Compositions, formulations, and methods for hair treatment

Abstract

This article provides compositions and formulations for hair treatment. It also provides methods for hair treatment, such as methods for preventing or treating hair loss or thinning. These methods can promote hair growth, hair repair, or hair thickening, or increase hair density or hair growth rate.

Description

Summary of the Invention

[0001] Hair loss or thinning can occur naturally or be chemically induced by prolonged use of certain chemicals (such as commercially available products or treatments). This type of hair loss or thinning is often accompanied by a lack of hair regrowth, leading to partial or complete baldness. While hair loss is often considered a male problem, at least one-third of women will experience thinning hair at some point in their lives.

[0002] The present invention provides a method for preventing or treating hair loss or thinning hair (whether or not a diagnosis of hair loss or thinning hair has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of a compound having formula (I), (II), (III), (IV), (V), (VI), (VII A), (VII B) or (VIII).

[0003] In some respects, this article discloses a method for preventing or treating hair loss or thinning (whether or not a diagnosis of hair loss or thinning has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (VII B): (VII B), or its salt, wherein: B is an aryl or heteroaryl group, wherein the heteroaryl group is selected from pyridine, pyrimidine, oxazole, furan, piperan, thiophene, isoxazole, benzimidazole, benzothiazole, and imidazopyridine; R1 is selected from hydrogen, C1-6 alkyl or C1-6 haloalkyl, -S-alkyl, -S-haloalkyl, -S(O)(O)Ra; wherein Ra is selected from the group consisting of hydrogen, C1-6 alkyl or C1-6 haloalkyl; R2 is selected from -OH, C1-6 alkoxy, C1-6 haloalkoxy, -SRb, -NH2, alkyl, and imine, wherein R2 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and... A group that makes up; and R3 and R4 are independently selected from the group consisting of hydrogen, C1-6 alkyl or C1-6 haloalkyl.

[0004] In some embodiments, B is a heteroaryl group. In some embodiments, the heteroaryl group is a furan. In some embodiments, R1 is hydrogen or S(O)(O)Ra. In some embodiments, Ra is methyl or ethyl. In some embodiments, R2 is imino or –SRb. In some embodiments, Rb is methyl or In some embodiments, R3 is hydrogen or ethyl. In some embodiments, R4 is hydrogen.

[0005] In some embodiments, the compound of formula (VII B) or a salt thereof is selected from: , or .

[0006] In some respects, this article discloses a method for preventing or treating hair loss or thinning (whether or not a diagnosis of hair loss or thinning has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (VII A): (VII A), or its salt, wherein: A is an aryl or heteroaryl group, wherein the heteroaryl group is selected from pyridine, pyrimidine, oxazole, furan, piperan, thiophene, isoxazole, benzimidazole, benzothiazole, and imidazopyridine; R1 is a C1-6 alkyl or C1-6 haloalkyl; and R2 is -C(O)OH, -C(O)O-alkyl or -C(O)O-haloalkyl.

[0007] In some embodiments, A is an aryl group. In some embodiments, the aryl group is a phenyl group. In some embodiments, R1 is a C1-6 alkyl group. In some embodiments, R2 is a -C(O)O-alkyl group.

[0008] In some embodiments, the compound of formula (VII A) is Or its salt.

[0009] In some respects, this article discloses a method for preventing or treating hair loss or thinning (whether or not a diagnosis of hair loss or thinning has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (VIII): (VIII), or its salt, wherein: m is 0, 1, or 2; and R x are each independently C1-6 alkyl, C5-8 aryl, C1-6 haloalkyl, alkylaryl, or haloalkylaryl.

[0010] In some embodiments, m is 2. In some embodiments, R x are each independently methyl or phenyl.

[0011] In some embodiments, the compound of formula (VIII) is Or its salt.

[0012] In some respects, this article discloses a method for treating hair loss or thinning hair (whether or not a diagnosis of hair loss or thinning hair has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (VII B): (VII B), or its salt, wherein: B is aryl or heteroaryl; R1 is selected from hydrogen, C1-6 alkyl or C1-6 haloalkyl, -S-alkyl, -S-haloalkyl, -S(O)(O)Ra; wherein Ra is selected from the group consisting of hydrogen, C1-6 alkyl or C1-6 haloalkyl; R2 is selected from -OH, C1-6 alkoxy, C1-6 haloalkoxy, -SRb, -NH2, alkylamino, and imino, wherein R2 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and... A group that makes up; and

[0013] R3 and R4 are independently selected from the group consisting of hydrogen, C1-6 alkyl or C1-6 haloalkyl.

[0014] In some embodiments, B is a heteroaryl group. In some embodiments, the heteroaryl group is a furan. In some embodiments, R1 is hydrogen or S(O)(O)Ra. In some embodiments, Ra is methyl or ethyl. In some embodiments, R2 is imino or –SRb. In some embodiments, Rb is methyl or In some embodiments, R3 is hydrogen or ethyl. In some embodiments, R4 is hydrogen. In some embodiments, the compound of formula (VII B) or a salt thereof is selected from: , or .

[0015] In some respects, this article discloses a method for treating hair loss or thinning hair (whether or not a diagnosis of hair loss or thinning hair has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (VII A): (VII A), or its salt, wherein: A is an aryl or heteroaryl group, wherein the heteroaryl group is selected from pyridine, pyrimidine, oxazole, furan, piperan, thiophene, isoxazole, benzimidazole, benzothiazole, and imidazopyridine; R1 is a C1-6 alkyl or C1-6 haloalkyl; and R2 is -C(O)OH, -C(O)O-alkyl or -C(O)O-haloalkyl.

[0016] In some embodiments, A is an aryl group. In some embodiments, the aryl group is a phenyl group. In some embodiments, R1 is a C1-6 alkyl group. In some embodiments, R2 is a -C(O)O-alkyl group.

[0017] In some embodiments, the compound of formula (VII A) is Or its salt.

[0018] In some respects, this article discloses a method for treating hair loss or thinning hair (whether or not a diagnosis of hair loss or thinning hair has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (VIII): (VIII), or its salt, wherein: m is 0, 1, or 2; and R x are each independently C1-6 alkyl, C5-8 aryl, C1-6 haloalkyl, alkylaryl, or haloalkylaryl.

[0019] In some embodiments, m is 2. In some embodiments, R x are each independently methyl or phenyl.

[0020] In some embodiments, the compound of formula (VIII) is Or its salt.

[0021] In some respects, this article discloses a method for preventing or treating hair loss or thinning (whether or not a diagnosis of hair loss or thinning has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (I): (I), or its salt, wherein: Y1 is either O or S; Y2 is either O or S; Y3 is either O or S; R 1 is selected from H, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl (e.g., phenyl) and aralkyl (e.g., benzyl), wherein the aryl or aralkyl group is substituted as required by one or more independent substituents selected from halogen, alkyl, alkoxy and haloalkoxy; R2 is selected from H, alkyl, alkenyl, haloalkyl, and haloalkenyl; A is an aryl (e.g., phenyl) or a heteroaryl (e.g., pyrimidinyl); p is 0, 1, 2, or 3; and Each of R x is independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, -OH, alkoxy, haloalkoxy, -O-extinyl-C(O)OH, nitro, -NH 2, alkylamino, dialkylamino and haloalkylamino; or, the two R x and the atoms they are attached to together form (e.g. C 4-C 6) cycloalkyl or (e.g. 5- or 6-membered) heterocyclic groups, wherein the cycloalkyl or heterocyclic group is substituted as required by one or more substituents independently selected from halogen, alkyl and haloalkyl.

[0022] In some embodiments, R2 is selected from (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkyl, and (e.g., C1-6, such as C1-4) haloalkenyl. In some embodiments, Y1 is S. In some embodiments, Y3 is S. In some embodiments, A is Where Q1 and Q2 are each independently CH or N. In some embodiments, A is or In some embodiments, the compound of formula (I) has the structure of formula (I A1) or (I A2): (I A1) or (I A2), where: Rx1, Rx2, Rx3, Rx1, Rx2, and Rx3 are each independently selected from halogens, (e.g., C1-6, such as C1-4) alkyl groups, (e.g., C1-6, such as C1-4) haloalkyl groups, (e.g., C1-6, such as C1-4) alkenyl groups, (e.g., C1-6, such as C1-4) haloalkenyl groups, -OH groups, (e.g., C1-6, such as C1-4) alkoxy groups, (e.g., C1-6, such as C1-4) haloalkoxy groups, -O-alkyl-C(O)OH groups, nitro groups, -NH2 groups, (e.g., C1-6, such as C1-4) alkylamino groups, (e.g., C1-6, such as C1-4) dialkylamino groups, and (e.g., C1-6, such as C1-4) haloalkylamino groups. In some embodiments, the compound of formula (I) has the structure of formula (I B1): (I B1), where: R x4 and R x5 are each independently selected from halogens, (e.g., C1-6, such as C1-4) alkyl groups, (e.g., C1-6, such as C1-4) haloalkyl groups, (e.g., C1-6, such as C1-4) alkenyl groups, (e.g., C1-6, such as C1-4) haloalkenyl groups, -OH groups, (e.g., C1-6, such as C1-4) alkoxy groups, (e.g., C1-6, such as C1-4) haloalkoxy groups, -O-alkyl-C(O)OH groups, nitro groups, -NH2 groups, (e.g., C1-6, such as C1-4) alkylamino groups, (e.g., C1-6, such as C1-4) dialkylamino groups, and (e.g., C1-6, such as C1-4) haloalkylamino groups. In some embodiments, the compound of formula (I) has the structure of formula (I B2): (I B2), where: R x6 and R x7 are each independently selected from halogen, (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) haloalkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkenyl, -OH, (e.g., C1-6, such as C1-4) alkoxy, (e.g., C1-6, such as C1-4) haloalkoxy, -O-alkyl-C(O)OH, nitro, -NH2, (e.g., C1-6, such as C1-4) alkylamino, (e.g., C1-6, such as C1-4) dialkylamino and (e.g., C1-6, such as C1-4) haloalkylamino; or, R x6 and R x7 and the atoms it is attached to form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is, as desired, substituted with one or more substituents independently selected from halogens, (e.g., C1-6, such as C1-4) alkyl groups, and (e.g., C1-6, such as C1-4) haloalkyl groups. In some embodiments, the compound of formula (I) has the structure of formula (I C1) or (I C2): (IC1) or (I C2), where: R x8 and R x9 are each independently selected from halogen, (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) haloalkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkenyl, -OH, (e.g., C1-6, such as C1-4) alkoxy, (e.g., C1-6, such as C1-4) haloalkoxy, -O-epylalkyl-C(O)OH, nitro, -NH2, (e.g., C1-6, such as C1-4) alkylamino, (e.g., C1-6, such as C1-4) dialkylamino and (e.g., C1-6, such as C1-4) haloalkylamino.

[0023] In some embodiments, the compound of formula (I) or a salt thereof is selected from: , , , , , , , , , , , , , , , , and Salt of any one of them.

[0024] In some embodiments, the present invention provides a method for preventing or treating hair loss or thinning (whether or not a diagnosis of hair loss or thinning has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (II): (II), or its salts, wherein: Ry is each independently an alkyl or haloalkyl group; m is 0, 1, or 2; L 1 is selected from the following bonds: -O-, -S-, -N(Ra1)-, -C(O)-, -C(O)-, -C(O)-, -C(O)-, -C(O)-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(Ra2)-, -N(Ra3)C(O)-, -N(Ra4)C(O)N(Ra5)-, -N(Ra6)C(O)O-, -OC(O)N(Ra7)-, -S(O) 2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O) 2-, -S(O) 2O-, -N(Ra8)S(O) 2-, -S(O) 2N(Ra9)-, -N(R -S(O)N(Ra11)-, -N(Ra12)S(O)2N(Ra13)- and -N(Ra14)S(O)N(Ra15)-; and R1 is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, cycloalkyl, alkylcycloalkyl, halocycloalkyl, aryl (e.g., phenyl), alkylaryl, heteroaryl, -O-aryl, -O-alkylaryl and -O-heteroaryl.

[0025] In some embodiments, the compound of formula (II) has the structure of formula (II A): (II A). In some embodiments, Ry is a C1-C6 (e.g., C1-C4) alkyl (e.g., methyl). In some embodiments, m is 1. In some embodiments, L1 is selected from -C(O)-, -C(O)-alkyl-O-, and -S(O)2-. In some embodiments, R1 is selected from alkyl, cycloalkyl, aryl, alkylaryl, -O-aryl, and -O-alkylaryl.

[0026] In some embodiments, the compound of formula (II) or a salt thereof is selected from: , , , , and Salt of any one of them.

[0027] In some embodiments, the present invention provides a method for preventing or treating hair loss or thinning (whether or not a diagnosis of hair loss or thinning has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (III): (III), Or its salt, wherein: A is aryl or heteroaryl; p is 0, 1, or 2; Ry are each independently an alkyl or haloalkyl group; q is 0, 1, or 2; Rz are each independently an alkyl or haloalkyl group; and R1 and R2 are each independently selected from H, aryl groups substituted as needed, -NH-C(O)-NH-cycloalkyl (e.g., adamantyl), -C(O)-NH-cycloalkyl, and -NH-C(O)-cycloalkyl; or, Alternatively, R1 and R2 may be bonded together with the nitrogen atom to which they are attached to form an N-heterocyclic group (e.g., piperazine group) or -N=Rc, where Rc is an aryl group or a heteroaryl group that is substituted as desired.

[0028] In some embodiments, R1 and R2 are bonded together with the nitrogen atoms to which they are attached to form , , or Rx is selected from alkyl, haloalkyl, -extinyl-OH, -extinyl-O-alkyl, -extinyl-aryl, and -extinyl-extinylaryl-alkyl. In some embodiments, R1 and R2 are bonded together with the nitrogen atom to which they are attached to form , , or In some embodiments, R1 and R2 are bonded to their attached nitrogen atoms to form a piperazine group, which is substituted as desired. In some embodiments, A is a pyridyl group ( ).

[0029] In some embodiments, the compound of formula (III) or a salt thereof is selected from: , , , and Salt of any one of them.

[0030] In some embodiments, the present invention provides a method for preventing or treating hair loss or thinning (whether or not a diagnosis of hair loss or thinning has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (IV): (IV), or its salt, wherein: A is a heteroaryl group; q is 0, 1, 2, or 3; and R x is selected from alkyl, haloalkyl, alkoxy, haloalkoxy, -SH, alkylthio, aryl, and alkoxyaryl.

[0031] In some embodiments, the compound of formula (IV) or a salt thereof is selected from: , , and Salt of any one of them.

[0032] In some embodiments, the present invention provides a method for preventing or treating hair loss or thinning (whether or not a diagnosis of hair loss or thinning has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (V): (V), or its salt, wherein: R1 is H or, as needed, a substituted aryl group; Rm and Rn are bonded together with the nitrogen atom to which they are attached to form an N-heterocyclic group, wherein the N-heterocyclic group is substituted as needed with one or more substituents selected from alkyl, -S(O)H, -S(O)2H, -S(O)-alkyl and -S(O)2-alkyl; Q1 can be NR a1, CR b1R b2, or S; Q3 is N or CR b3; and Q2 is either NR a2 or CR b4R b5; where: Ra1, Ra2, Rb1, Rb2, Rb3, Rb4 and Rb5 are each independently selected from H, aryl groups as needed, alkylaryl groups as needed, and arylalkyl groups as needed.

[0033] In some embodiments, Q1 is CR b1R b2 or S. In some embodiments, Q3 is CR b3.

[0034] In some embodiments, the compound of formula (V) or a salt thereof is selected from: , , and Salt of any one of them.

[0035] In some embodiments, the present invention provides a method for preventing or treating hair loss or thinning hair (whether or not a diagnosis of hair loss or thinning hair has been made), the method comprising administering to an individual in need a composition comprising a compound having the structure of formula (VI): (VI), or its salt, wherein: L 0 is selected from -C(O)-, -O-, -S-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2-, -NH- and L1 is selected from -C(O)-, -O-, -S-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2- and -NH-; p, q, and m are each independently 0, 1, or 2; Rx, Ry, and Rz are each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -OH, -C(O)OH, or -extinyl-C(O)OH; A is aryl or heteroaryl; L 2 represents alkylene, -C(O)-, -O-, -S-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2-, -N(H)S(O) 2-, -S(O) 2N(H)-, -alkylene-N(H)S(O) 2-, -S(O) 2N(H)-alkylene-, -NH-, -N= and -CH=NN=; and B is an aryl group that is substituted as needed, or a heteroaryl group that is substituted as needed.

[0036] In some embodiments, L0 is In some embodiments, A is phenyl or piperazine. In some embodiments, B is selected from... , , and In some embodiments, L2 is selected from alkylene, -S(O)2N(H)-alkylene, and -CH=NN=. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, q is 0. In some embodiments, m is 0. In some embodiments, m is 2. In some embodiments, Rx is each independently cyano, alkyl, alkoxy, or nitro. In some embodiments, Rz is each independently -OH, -C(O)OH, or -alkylene-C(O)OH.

[0037] In some embodiments, the compound of formula (VI) or a salt thereof is selected from: , , , , and Salt of any one of them.

[0038] In some embodiments, the present invention provides a method for preventing or treating hair loss or thinning hair (whether or not a diagnosis of hair loss or thinning hair has been made), the method comprising administering a composition to an individual in need, the composition comprising compounds selected from the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , and Salt of any one of them.

[0039] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the method includes at least one additive selected from the group consisting of pharmaceutically acceptable carriers, excipients, adjuvants, and diluents. In some embodiments, the composition is a cosmetic composition. In some embodiments, the method further includes at least one additive selected from the group consisting of cosmetically acceptable carriers, excipients, adjuvants, and diluents. In some embodiments, the cosmetic composition is formulated as a toner, lotion, cream, gel, shampoo, soap, serum, spray, or oil. In some embodiments, the hair loss is selected from androgenic alopecia, alopecia areata, androgenetic alopecia, gynecological alopecia, postpartum alopecia, seborrheic alopecia, non-rigid alopecia, senile alopecia, chemotherapy-induced alopecia, radiation-induced alopecia, male pattern baldness, female pattern baldness, cicatricial alopecia, telogen effluvium, traction alopecia, and anagen effluvium. In some embodiments, the method promotes hair strength, hair growth, hair repair, or hair thickening in the individual. In some embodiments, the individual has not yet been diagnosed. In some embodiments, the method increases the individual's hair density or hair growth rate. In some embodiments, the hair is head hair, eyelashes, eyebrows, or facial hair. [Incorporated by reference] []

[0040] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if specifically and individually indicated that each individual publication, patent or patent application is incorporated by reference. Simple Explanation of the Diagram

[0041] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description of exemplary embodiments (in which the principles of the invention are utilized), and the accompanying drawings (also referred to herein as "Figure" and "FIG."), in which:

[0042] Figure 1 depicts an exemplary depiction of the dose-response curve of compound VII-3 according to one or more embodiments of the present invention.

[0043] Figure 2A shows a schematic representation of a model system according to one or more embodiments of the present invention. Caco-2 cells were cultured on transwells until a monolayer was formed, mimicking the intestinal cell barrier. The cultures were treated on the apical side with an exemplary compound (VII-3) or a mediator control (0.1% v / v DMSO) for 24 hours and then cultured in a medium containing a fluorescent dye (Lucifer Yellow, labeled "F").

[0044] Figure 2B shows the apparent permeability of Caco-2 monolayers treated with DMSO and exemplary compound (VII-3) according to one or more embodiments of the present invention. No difference in apparent permeability was observed. Data represent mean ± standard deviation and represent at least two replicates.

[0045] Figure 3A shows a representative diagram of TK.6 cells treated with an exemplary compound (VII-3) with or without S9 metabolic activation according to one or more embodiments of the present invention. Methyl methanesulfonate (a known genotoxic alkylating agent) was used as a positive control for micronucleus detection.

[0046] Figures 3B and 3C show the quantification of TK.6 micronucleus assay after treatment with various exemplary compounds across a range of concentrations according to one or more embodiments of the present invention.

[0047] Figure 3D illustrates the standardized β-galactosidase activity (e.g., quantified by absorbance) of a known genotoxin (4-NQ; 4-nitroquinoline-1-oxide) and exemplary compounds at various concentrations using the SOS chromogenic assay according to one or more embodiments of the present invention. This SOS chromogenic assay is a well-established bacterial-based test for genotoxicity.

[0048] Figure 3E shows the normalized reactive oxygen species (ROS) activity in follicular dermal papillary cells treated with the exemplary compound at 5 μg / mL after 24 hours, relative to the mediator control (0.1% v / v DMSO).

[0049] Figure 3F shows the activity of standardized apoptosis protease 3 / 7 in HepG2 cells (a standardized hepatocyte cell line commonly used to study apoptosis induced by small molecules). Cells were treated with exemplary compounds spanning >2 logarithmic concentrations or with mediators containing the corresponding % v / v - matched amounts of DMSO. Data represent mean ± standard deviation and represent at least two replicates.

[0050] Figure 4A shows the standardized ARE-luciferase activity using a known sensitizing compound (cinnamaldehyde) and exemplary compounds according to one or more embodiments of the present invention.

[0051] Figures 4B to 4E illustrate in vitro dendritic cell sensitization assays according to one or more embodiments of the present invention. Dendritic cell activation is broadly associated with downstream immunogenicity. CD14+ cells from peripheral monocytes of human donors were harvested and differentiated into immature monocyte-derived DCs using granulocyte-macrophage community-stimulating factor (GM-CSF) and interleukin-4 (IL-4), and then treated with exemplary compounds. Killed E. coli (E. coli) and TNF-α were used as positive controls. Figure 4B shows a representative graph illustrating changes in HLA-DR expression. The expression of CD80 (Figure 4C), PDL-1 (Figure 4D), and CD141 (Figure 4E) after administration of various exemplary compounds was quantified by mean fluorescence intensity (MFI). Data represent mean ± standard deviation and represent at least two replicates.

[0052] Figure 5A shows a representative image of an ex vivo epithelial sample of epidermal tissue surrounding hair follicles 24 hours post-treatment. The sample was stained with apoptosis protein-3 (red) and DAPI (cyan). The inset shows a representative image of the ex vivo skin model.

[0053] Figure 5B shows the mean corrected fluorescence of cells stained for apoptosis protein-3. Images and data represent tissues derived from n=2 donors.

[0054] Figure 6 shows exemplary photographs of hair from individuals in the Clinical Consumer Perception Study. The photographs were taken 6 weeks later. Individuals were female and aged 27 to 65 years. Every two days, in the morning or evening, individuals used a simple water-based formulation containing the exemplary compound (at 0.02% v / v) on dry or towel-dried hair. Approximately 2 mL was applied directly to the hair strands. This study did not require randomization, and individuals could not see the name of the test material.

[0055] Figures 7A and 7B show the normalized proliferation of proliferating follicular papillary cells 48 hours after pretreatment with the exemplary compound (VII-3) under a series of pH conditions (Figure 7A) and temperature conditions (Figure 7B). Data represent mean ± standard deviation and represent n=2 donors. Implementation

[0056] [Cross-reference] []

[0057] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 231,533, filed August 10, 2021, which is incorporated herein by reference in its entirety.

[0058] While preferred embodiments of the invention have been shown and described herein, those skilled in the art will understand that such embodiments are provided by way of example only. Many changes, variations, and substitutions will be made by those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used to practice the invention. It is intended that the scope of the invention be defined by the following claims and the methods and structures within the scope of such claims and their equivalents.

[0059] In some embodiments, the present invention provides a method for preventing or treating hair loss or thinning hair (whether or not a diagnosis of hair loss or thinning hair has been made). [definition] []

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0061] As used in this specification and the claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include the plural.

[0062] The terms "C xy" or "C xC y" when used in conjunction with a chemical moiety (such as alkyl, alkenyl, or alkynyl) are intended to include groups containing x to y carbons in the chain. For example, the term "C 1-6 alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups containing 1 to 6 carbons.

[0063] The terms "C xy alkenyl" and "C xy ynyl" refer to substituted or unsubstituted unsaturated aliphatic groups that are similar in length and possible substitution of the alkyl groups described above, but each contains at least one double or triple bond.

[0064] The term "aryl" refers to an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system. An aromatic monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and carbon atoms, with five to eighteen carbon atoms, wherein at least one of the rings in the ring system is aromatic, that is, it contains a cyclic, delocalized (4n+2) π-electron system according to Hückel's theory. Ring systems derived from aryl include (but are not limited to) groups such as benzene, benzo[a], dihydroindene, indene, tetrahydronaphthalene, and naphthalene.

[0065] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl groups can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, spirobicyclic rings, and 5- to 12-membered bridging rings. In some embodiments, the cycloalkyl group comprises three to ten carbon atoms. In other embodiments, the cycloalkyl group comprises five to seven carbon atoms. The cycloalkyl group may be linked to the rest of the molecule via a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0066] The term "halo" or "halogen" or "halide" refers to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

[0067] The term "haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the haloalkyl group may be further substituted as required, as described herein.

[0068] The term "heterocycle," as used herein, refers to a saturated, unsaturated, or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridging rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, provided the valence allows. In one exemplary embodiment, the aromatic ring (e.g., pyridyl) may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocyclics further include helical bicyclics, such as 5-membered to 12-membered helical bicyclics.

[0069] "Heteroaryl" or "aromatic heterocycle" refers to a group derived from a heteroaryl ring comprising one to eleven carbon atoms and at least one heteroatom, wherein the heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems, wherein at least one of the rings in such a ring system is aromatic, that is, it contains a cyclic, nonlocal (4n+2) π–electron system according to Hückel's theory. The complex atoms in the heteroaryl group may be oxidized as needed. One or more nitrogen atoms (if present) may be quaternized as needed. The heteroaryl group may be attached to the rest of the molecule via any atom of the heteroaryl group (with permissible valence, such as the carbon or nitrogen atom of the heteroaryl group). Examples of heteroaryl groups include (but are not limited to) pyridine, pyrimidine, oxazole, furan, piperan, thiophene, isoxazole, benzimidazole, benzothiazole, and imidazopyridine. "X-membered heteroaryl" refers to the number of endocytic atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 endocytic atoms, such as triazole, oxazole, thiophene, etc.

[0070] The term "substituted" refers to a portion having a substituent that replaces one or more hydrogen atoms on a carbon atom or a substituted heteroatom (e.g., NH or NH₂ in a compound). It should be understood that "substituted" or "substituted-to" includes the implicit limitation that such substitution is based on the permissible valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations (such as by rearrangement, cyclization, elimination, etc.). In some embodiments, "substituted" refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom (e.g., replacing two hydrogen atoms on a single carbon atom with a side-oxygen group, imine group, or thionyl group). As used herein, the term "substituted" encompasses all permissible substituents including organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents may be one or more and may be the same or different.

[0071] In some embodiments, the substituent may include any substituent described herein, such as: halogen, hydrogen, side oxygen (=O), thionyl (=S), cyano (-CN), nitro (-NO₂), imino (=NH), oxime (=N-OH), nitrile (=N-NH₂), -R bb-OR aa, -R bb-OC(O)-R aa, -R bb-OC(O)-OR aa, -R bb-OC(O)-N(R aa) 2, -R bb-N(R aa) 2, -R bb-C(O)R aa, -R bb-C(O)OR aa, -R bb-C(O)N(R aa) 2, -R bb-OR cc-C(O)N(R aa) 2, -R bb-N(R aa)C(O)OR aa, -R bb-N(R aa)C(O)R aa, -R bb-N(Raa)S(O) tRaa (where t is 1 or 2), -R bb-S(O) tRaa (where t is 1 or 2), -R bb-S(O) tORaa (where t is 1 or 2) and -R bb-S(O) tN(Raa)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, arylenyl, arylynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which may be modified as required by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, syloxy group (=O), thionyl (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R bb-ORaa, -R bb-OC(O)-R aa, -R bb-OC(O)-OR aa, -R bb-OC(O)-N(R aa) 2, -R bb-N(R aa) 2, -R bb-C(O)R aa, -R bb-C(O)OR aa, -R bb-C(O)N(R aa) 2, -R bb-OR cc-C(O)N(R aa) 2, -R bb-N(R aa)C(O)OR aa, -R bb-N(R aa)C(O)R aa, -R bb-N(R aa)S(O) tR aa (where t is 1 or 2), -R bb-S(O) tR aa (where t is 1 or 2), -R bb-S(O) tOR aa (where t is 1 or 2) and -R bb-S(O) tN(R aa) 2 (where t is 1 or 2) replaces;Each Raa group is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl. Each Raa group (with permissible valence) may, as needed, be derived from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, septyl group (=O), thionyl group (=S), cyano (-CN), nitro (-NO₂), imino group (=NH), oxime (=N-OH), hydrazine (=N-NH₂), -Rbb-ORaa, -Rbb-OC(O)-Raaa, -Rbb-OC(O)-ORaa, -Rbb-OC(O)-N(Raa)₂, -Rbb-N(Raa)₂, -Rbb-C(O)Raaa, -Rbb-C(O)ORaa, -Rbb-C(O)N(Raa) 2. Substitutions of -R bb-OR cc-C(O)N(Raa) 2, -R bb-N(Raa)C(O)OR aa, -R bb-N(Raa)C(O)Raa, -R bb-N(Raa)S(O) tRaa (where t is 1 or 2), -R bb-S(O) tRaa (where t is 1 or 2), -R bb-S(O) tOR aa (where t is 1 or 2), and -R bb-S(O) tN(Raa) 2 (where t is 1 or 2); wherein each R bb is independently selected from a straight-chain or heavy-chain or branched amino, alkenyl, or ynyl chain, and each R cc is a straight-chain or branched alkyl, alkenyl, or ynyl chain.

[0072] Double bonds to oxygen atoms (such as side oxygen atoms) are represented herein as "=O" and "(O)". Double bonds to nitrogen atoms are represented as "=NR" and "(NR)". Double bonds to sulfur atoms are represented as "=S" and "(S)".

[0073] The phrase "medically acceptable" in this article refers to compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications (in accordance with a reasonable benefit / risk ratio).

[0074] The phrase “medically acceptable excipient” or “medically acceptable carrier” as used herein means, as in this article, a pharmaceutically acceptable material, composition, or medium, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is harmless to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil and cottonseed oil. (10) Safflower oil, sesame oil, olive oil, corn oil and soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Pyrothermic water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic compatible substances used in pharmaceutical formulations.

[0075] The term "salt" or "medically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in this art. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, particularly isopropylamine, trimethylamine, diethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0076] In some embodiments, the term "cosmetically acceptable salt" means any salt that is cosmetically tolerable if suitably used in cosmetic treatments (especially if used or applied to humans and / or mammals). In some embodiments, such salts include (but are not limited to) salts for forming base addition salts, inorganic salts such as, for example and in a non-limiting sense, lithium, sodium, potassium, calcium, magnesium, or aluminum, or organic salts such as, for example and in a non-limiting sense, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine, or piperazine; or acid addition salts, organic salts such as, for example and in a non-limiting sense, acetates, citrates, lactates, malonates, maleates, tartrates, fumarates, benzoates, aspartate, glutamate, succinates, oleates, trifluoroacetates, oxalates, papoates, or gluconates, or inorganic salts such as, for example and in a non-limiting sense, chlorides, sulfates, borates, or carbonates.

[0077] "Cosmetic effective amount," as used herein, refers to the amount of compound sufficient to improve an individual's physical appearance. It should be understood that the "cosmetic effective" amount can vary from person to person due to many factors, including, for example, an individual's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the prescribing physician's judgment.

[0078] The phrase "cosmetically acceptable excipient" or "cosmetically acceptable carrier," as used herein, includes pharmaceutical cream bases, oil-in-water emulsions, water-in-oil emulsions, gels, or similar formulations. Those skilled in the art will understand that suitable carriers typically contain ingredients commonly found in cosmetics and cosmeceuticals, such as: oils, waxes, or other standard fatty substances, or known gelling agents and / or thickeners; emulsifiers; moisturizing agents; emollients; sunscreens; hydrophilic or lipophilic surfactants; free radical scavengers; preservatives; alkalizing or acidifying agents; fragrances; surfactants; fillers; natural products or extracts of natural products, such as aloe vera or green tea extracts; vitamins; or coloring materials.

[0079] The term "in vivo" generally refers to events that occur within an individual's body.

[0080] The term "in vitro" generally refers to an event that occurs outside of an individual. For example, in vitro assays include any assay performed outside of an individual. In vitro assays include cell-based assays using live or dead cells. In vitro assays also include cell-free assays that do not use intact cells.

[0081] "Optional" or "as needed" means that the event or situation described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "substituted aryl group as needed" means that the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups.

[0082] "Pharmaceutical acceptable carriers, diluents, or excipients" include (but are not limited to) any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes, colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the United States Food and Drug Administration for use in humans or livestock. [Compounds and Compositions] []

[0083] This invention provides compounds, salts thereof, compositions thereof, and formulations for hair treatment. These compounds or salts thereof may have structural formulas (I), (II), (III), (IV), (V), (VI), (VII A), (VII B), or (VIII). These compounds or salts thereof may be selected from those listed below. [surface] [1] [to]

[10] The compounds disclosed herein and their salts may be used in the methods of this invention.

[0084] [, Mode , ] [, ( , ] VII B [)] [, and its daughter compounds , ] [, , ]

[0085] In some cases, this paper reveals a compound having the structure of formula (VII B): [, , ] (VII B), or its salt, wherein: B is an aryl or heteroaryl group, wherein the heteroaryl group is selected from pyridine, pyrimidine, oxazole, furan, piperan, thiophene, isoxazole, benzimidazole, benzothiazole, and imidazopyridine; R1 is selected from hydrogen, C1-6 alkyl or C1-6 haloalkyl, -S-alkyl, -S-haloalkyl, -S(O)(O)Ra; wherein Ra is selected from the group consisting of hydrogen, C1-6 alkyl or C1-6 haloalkyl; R2 is selected from -OH, C1-6 alkoxy, C1-6 haloalkoxy, -SRb, -NH2, alkylamine, and imine, wherein R2 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and... A group that makes up; and R3 and R4 are independently selected from the group consisting of hydrogen, C1-6 alkyl or C1-6 haloalkyl. [, , ]

[0086] In some embodiments of compounds (or salts thereof) having structural formula (VII B), B is a heteroaryl group. In some embodiments, the heteroaryl group is a furan. In some embodiments, R1 is hydrogen or S(O)(O)Ra. In some embodiments, Ra is methyl or ethyl. In some embodiments, R2 is imino or –SRb. In some embodiments, Rb is methyl or In some embodiments, R3 is hydrogen or ethyl. In some embodiments, R4 is hydrogen.

[0087] In some embodiments, compounds having structural formula (VII B) are selected from those listed in Table 1 and their salts. [surface] [1.] [Group] [I] [Exemplary compounds] [] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] VII-2 1-(ethylsulfonylurea)-3-(2-furanyl)-1H-1,2,4-triazol-5-amine 242.260 VII-3 3-(2-furanyl)-1-(methylsulfonylurea)-5-(methylthio)-1H-1,2,4-triazole 259.312 VII-4 2-[[4-ethyl-5-(2-furanyl)-4H-1,2,4-triazol-3-yl]thio]-1-[4-(1-pyrrolidylsulfonyl)phenyl]-ethyl ketone 446.554

[0088] [, Mode , ] [, (I) , ] [, and its daughter compounds , ] [, , ]

[0089] In some states, this paper reveals a compound having the structure of formula (VII A): [, , ] (VII A), or its salt, wherein: A is an aryl or heteroaryl group, wherein the heteroaryl group is selected from pyridine, pyrimidine, oxazole, furan, piperan, thiophene, isoxazole, benzimidazole, benzothiazole, and imidazopyridine; R1 is a C1-6 alkyl or C1-6 halogen; and R2 is -C(O)OH, -C(O)O-alkyl or -C(O)O-halogen.

[0090] In some embodiments of compounds (or salts thereof) having the structural formula (VII A), A is aryl. In some embodiments, the aryl group is phenyl. In some embodiments, R1 is a C1-6 alkyl group. In some embodiments, the C1-6 alkyl group is methyl. In some embodiments, R2 is a -C(O)O-alkyl group.

[0091] In some embodiments, the compound having structural formula (VII A) is the compound shown in Table 2 or a salt thereof. [surface] [2.] [Group] [II] [Exemplary compounds] [] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] VII-1 Methyl 1,4-dihydro-6-(methylsulfonylurea)-4-sideoxy-2-phenyl-5-pyrimidinecarboxylate 308.315

[0092] [, Mode , ] [, (I) , ] [, and its daughter compounds , ] [, , ]

[0093] In some states, this paper reveals a compound having the structure of formula (VIII): [, , ] (VIII), or its salt, wherein: m is 0, 1, or 2; and R x are each independently C1-6 alkyl, C5-8 aryl, C1-6 haloalkyl, alkylaryl, or haloalkylaryl. [, , ]

[0094] In some embodiments of compounds (or salts thereof) having structural formula (VIII), m is 2. In some embodiments, R x are each independently methyl or phenyl. [, , ]

[0095] In some embodiments, the compound having structural formula (VIII) is the compound shown in Table 3 or a salt thereof. [surface] [3.] [Group] [III] [Exemplary compounds] [] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] VII-25 5-Methyl-3-[(4-sideoxy-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl]-5-phenyl-2,4-imidazolidinedione 348.362

[0096] [, Mode , ] [, (I) , ] [, and its daughter compounds , ] [, , ]

[0097] In some states, this paper reveals a compound having the structure of formula (I): (I); or its salt, wherein: Y1 is either O or S; Y2 is either O or S; Y3 is either O or S; R 1 is selected from H, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl (e.g., phenyl) and aralkyl (e.g., benzyl), wherein the aryl or aralkyl group is substituted as required by one or more independent substituents selected from halogen, alkyl, alkoxy and haloalkoxy; R2 is selected from H, alkyl, alkenyl, haloalkyl, and haloalkenyl; A is an aryl (e.g., phenyl) or a heteroaryl (e.g., pyrimidinyl); p is 0, 1, 2, or 3; and R x are each independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, -OH, alkoxy, haloalkoxy, -O-alkyl-C(O)OH, nitro, -NH2, alkylamino, dialkylamino and haloalkylamino; or, Alternatively, the two R x atoms together with the atoms they are attached to form (e.g., C4-C6) cycloalkyl or (e.g., 5- or 6-membered) heterocyclic groups, wherein the cycloalkyl or heterocyclic group is substituted as required by one or more independent substituents selected from halogens, alkyl groups and haloalkyl groups.

[0098] In some embodiments of compounds (or salts thereof) having structural formula (I), R2 is selected from (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkyl, and (e.g., C1-6, such as C1-4) haloalkenyl. In some embodiments, Y1 is S. In some embodiments, Y3 is S. In some embodiments, A is Where Q1 and Q2 are each independently CH or N. In some embodiments, A is or .

[0099] In some embodiments, a compound having structural formula (I) (or a salt thereof) has structural formula (IA1) or (IA2): (I A1) or (I A2); or its salt, wherein: R x1, R x2, R x3, R x1', R x2' and R x3' are each independently selected from halogen, (e.g. C1-6, such as C1-4) alkyl, (e.g. C1-6, such as C1-4) haloalkyl, (e.g. C1-6, such as C1-4) alkenyl, (e.g. C1-6, such as C1-4) haloalkenyl, -OH, (e.g. C1-6, such as C1-4) alkoxy, (e.g. C1-6, such as C1-4) haloalkoxy, -O-epylalkyl-C(O)OH, nitro, -NH2, (e.g. C1-6, such as C1-4) alkylamino, (e.g. C1-6, such as C1-4) dialkylamino and (e.g. C1-6, such as C1-4) haloalkylamino.

[0100] In some embodiments of compounds (or salts thereof) having the structural formula (IA1) or (IA2), R2 is selected from (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkyl, and (e.g., C1-6, such as C1-4) haloalkenyl. In some embodiments, Y1 is S. In some embodiments, Y3 is S. In some embodiments, A is Where Q1 and Q2 are each independently CH or N. In some embodiments, A is or .

[0101] In some embodiments, a compound having structural formula (I) (or a salt thereof) has structural formula (I B1): (I B1), where: R x4 and R x5 are each independently selected from halogen, (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) haloalkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkenyl, -OH, (e.g., C1-6, such as C1-4) alkoxy, (e.g., C1-6, such as C1-4) haloalkoxy, -O-epylalkyl-C(O)OH, nitro, -NH2, (e.g., C1-6, such as C1-4) alkylamino, (e.g., C1-6, such as C1-4) dialkylamino and (e.g., C1-6, such as C1-4) haloalkylamino.

[0102] In some embodiments of compounds (or salts thereof) having the structural formula (I B1), R2 is selected from (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkyl, and (e.g., C1-6, such as C1-4) haloalkenyl. In some embodiments, Y1 is S. In some embodiments, Y3 is S. In some embodiments, A is Where Q1 and Q2 are each independently CH or N. In some embodiments, A is or .

[0103] In some embodiments, a compound having structural formula (I) (or a salt thereof) has structural formula (I B2): (I B2), where: R x6 and R x7 are each independently selected from halogen, (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) haloalkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkenyl, -OH, (e.g., C1-6, such as C1-4) alkoxy, (e.g., C1-6, such as C1-4) haloalkoxy, -O-alkyl-C(O)OH, nitro, -NH2, (e.g., C1-6, such as C1-4) alkylamino, (e.g., C1-6, such as C1-4) dialkylamino and (e.g., C1-6, such as C1-4) haloalkylamino; or, Alternatively, Rx6 and Rx7 together with the atoms they are attached to form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is substituted as needed by one or more substituents independently selected from halogens, (e.g., C1-6, such as C1-4) alkyl groups and (e.g., C1-6, such as C1-4) haloalkyl groups.

[0104] In some embodiments of compounds (or salts thereof) having the structural formula (I B2), R2 is selected from (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkyl, and (e.g., C1-6, such as C1-4) haloalkenyl. In some embodiments, Y1 is S. In some embodiments, Y3 is S. In some embodiments, A is Where Q1 and Q2 are each independently CH or N. In some embodiments, A is or .

[0105] In some embodiments, a compound having structural formula (I) (or a salt thereof) has structural formula (I C1) or (I C2): (IC1) or (I C2), in: R x8 and R x9 are each independently selected from halogen, (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) haloalkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkenyl, -OH, (e.g., C1-6, such as C1-4) alkoxy, (e.g., C1-6, such as C1-4) haloalkoxy, -O-epylalkyl-C(O)OH, nitro, -NH2, (e.g., C1-6, such as C1-4) alkylamino, (e.g., C1-6, such as C1-4) dialkylamino and (e.g., C1-6, such as C1-4) haloalkylamino.

[0106] In some embodiments of compounds (or salts thereof) having the structural formula (I C1) or (I C2), R2 is selected from (e.g., C1-6, such as C1-4) alkyl, (e.g., C1-6, such as C1-4) alkenyl, (e.g., C1-6, such as C1-4) haloalkyl, and (e.g., C1-6, such as C1-4) haloalkenyl. In some embodiments, Y1 is S. In some embodiments, Y3 is S. In some embodiments, A is Where Q1 and Q2 are each independently CH or N. In some embodiments, A is or .

[0107] In some embodiments, compounds having structural formula (I) are selected from those listed in Table 4 and their salts. [surface] [4.] [Group] [IV] [Exemplary compounds] [] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] I-1 5-[[4-hydroxy-3-methoxy-5-(2-propen-1-yl)phenyl]methylene]-1-[4-(1-methylethyl)phenyl]-2,4,6(1H,3H,5H)-pyrimidinyltrione 420.465 I-2 1-(3,5-Dimethylphenyl)-5-[[3-ethoxy-4-hydroxy-5-(2-propen-1-yl)phenyl]methylene]-2,4,6(1H,3H,5H)-pyrimidinyltrione 420.465 I-3 1-(3,5-Dimethylphenyl)-5-[[4-hydroxy-3-methoxy-5-(2-propen-1-yl)phenyl]methylene]-2,4,6(1H,3H,5H)-pyrimidinyltrione 406.438 I-4 1-(3,4-Dimethylphenyl)-5-[[4-hydroxy-3-methoxy-5-(2-propen-1-yl)phenyl]methylene]-2,4,6(1H,3H,5H)-pyrimidinyltrione 406.438 I-5 5-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]-1-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinyltrione 382.372 I-6 5-[(2,4-Dimethoxyphenyl)methylene]-1-(2-propen-1-yl)-2,4,6(1H,3H,5H)-pyrimidinyltrione 316.313 I-7 5-[[3-methoxy-4-(2-propen-1-yloxy)phenyl]methylene]-1-(2-propen-1-yl)-2,4,6(1H,3H,5H)-pyrimidinyltrione 342.351 I-8 5-[[3-ethoxy-4-hydroxy-5-(2-propen-1-yl)phenyl]methylene]dihydro-2-thionoyl-4,6(1H,5H)-pyrimidinide 332.381 I-9 Dihydro-5-[[4-hydroxy-3-methoxy-5-(2-propen-1-yl)phenyl]methylene]-2-thiono-4,6(1H,5H)-pyrimidinide 318.354 I-10 5-[[4-ethoxy-3-methoxy-5-(2-propen-1-yl)phenyl]methylene]dihydro-1-methyl-2-thionoyl-4,6(1H,5H)-pyrimidinide 360.435 I-1I (5E)-5-[(2,4-dimethoxyphenyl)methylene]-1-methyl-2,4,6(1H,3H,5H)-pyrimidinyltrione 290.275 I-12 5-[(1-Butyl-2,3-dihydro-1H-indol-5-yl)methylene]-1-methyl-2,4,6(1H,3H,5H)-pyrimidintrione 327.384 I-13 5-[[2-(dimethylamino)-5-pyrimidinyl]methylene]-1-methyl-2,4,6(1H,3H,5H)-pyrimidintrione 275.268 I-14 2-[3-[(tetrahydro-1-methyl-2,4,6-trisyloxy-5(2H)-pyrimidinyl)methyl]phenoxy]acetic acid 304.258 I-15 5-[(2-hydroxy-3-methoxy-5-nitrophenyl)methylene]-1-methyl-2,4,6(1H,3H,5H)-pyrimidinyltrione 321.245 I-16 5-[[4-hydroxy-3-methoxy-5-(2-propen-1-yl)phenyl]methylene]-1-methyl-2,4,6(1H,3H,5H)-pyrimidinyltrione 316.313 I-17 Dihydro-5-[[4-hydroxy-3-methoxy-5-(2-propen-1-yl)phenyl]methylene]-1-(4-methoxyphenyl)-2-thiono-4,6(1H,5H)-pyrimidinide 424.478 I-18 5-[[3-ethoxy-4-hydroxy-5-(2-propen-1-yl)phenyl]methylene]dihydro-1-(2-methoxyphenyl)-2-thionoyl-4,6(1H,5H)-pyrimidinide 438.505

[0108] [, Mode , ] [, (II) , ] [, Compounds and salts , ] [, , ]

[0109] In some states, this paper reveals a compound represented by formula (II): (II), or its salt, wherein: Ry are each independently an alkyl or haloalkyl group; m is 0, 1, or 2; L 1 is selected from the following bonds: -O-, -S-, -N(Ra1)-, -C(O)-, -C(O)-, -C(O)-, -C(O)-, -C(O)-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(Ra2)-, -N(Ra3)C(O)-, -N(Ra4)C(O)N(Ra5)-, -N(Ra6)C(O)O-, -OC(O)N(Ra7)-, -S(O) 2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O) 2-, -S(O) 2O-, -N(Ra8)S(O) 2-, -S(O) 2N(Ra9)-, -N(R a10)S(O)-, -S(O)N(Ra11)-, -N(Ra12)S(O)2N(Ra13)- and -N(Ra14)S(O)N(Ra15)-; and R 1 is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, cycloalkyl, alkylcycloalkyl, halocycloalkyl, aryl (e.g., phenyl), alkylaryl, heteroaryl, -O-aryl, -O-alkylaryl and -O-heteroaryl.

[0110] In some embodiments, a compound having structural formula (II) (or a salt thereof) has structural formula (II A): (II A)

[0111] In some embodiments, for compounds or salts of formula (II) or (II A), Ry is a C1-C6 (e.g., C1-C4) alkyl (e.g., methyl). In some embodiments, m is 1. In some embodiments, L1 is selected from -C(O)-, -C(O)-alkyl-O-, and -S(O)2-. In some embodiments, R1 is selected from alkyl, cycloalkyl, aryl, alkylaryl, -O-aryl, and -O-alkylaryl.

[0112] In some embodiments, compounds having structural formula (II) are selected from those listed in Table 5 and their salts. [surface] [5.] [Group] [V] [Exemplary compounds] [] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] II-1 Cyclohexyl[4-[4-(4-methylphenyl)-1-phthalazinyl]-1-piperazinyl]-methyl ketone 414.553 II-2 (4-Methylphenyl)[4-[4-(4-methylphenyl)-1-phthalazinyl]-1-piperazinyl]-methyl ketone 422.532 II-3 1-(4-Methylphenyl)-4-[4-(Methylsulfonylmethane)-1-piperazinyl]-phthalazine 382.489 II-4 1-[4-[4-(4-methylphenyl)-1-phthalazinyl]-1-piperazinyl]-1-propanone 360.461 II-5 2-(4-Methylphenoxy)-1-[4-[4-(4-methylphenyl)-1-phthalazinyl]-1-piperazinyl]-ethyl ketone 452.558 II-6 1-[4-[4-(4-methylphenyl)-1-phthalazinyl]-1-piperazinyl]-1-butanone 374.488

[0113] In some states, this paper reveals a compound represented by formula (III): (III), or its salt, wherein: A is aryl or heteroaryl; p is 0, 1, or 2; Ry is independently an alkyl or haloalkyl group; q is 0, 1, or 2; Rz are each independently an alkyl or haloalkyl group; and R1 and R2 are each independently selected from H, aryl groups substituted as needed, -NH-C(O)-NH-cycloalkyl (e.g., adamantyl), -C(O)-NH-cycloalkyl, and -NH-C(O)-cycloalkyl; or, Alternatively, R1 and R2 may be bonded together with the nitrogen atom to which they are attached to form an N-heterocyclic group (e.g., piperazine group) or -N=Rc, where Rc is an aryl group or a heteroaryl group that is substituted as desired.

[0114] In some embodiments, for compounds or salts of formula (III), R1 and R2 are bonded together with the nitrogen atoms to which they are attached to form , , or Rx is selected from alkyl, haloalkyl, -extinyl-OH, -extinyl-O-alkyl, -extinyl-aryl, and -extinyl-extinylaryl-alkyl. In some embodiments, R1 and R2 are bonded together with the nitrogen atom to which they are attached to form , , or In some embodiments, R1 and R2 are bonded to their attached nitrogen atoms to form a piperazine group, which is substituted as desired. In some embodiments, A is a pyridyl group ( ).

[0115] In some embodiments, compounds having structural formula (III) are selected from those listed in Table 6 and their salts. [surface] [6.] [Group] [VI] [Exemplary compounds] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] III-1 [4-(4-methoxyphenyl)-1-piperazinyl][2-(2-thienyl)-4-quinolinyl]-methyl ketone 429.545 III-2 6-Methyl-N-[1-[(3-methylphenyl)methyl]-1H-1,2,4-triazol-3-yl]-2-(3-pyridyl)-4-quinoline carboxamide 434.503 III-3 2-(3,4-Dimethylphenyl)-N-[4-[(3,5-Dimethyl-1H-pyrazol-1-yl)methyl]phenyl]-4-quinoline carboxamide 460.581 III-4 N-[5-(2-ethoxyethyl)-1,3,4-thiadiazol-2-yl]-2-phenyl-4-quinoline carboxamide 404.495 III-5 2-(2,4-Dimethylphenyl)-4-quinolinecarboxylic acid, 2-[(tricyclo[3.3.1.1 3,7]dec-1-ylamino)carbonyl] acehydrazine 468.601

[0116] In some states, this paper discloses a compound represented by formula (IV): (IV), or its salt, wherein: A is a heteroaryl group; q is 0, 1, 2, or 3; and R x is selected from alkyl, halogen, alkoxy, halogenalkoxy, -SH, alkylthio, aryl, and alkoxyaryl.

[0117] In some embodiments, compounds having structural formula (IV) are selected from those listed in Table 7 and their salts. [surface] [7.] [Group] [VII] [Exemplary compounds] [ID #] [Chemical Structure] Chemical name molecular weight IV-1 4-[[[5-[(1,1-dimethylethyl)amino]-1,3,4-thiadiazol-2-yl]thio]methyl]-7-hydroxy-2H-1-benzopyran-2-one 363.464 IV-2 7-Hydroxy-4-[[[5-(methylthio)-1,3,4-thiadiazol-2-yl]thio]methyl]-2H-1-benzopyran-2-one 338.435 IV-3 2-[[(7-hydroxy-2-sideoxy-2H-1-benzopyran-4-yl)methyl]thio]-3-(2-methoxyphenyl)-4(3H)-quinazolone 458.495 IV-4 2-[[(7-hydroxy-2-sideoxy-2H-1-benzopyran-4-yl)methyl]thio]-6-methyl-5-(2-methylbutyl)-thieno[2,3-d]pyrimidin-4(1H)-one 442.562

[0118] In some states, this paper reveals a compound represented by formula (V): (V), or its salt, wherein: R1 is H or, as needed, a substituted aryl group; Rm and Rn are bonded together with the nitrogen atom to which they are attached to form an N-heterocyclic group, wherein the N-heterocyclic group is substituted as needed with one or more substituents selected from alkyl, -S(O)H, -S(O)2H, -S(O)-alkyl and -S(O)2-alkyl; Q1 can be NR a1, CR b1R b2, or S; Q3 is N or CR b3; and Q2 is either NR a2 or CR b4R b5; where: Ra1, Ra2, Rb1, Rb2, Rb3, Rb4 and Rb5 are each independently selected from H, aryl groups as needed, alkylaryl groups as needed, and arylalkyl groups as needed.

[0119] In some embodiments, for compounds or salts of formula (V), Q1 is CR b1R b2 or S. In some embodiments, Q3 is CR b3.

[0120] In some embodiments, compounds having structural formula (V) are selected from those listed in Table 8 and their salts. [surface] [8.] [Group] [VIII] [Exemplary compounds] [] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] V-1 1-[(4-methylphenyl)methyl]-4-(1-pyrrolidinyl)-1H-pyrazolo[3,4-d]pyrimidine 293.374 V-2 1-(2,4-Dimethylphenyl)-4-(1-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidine 307.401 V-3 4-(2-methyl-1-piperidinyl)-2,6-diphenyl-thieno[2,3-d]pyrimidine 385.536 V-4 4-[4-(ethylsulfonylurea)-1-piperazinyl]-5H-pyrrolo[3,2-d]pyrimidine 295.368

[0121] In some states, this paper reveals a compound represented by formula (VI): (VI), or its salt, wherein: L 0 is selected from -C(O)-, -O-, -S-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2-, -NH- and L1 is selected from -C(O)-, -O-, -S-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2- and -NH-; p, q, and m are each independently 0, 1, or 2; Rx, Ry, and Rz are each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -OH, -C(O)OH, or -extinyl-C(O)OH; A is aryl or heteroaryl; L 2 represents alkylene, -C(O)-, -O-, -S-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2-, -N(H)S(O) 2-, -S(O) 2N(H)-, -alkylene-N(H)S(O) 2-, -S(O) 2N(H)-alkylene-, -NH-, -N= and -CH=NN=; and B is an aryl group that is substituted as needed, or a heteroaryl group that is substituted as needed.

[0122] In some embodiments, for compounds or salts of formula (VI), L0 is... In some embodiments, A is phenyl or piperazine. In some embodiments, B is selected from... , , and In some embodiments, L2 is selected from alkylene, -S(O)2N(H)-alkylene, and -CH=NN=. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, q is 0. In some embodiments, m is 0. In some embodiments, m is 2. In some embodiments, Rx is each independently cyano, alkyl, alkoxy, or nitro. In some embodiments, Rz is each independently -OH, -C(O)OH, or -alkylene-C(O)OH.

[0123] In some embodiments, compounds having structural formula (VI) are selected from those listed in Table 9 and their salts. [surface] [9.] [Group] [IX] [Exemplary compounds] [] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] VI-1 [4-(1,3-benzodioxapenten-5-ylmethyl)-1-piperazinyl][1-(phenylsulfonyl)-4-piperidinyl]-methyl ketone 471.579 VI-2 4-[[4-[[4-(1,3-benzodioxapenten-5-ylmethyl)-1-piperazinyl]carbonyl]-1-piperidinyl]sulfonyl]benzylnitrile 496.589 VI-3 [4-(1,3-benzodioxapenten-5-ylmethyl)-1-piperazinyl][1-[(4-methoxy-3-methylphenyl)sulfonyl]-4-piperidinyl]-methyl ketone 515.632 VI-4 [4-(2-Benzothiazolylmethyl)-1-piperazinyl][1-[(4-methylphenyl)sulfonyl]-4-piperidinyl]-methyl ketone 498.674 VI-5 4-Methoxy-N-[4-[[(2-phenylethyl)amino]sulfonyl]phenyl]benzenesulfonamide 446.550 VI-6 4,5-Dihydro-2-[2-[[4-[[(4-nitrophenyl)sulfonyl]oxy]phenyl]methylene]hydrazyl]-4-sideoxy-5-thiazolic acid 478.464

[0124] [, Other compounds and their salts , ] [, , ]

[0125] In some embodiments, the compounds disclosed herein are selected from those listed in Table 10 and their salts. [surface] [10.] [Group] [X] [Exemplary compounds] [] [ID #] [Chemical Structure] [Chemical Name] [Molecular weight] VII-5 N-[4-(aminocarbonyl)phenyl]-3-phenyl-1,2,4-oxadiazole-5-butyramine 350.378 VII-6 1-[4-[[4-[[(2-methoxy-2-sideoxyethyl)amino]carbonyl]phenyl]amino]carbonyl]phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester 464.478 VII-7 1-[4-[[[4-(ethylsulfonyl)phenyl]amino]carbonyl]phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester 441.509 VII-8 5-Methyl-1-[3-[[[1-(2-pyrimidinyl)-4-piperidinyl]carbonyl]amino]phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester 434.500 VII-9 Spiro[cycloheptane-1,4'(1'H)-[1,3,5]triazinco[1,2-a]benzimidazole]-2'-amine 269.352 VII-10 3,4,5,6-Tetrahydro-1-phenyl-1,4-diazapuno[6,5-b]indol-2(1H)-one 277.327 VII-11 Spiro[cyclohexane-1,4'(3'H)-[1,3,5]triazinco[1,2-a]benzimidazole]-2'-amine 255.325 VII-12 2-(3,5-Dimethylphenyl)-2,3-dihydro-1H-isoindole 223.319 VII-13 2-Cyclohexyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione 233.311 VII-14 2-[3-(4-methoxyphenyl)propyl]-1H-benzimidazole 266.344 VII-15 2-[4-[(3-methylphenyl)methyl]-1-piperazinyl]-pyrimidine 268.364 VII-16 N-(4-methoxyphenyl)-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-syloxyethyl]-benzenesulfonamide 495.601 VII-17 2-[2-[4-(diphenylmethyl)-1-piperazinyl]-2-sideoxyethyl]-2H-1,4-benzothiazine-3(4H)-one 457.599 VII-18 1-(1-Naphthylcarbonyl)-4-(2-Thienylcarbonyl)-(9CI)piperazine 350.443 VII-19 21-(3-Carboxy-1-Sideoxypropoxy)-11,17-Dihydroxy-,(11β)-Pregn-1,4-diene-3,20-dione 460.523 VII-20 N1,N4-Diethyl-N1,N4-bis(phenylmethyl)-1,4-phenylenediamine 400.522 VII-21 N-[2-(1,2-dimethyl-1H-indol-3-yl)ethyl]-4-[4-methyl-3-(4-morpholinylsulfonylurea)phenyl]-1-sideoxy-2(1H)-phthalazine acetamide 613.740 VII-22 4,5,6,7-Tetrahydro-2-[[2-(4-methoxyphenyl)acetyl]amino]-6-methyl-N-(3-nitrophenyl)-benzo[b]thiophene-3-methamide 479.558 VII-23 3,3'-[[5-(benzoylamino)-1,3-epoxyphenyl]bis(carbonylimino)]bis-benzoate dimethyl ester (9CI) 551.555 VII-24 4-(1,1-Dimethylethyl)-N-[[(2-methyl-5-oxazolo[4,5-b]pyridin-2-ylphenyl)amino]thionylmethyl]-benzylamine 444.560 VII-26 N-[3,5-Dimethyl-1-[(2-methylphenyl)methyl]-1H-pyrazol-4-yl]-benzo[b]thiophene-3-methamide 375.497

[0126] In some embodiments, the compounds disclosed herein are selected from any or a combination of those shown in Tables 1 to 10 (or any subgroup thereof) and their salts.

[0127] For the synthetic methods of the compounds disclosed herein, see, for example, WO 2009031709 A1; Journal of Praktische Chemie (Leipzig), 323 (2), 3030310, 1981; European Journal of Medicinal Chemistry, 47, 138-142, 2012; Pharmaceutical Chemistry Journal, 41, 70–473, 2007; AMAJ Diseases Children, 97, 66-71, 1959; WO2003072099 A1; Chemiker-Zeitung, 111, 159-166, 1987; Journal of Heterocyclic Chemistry, 25(3), 959-968, 1988; and Russian Chemical Bulletin, 52(6), 1386-1398, 2003, which are all incorporated herein by reference.

[0128] The compounds of the present invention also include crystalline and amorphous forms of such compounds, pharmaceutically acceptable salts, and active metabolites of such compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including dehydrated polymorphs), configurational polymorphs, and amorphous forms of such compounds, as well as mixtures thereof.

[0129] This invention includes salts of the compounds disclosed herein, particularly pharmaceutically acceptable salts. Compounds of this invention having sufficiently acidic, sufficiently basic, or both functional groups can react with many inorganic bases and any of inorganic and organic acids to form salts. Alternatively, inherently charged compounds (such as those having a quaternary nitrogen) can form salts with suitable counterions (e.g., halide ions, such as bromide, chloride, or fluoride ions, especially bromide ions).

[0130] The compounds described herein may exist in some cases as diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include all diastereomers, enantiomers, and epimers, as well as suitable mixtures thereof. Separation of stereoisomers may be performed by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis.

[0131] The methods and compositions described herein include the use of both amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of such compounds having the same type of activity are included within the scope of this invention. Furthermore, the compounds described herein may be in non-solventized and solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, and the like). The solvated forms of the compounds presented herein are also considered to be disclosed herein. []

[0132] The synthetic chemical transformations and methods applicable to the synthesis of the compounds described herein are known in this art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0133] [, Composition , ] [, , ]

[0134] This invention provides compositions of the compounds disclosed herein and their salts. The compositions may further comprise at least one additive selected from the group consisting of carriers, excipients, adjuvants, and diluents. The compositions can be formulated as toners, emulsions, creams, gels, shampoos, soaps, serums, sprays, or oils.

[0135] In some embodiments, the composition is a pharmaceutical composition. The pharmaceutical composition may further comprise at least one additive selected from the group consisting of pharmaceutically acceptable carriers, excipients, adjuvants, and diluents.

[0136] In some embodiments, the composition is a cosmetic composition. The cosmetic composition may further comprise at least one additive selected from the group consisting of cosmetically acceptable carriers, excipients, adjuvants, and diluents. The cosmetic composition may be formulated as a colorant, lotion, cream, gel, shampoo, soap, serum, spray, or oil. [method] []

[0137] Methods for hair treatment using the compounds or salts disclosed herein are also provided herein.

[0138] In some embodiments, this document discloses a method or treatment for hair loss or thinning hair, comprising administering to an individual in need a composition comprising a compound or salt described herein, or a composition described herein. The compound or salt thereof may have a structural formula of (I), (II), (III), (IV), (V), (VI), (VII A), (VII B), or (VIII). The compound or salt thereof may be selected from any one of those listed in Tables 1 to 10 or any subgroup thereof, or any combination thereof. A diagnosis of hair loss or thinning hair may or may not have been made. In some embodiments of any method described herein, the individual may have been diagnosed with hair loss or thinning hair. In some embodiments of any method described herein, the individual may not have been diagnosed with hair loss or thinning hair. In some embodiments, the method promotes hair growth, hair repair, or hair thickening in the individual. In some embodiments, the method increases hair density or hair growth rate in the individual. In some embodiments, the hair loss is selected from androgenetic alopecia, alopecia areata, androgenetic alopecia, gynecological alopecia, postpartum alopecia, seborrheic alopecia, non-rigid alopecia, senile alopecia, chemotherapy-induced alopecia, radiation-induced alopecia, male pattern baldness, female pattern baldness, scarring alopecia, telogen effluvium of alopecia areata, traction alopecia, and anagen effluvium. In some embodiments, the hair is scalp hair, eyelashes, eyebrows, or facial hair. [Example] []

[0139] The present invention will now be described in general terms, and the invention will be more readily understood by reference to the following examples, which are included but not intended to limit the invention in any way, only for the purpose of illustrating certain aspects and embodiments of the invention.

[0140] [Example] [1] [Human follicular dermal papillary cells] [(hFDPC)] [Proliferation Test] []

[0141] The ability of the compounds or salts of this invention to increase the proliferation of human hair follicle dermal papillary cells (hFDPCs) was tested using cell viability assays (such as the Promega CellTiter-Glo® luminescent cell viability assay, the MTT cell proliferation assay (ATCC® 30-1010K), or cell counting). Table 11 shows the results. In Table 8, A represents an increase in hFDPC proliferation of less than 20%, B represents 20% to 40%, and C represents an increase in hFDPC proliferation of more than 40%. For this assay, hFDPCs were cultured on assembled culture-treated plastic substrates supplemented with indirubin-39-oxime (BIO), recombinant bone morphogenetic protein-2 (BMP-2), and basal fibroblast growth factor (FGFβ), a combination previously found to preserve in situ dermal papillary gene signatures. Exemplary results using compound VII-3 are shown in Figure 1. [surface] [11.] [based on] [hFDPC] [Evaluation of Small Molecules Proliferating] [] [ID #] [Chemical Structure] [hFDPC] [Percentage increase in proliferation] [(%) I-1 A I-2 B I-3 A I-4 A I-5 B I-6 A I-7 A I-8 B I-9 BI-10 A I-1I A I-12 BI-13 A I-14 A I-15 BI-16 A I-17 CI-18 B II-1 A II-2 B II-3 B II-4 B II-5 B II-6 B III-1 A III-2 A III-3 B III-4 B III-5 A IV-1 B IV-2 A IV-3 B IV-4 The V-1 The V-2 A V-3 B V-4 A VI-1 A VI-2 B VI-3 B VI-4 A VI-5 A VI-6 A VII-1 C VII-2 A VII-3 B VII-4 A VII-5 A VII-6 A VII-7 B VII-8 A VII-9 B VII-10 B VII-11 A VII-12 A VII-13 A VII-14 A VII-15 A VII-16 A VII-17 A VII-18 A VII-19 A VII-20 A VII-21 A VII-22 A VII-23 B VII-24 A VII-25 B VII-26 AA represents an increase in hFDPC proliferation of less than 20%, B represents 20% to 40%, and C represents an increase in hFDPC proliferation of more than 40%.

[0142] [Example] [2] [Based on the detection of keratinocytes]

[0143] The ability of the compounds or salts of this invention to affect proliferation was determined by culturing human adult epidermal keratinocytes on poly-L-lysine-treated plates and using cell viability assays such as the Promega CellTiter-Glo® luminescent cell viability assay, the MTT assay (ATCC® 30-1010K), or cell counts after 48 hours. The compounds or salts were added at different concentrations spanning at least two logarithmic levels.

[0144] [Example] [3] [Based on fibroblast detection]

[0145] The ability of the compounds or salts of this invention to affect the proliferation of human adult dermal fibroblasts was tested using cell viability assays, such as the Promega CellTiter-Glo® luminescent cell viability assay, the MTT assay (ATCC® 30-1010K), or cell counts after 48 hours. The compounds or salts were added at different concentrations spanning at least a 2 logarithmic range.

[0146] [Example] [4] [Based on endothelial cell testing]

[0147] The ability of the compounds or salts of this invention to affect the proliferation of human adult dermal microvascular endothelial cells was tested using cell viability assays, such as the Promega CellTiter-Glo® luminescent cell viability assay, the MTT cell proliferation assay (ATCC® 30-1010K), or cell counts after 48 hours. The compounds or salts were added at different concentrations spanning at least a 2 logarithmic range. []

[0148] [Example] [5] [Computer simulation security] [ / ] [Toxicological Studies] []

[0149] The safety / toxicological profile of compounds was determined by screening chemical structures using a range of computational models. These included the Pred-hERG 4.2 cardiotoxicity model and the NeuroDeRisk IL Profiler neurotoxicity model, as well as reproductive and developmental toxicity, carcinogenicity (genotoxic and non-genotoxic), skin sensitization, DNA mutation, and chromosomal aberration models from the QSAR Toolbox. []

[0150] [Example] [6] [Security] [ / ] [Toxicological Studies] []

[0151] The safety / toxicological profile of the compounds or salts of the present invention was assessed through a series of in vitro genotoxicity assays, including the SOS-chromogenic assay for determining bacterial genotoxicity and the TK.6 micronucleus assay for determining chromosomal damage and positive mutations. Standard reactive oxygen species (ROS) and apoptosis protease 3 / 7 assays were performed to determine general cytotoxicity. In addition, a series of sensitization tests were performed to predict any potential skin sensitivities. These included direct peptide reactivity assays to assess haptenization, the KeratinoSens reporter assay to determine potential sensitivities via activation of cellular protection pathways, and immunoassays using human immature monocyte-derived dendritic cells to assess any potential immunogenicity.

[0152] Future research will include mechanism-oriented studies, focusing on the metabolism and transport of the compounds or salts of this invention to induce or inhibit cytochrome P450, passive / active transport using the Caco-2 cell line, and compound efflux using the MDR-MDCK cell line, all with well-established assays. Safety and toxicity studies will also include functional cardiotoxicity and neurotoxicity in human iPSC-derived cardiomyocytes and neurons. Finally, a repeated insult patch test will be conducted on 200 human individuals using the compounds or salts of this invention to predict induced allergic contact dermatitis and related reactions.

[0153] [Example] [7] [Efficacy Research] []

[0154] The functional profile of the compounds or salts of this invention continues to be investigated in numerous 3D cell and in vitro models, ultimately leading to clinical trials. Furthermore, transcriptomic and proteomic analyses will be performed based on relevant genes and proteins with well-defined functional roles, such as VEGF or β-catenin on cells exposed to the compounds or salts of this invention. The "two-cell assembly" (TCA) 3D co-culture model will continue to be used, involving coating human outer root sheath cells (hORS) onto the top of dense spheroids of human follicular papillary cells. hFDPC supports polar overgrowth of hORS, similar to a bulb-in-a-dish culture. Additionally, the compounds or salts of this invention will be processed based on live human skin (containing hair) grafts excised from cosmetic surgery, and their targeted activation of follicular papillary cells will be evaluated in histological studies. Finally, a clinical efficacy trial will be conducted in 30 human individuals with hair loss or thinning hair to determine the effectiveness of the compounds or salts of this invention in promoting hair growth. Further trials can then be conducted on more individuals and across a wider range of age groups and demographics.

[0155] [Example] [8] [Mechanism Analysis] []

[0156] Using transcriptomics data, a series of computational analyses will be performed to identify potential mechanisms of action. These may include denaturation analysis (DE), followed by GO term and pathway enrichment to characterize the bioimaging of exemplary chemicals. Furthermore, pseudo-time and cell circulation analyses will be performed to investigate the developmental effects of these chemicals on target cells. Insights from other studies and models will be validated.

[0157] [Example] [9] [The exemplary compound will not be destroyed] [Caco-2] [Integrity of the intestinal cell barrier in a monolayer system] []

[0158] This example demonstrates the measurement of the transpolarized flux of compounds in Caco-2 cell monolayers and the resulting data that can be used to predict in vivo uptake of the compounds. Figure 2A is a schematic representation of the model system. Caco-2 cells were cultured in Transwells until monolayers formed, mimicking the intestinal cell barrier. Cultures were treated on the apical side with either the exemplary compound (VII-3) or the mediator control (0.1% v / v DMSO) for 24 hours and then cultured in a medium containing a fluorescent dye (Roche Yellow, labeled "F"). Figure 2B shows the apparent permeability of Caco-2 monolayers treated with DMSO and the representative compound. No difference in apparent permeability was observed. Data represent mean ± standard deviation and represent at least two replicates.

[0159] [Example]

[10] [The exemplary compound does not exhibit genotoxic conversion potential] []

[0160] TK.6 lymphoblasts are a well-established cell line commonly used for gene mutation analysis. They are heterozygous for the thymidine kinase (TK) gene and can detect positive mutations and chromosomal damage, which are manifested as micronuclei and can be detected by flow cytometry.

[0161] TK.6 cells were cultured for 24 hours with or without S9 metabolic activation after being treated with the exemplary compound or a mediator control (0.1% v / v DMSO). Figure 3A shows a representative graph of TK.6 cells treated with the exemplary compound (VII-3) with or without S9 metabolic activation. Methyl methanesulfonate (a known genotoxic alkylating agent) was used as a positive control for micronucleus detection. By comparison of the graphs, the representative compound did not exhibit genotoxic effects.

[0162] Micronucleus assays were also performed to determine whether these compounds were genotoxic by assessing the presence of micronuclei. Figure 3B shows the quantification of the TK.6 micronucleus assay after treatment with various exemplary compounds across a range of concentrations in the absence of S9 metabolic activation. Figure 3C shows the quantification of the TK.6 micronucleus assay after treatment with various exemplary compounds across a range of concentrations in the presence of S9 metabolic activation. Figures 3B and 3C, when combined, show that exemplary compounds VII-3, VII-1, VII-14, and II-4 did not promote any micronucleus formation, thus confirming no genotoxic conversion potential in the absence or presence of S9 metabolic activation. I-17 induced genotoxicity at concentrations >3.125 μg / mL.

[0163] Figure 3D shows the standardized β-galactosidase activity (e.g., quantified by absorbance) of a known genotoxin (4-NQ; 4-nitroquinoline-1-oxide) and representative compounds at various concentrations using the SOS chromogenic assay. This SOS chromogenic assay is a well-established bacterial-based test for genotoxicity. Similar to the results of the micronucleus assay, compounds VII-3, VII-1, and II-4 did not exhibit any genotoxic effects.

[0164] Normalized reactive oxygen species (ROS) activity in follicular dermal papillary cells was analyzed 24 hours after treatment with 5 μg / mL of the exemplary compound relative to the mediator control (0.1% v / v DMSO). Increased ROS levels are detrimental to cell homeostasis, structure, and function, causing oxidative stress. As shown in Figure 3E, I-18 exhibited higher ROS levels compared to other compounds.

[0165] HepG2 cells are immortalized hepatocytes commonly used to study apoptosis induced by small molecules. The normalized apoptotic protease-3 / 7 activity in HepG2 cells was measured, as shown in Figure 3F. Cells were treated with exemplary compounds spanning a >2 logarithmic concentration range or with mediators containing the corresponding % v / v – matched amounts of DMSO. Data represent mean ± standard deviation and represent at least two replicates. Except for compound I-17, which caused significant activation of apoptotic protease-3 / 7 at the highest concentration, compounds VII-3, VII-1, VII-14, and II-4 did not show any activation of apoptotic proteases across the 2 logarithmic concentration range.

[0166] [Example]

[11] [The exemplary compounds do not exhibit any skin sensitization potential or immunogenicity.] []

[0167] The Nrf2-ARE pathway is a key regulator of the cellular protective response to oxidative stress and an early indicator of skin sensitization. Nrf2 (a factor associated with nuclear factor erythrocyte 2) is a transcription factor that binds to the antioxidant response element (ARE). By fusing ARE to the light-producing luciferase gene and performing the KeratinoSens Nrf2-ARE reporter assay, the direct correlation between luciferase signaling and Nrf2-ARE pathway activation was demonstrated.

[0168] Standardized ARE-luciferase activity was determined using a known sensitizing compound (cinnamaldehyde) and exemplary compounds. Compound VII-1 exhibited sensitization potential (Figure 4A).

[0169] To assess skin sensitization potential or immunogenicity, an in vitro dendritic cell sensitization assay was also performed. Dendritic cell activation is broadly associated with downstream immunogenicity. CD14+ cells from peripheral monocytes of human donors were harvested and differentiated into immature monocyte-derived DCs using granulocyte-macrophage community-stimulating factor (GM-CSF) and interleukin-4 (IL-4), and then treated with the exemplary compounds. Killed E. coli (E. coli) and TNF-α were used as positive controls. Figure 4B shows a representative plot illustrating changes in HLA-DR expression. Figures 4C, 4D, and 4E show the expression of CD80, PDL-1, and CD141, respectively, quantified by mean fluorescence intensity (MFI) after administration of the various exemplary compounds. Data represent mean ± standard deviation and represent at least two replicates. The exemplary compounds did not exhibit any skin sensitization potential or immunogenicity.

[0170] [Example]

[12] [Exemplary compounds do not induce apoptotic proteases in isolated skin tissue] [-3] [activation] []

[0171] Skin tissue containing hair from cosmetic surgery was biopsied and punctured to prepare ready-to-use skin models (Genoskin). These samples were preserved and cultured for 24 hours with a mediator control (distilled water) or an exemplary compound for in vitro testing, and then processed for use in two-photon microscopy.

[0172] Figure 5A shows a representative image of an ex vivo epithelial sample of epidermal tissue surrounding hair follicles 24 hours post-treatment. The sample was stained with DAPI and targeted to apoptosis protein-3. The inset shows a representative image of the ex vivo skin model.

[0173] The mean corrected fluorescence of cells stained with apoptosis protein-3 was measured for samples treated with various representative compounds. Images and data represent tissues derived from n=2 donors. As shown in Figure 5B, the exemplary compounds did not induce apoptosis protein-3 activation in ex vivo skin tissue.

[0174] Example

[13] [Clinical Repetitive Stimulation Patch Testing]

[0175] The clinical trial was conducted by Eurofins | CRL, Inc. The trial followed established standardized procedures for designing a clinical test that ensures the well-being of the individuals in the clinical study and the generation of reliable research data. A total of 239 male and female individuals (aged 18 to 70 years) were selected to participate in the study. The objective of the study was to determine the potential of the test material containing 0.02% v / v of the exemplary compound to induce dermal irritation and / or sensitization after repeated patch application. [, , ] [] [surface] [12.] [Clinical Repetitive Stimulation Patch Test] [] Completed individual gender Patch type Adverse reactions 218 / 239 (20 individuals were lost during the follow-up period, and 1 individual was excluded due to an irrelevant event) 58 men and 160 women Closed 0 / 218 (0%) One individual presented with erythema, papules, pustules, and post-inflammatory hypopigmentation with comedones due to an unrelated event and was excluded from the study.

[0176] [Example]

[14] [Clinical Consumer] [Perception] [Research] []

[0177] The clinical trial was conducted by Eurofins | CRL, Inc. The test followed established standardized procedures designed to ensure the well-being of individuals in the clinical study and the generation of reliable research data. Participants were female and aged 27 to 65 years. Every two days, in the morning or evening, participants applied a simple water-based formulation containing the exemplary compound VII-3 (at 0.02% v / v) to dry or towel-dried hair. Approximately 2 mL was applied directly to the hair. This study did not require randomization, and participants could not see the name of the test material. [surface] [13.] [Using compounds] [VII-3] [Clinical Consumer Perception Research] [] Research question Completed individual Adverse effects analyze blindness Individuals showing improvements in their hair appearance Individuals with less hair loss and denser hair Individuals who observed an increase in hair growth and thickness 32 / 35 (Three individuals were lost during the follow-up period) 0 / 32 (0%) 6 Weeks (Digital Microfilm) Individuals cannot see the name of the test material. 31 / 32 (97%) 28 / 32 (87%) 26 / 32 (82%)

[0178] [Example]

[15] [Clinical Consumer] [Perception] [Hair samples from individuals in the study] []

[0179] Photographs of the individuals' hair were taken 6 weeks after treatment with the representative compound (Figure 6). The individuals were female and aged 27 to 65 years. Every two days, in the morning or evening, the individuals applied a simple water-based formulation containing the exemplary compound VII-3 (at 0.02% v / v) to dry or towel-dried hair. Approximately 2 mL was applied directly to the hair strands. This study did not require randomization, and the individuals could not see the name of the test material. Figure 6 highlights specific areas of the participants' scalps, allowing for comparison of images taken before and after the study. Based on clinical observations, 97% of the women reported improved hair appearance, while 82% reported increased hair growth and thickness.

[0180] [Example]

[16] [Example compounds with cross-physiological relevance] [pH] [And the temperature range is functionally stable] []

[0181] Exemplary compound (VII-3) was prepared in various solvents (DMSO; dimethyl sulfoxide, DMI; dimethyl isosorbide anhydride, or a 1:1 mixture of dimethyl isosorbide and ethanol), diluted in pH-adjusted water, and allowed to stand for 7 days at different temperatures. Human follicular papillary cells were administered the exemplary compound at 5 μg / mL, further supplemented with 6-bromoindorubin-39-oxime (BIO), recombinant bone morphogenetic protein-2 (BMP-2), and basic fibroblast growth factor (FGFβ), a combination previously found to preserve in situ dermal papillary gene signatures. Normalized proliferating follicular papillary cell proliferation was analyzed 48 hours after treatment with the exemplary compound pretreated across a range of pH conditions (Fig. 7A) and temperature conditions (Fig. 7B). Data represent mean ± standard deviation and represent n=2 donors. The results show that the exemplary compound is functionally stable across physiologically relevant pH and temperature ranges.

[0182] [Example]

[17] [:compound] [VII-3] [One exemplary synthesis method] []

[0183] The exemplary compound VII-3 was synthesized following reaction diagram 1 given below; [Reaction Diagram] [1] []

[0184] The synthesis can be carried out in two different ways. As a first method, NaOH was added to an aqueous solution of EtOH (100 ml water and 100 ml EtOH) over 20 minutes at room temperature. 3-(furan-2-yl)-1H-1,2,4-triazol-5(4H)-thione (20 g, 0.1 mol) was added in portions with stirring at room temperature. The mixture was stirred for 1 hour at room temperature. MeI was added dropwise over 25 minutes with stirring for 12 hours at room temperature. The solution was evaporated to half its volume under reduced pressure (50 °C, 20 mm), the precipitate was filtered off, washed with water (3 x 100 ml), and then dried. The final yield of the target compound was 68%.

[0185] The compound was also synthesized using the second method as follows. 3-(furan-2-yl)-5-(methylthio)-4H-1,2,4-triazole (18 g) was mixed with anhydrous THF (125 ml), and NEt3 was added dropwise at 5°C. NaOH was added to an aqueous solution of EtOH (100 ml water and 100 ml EtOH) over 20 minutes at room temperature. The mixture was cooled to 5°C, and MeSO₂₂Cl was added dropwise. The mixture was stirred at 10°C for 1 hour, then at room temperature for 12 hours. 500 ml of water was added, and the mixture was stirred for 1 hour. The precipitate was filtered, washed with water (3 x 80 ml), and then dried. The product was purified by column chromatography (eluent MTBE / CH₂Cl 250 / 50). The solvent was evaporated. The final yield of the target compound was 72%.

[0186] While preferred embodiments of the invention have been shown and described herein, those skilled in the art will understand that such embodiments are provided by way of example only. Many changes, variations, and substitutions will be made by those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used to practice the invention. It is intended that the scope of the invention be defined by the following claims and the methods and structures within the scope of such claims and their equivalents.

Claims

1. Use of a composition comprising a compound for preparing a pharmaceutical product for treating hair loss or thinning hair, wherein the compound is selected from compound VII-2, compound VII-3, compound VII-4 or a salt thereof: (VII-2), (VII-3) or (VII-4).

2. As claimed in claim 1, wherein the composition comprises compound VII-2 or a salt thereof.

3. As claimed in claim 1, wherein the composition comprises compound VII-3 or a salt thereof.

4. As claimed in claim 1, wherein the composition comprises compound VII-4 or a salt thereof.

5. The use as claimed in any of claims 1 to 4, wherein the composition is a cosmetic composition.

6. As claimed in claim 5, wherein the composition further comprises at least one additive selected from the group consisting of cosmetically acceptable carriers, excipients, adjuvants and diluents, and wherein the cosmetic composition is formulated as a toner, lotion, cream, gel, shampoo, soap, serum, spray or oil.

7. For any of the uses in claims 1 to 4, wherein the hair loss or thinning is selected from androgenic alopecia, alopecia areata, androgenetic alopecia, gynecological alopecia, postpartum alopecia, seborrheic alopecia, non-rigid alopecia, senile alopecia, chemotherapy-induced alopecia, radiation-induced alopecia, male pattern baldness, female pattern baldness, cicatricial alopecia, telogen effluvium, traction alopecia, and anagen effluvium, or a combination thereof.

8. The use of any one of claims 1 to 4, wherein the use includes promoting hair strength, hair growth, hair repair or hair thickening in the individual, increasing hair density or hair growth rate in the individual, or reducing hair loss in the individual, or a combination thereof.

9. The use of any of claims 1 to 4, wherein the hair includes head hair, eyelashes, eyebrows, facial hair, or a combination thereof.

10. A non-treatment method for promoting hair strength, hair repair or hair thickening and / or increasing hair density and / or reducing hair loss, the method comprising applying to hair a composition comprising a compound having the structure of compound VII-2, compound VII-3, compound VII-4 or a salt thereof: (VII-2), (VII-3) or (VII-4).

11. The non-treatment method as claimed in claim 10, wherein the compound is compound VII-2 or a salt thereof.

12. The non-treatment method as claimed in claim 10, wherein the compound is compound VII-3 or a salt thereof.

13. The non-treatment method as claimed in claim 10, wherein the compound is compound VII-4 or a salt thereof.

14. A non-therapeutic method as claimed in any of claims 10 to 13, wherein the composition is a cosmetic composition.

15. The non-treatment method of claim 14, wherein the composition further comprises at least one additive selected from the group consisting of cosmetically acceptable carriers, excipients, adjuvants and diluents, and wherein the cosmetic composition is formulated as a toner, lotion, cream, gel, shampoo, soap, serum, spray or oil.

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