,075,114; and 5,876,759, each of which is hereby incorporated by reference in its entirety.

[0075] Non-limiting examples of sweeteners include glucose (com syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic sweetener 3,6- dihydro-6-methyl-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.Lubricants and glidants

[0076] The lubricant compositions may be utilized to lubricate ingredients that form a pharmaceutical composition. As a glidant, the lubricant facilitates removal of solid dosage forms during the manufacturing process. Non-limiting examples of lubricants and glidants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The pharmaceutical composition will generally comprise from about 0.01 % to about 10% by weight of a lubricant. In some aspects, the pharmaceutical composition will comprise from about 0.1 % to about 5% by weight of a lubricant. In a further aspect, the pharmaceutical composition will comprise from about 0.5% to about 2% by weight of a lubricant.Dispersants

[0077] Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodiumstarch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants.Colorants

[0078] Depending upon the aspect of the disclosure, it may be desirable to include a coloring agent. Suitable color additives include but are not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants, may be suitable for use in various aspects of the disclosure. pH modifiers

[0079] Non-limiting examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate.Chelating agents

[0080] A chelating agent may be included as an excipient to immobilize oxidative groups, including but not limited to metal ions, in order to inhibit the oxidative degradation of the morphinan by these oxidative groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA).Antimicrobial agents

[0081] An antimicrobial agent may be included as an excipient to minimize the degradation of the compound according to this disclosure by microbial agents, including but not limited to bacteria and fungi. Non-limiting examples of antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.Release-controlling polymers

[0082] Release-controlling polymers may be included in the various aspects of the solid dosage pharmaceutical compositions incorporating compounds according to this disclosure. In one aspect, the release-controlling polymers may be used as a tablet coating. In other aspects, including but not limited to bilayer tablets, a release-controlling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold. Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.

[0083] Suitable hydrophilic release-controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabic gum, carrageens gum, ghafti gum, guar gum, karaya gum, locust bean gum, okra gum, tragacanth gum, scleroglucan gum, xanthan gum, hypnea, laminaran, acrylic polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of maleic anhydride propylene or copolymers of maleic anhydride isobutylene), crosslinked polyvinyl alcohol and poly N-vinyl-2- pyrrolidone, diesters of polyglucan, polyacrylamides, polyacrylic acid, polyamides, polyethylene glycols, polyethylene oxides, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrenes, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof.Coatings

[0084] A solid dosage comprising a compound according to this disclosure may comprise a coating, wherein such a coating may control release of the compound, act as a moisture barrier, or buffer or modify pH. A “control releasing coat” or “controlled release coat” as used herein is defined to mean a functional coat which can for example comprise at least one pH independent polymer, pH dependent polymer (for example enteric or reverse enteric type polymers), soluble polymer, insoluble polymer, lipids, lipidic materials, or combinations thereof. The coating, when applied onto a dosage form, may slow (for example when applied to a normal release matrix dosage form), further slow (for example when applied to a controlled release matrix dosage form) or modify the rate of release of a compound according to this disclosure when applied to an uncoated dosage form. For example, the control releasing coat can bedesigned such that when the control releasing coat is applied to a dosage form, the dosage form in conjunction with the control releasing coat can exhibit the release of the compound according to this disclosure, such as a “modified-release”, “controlled- release”, “sustained-release”, “extended-release”, “delayed-release”, “prolonged- release,” or combinations thereof. The “control releasing coat” may optionally comprise additional materials that may alter the functionality of the control releasing coat.

[0085] The term “moisture barrier” as used herein is one which impedes or retards the absorption of moisture. Compounds according to this disclosure may be hygroscopic and, as such, may be susceptible to decomposition over time under highly humid conditions. The proportion of the components of the moisture barrier and the amount of the moisture barrier optionally applied onto the control-releasing coating or onto the core are typically such that the moisture barrier does not fall within the USP definition and requirement for an enteric coat. Suitably, the moisture barrier may comprise an enteric and / or acrylic polymer, suitably an acrylic polymer, optionally a plasticizer, and a permeation enhancer. The permeation enhancer is a hydrophilic substance, which allows water to enter without physical disruption of the coating. The moisture barrier may additionally comprise other conventional inert excipients, which may improve processing of an extended-release formulation.

[0086] Coating and matrix materials which may be used in accordance with the present disclsoure are those known in the art for use in controlled-release formulations, such as synthetic polymers of the polyvinyl type, e.g., polyvinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, and polyvinylpyrrolidone; synthetic polymers of the polyethylene type, e.g., polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, such as cellulosic 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), for example aluminum monostearate, cetylalcohol, hydrogenated beef tallow, hydrogenated castor oil, 12- hydroxystearl alcohol, glyceryl mono- or dipalmitate; glyceryl mono-, di- or tristearate; myristyl alcohol, stearic acid, stearyl alcohol, and polyethyleneglycols; waxes; sugars and sugar alcohols.

[0087] The pH-buffering properties of a coating may be strengthened by introducing into the coating substances chosen from a group of compounds usually used inantacid formulations, for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate; composite aluminum / magnesium compounds, for example Al2O3-6MgO CO2'12H2O, (Mg6Al2(OH)16CO3'4H2O), MgO Al2O3'2SiO2.nH2O, aluminum bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH-buffering compounds, for example the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.

[0088] A pH-dependent coating serves to release the drug in desired areas of the gastrointestinal (Gl) tract, e.g., the stomach or small intestine. When a pH- independent coating is desired, the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the Gl tract. When the coating is formulated to release a compound according to this disclosure in the intestines (especially the upper small intestines), the coating is often called an “enteric coating”. A pH-dependent coating may include, but is not limited to, acrylic acid polymers and copolymers, for example polymers formed from acrylic acid, methacrylic acid, methyl acrylate, ammino- methylacrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate (e.g., Eudragit™); cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; shellac (purified lac); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate (PVAP), vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; zein; and salts and combinations thereof.Nanoparticles

[0089] The compositions or dosage forms may comprise nanoparticles wherein each of the nanoparticles comprises a carrier entity and at least one active, wherein the active is arranged on an outside surface of the nanoparticles and wherein the nanoparticles are capable of binding to a predetermined epitope in vivo. In another aspect, provided herein are nanoparticle compositions comprising nanoparticles, wherein each of the nanoparticles comprises at least one active, wherein active isarranged on a surface of the nanoparticles such that the binding with subject’s receptors or cells is directed outward from that surface and wherein the nanoparticles are capable of binding to a predetermined epitope in vivo. In other embodiments, the nanoparticles multimerize, e.g. dimerize. Multimerization may be observed as multiples of the weight or size of the unit molecule, e.g. 160 nm particles multimerize to about 320 nm, 480 nm, 640 nm, etc. In some embodiments, less than 20% of the population are multimers. In some embodiments, more than 80% of the population are multimers.Liposomes

[0090] In one alternative embodiment, a liposome delivery vehicle may be utilized. Liposomes, depending upon the structural and chemical properties, may be used for delivery of the compound of Formula (I), Formula (II), Formula (III) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (I I IA), (IIIB), and (IIIC)), a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof. Generally, liposomes are spherical vesicles with a phospholipid bilayer membrane. The lipid bilayer of a liposome may fuse with other bilayers (e.g., the cell membrane), thus delivering the contents of the liposome to cells.

[0091] Liposomes may be comprised of a variety of different types of phospholipids having varying hydrocarbon chain lengths. Phospholipids generally comprise two fatty acids linked through glycerol phosphate to one of a variety of polar groups. Suitable phospholipids include phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). The fatty acid chains comprising the phospholipids may range from about 6 to about 26 carbon atoms in length, and the lipid chains may be saturated or unsaturated. Suitable fatty acid chains include (common name presented in parentheses) n-dodecanoate (laurate), n- tretradecanoate (myristate), n-hexadecanoate (palmitate), n-octadecanoate (stearate), n-eicosanoate (arachidate), n-docosanoate (behenate), n-tetracosanoate (lignocerate), cis-9-hexadecenoate (palmitoleate), cis-9-octadecanoate (oleate), cis,cis-9, 12- octadecandienoate (linoleate), all cis-9, 12, 15-octadecatrienoate (linolenate), and all cis-5,8, 11 ,14-eicosatetraenoate (arachidonate). The two fatty acid chains of a phospholipid may be identical or different. Acceptable phospholipids include dioleoyl PS, dioleoyl PC, distearoyl PS, distearoyl PC, dimyristoyl PS,dimyristoyl PC, dipalmitoyl PG, stearoyl, oleoyl PS, palmitoyl, linolenyl PS, and the like.

[0092] The phospholipids may come from any natural source, and, as such, may comprise a mixture of phospholipids. For example, egg yolk is rich in PC, PG, and PE, soybeans contain PC, PE, PI, and PA, and animal brain or spinal cord is enriched in PS. Phospholipids may come from synthetic sources too. Mixtures of phospholipids having a varied ratio of individual phospholipids may be used.Mixtures of different phospholipids may result in liposome compositions having advantageous activity or stability of activity properties. The above mentioned phospholipids may be mixed, in optimal ratios with cationic lipids, such as N-(1 -(2,3- dioleolyoxy)propyl)-N,N,N- trimethyl ammonium chloride, 1 , 1 ’-dioctadecyl-3, 3, 3’, 3’- tetramethylindocarbocyanine perchloarate, 3,3’-deheptyloxacarbocyanine iodide, 1 ,T-dedodecyl-3, 3, 3’, 3’- tetramethylindocarbocyanine perchloarate, 1 ,T-dioleyl- 3,3,3’,3'-tetramethylindo carbocyanine methanesulfonate, N-4- (delinoleylaminostyryl)-N-methylpyridinium iodide, or 1 , 1 , -dilinoleyl-3,3,3’,3’- tetramethylindocarbocyanine perchloarate.

[0093] Liposomes may optionally comprise sphingolipids, in which spingosine is the structural counterpart of glycerol and one of the one fatty acids of a phosphoglyceride, or cholesterol, a major component of animal cell membranes. Liposomes may optionally contain pegylated lipids, which are lipids covalently linked to polymers of polyethylene glycol (PEG). PEGs may range in size from about 500 to about 10,000 daltons.

[0094] Liposomes may further comprise a suitable solvent. The solvent may be an organic solvent or an inorganic solvent. Suitable solvents include, but are not limited to, dimethylsulfoxide (DMSO), methylpyrrolidone, N-methylpyrrolidone, acetro nitrile, alcohols, dimethylformamide, tetrahydrofuran, or combinations thereof.Emulsions

[0095] The pharmaceutical composition and dosage forms may be formulated as part of a microemulsion. Microemulsions are generally clear, thermodynamically stable solutions comprising an aqueous solution, a surfactant, and “oil." The "oil" in this case, is the supercritical fluid phase. The surfactant rests at the oil-water interface. Any of a variety of surfactants are suitable for use in microemulsion formulationsincluding those described herein or otherwise known in the art. The aqueous microdomains suitable for use according to the present disclosure generally will have characteristic structural dimensions from about 5 nm to about 100 nm. Aggregates of this size are poor scatterers of visible light and hence, these solutions are optically clear. As will be appreciated by a skilled artisan, microemulsions can and will have a multitude of different microscopic structures including sphere, rod, or disc shaped aggregates. In one embodiment, the structure may be micelles, which are the simplest microemulsion structures that are generally spherical or cylindrical objects. Micelles are like drops of oil in water, and reverse micelles are like drops of water in oil. In an alternative embodiment, the microemulsion structure is the lamellae. It comprises consecutive layers of water and oil separated by layers of surfactant. The “oil” of microemulsions optimally comprises phospholipids.

[0096] Any of the phospholipids detailed above for liposomes are suitable for embodiments directed to microemulsions. A composition comprising at least one antitumor therapeutic derivative may be encapsulated in a microemulsion by any method generally known in the art.

[0097] In yet another embodiment, the composition comprising the compound of Formula (I), Formula (II), Formula (II’), Formula (III), and / or Formula (IV) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIC), (I I IA), (IIIB), (IIIC), (IVA), and (IVB)), or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof may be delivered in a dendritic macromolecule, or a dendrimer. In yet another embodiment, the composition comprising one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof may be delivered in a dendritic macromolecule, or a dendrimer. Generally, a dendrimer is a branched tree-like molecule, in which each branch is an interlinked chain of molecules that divides into two new branches (molecules) after a certain length. This branching continues until the branches (molecules) become so densely packed that the canopy forms a globe. Generally, theproperties of dendrimers are determined by the functional groups at their surface. For example, hydrophilic end groups, such as carboxyl groups, would typically make a water-soluble dendrimer. Alternatively, phospholipids may be incorporated in the surface of a dendrimer to facilitate absorption across the skin. Any of the phospholipids detailed for use in liposome embodiments are suitable for use in dendrimer embodiments. Any method generally known in the art may be utilized to make dendrimers and to encapsulate compositions as disclosed herein. For example, dendrimers may be produced by an iterative sequence of reaction steps, in which each additional iteration leads to a higher order dendrimer. Consequently, they have a regular, highly branched 3D structure, with nearly uniform size and shape. Furthermore, the final size of a dendrimer is typically controlled by the number of iterative steps used during synthesis. A variety of dendrimer sizes are suitable for use according to the present disclosure. Generally, the size of dendrimers may range from about 1 nm to about 100 nm.Dosage Forms

[0098] One aspect of the disclosure encompasses dosage forms comprising the compound of Formula (I), Formula (II), Formula (II’), Formula (III) (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIC), (IIIA), (IIIB), and (I I IC)), or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof.

[0099] Another aspect of the disclosure encompasses dosage forms comprising one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof.

[0100] The dosage form may comprise the compound(s) from about 1 microgram to about 50 g, from about 1 mcg to about 5,000 mg, from about 1 mcg to about 1 ,000 mg, from about 1 mcg to about 500 mg, from about 50 mcg to about 400 mg, from about 75 mcg to about 150 mg, from about 150 mcg to about 200 mg, from about 40mcg to about 150 mg, from about 80 mcg to about 120 mg, or from about 180 mcg to about 100 mg. For instance, the dosage form can comprise 1 , 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 or more mcg of the compound. In some aspect, the dosage forms can comprise from 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.

[0101] Dosage forms include those formulated for extended or slow release, and those formulated for immediate release. For example, an immediate release dosage form may include a crystalline form or polymorph of the compound. For example, a fast-dissolve oral dosage form may include for example a hydrochloride salt.

[0102] Dosage forms also include those formulated for topical administration. In one aspect, such topical administration is aimed at delivery to the scalp, to the skin, and / or to the hair fiber or hair follicles. For instance, a dosage form can be formulated as one or more of a gel, ointment, emulsion, microemulsion, lipids, liposomes, nanosomes, solution, suspension, paste, gel, foam, spray, lotion, or cream. In one aspect, a topical administration dosage form is a transdermal patch. When the dosage form is formulated as a transdermal patch, the transdermal patch can contain from at or about 40 mcg to at or about 60 mg, from at or about 80 mcg to at or about 50 mg, or from about 180 mcg to at or about 40 mg of the compound in crystalline form.

[0103] Dosage forms can alternatively be formulated for oral administration. Dosage forms formulated for oral administration can be tablets to swallow, chew, or dissolve in water or under the tongue, capsules and chewable capsules, powders, granules, teas, drops, or liquid medications or syrups. In some aspect, the dosage form is an enteric coated oral formulation.

[0104] When the dosage form is an enteric coated oral formulation, the formulation can comprise from about 0.1 mcg to about 60 mg the compound. An enteric coated oral formulation can also contain the compound or its salt in crystalline form. The salt can be a fumarate salt, a sulfate salt, a mesylate salt, a dihydrogen phosphate salt, an edisylate salt, a benzoate salt, a hydrochloride salt, and an oxalate salt.

[0105] Dosage forms also encompass those formulated for subcutaneous and / or intramuscular injection. For example, an intramuscular dosage form may comprisethe compound in crystal form, dissolved in an oil matrix for intramuscular injection, or alternatively prepared as a suspension for intramuscular injection. A dosage form formulated for subcutaneous or intramuscular injection may comprise the compound in a salt or crystal form as disclosed herein, prepared as microspheres using methods known in the art. Alternatively, the compound or salt form may be coated, for example using Atomic Layer Deposition (ALD) techniques, with a thin layer coating such as a coating of zinc oxide, and used in a formulation for subcutaneous or intramuscular injection. Alternatively, the compound may be dissolved in a biodegradable polymer matrix, and then implanted subcutaneously (or used in a transdermal patch as detailed further below).Kits

[0106] A further aspect of the present disclosure provides kits comprising the compound, its composition or dosage form for use with a method of the disclosure. The kits may comprise containers to hold the composition comprising the compound of Formula (I), Formula (II), Formula (II’), Formula (III), or Formula (IV), (including, but not limited to, the compounds of Formula (IA), (IB), (HA), (IIB), (IIC), (IIIA), (IIIB), (I I IC), (IVA), and (IVB)), or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof, and an instruction of use. The kits may comprise containers to hold the composition comprising one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof, and an instruction of use. The kits generally include instructions for carrying out the methods detailed in the present disclosure. Instructions included in the kits may be affixed to packaging material or may be included as a package insert. While the instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term “instructions” may include the address of an internetsite that provides the instructions.DEFINITIONS

[0107] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991 ); and Hale & Marham, The Harper Collins Dictionary of Biology (1991 ). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0108] When introducing elements of the present disclosure or the preferred aspects(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0109] The term “comprising” means “including, but not necessarily limited to”; it specifically indicates open-ended inclusion or membership in a so-described combination, group, series and the like. The terms “comprising” and “including” as used herein are inclusive and / or open-ended and do not exclude additional, unrecited elements or method processes. The term “consisting essentially of” is more limiting than “comprising” but not as restrictive as “consisting of.” Specifically, the term “consisting essentially of” limits membership to the specified materials or steps and those that do not materially affect the essential characteristics of the claimed invention.

[0110] The term “alkyl,” as used herein, describes groups that are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.

[0111] The term “alkenyl,” as used herein, describes groups that are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl,propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.

[0112] The term “alkynyl,” as used herein, describes groups that are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.

[0113] The term “aromatic,” as used herein, alone or as part of another group denotes optionally substituted homo- or heterocyclic conjugated planar ring or ring system comprising delocalized electrons. These aromatic groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic groups containing from 5 to 14 atoms in the ring portion. The term “aromatic” encompasses “aryl” groups defined below.

[0114] The terms "aryl" or "Ar," as used herein, alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.

[0115] The terms “carbocyclo” or “carbocyclic” as used herein, alone or as part of another group denote optionally substituted, aromatic or non-aromatic, homocyclic ring or ring system in which all of the atoms in the ring are carbon, with preferably 5 or 6 carbon atoms in each ring. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.

[0116] The terms "halogen" or "halo," as used herein, alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.

[0117] The term “heteroatom,” as used herein, refers to atoms other than carbon and hydrogen. The term "heteroaromatic," as used herein, alone or as part of another group denotes optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group may have 1 to 4 oxygen, nitrogen, silicone, and / or sulfate atoms (e.g. 1 or 2 oxygen atoms and / or 1 to 4 nitrogen atoms) in the ring, and is bonded to the remainder of the molecule through a carbon. Exemplary groups include furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl, and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.

[0118] The terms "heterocyclo" or "heterocyclic," as used herein, alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group may have 1 or 2 oxygen atoms and / or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo groups include heteroaromatics as described above. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.

[0119] The terms "hydrocarbon" and “hydrocarbyl,” as used herein, refer to organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties 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 alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.

[0120] The compounds described herein may have asymmetric centers. Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active or racemic form. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

[0121] As used herein, the terms “disease”, “disorder” or “medical condition” are used interchangeably. Each includes, but is not limited to, any condition or disease manifested as one or more physical and / or psychological symptoms for whichtreatment is desirable, and includes previously and newly identified diseases and other disorders.

[0122] The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a condition, or one or more of the symptoms associated with the condition; or alleviating or eradicating the cause(s) of the condition itself.

[0123] The terms "manage," "managing," and "management" encompass preventing the recurrence of the specified disease, disorder, or condition in a patient who has already suffered from the disease, disorder, or condition, and / or lengthening the time that a patient who has suffered from the disease, disorder, or condition remains in remission. The terms encompass modulating the threshold, development and / or duration of the disease, disorder, or condition, or changing the way that a patient responds to the disease, disorder, or condition.

[0124] The terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition

[0125] As used herein, the term "effective amount" refers to an amount of an agent (such as a mixture of RNAs) that provides a desired biological, therapeutic, preventive, and / or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, prevention, and / or alleviation of one or more of the signs, symptoms, or causes of a disease (such as advanced stage solid tumor cancer). In some embodiments, an effective amount comprises an amount sufficient to cease hair loss or reduce the amount of hair loss. In some embodiments, an effective amount is an amount sufficient to decrease the hair depigmentation or hair graying. In some embodiments, an effective amount is an amount sufficient to delay hair graying. In some embodiments, an effective amount is an amount sufficient to prevent or delay onset of hair graying.

[0126] The term "co-administered" or "co-administration" or the like as used herein refers to administration of two or more agents concurrently, simultaneously, or essentially at the same time, either as part of a single formulation or as multiple formulations that are administered by the same or different routes. "Essentially at the same time" as used herein means within about 1 minute, 5 minutes, 10 minutes, 15minutes, 30 minutes, 1 hour, 2 hours, or 6 hours period of each other.

[0127] As used herein, the term “polypeptide” means any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e. , peptide isosteres. Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well-known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.

[0128] As used herein an “antibody” or “intact antibody” typically refers to a Y-shaped tetrameric protein comprising two heavy (H) and two light (L) polypeptide chains held together by covalent disulfide bonds and non-covalent interactions. Each light chain is composed of one variable domain (VL) and one constant domain (CL). Each heavy chain comprises one variable domain (VH) and a constant region, which in the case of IgG, IgA, and IgD antibodies, comprises three domains termed CH1 , CH2, and CH3 (IgM and IgE have a fourth domain, CH4). In IgG, IgA, and IgD classes the CH1 and CH2 domains are separated by a flexible hinge region, which is a proline and cysteine rich segment of variable length (from about 10 to about 60 amino acids in various IgG subclasses). The variable domains in both the light and heavy chains are joined to the constant domains by a “J” region of about 12 or more amino acids and the heavy chain also has a “D” region of about 10 additional amino acids. Each class of antibody further comprises inter-chain and intra-chain disulfide bonds formed by paired cysteine residues.

[0129] As used herein the term “antibody” includes polyclonal antibodies, multiclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, CDR grafted antibodies, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies, including muteins and variants thereof, immunospecific antibody fragments such as Fd, Fab, F(ab')2, F(ab') fragments, single-chain fragments (e.g. ScFv and ScFvFc); and derivatives thereof including Fc fusions and other modifications, and any otherimmunoreactive molecule so long as it exhibits preferential association or binding with a determinant. Moreover, unless dictated otherwise by contextual constraints the term further comprises all classes of antibodies (i.e. IgA, IgD, IgE, IgG, and IgM) and all subclasses (i.e., lgG1 , lgG2, lgG3, lgG-4, lgA1 , and lgA2). Heavy-chain constant domains that correspond to the different classes of antibodies are typically denoted by the corresponding lower case Greek letter a, 5, E, y, and p, respectively. Light chains of the antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (K) and lambda (A), based on the amino acid sequences of their constant domains.

[0130] As used herein, the term “subject” means that preferably the subject is a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., cynomolgus monkey, rats, mice, guinea pigs and the like). For a human subject, a person aged 65 or older is referred to as 'elderly'.

[0131] As used herein, the administration of an agent or drug to a subject or patient includes self-administration and the administration by another. It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean “substantial”, which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.EXAMPLES

[0132] The publications discussed above are provided solely for their disclosure before the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0133] The following examples are included to demonstrate the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors to function well in the practice of the disclosure. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes could be made in the disclosure and still obtain a like or similar result without departing from the spirit and scope of thedisclosure, therefore all matter set forth is to be interpreted as illustrative and not in a limiting sense.EXAMPLE 1 : STUDY DESIGN

[0134] This study was to screen for small molecule compounds that activate Stem- Cell Factor (SCF) promoter using Green-Fluorescence Protein (GFP) as a readout. FIG. 1 depicts the test flow. Candidate hits included those having positive results in the primary screening (such as high-throughput screening) and in the cherry pick screen in both mouse and human cells. FIG. 2 and FIG. 3 depict the flow chart for the high-throughput screening (HTS) steps and the flow chart of Cherry-Pick HTS and TaqMan PCR, respectively. Further, the candidate hits had positive results in the in vitro validation assays, including GFP signal in the SCF-GFP keratinocytes assays but no signal in wild-type control keratinocytes (i.e. no auto-fluorescence). Candidate hits also had mild expression of GFP / SCF in the validation assay as too much SCF upregulation was not desired. The candidate hits were positive in PCR assays to upregulate SCF, which was a much more sensitive assay than GFP. Additionally, the candidate hits were positive in the in vivo validation assays, and positive in the in vivo pre-clinical assays to reverse hair graying.EXAMPLE 2: SCREENING RESULTS

[0135] The study generated a small molecular library with about 300,000 compounds in 987 plates (384-well plats). All compounds have been screened, and represented about 562.8 million cells. The primary hits included 35,186 compounds (about 11.7% of the library). Their two-point corrected ratio (GFP signal) ranged from 6.0% to 152.1 %, and the cell number single point corrected ratio (CNSPC) ranged from about -99.3% to about 52.1 %. The maximum number of cherry pick compounds allowed for retesting included about 1 ,920 compounds, all of which were completed cherry pick testing. From the 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, cpd715, cpd717, cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078,cpd2125, and cpd2152, the structures of which are shown above. Compounds selected by HTS image analysis were compared with those selected by RT-PCT (Cherry-pick at 1stthrough 52ndrounds). The comparison and filter results were shown in FIG. 4. FIGS. 5-7 show the heatmap of 109 compounds at 0.21 pM, the heatmap of 126 compounds at 0.83 pM, the heatmap of 195 compounds at 2.5 pM, respectively. And FIGS. 8-11 show the heatmap of 51 compounds overlapped at all three concentrations, at 0.21 pM, at 0.83 pM, and at 2.5 pM respectively. The compound selection criteria based on RT-PCT included filter criteria of upregulating SCF or GFP mRNA expression over 1.5 times in either mouse or human keratinocyte cell lines. Total 298 compounds out of the 1 ,920 compounds were selected. FIG. 12 shows 22 compounds were selected through the overlap between the 109 compounds (at 0.27 pM) selected through HTS and the 298 compounds selected by TaqMan RT-PCR. Similarly, FIG. 13 shows 26 compounds were selected through the overlap between the 126 compounds (at 0.83 pM) selected through HTS and the 298 compounds selected by TaqMan RT-PCR. FIG. 14 shows 34 compounds were selected through the overlap between the 161 compounds (at 2.5 pM) selected through HTS and the 298 compounds selected by TaqMan RT-PCR. FIG. 15 shows 14 compounds were selected through the overlap between the 51 compounds (at all three concentrations: 2.5 pM, 0.83 pM, and 0.27 pM) selected through HTS and the 298 compounds selected by TaqMan RT-PCR. FIGS. 16A, 16B and 16C depict cluster analysis of compounds (cpds).EXAMPLE 3: BIOLOGICAL TESTING RESULTS

[0136] The screened compounds were tested using an in vitro assay involving vinculin and in human cell line K562. The test results were shown in FIG. 17. The screened compounds were also tested in another in vivo test by topical application of the compounds to mice tail skin as shown in FIG. 18. The testing steps included preparing 1 pM of the compounds in DMSO, topically applying 15 pl to the tail once per day for one week. At the end of one week, harvested the skin and prepared the lysate for western and immunohistochemistry analysis. FIG. 19 shows that some compounds increased SCF protein expression in the above in vivo assay. FIGS. 20A, 20B and 20C show IHC staining of SCF by DMSO, CPD755 and CPD 256, respectively.EXAMPLE 4. SUMMARY

[0137] In summary, various compounds were tested as shown in Table 1 below. These compounds are tested through target identification, including western blot and RT-PCR analysis on multiple human and mouse cell lines, such as keratinocyte cell lines, fibroblast, and leukemia cell lines. Some of these compounds are also tested in vivo (in animals) using SCF-BFP / WT mice for in vivo testing.TABLE 1 : Summary of Tested Compounds

[0138] Ultimately, the study is to identify the protein(s) that the small molecule drug is targeting, which may or may not be directly targeting SCF. To this end, a combination of quantitative proteomics and affinity chromatography can be used. The method includes SILA (stable isotope labeling by amino acids in cell culture, as shown in FIG. 21 ) and uses Affinity Chromatography to allow a small molecule of interest coupling to an affinity matrix. The small molecule is allowed to bind to the affinity matrix and separated from those unbound molecules. Then, mass spectrometry is used to identify proteins that bind with the small molecule. Alternatively or in addition, a photo-affinity chromatography is to be used for target identification as shown in FIG. 22. In this method, a small molecule is modified with benzophenone and a terminal alkyne group. The benzophenone group is photo-reactive; in the presence of UV light, it will generate a di-radical that will covalently modify a nearby amino acid. Proteins that bind to the SM-probe are labelled by a “click” reaction (a chemical process whereby the alkyne group is conjugated to the azide moiety), and bound proteins are visualized by SDS-Page and in-gel fluorescence scanning.

Claims

WE CLAIM1 . A compound selected from a compound of Formula I, Formula II, Formula II’, Formula III, Formula IVa pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof, wherein:Ri is a substituted or unsubstituted cycloalkyl;R2 is an alkyl;R3 is a substituted or unsubstituted aryl,R4 is a substituted or unsubstituted heterocycloalkyl,R4’ is a substituted or unsubstituted heterocycloalkyl,Rs is a substituted or unsubstituted aryl,Rs’ is a substituted or unsubstituted aryl,Re is a substituted or unsubstituted nitrogen containing heterocycloalkyl,R7 is -NH(C=O)-Ri7 or -O(C=O)-Ri7 wherein R17 is a substituted or unsubstituted alkyl, alkenyl, or aryl; andRs is hydrogen, hydroxy, or an alkyl.

2. The compound of claim 1 , wherein the compound is a compound of Formula I.

3. The compound of claim 2, wherein R1 is cyclohexane.

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

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

6. The compound of claim 1 , wherein the compound is a compound of Formula II.

7. The compound of claim 6, wherein R4 or R4’ is each independently a substituted pyrrolidine.

8. The compound of claim 7, wherein R4 or R4’ is each independently a pyrrolidine substituted with an alkyl or a carbonyl.

9. The compound of any one of claims 6 to 8, wherein Rs or Rs’ is each independently a phenyl substituted with a carboxylic acid or an ester.

10. The compound of claim 1 , wherein the compound is a compound of Formula III.11 . The compound of claim 10, wherein Re is a substituted or unsubstituted azepine or a substituted or unsubstituted piperidine.

12. The compound of claim 11 , wherein Re is an unsubstituted azepine.

13. The compound of claim 11 , wherein Re is an alkyl substituted piperidine.

14. The compound of claim 1 , wherein the compound is a compound of Formula IV.

15. The compound of claim 14, wherein R7 is -NH(C=O)-Ri7, Rs is hydrogen, and R17 is an aryl-substituted alkenyl.

16. The compound of claim 14, wherein R7 is -O(C=O)-Ar and Rs is hydroxy.

17. The compound of any one of claims 1 to 16 selected from:or a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate or a prodrug thereof.

18. A compound having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof.

19. The compound of claim 18, having the structure of cpd34, cpd 37, cpd 65, cpd 257, cpd557, cpd 1107, cpd1840, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof.

20. The compound of claim 18, having the structure of cpd 571 , cpd 621 , cpd 644, cpd715, cpd758, cpd 2152, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof.21 . The compound of claim 18, having the structure of cpd 256, cpd 755, cpd 795, cpd 2062, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, or a prodrug thereof.

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

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

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

25. The pharmaceutical dosage form of claim 24, wherein the dosage form comprises an oral dosage form, a topical dosage form, or a hair follicle dosage form.

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

27. The method of claim 26, wherein the hair loss and / or hair depigmentation is associated with aging.

28. The method of claims 26 or 27, wherein the subject is human.

29. The method of any one of claims 23 to 25, wherein the subject is an elder human.

30. A method of activating a stem cell factor (SCF) promoter in a cell, the method comprising contacting the cell with a compound of any one of claims 1 to 21 or any combination thereof.31 . The method of claim 27, further comprising increasing SCF expression in the cell.

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 claims 22 or 23, or the dosage form of claims 24 or 25, in a method of treating hair loss and / or hair depigmentation in a subject, comprising administering the compound(s) to the subject in need of such treatment.

34. Use of one or more compounds having the structure of any one of 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, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152 as disclosed herein, a pharmaceutically acceptable salt, a polymorph, a stereoisomer, a solvate, a prodrug thereof, or any combination thereof, in a method of treating hair loss and / or hair depigmentation in a subject, comprising administering the compound(s) to the subject in need of such treatment.

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