Small molecule modulators of GP130 signaling pathway

Abstract

Disclosed herein are small molecule compounds, compositions, formulations, and methods that modulate gp130. The compounds, compositions, and formulations described herein are capable of modulating pro-inflammatory responses, fibrosis responses, and / or regenerative responses. The present disclosure also provides methods of treating or ameliorating diseases, disorders, and conditions associated with gp130 activity, particularly those associated with inflammatory and degenerative disorders, or combinations thereof.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 333,102, filed on April 20, 2022, which is incorporated herein by reference in its entirety and for all purposes. Field of the invention

[0003] The present disclosure provides small molecule modulators of gp130, compositions (e.g., pharmaceutical compositions), formulations, and methods of using them. In one aspect, the small molecule modulators described herein are capable of modulating pro - inflammatory responses, fibrotic responses, and / or regenerative responses. The present disclosure provides methods of treating or ameliorating diseases, disorders, and conditions associated with gp130 activity, particularly those associated with inflammatory and degenerative disorders or combinations thereof. Background of the invention

[0004] Glycoprotein 130 (gp130), which is ubiquitously expressed in the human body, is a shared subunit of the receptor complexes of at least nine cytokines (IL - 6, OSM, LIF, IL - 11, CNTF, CLC, IL - 27, CT - 1, and NP), which mediate highly diverse biological processes. The best - characterized aspects of this receptor and its associated cytokines are the ability to promote or inhibit inflammation and regeneration. Thus, (dys)regulation of gp130 expression, activation, or associated signaling pathways is associated with a variety of human diseases, including inflammatory, fibrotic, degenerative, and proliferative diseases and conditions such as inflammaging. For example, glycoprotein 130 (gp130) is a common receptor subunit of the interleukin - 6 (IL - 6) cytokine family, which has been shown to increase keratinocyte proliferation and promote matrix deposition (anabolism) in dermal fibroblasts.

[0005] After an IL - 6 family member cytokine binds to its receptor complex through classical signaling, it induces intracellular signaling pathways through gp130 homodimerization, including phosphorylation of the receptor complex and intracellular proteins (Murakami et al., 1993). However, even though the receptor complex activates tyrosine kinases, the molecules in the receptor complex do not have an enzymatic catalytic domain in their cytoplasmic regions. The discovery of Janus kinases (JAKs), STAT molecules, and negative regulators such as suppressors of cytokine signaling (SOCS) has provided new insights into cytokine signaling and is the basis for understanding the role of cytokines in health and disease.

[0006] Researchers have demonstrated that signaling through gp130 can have context - specific and cytokine - specific effects on anti - inflammatory and anti - degenerative outputs (Shkhyan R, Van Handel B, Bogdanov J, et al. Annals of the Rheumatic Diseases 2018;77:760 - 769.). Specifically, certain ligands such as oncostatin M strongly promote MAPK - nuclear factor - κB (NF - κB) activity while promoting relatively less STAT3 activation, while other ligands such as LIF and IL - 6 lead to activation of both pathways.

[0007] The binding of IL - 6 to its cell - surface receptor activates JAK, which phosphorylates six tyrosine residues in the cytoplasmic domain of gp130. The first pathway of gp130 signaling mediated by five distal tyrosine residues (YXXQ motif) is involved in STAT3 activation. STAT3 is an important transcription factor that transmits signals to the nucleus as a result of JAK phosphorylation and activation of cytokine receptor - associated kinases. Cytokine receptor - associated kinases phosphorylate STAT, which then homodimerizes or heterodimerizes via its SH2 domain and translocates into the nucleus to bind specific DNA elements to regulate gene expression (Masaaki Murakami et al., Immunity, 2019). STAT3 promotes and regulates the transcription of target genes involved in proliferation, apoptosis, and differentiation. Dysregulation of the JAK / STAT pathway is associated with a variety of human skin disorders.

[0008] The second pathway is related to the binding of SHP2 to Y759, which mediates the activation of the ERK MAPK cascade through the adaptor molecules GAB1 and GAB2. Additionally, phosphorylated Y759 also serves as a binding site for SOCS3 (Kubo et al., 2003).

[0009] The third pathway of gp130 signaling is mediated by the Src - family kinase Yes, which directly binds to gp130 through amino acid residues 812 - 827 (Taniguchi et al., 2015). Yes activates the Yes - associated protein (YAP) - Notch pathway in response to IL - 6 or through the activated form of gp130.

[0010] NF - κB is a potent pro - inflammatory nuclear transcription factor and is considered a central mediator of the inflammatory response. IL - 6 activates NF - κB, which in turn triggers pro - inflammatory pathways (Wang L. et al., J Immunol. 2003).

[0011] Although the stratum corneum is an obvious permeability barrier, delivery through the skin remains a very attractive option. Topical treatment of skin disorders clearly targets the disease site, thus minimizing adverse side effects in other parts of the body. However, mainly due to high hydrophobicity, many active compounds intended for transdermal administration are poorly soluble in water, thus posing challenges in formulating these small molecules. There is a need in the art for improved transdermal administration formulations of such compounds.

[0012] Accordingly, there is a need for new compounds with increased potency, decreased metabolic liability, and improved physicochemical properties (solubility, efficacy, functional groups) for successful clinical outcomes in treating or improving diseases, disorders, and conditions associated with gp130 activity.

[0013] The applicant herein provides a series of small molecule modulators of the gp130 signaling pathway with improved properties (including, but not limited to, improved "drug-like" properties). SUMMARY OF THE INVENTION

[0014] In one aspect, there is provided a compound having the structure of formula (I):

[0015]

[0016] Wherein:

[0017] X is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl, or an optionally substituted aryl;

[0018] Y is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl, or an optionally substituted aryl, or is absent;

[0019] Z is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl, or an optionally substituted aryl, or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl;

[0020] L 1 is an optionally substituted alkyl, an optionally substituted alkenyl, alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, -O-, -S-, or -N(R 1a )-, or is absent;

[0021] L 2 is an optionally substituted alkyl, an optionally substituted alkenyl, alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, -O-, -S-, or -N(R 1a )-, or is absent;

[0022] R 1is H or a C1-C6 alkyl group;

[0023] Each R 1a is H or a C1-C6 alkyl group;

[0024] or

[0025] its pharmaceutically acceptable salts.

[0026] In certain embodiments, in formula (I), X may suitably be:

[0027]

[0028]

[0029] and Y is

[0030]

[0031] or absent;

[0032] wherein,

[0033] X 1 to X 18 are each independently -C(R 2 )=, -N=, -O- or -S-;

[0034] X 19 and X 20 are each independently -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0035] Y 1 , Y 2 , Y 3 and Y 4 are each independently -C(R 2 )= or -N=;

[0036] Y 5 and Y 8 are each independently -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0037] Y 6 and Y 7 are each independently -C(R 2 )- or N;

[0038] R 2 and R 3Independently is H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy,

[0039]

[0040]

[0041] R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy,

[0042]

[0043] R 1a and R 2a are each independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl or (C1-C3)alkoxy;

[0044] v is 0, 1 or 2; and

[0045] n is 0, 1, 2, 3, 4 or 5.

[0046] In certain embodiments, Z can be:

[0047] or absent;

[0048] Z 1 to Z 9 are each independently -C(R 2 )=, -N=, -O- or -S-;

[0049] Z 10 is -C(R 2 )- or N;

[0050] Z 11 、Z 12 and Z 13 are each independently -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0051] R 2 and R 3 are independently H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy,

[0052]

[0053] R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy,

[0054]

[0055] R 1a and R 2a are each independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl or (C1-C3)alkoxy; and

[0056] n is 0, 1, 2, 3, 4 or 5.

[0057] In one aspect, there is provided a compound having a structure of formula (X-I):

[0058]

[0059] wherein:

[0060] A is O or S;

[0061] X is optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted heteroaryl or optionally substituted aryl;

[0062] Y is optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted heteroaryl or optionally substituted aryl, or is absent;

[0063] Z is optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted heteroaryl or optionally substituted aryl or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl;

[0064] L 1 is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -O-, -S- or -N(R 1a )-, or is absent;

[0065] L 2 is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -O-, -S- or -N(R 1a )-, or is absent;

[0066] L3 is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -C(O)-, NH-C(O)-, -C(O)-NH-, -O-, -S- or -N(R 1a ), or is absent;

[0067] R 1 is H or C1-C6 alkyl;

[0068] Each R 1a is H or C1-C6 alkyl;

[0069] or

[0070] its pharmaceutically acceptable salts.

[0071] In certain embodiments, in formula (X-I), X may suitably be:

[0072]

[0073] and Y is

[0074]

[0075] or is absent; wherein,

[0076] X 1 to X 18 are each independently -C(R 2 )=, -N=, -O- or -S-;

[0077] X 19 and X 20 are each independently -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0078] Y 1 , Y 2 , Y 3 and Y 4 are each independently -C(R 2 )= or -N=;

[0079] Y 5 and Y 8 are each independently -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0080] Y 6 and Y7 Each independently is -C(R 2 )- or N;

[0081] R 2 and R 3 are independently H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3,

[0082]

[0083] R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy,

[0084]

[0085] R 1a and R 2a are each independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl or (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl or (C3-C6)branched alkoxy;

[0086] v is 0, 1 or 2; and

[0087] n is 0, 1, 2, 3, 4 or 5.

[0088] In certain embodiments, Z can be:

[0089] or absent;

[0090] Z 1 to Z 9 Each independently is -C(R 2 )=, -N=, -O- or -S-;

[0091] Z 10is -C(R 2 )- or N;

[0092] Z 11 、Z 12 and Z 13 each independently is -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0093] R 2 and R 3 are independently H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3,

[0094]

[0095] R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy,

[0096]

[0097] R 1a and R 2a each independently is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl or (C3-C6)branched alkoxy; and

[0098] n is 0, 1, 2, 3, 4 or 5.

[0099] In another aspect, the compound of formula (X-I) may have the structure of formula (X-I-A):

[0100]

[0101] X, Y, Z, L 1 , L 2 , L 3 and R 1 As described above.

[0102] In another aspect, the compound of formula (X-I) can have the structure of formula (X-I-B):

[0103]

[0104] X, Y, Z, L 1 , L 2 , L 3 and R 1 As described above.

[0105] In certain aspects, L 3 is selected from -C(O)-, NH-C(O)-, -C(O)-NH-, -O-, -S- or -NH-, or is absent. In certain aspects, L 3 is absent. In certain aspects, L 3 is -C(O)-.

[0106] In another aspect, the compounds of the present disclosure can have the structure of formula (II):

[0107]

[0108] wherein X 8 to X 15 , L 1 and Z are as disclosed above, and their pharmaceutically acceptable salts.

[0109] In another aspect, the compounds of the present disclosure can have the structure of formula (IIa):

[0110]

[0111] wherein L 1 and Z are as disclosed above, and their pharmaceutically acceptable salts.

[0112] In another aspect, the compounds of the present disclosure can have the structure of formula (III):

[0113]

[0114] wherein X 1 , X 2 , X 3 , Y, L 2 and Z are as disclosed above, and their pharmaceutically acceptable salts.

[0115] In another aspect, the compounds of the present disclosure may have the structure of formula (IIIa):

[0116]

[0117] wherein L 2 and Z are as disclosed above, and their pharmaceutically acceptable salts.

[0118] In another aspect, the compounds of the present disclosure may have the structure of formula (IV):

[0119]

[0120] wherein Y, X, L 1 , Z 1 , Z 2 , Z 3 and Z 4 are as disclosed above, and their pharmaceutically acceptable salts.

[0121] In another aspect, the compounds of the present disclosure may have the structure of formula (IVa):

[0122]

[0123] wherein Y, X and L 1 are as disclosed above, and their pharmaceutically acceptable salts.

[0124] In another aspect, there is provided a compound of the above formula, wherein L 1 is absent.

[0125] In another aspect, there is provided a compound of the above formula, wherein L 1 is optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkenyl, (C1-C3) alkynyl, optionally substituted 5-6 membered cycloalkyl, optionally substituted 5-6 membered cycloalkenyl, -O-, -S- or -N(R 1a ).

[0126] In another aspect, there is provided a compound of the above formula, wherein L 2 is absent.

[0127] In another aspect, there is provided a compound of the above formula, wherein L 2 is optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkenyl, (C1-C3) alkynyl, optionally substituted 5-6 membered cycloalkyl, optionally substituted 5-6 membered cycloalkenyl, -O-, -S- or -N(R 1a ).

[0128] In another aspect, there is provided a compound of the above formula, wherein L 1 is selected from the group consisting of:

[0129]

[0130] In another aspect, there is provided a compound of the above formula, wherein L 2 is selected from the group consisting of:

[0131]

[0132] In another aspect, there is provided a compound of the above formula, wherein X is selected from the group consisting of:

[0133]

[0134]

[0135]

[0136]

[0137] In another aspect, there is provided a compound of the above formula, wherein Z is selected from the group consisting of:

[0138]

[0139]

[0140]

[0141]

[0142] In one aspect, there is provided a pharmaceutical composition comprising one or more of the compounds described herein.

[0143] In one aspect, there is provided a method of treating inflammation, an inflammatory disease or disorder, reducing joint pain, preventing joint degeneration or promoting cartilage regeneration in a human subject 25 years of age or older in need thereof. The method comprises administering to the subject an effective amount of a compound or composition described herein.

[0144] In one aspect, there is provided a method of treating cell proliferative diseases and disorders enhanced by gp130 activation in a human subject in need thereof. The method comprises administering to the subject an effective amount of a compound or composition described herein.

[0145] In one aspect, there is provided a method of treating or ameliorating a pain disorder enhanced by gp130 activation in a human subject in need thereof. The method comprises administering to the subject an effective amount of a compound or composition described herein. Specifically, the pain disorder is selected from the group consisting of neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, musculoskeletal pain, craniofacial pain, other somatic-form pain, and referred pain.

[0146] In one aspect, there is provided a method of modulating an IL-6 family cytokine-mediated inflammatory response in a cell. The method comprises contacting the cell with a compound or composition described herein.

[0147] In one aspect, there is provided a composition comprising a pharmaceutically acceptable carrier and a compound or composition described herein.

[0148] In one aspect, there is provided a method of treating an acute or chronic inflammatory condition. The method comprises administering to a subject an effective amount of a compound or composition described herein.

[0149] In one aspect, there is provided a method of reducing an activated inflammatory pathway in a cell. The method comprises contacting the cell with a compound or composition described herein.

[0150] In one aspect, there is provided a method of inhibiting the production or induction of a pro-inflammatory gene, cytokine, or mediator. The method comprises contacting a cell or a subject with a compound or composition described herein.

[0151] In one aspect, there is provided a method of inhibiting the production or induction of an extracellular matrix degrading enzyme, the method comprising contacting a cell or a subject with a compound or composition described herein.

[0152] In one aspect, there is provided a method of modulating STAT3 and / or MYC levels in a cell. The method comprises contacting the cell with a compound or composition described herein.

[0153] In one aspect, there is provided a topical formulation comprising a compound described herein.

[0154] In one aspect, there is provided a method of reducing or preventing inflammaging in a target tissue of a human subject in need thereof. The method comprises contacting the target tissue with an effective amount of a topical formulation described herein.

[0155] In one aspect, there is provided a method of preparing a topical formulation of a compound, the amount of the compound being effective to significantly modulate the activity or expression of a member of the gp130 signaling pathway in a target population of human skin cells.

[0156] In one aspect, a method of treating a subject having a skin disorder is provided. The method includes administering a topical formulation to the subject, the amount of the topical formulation being effective to modulate gp130 signaling in a target population of human skin cells.

[0157] In one aspect, a method for cosmetic use is provided. The method includes applying a topical formulation comprising one or more of the compounds disclosed herein to a skin area of a subject.

[0158] Other aspects of the invention are disclosed hereinafter.

[0159] All publications, patent applications, patents, and other references mentioned are incorporated by reference in their entirety. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting. The citation of references herein should not be construed as an admission that the references are prior art to the present invention. Detailed Description

[0160] Modulators of the gp130 signaling pathway and / or downstream pathway members such as STAT-3 and NF-κB are disclosed herein.

[0161] Methods and compositions for treating a subject in need thereof are also disclosed herein, wherein the subject has a disorder regulated by the gp130 signaling pathway and / or downstream pathway members such as STAT-3 and NF-κB.

[0162] Methods and compositions for treating a subject in need thereof are also disclosed herein, wherein the subject has an inflammatory disorder regulated by the gp130 signaling pathway and / or downstream pathway members such as STAT-3 and NF-κB.

[0163] Methods and compositions for treating a subject in need thereof are also disclosed herein, wherein the subject has a proliferative disorder. In an embodiment, the proliferative disorder is cancer. In certain embodiments, the proliferative disorder is a cancer regulated by the gp130 signaling pathway and / or downstream pathway members such as STAT-3 and NF-κB. In certain embodiments, the proliferative disorder is skin cancer. Methods and compositions for treating a subject having mild to moderate photo damage on human skin cells (e.g., facial skin cells) by applying a novel cream formulation suitable for cosmetic treatment are also disclosed herein, the cream formulation comprising one or more modulators of the gp130 signaling pathway and / or downstream pathway members such as STAT-3 and NF-κB.

[0164] The following disclosure provides compositions comprising such modulators, methods of use, and methods of preparation of skin care products for eliminating these conditions.

[0165] Specifically, a study is disclosed herein that aims to evaluate the efficacy of the compositions disclosed herein when used by women and men with mild to moderate photodamage to the face over 8 weeks.

[0166] Unless otherwise defined, all technical terms, symbols, and other scientific terms used herein are intended to have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. In some instances, terms with commonly understood meanings are defined herein for clarity and / or for ease of reference, and such definitions included herein are not necessarily to be construed as representing a difference from the meaning commonly understood in the art. The techniques and procedures described or referenced herein are generally well understood by those of ordinary skill in the art and are commonly employed using conventional methods.

[0167] Definitions

[0168] All references cited herein are incorporated by reference in their entirety as if fully set forth.

[0169] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings that are commonly understood by one of ordinary skill in the art to which this disclosure pertains. It should be understood that the present disclosure is not limited to the particular methods, protocols, and reagents, etc., described herein and may, therefore, vary. Definitions of common terms can be found in: Singleton et al., Dictionary of Microbiology and Molecular Biology, 3rd ed., J. Wiley & Sons, New York, NY (2001); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure, 5th ed., J. Wiley & Sons, New York, NY (2001); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012); Jon Lorsch (ed.), Laboratory Methods in Enzymology: DNA, Elsevier, (2013); Frederick M. Ausubel (ed.), Current Protocols in Molecular Biology (CPMB), John Wiley and Sons, (2014); John E. Coligan (ed.), Current Protocols in Protein Science (CPPS), John Wiley and Sons, Inc., (2005); and Ethan M. Shevach, Warren Strobe, (eds.) Current Protocols in Immunology (CPI) (John E. Coligan, ADA M. Kruisbeek, David H. Margulies, John Wiley and Sons, Inc., (2003); each of which provides one of ordinary skill in the art with general guidance on many of the terms used in this application.

[0170] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a chondrocyte" includes a plurality of such chondrocytes, and reference to "an antagonist" includes reference to one or more antagonists or equivalents thereof known to those skilled in the art, and so forth.

[0171] The terms "comprising", "such as", etc. are intended to express inclusion but not limitation, unless otherwise specifically noted.

[0172] As used herein, the term "comprising" also specifically includes embodiments of "consisting of the listed elements" and "consisting essentially of the listed elements", unless otherwise specifically noted. Similarly, "comprising" and "including" are used interchangeably and are not intended to be restrictive.

[0173] In addition, unless otherwise stated, the use of "or" means "and / or".

[0174] It should be further understood that when the description of various embodiments uses the term "comprising", those skilled in the art will understand that in certain specific cases, an embodiment can alternatively be described using the language "consisting essentially of" or "consisting of".

[0175] The term "about" indicates and encompasses the indicated value and ranges above and below that value. In certain embodiments, the term "about" indicates the specified value ±10%, ±5%, or ±1%. In certain embodiments, where applicable, the term "about" indicates the specified value ± one standard deviation of that value.

[0176] The term "alkyl" denotes an organic group composed of carbon and hydrogen atoms, which contains covalent single bonds between the carbons. Generally, "alkyl" as used in the present disclosure denotes an organic group containing from 1 to 30 carbon atoms, unless otherwise stated. If there is more than 1 carbon, the carbons can be linked in a linear fashion, or alternatively if there are more than 2 carbons, the carbons can also be linked in a branched fashion such that the parent chain contains one or more secondary, tertiary, or quaternary carbons. The alkyl can be substituted or unsubstituted, unless otherwise stated.

[0177] The term "alkenyl" refers to an organic group composed of carbon and hydrogen atoms, which contains at least one covalent double bond between two carbons. Generally, "alkenyl" as used in the present disclosure refers to an organic group containing 2 to 30 carbon atoms, unless otherwise specified. Although a C2-alkenyl can form a double bond with the carbon of the parent chain, an alkenyl group with three or more carbons can contain more than one double bond. In some cases, the alkenyl group will be conjugated, in other cases, the alkenyl group will not be conjugated, and in still other cases, the alkenyl group can have conjugated segments and non-conjugated segments. Additionally, if there are more than 2 carbons, the carbons can be connected in a linear manner, or alternatively if there are more than 3 carbons, the carbons can also be connected in a branched manner such that the parent chain contains one or more secondary, tertiary, or quaternary carbons. The alkenyl can be substituted or unsubstituted, unless otherwise specified.

[0178] The term "alkynyl" refers to an organic group composed of carbon and hydrogen atoms, which contains a covalent triple bond between two carbons. Generally, "alkynyl" as used in the present disclosure refers to an organic group containing 2 to 30 carbon atoms, unless otherwise specified. Although a C2-alkynyl can form a triple bond with the carbon of the parent chain, an alkynyl group with three or more carbons can contain more than one triple bond. If there are more than 2 carbons, the carbons can be connected in a linear manner, or alternatively if there are more than 4 carbons, the carbons can also be connected in a branched manner such that the parent chain contains one or more secondary, tertiary, or quaternary carbons. The alkynyl can be substituted or unsubstituted, unless otherwise specified.

[0179] The term "aryl" refers to a conjugated planar ring system with a delocalized π electron cloud, which contains only carbon as ring atoms. "Aryl" for the purposes of the present disclosure encompasses 1 to 7 aryl rings, where when the aryl has more than 1 ring, the aryl rings are connected such that they are linked, fused, or a combination thereof. The aryl can be substituted or unsubstituted, or in the case of more than one aryl ring, one or more rings can be unsubstituted, one or more rings can be substituted, or a combination thereof. More specifically, substituted aryl groups include acetylphenyl groups, especially 4-acetylphenyl groups; fluorophenyl groups, especially 3-fluorophenyl and 4-fluorophenyl groups; chlorophenyl groups, especially 3-chlorophenyl and 4-chlorophenyl groups; methylphenyl groups, especially 4-methylphenyl groups, and methoxyphenyl groups, especially 4-methoxyphenyl groups.

[0180] As used herein, the term "heteroaryl", by itself or as part of another group, refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring members (i.e., 5- to 14-membered heteroaryl) containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has 3 heteroatoms. In another embodiment, the heteroaryl has 2 heteroatoms. In another embodiment, the heteroaryl has 1 heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having 4 carbon atoms and 1 sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having 5 carbon atoms and 1 nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuryl, benzoxazinonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is selected from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

[0181] As used herein, the term "heteroalkyl", by itself or as part of another group, means a stable straight or branched hydrocarbon group having from 1 to 10 carbon atoms and at least 2 heteroatoms selected from O, N, or S, said heteroatoms may be the same or different, wherein the sulfur atom may optionally be oxidized. The heteroatoms may be located at any internal position of the heteroalkyl group or at the position where the heteroalkyl group is attached to the remainder of the molecule. In one embodiment, the heteroalkyl contains two oxygen atoms. In another embodiment, the heteroalkyl contains 1 oxygen atom and 1 nitrogen atom. In another embodiment, the heteroalkyl contains two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include -OCH2CH2NH2, -NHCH2CH2OCH3, and -OCH2CH2OCH3.

[0182] The term "contact" is used in its plain and ordinary sense and refers to the process of allowing at least two different substances (e.g., chemical compounds, including biomolecules or cells) to become close enough to react, interact, or physically touch. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from intermediates that may be generated in the reaction mixture from one or more of the added reagents.

[0183] As used in this disclosure, the terms "cycloalkane", "cycloalkyl" mean an alkyl group having at least 3 carbon atoms but not more than 12 carbon atoms, said carbon atoms being joined together to form a ring. "Cycloalkyl" for the purposes of this disclosure encompasses from 1 to 7 cycloalkyl rings, wherein when there is more than 1 cycloalkyl ring, the cycloalkyl rings are joined such that they are linked, fused, or a combination thereof. The cycloalkyl may be substituted or unsubstituted, or in the case of more than one cycloalkyl ring, one or more rings may be unsubstituted, one or more rings may be substituted, or a combination thereof.

[0184] As used in this disclosure, the terms "cycloalkene", "cycloalkenyl" mean an alkene having at least 3 carbon atoms but not more than 12 carbon atoms, said carbon atoms being joined together to form a ring. "Cycloalkenyl" for the purposes of this disclosure encompasses from 1 to 7 cycloalkenyl rings, wherein when there is more than 1 cycloalkenyl ring, the cycloalkenyl rings are joined such that they are linked, fused, or a combination thereof. The cycloalkenyl may be substituted or unsubstituted, or in the case of more than one cycloalkenyl ring, one or more rings may be unsubstituted, one or more rings may be substituted, or a combination thereof.

[0185] "Disease" or "disorder" refers to the state of being or health condition of a patient or subject that can be treated with the compounds / molecules or methods provided herein. Diseases as used herein can refer to inflammatory diseases and disorders as well as immune diseases and disorders such as cartilage degenerative diseases, joint surface injuries, or arthritis (including rheumatoid arthritis), psoriasis, inflammatory bowel disease, aging, lupus, rosacea, fibrosis, etc.

[0186] For the purposes of this disclosure, the term "extended fused ring system" refers to a group that contains at least 2 ring structures, but no more than 7 ring structures. The "extended fused ring system" contains at least one ring functional group that is different from another ring functional group. Examples of ring groups include, but are not limited to, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and heterocycle. Each ring can be optionally substituted. The rings that make up the extended fused ring system can be linked such that they are connected, fused, or a combination thereof.

[0187] The term "functional group" or "FG" refers to a specific group of atoms within a molecule that is responsible for the characteristic chemical reactions of those molecules. Although the same functional group will undergo the same or similar chemical reactions regardless of the size of the molecule to which it belongs, its relative reactivity can be modified by nearby functional groups. The atoms of a functional group are connected to each other and to the rest of the molecule by covalent bonds. Examples of FGs that can be used in this disclosure include, but are not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, halogen, hydroxy, anhydride, carbonyl, carboxy, carbonate, carboxylate, aldehyde, halocarbonyl, ester, hydroperoxy, peroxy, ether, orthoester, carboxamide, amine, imine, imide, azide, azo, cyanate, isocyanate, nitrate, nitrile, isonitrile, nitroso, nitro, nitrosooxy, pyridyl, mercapto, sulfide, disulfide, sulfinyl, sulfo, thiocyanate, isothiocyanate, thiocarbonyl, phosphino, phosphonyl, phosphate, Si(OH)3, Ge(OH)3, Sn(OH)3, Si(SH)4, Ge(SH)4, AsO3H, AsO4H, P(SH)3, As(SH)3, SO3H, Si(OH)3, Ge(OH)3, Sn(OH)3, Si(SH)4, Ge(SH)4, Sn(SH)4, ASO3H, ASO4H, P(SH)3, and As(SH)3.

[0188] The term "gp130" as used herein refers to glycoprotein 130, a cell surface receptor that is ubiquitously expressed in vivo and is named by the gene name IL6ST. Activation of gp130 is essential for a variety of physiological functions, including but not limited to the acute phase response to injury and infection, fertility, metabolism, hematopoiesis, neuroprotection, anti-angiogenesis, and melanoma and tumor cell inhibition. Gpl30 is activated by ligands from the IL-6 cytokine family, including but not limited to IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and cardiotrophin-like cytokine (CLC). Activation of gp130 signaling is typically achieved by the binding of a ligand to another cell surface receptor that forms a complex with gp130, thereby activating it. LIF, CT-1, CNTF, OSM, and CLC form heterodimers of gp130 and LIFR, while OSM can also form heterodimers of gp130 and OSMR; IL-11 and IL-6 promote the formation of heterodimers of gp130 and IL-11Ra and IL-6R, respectively. Thus, LIF, CT-1, CNTF, OSM, and CLC can directly activate gp130 signaling by first binding to gp130, or indirectly activate gp130 signaling by binding to LIFR / OSMR and then recruiting gp130 to the complex. Ligands of the IL-6 cytokine family trigger the JAK / STAT pathway, the first event of which is the homo- or hetero-dimerization of ligand-induced signal transduction receptor subunits. All IL-6-type cytokines recruit gp130 to their receptor complexes. They signal either through gp130 alone or through gp130 in combination with LIFR, OSMR, IL-11Ra, or IL-6R, all of which are capable of activating Jaks and recruiting STAT proteins.

[0189] The terms "gp130 receptor", "gp130", "gp130 protein", "IL6ST receptor", "IL6ST", or "IL6ST protein" are used interchangeably herein and are used according to their common ordinary meaning (e.g., the transmembrane protein "glycoprotein 130") and refer to proteins with the same or similar names, as well as functional fragments and homologs thereof.

[0190] For the purposes of the present disclosure, the term "hetero" when used as a prefix, such as in heteroalkyl, heteroalkenyl, heteroalkynyl, or heterohydrocarbyl, denotes a particular hydrocarbon having one or more carbon atoms replaced by non-carbon atoms as part of the parent chain. Examples of such non-carbon atoms include, but are not limited to, N, O, S, Si, Al, B, and P. If there is more than one non-carbon atom in the hetero-based parent chain, the atoms may be the same element or may be a combination of different elements, such as N and O.

[0191] The term "heterocyclic" or "heterocyclic group": as used in the present disclosure, denotes a ring structure containing at least 1 non-carbon ring atom. "Heterocyclic" for the purposes of the present disclosure encompasses rings of 1 to 7 heterocycles, where when the heterocycles are more than 1 ring, the heterocyclic rings are linked such that they are connected, fused, or a combination thereof. The heterocycle can be heteroaryl or non-aromatic, or in the case of more than one heterocyclic ring, one or more rings can be non-aromatic, one or more rings can be heteroaryl, or a combination thereof. The heterocycle can be substituted or unsubstituted, or in the case of more than one heterocyclic ring, one or more rings can be unsubstituted, one or more rings can be substituted, or a combination thereof. Generally, the non-carbon ring atoms are N, O, S, Si, Al, B, or P. In the case where there is more than one non-carbon ring atom, these non-carbon ring atoms can be the same element or a combination of different elements, such as N and O. Examples of heterocycles include, but are not limited to: monocyclic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, tetrahydrothiophene, piperidine, 1,2,3,6-tetrahydropyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-1H-azepine, homopiperazine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethylene oxide; and polycyclic heterocycles such as indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, Pyridine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2 - benzisoxazole, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzotriazole, thioxanthine, carbazole, carboline, acridine, pyrrolizidine, and quinolizine. In addition to the polycyclic heterocycles described above, heterocycles include such polycyclic heterocycles: wherein the ring fusion between two or more rings includes more than one bond shared by two rings and more than two atoms shared by two rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane, and 7 - oxabicyclo[2.2.1]heptane.

[0192] As used herein, "prevention" refers to preventing a disease or disorder in a patient, e.g., a skin disorder. For example, if an individual at risk of developing a skin disease or other form of skin disorder is treated by the method of the present invention and then does not develop a skin disorder, then for at least a period of time, the disease in that individual is prevented.

[0193] The term "effective amount" refers to the amount of a compound, formulation, material, or composition described herein that is effective in achieving a particular cosmetic result.

[0194] The term "topical" administration of a formulation as disclosed herein means applying the formulation to the skin of a patient. For the purpose of applying a formulation, topical application to the skin should include application to the stratum corneum. The topical formulations described herein are capable of facilitating the delivery of an active ingredient through the epidermis by carrying the component having the activity of the active ingredient through epidermal cells and through the basement membrane into the dermis.

[0195] The term "subject" is intended to include such living organisms: wherein the application of the compositions and methods disclosed herein is beneficial for eliminating at least one sign of aging or at least one medical skin disorder.

[0196] The term "cosmetic" refers to a cosmetic product that is used to improve appearance or a person's self - perception; a cosmetic must provide a visible result without side effects and should look natural.

[0197] The term "chelating agent" or "chelating reagent" refers to any molecule or moiety that is capable of forming a complex (i.e., "chelate") with a metal ion. In certain exemplary embodiments, a chelating agent refers to any molecule or moiety that "binds" a metal ion in solution such that it is not available for a chemical / enzymatic reaction. Chelating agents typically have two or more unshared electron pairs available for donation to a metal ion. The metal ion is typically coordinated to the chelating agent through two or more electron pairs.

[0198] As used herein, the term "prevention" refers to the prevention or protective treatment of a disease or disease state.

[0199] Throughout this disclosure, aspects of the disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges and individual numerical values within that range. For example, a range description such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99% identity includes things having 95%, 96%, 97%, 98%, or 99% identity, and includes subranges such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98%, and 98-99% identity. This applies regardless of the size of the range.

[0200] The term "modulator" refers to a composition that, relative to the absence of the modulator, increases or decreases the level or function of a target molecule or the physical state of a molecular target.

[0201] The term "inflammation" refers to the complex biological response of the body to a stimulus (e.g., a pathogen, cell damage, or irritant). When persistent for a long time, inflammation can lead to an inflammatory disease or disorder. Factors triggered during an inflammatory response include pro-inflammatory cytokines (e.g., TNF-a, IL-1, IFN-γ, MCP-1, IL-6), cell migration (e.g., monocytes, macrophages, lymphocytes, plasma cells), and serum proteins (e.g., serum amyloid A (SAA) and serum amyloid P (SAP)). Inflammation can be local (e.g., vascular inflammation) or systemic.

[0202] An "inflammatory disorder" or "inflammatory disease" refers to a condition characterized by inflammation in cells, tissues, or the body. Inflammatory diseases and disorders include, but are not limited to, hypersensitivity reactions (e.g., allergies), asthma, autoimmune diseases (e.g., rheumatoid arthritis and osteoarthritis, lupus, multiple sclerosis), cancer, diabetes, inflammatory bowel disease (IBD), or cardiovascular diseases (e.g., atherosclerosis), NAFLD, NASH, hepatitis, fibrosis, and cirrhosis.

[0203] "Inflammaging" as described herein refers to inflammation, particularly skin inflammation, as a biological response of body tissues to environmental challenges such as sunlight and wind, as well as internal drivers such as diet, alcohol, and smoking, and other potentially harmful stimuli, which promotes harmful biological responses, leading to visible signs of aging such as the appearance of fine lines and wrinkles, hyperpigmentation, and increased laxity. The harmful stimuli can include, but are not limited to, pathogens, bacteria, viruses, fungi, damaged cells, and other irritants known to those skilled in the art. Inflammation can be a protective immune response, which can involve, for example, immune cells, white blood cells, blood vessels, molecular mediators, and other small molecules. Signs of inflammation can include, but are not limited to, pain, fever, swelling, and / or loss of function. Inflammation can be acute or chronic.

[0204] The term "fused ring system" refers to an optionally substituted ring structure containing at least two rings, and wherein the rings are connected together by linking, fusion, or a combination thereof. The fused ring system comprises a combination of different ring types, including cycloalkyl, cycloalkenyl, aryl, and heterocycle.

[0205] The term "pharmaceutically acceptable", as in pharmaceutically acceptable salts or pharmaceutically acceptable counterions, refers to a compound, salt, or ion that is tolerated by a subject for local or internal use.

[0206] The term "pharmaceutically acceptable salt" refers to salts formed from the compounds disclosed herein. Salt formation can be used as a means to modify the properties of the compounds disclosed herein, e.g., increasing or decreasing the solubility of the compound, enhancing the stability of the compound, reducing the toxicity of the compound, and / or reducing the hygroscopicity of the compound. There are a variety of chemically diverse acids and bases, which have a range of pKa values, molecular weights, solubilities, and other properties that can be used to prepare pharmaceutically acceptable salts of the compounds disclosed herein. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, mesylate, esylate, benzenesulfonate, tosylate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the present disclosure can form pharmaceutically acceptable salts with various amino acids. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For additional examples of medicinal salts that can be used to practice the present disclosure, see P.H. Stahl and C.G. Wermuth (eds.), Pharmaceutical Salts: Properties, Selection, and Use (2nd Edition 2011) Wiley and Sons Publisher, ISBN: 978-3-90639-051-2.

[0207] The term "pharmaceutically acceptable counterion" refers to pharmaceutically acceptable cations including, but not limited to, alkali metal cations (e.g., Li + , Na + , K + ), alkaline earth metal cations (e.g., Ca 2+ , Mg 2+ ), non-toxic heavy metal cations, and ammonium (NH4 + ) and substituted ammonium (N(R')4 +, wherein R' is hydrogen, alkyl or substituted alkyl, i.e., including methyl, ethyl or hydroxyethyl, specifically, trimethylammonium, triethylammonium and triethanolammonium cations); or a pharmaceutically acceptable anion, including but not limited to halides (e.g., Cl", Br"), sulfates, acetates (e.g., acetate, trifluoroacetate), ascorbate, aspartate, benzoate, citrate and lactate.

[0208] "Subject" generally refers to mammals such as human patients and non-human primates, as well as laboratory animals such as rabbits, rats and mice and other animals. Animals include all vertebrates, e.g., mammals and non-mammals, such as sheep, dogs, cows, chickens, amphibians and reptiles.

[0209] The term "substantially" when used to modify a term means that the term modified includes only minor variations in dimensions, purity, structure, etc. Thus, "substantially uniform in size" means that the material varies from the average size by no more than 1%, 5%, 10%, 20% or 30% (or any value therebetween).

[0210] For heterocycles, etc., the term "substituted" means a structure in which the parent chain contains one or more substituents.

[0211] The term "substituent" means an atom or group of atoms that replaces a hydrogen atom. For the purposes of this disclosure, substituents will include deuterium atoms.

[0212] The term "therapeutically effective amount" means an amount of a compound, molecule or composition of this disclosure that alleviates one or more symptoms (and grammatical equivalents of this phrase) associated with a disease or disorder to be treated or the severity or frequency of said symptoms, or eliminates said symptoms.

[0213] The term "prophylactically effective amount" of a drug is an amount of such drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or recurrence) of an injury, disease, condition or disorder, or reducing the likelihood of the onset (or recurrence) of an injury, disease, condition or disorder or their symptoms. A complete prophylactic effect does not necessarily occur upon administration of a single dose and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amount will depend on the purpose of the treatment and will be determinable by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, ed., Lippincott, Williams & Wilkins).

[0214] For hydrocarbons, heterocycles, etc., the term "unsubstituted" means a structure in which the parent chain contains no substituents.

[0215] For hydrocarbons, heterocycles, etc., the term "optionally substituted" means a structure in which the parent chain contains substituents or no substituents. As a non-limiting example, substituents used herein, either by themselves or as part of another group, represent an unsubstituted or C1-3 substituted alkyl group, where each substituent is independently alkyl, hydroxy, halogen, amino, alkylamino, aminoalkyl, nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, thioalkyl, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carbamate, carboxy, alkoxycarbonyl and carboxyalkyl.

[0216] In one embodiment, the term "modulate" means increase and / or induce and / or promote and / or activate. In an alternative embodiment, the term "modulate" means decrease and / or reduce and / or inhibit.

[0217] In one embodiment, the term "modulate" means upregulate. In an alternative embodiment, the term "modulate" means downregulate.

[0218] The term "small molecule" refers to a molecule that has a biological effect and a molecular weight of less than 10,000 Daltons. In certain embodiments, the small molecule has a molecular weight of less than 5,000 Daltons. In certain embodiments, the small molecule has a molecular weight of less than 2,500 Daltons. In certain embodiments, the small molecule has a molecular weight of less than 1,000 Daltons. In certain embodiments, the small molecule has a molecular weight of less than 800 Daltons. In certain embodiments, the small molecule has a molecular weight of less than 500 Daltons.

[0219] As used herein, the terms "compound" and "small molecule" are used interchangeably and are not intended to be limiting.

[0220] As used herein, the term "pain" refers to any unpleasant sensory experience, usually associated with a physical disorder. The physical disorder may or may not be apparent to a clinician. There are two types of pain: chronic and acute. "Acute pain" is pain of short duration that occurs suddenly. For example, one type of acute pain is cutaneous pain felt when the skin or other superficial tissues are injured, such as pain caused by a cut or a burn. Cutaneous nociceptors terminate just beneath the skin, and because of the high concentration of nerve endings, a distinct, short-lived, local pain is produced. "Chronic pain" is pain other than acute pain. Chronic pain includes neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, and referred pain.

[0221] As used herein, a wavy line that intersects another line connected to an atom indicates that the atom is covalently bonded to another entity that is present but not depicted in the structure. A wavy line that does not intersect a line but is connected to an atom indicates that the atom interacts with another atom through a bond or some other type of recognizable association.

[0222] Bonds indicated by straight lines and dashed lines indicate bonds that can be either covalent single bonds or alternatively covalent double bonds. However, if forming a covalent double bond would exceed the maximum valence of the atom, the bond will be a covalent single bond.

[0223] It should be understood that many of the reagents and starting materials used in the protocols presented herein can be readily obtained from various commercial suppliers, such as Sigma-Aldrich, Alfa Aesar, Tokyo Chemical Industry Co., LTD, etc. In addition, many of these same reagents and starting materials can be modified by using standard organic synthetic reactions to introduce additional functional groups.

[0224] Small molecule regulator

[0225] The present invention relates to small molecule modulators of gp130. The present invention also relates to pharmaceutical compositions comprising at least one small molecule modulator of gp130. In addition, topical formulations of small molecule modulators of the gp130 signaling cascade (e.g., gp130, STAT-3 or NF-κB), methods of preparing such formulations, and methods of use are disclosed herein. In certain embodiments, the pharmaceutical composition comprises a topical formulation. In one non-limiting example, the novel topical formulation disclosed herein comprises a gp130 signaling modulator (e.g., a STAT-3 agonist) agonist for the repair of skin disorders.

[0226] In one aspect, the small molecule modulators of the present invention comprise one or more compounds of formula (I):

[0227]

[0228] Wherein:

[0229] X is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl or an optionally substituted aryl;

[0230] Y is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl or an optionally substituted aryl, or is absent;

[0231] Z is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl or an optionally substituted aryl or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl;

[0232] L 1 is an optionally substituted alkyl, an optionally substituted alkenyl, alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkyl-O-alkyl, -O-alkyl, -alkyl-O-, -O-, -S- or -N(R 1a )-, or is absent;

[0233] L 2 is an optionally substituted alkyl, an optionally substituted alkenyl, alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkyl-O-alkyl, -O-alkyl, -alkyl-O-, -O-, -S- or -N(R 1a )-, or is absent;

[0234] R 1 is H or C1-C6 alkyl;

[0235] Each R 1ais H or a C1-C6 alkyl;

[0236] or

[0237] a pharmaceutically acceptable salt thereof.

[0238] In another embodiment, a compound of the present disclosure is a compound having formula (I), wherein X is

[0239]

[0240]

[0241] and Y is

[0242]

[0243] or absent;

[0244] wherein,

[0245] X 1 to X 18 are each independently -C(R 2 )=, -N=, -O- or -S-;

[0246] X 19 and X 20 are each independently -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0247] Y 1 、Y 2 、Y 3 and Y 4 are each independently -C(R 2 )= or -N=;

[0248] Y 5 and Y 8 are each independently -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0249] Y 6 and Y 7 are each independently -C(R 2 )- or N;

[0250] R 2 and R 3Independently is H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, amino(C1-C3)alkyl, (C1-C3)alkylamino, (C1-C3)alkoxy,

[0251]

[0252] R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy,

[0253]

[0254] R 1a and R 2a each independently is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl or (C1-C3)alkoxy;

[0255] v is 0, 1 or 2; and

[0256] n is 0, 1, 2, 3, 4 or 5.

[0257] In another embodiment, a compound of the present disclosure is a compound having formula (I), wherein Z is

[0258] or absent;

[0259] Z 1 to Z 9 each independently is -C(R 2 )=, -N=, -O- or -S-;

[0260] Z 10 is -C(R 2 )- or N;

[0261] Z 11 、Z 12 and Z 13 each independently is -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0262] R 2 and R 3is independently H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy,

[0263]

[0264] R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy,

[0265]

[0266] R 1a and R 2a are each independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl or (C1-C3)alkoxy; and

[0267] n is 0, 1, 2, 3, 4 or 5.

[0268] In one aspect, there is provided a compound having a structure of formula (X-I):

[0269]

[0270] wherein:

[0271] A is O or S;

[0272] X is optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted heteroaryl or optionally substituted aryl;

[0273] Y is optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted heteroaryl or optionally substituted aryl, or is absent;

[0274] Z is optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted heteroaryl or optionally substituted aryl or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl;

[0275] L 1 is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -O-, -S- or -N(R 1a )-, or is absent;

[0276] L 2is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -O-, -S- or -N(R 1a )-, or is absent;

[0277] L 3 is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -C(O)-, NH-C(O)-, -C(O)-NH-, -O-, -S- or -N(R 1a )-, or is absent;

[0278] R 1 is H or C1-C6 alkyl;

[0279] Each R 1a is H or C1-C6 alkyl;

[0280] or

[0281] its pharmaceutically acceptable salts.

[0282] In certain embodiments, in formula (X-I), X may suitably be:

[0283]

[0284] and Y is

[0285] or is absent; wherein,

[0286] X 1 to X 18 are each independently -C(R 2 )=, -N=, -O- or -S-;

[0287] X 19 and X 20 are each independently -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0288] Y 1 、Y 2 、Y 3 and Y 4 are each independently -C(R 2 )= or -N=;

[0289] Y 5 and Y 8 are each independently -C(R 2 )(R 3)-, -N(R 4 )-, -O- or -S-;

[0290] Y 6 and Y 7 each independently is -C(R 2 )- or N;

[0291] R 2 and R 3 are independently H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, amino(C1-C3)alkyl, (C1-C3)alkylamino, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3,

[0292]

[0293] R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3,

[0294]

[0295] R 1a and R 2a each independently is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, -S(O)2N(H)(C1-C3)alkyl or -S(O)2N(H)CH3;

[0296] v is 0, 1 or 2; and

[0297] n is 0, 1, 2, 3, 4 or 5.

[0298] In certain embodiments, in formula (X-I), Z can be:

[0299] or absent;

[0300] Z 1 to Z 9 each independently is -C(R 2 )=, -N=, -O- or -S-;

[0301] Z 10 is -C(R 2 )- or N;

[0302] Z 11 , Z 12 and Z 13 each independently is -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-;

[0303] R 2 and R 3 are independently H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3,

[0304]

[0305] R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3,

[0306]

[0307] R 1a and R 2aEach is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, -S(O)2N(H)(C1-C3)alkyl or -S(O)2N(H)CH3; and

[0308] n is 0, 1, 2, 3, 4 or 5.

[0309] In another aspect, the compound of formula (X-I) can have the structure of formula (X-I-A):

[0310]

[0311] X, Y, Z, L 1 , L 2 , L 3 and R 1 as described above.

[0312] In another aspect, the compound of formula (X-I) can have the structure of formula (X-I-B):

[0313]

[0314] X, Y, Z, L 1 , L 2 , L 3 and R 1 as described above.

[0315] In certain aspects, L 3 is selected from -C(O)-, NH-C(O)-, -C(O)-NH-, -O-, -S- or -NH-, or is absent. In certain aspects, L 3 is absent. In certain aspects, L 3 is -C(O)-.

[0316] In another embodiment, the compound of the present disclosure is a compound having the structure of formula (II):

[0317] X 8 to X 15 , L 2 and Z as described above.

[0318] In another embodiment, the compound of the present disclosure is a compound having the structure of formula (IIb):

[0319] X 11 、 X 12 、 X 14 、 L 2 and Z are as described above.

[0320] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (IIc):

[0321] X 12 、 X 14 、 L 2 and Z are as described above.

[0322] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (IIa):

[0323] L 2 and Z are as described above.

[0324] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (III):

[0325]

[0326] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (IIIb):

[0327]

[0328] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (IIIc):

[0329]

[0330] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (IIIa):

[0331]

[0332] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (IV):

[0333]

[0334] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (IVb):

[0335]

[0336] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (IVa):

[0337]

[0338] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (V):

[0339]

[0340] In another embodiment, the compounds of the present disclosure are compounds having a structure selected from the group consisting of formulae (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi) and (Vj):

[0341]

[0342]

[0343] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (VI):

[0344]

[0345] In another embodiment, the compounds of the present disclosure are compounds having a structure selected from the group consisting of formulae (VIa), (VIb), (VIc), (VId), (VIe) and (VIf):

[0346]

[0347]

[0348] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (VII):

[0350]

[0351] In another embodiment, the compounds of the present disclosure are compounds having the structure of formula (VIII):

[0352]

[0353] In another embodiment, the compounds of the present disclosure are compounds having the structure of the present disclosure, wherein L 1 is absent.

[0354] In another embodiment, the compounds of the present disclosure are compounds having the structure of the present disclosure, wherein L1 Does not exist.

[0355] In another embodiment, a compound of the present disclosure is a compound having the structure of the present disclosure, wherein L 1 is an optionally substituted (C1-C3) alkyl, an optionally substituted (C1-C3) alkenyl, a (C1-C3) alkynyl, an optionally substituted 5-6 membered cycloalkyl, an optionally substituted 5-6 membered cycloalkenyl, -N(R 1a )-(C1-C3)alkyl-, -(C1-C3)alkyl-N(R 1a )-, -(C1-C3)alkyl-N(R 1a )-(C1-C3)alkyl-, -O-(C1-C3)alkyl-, -(C1-C3)alkyl-O-, -N(R 1a )-C(O)-, -C(O)-N(R 1a )-, -N(R 1a )-C(O)-N(R 1a )-, -O-C(O)-N(R 1a )-, -N(R 1a )-C(O)-O-, -O-, -S- or -N(R 1a )-.

[0356] In another embodiment, a compound of the present disclosure is a compound having the structure of the present disclosure, wherein L 2 is an optionally substituted (C1-C3) alkyl, an optionally substituted (C1-C3) alkenyl, a (C1-C3) alkynyl, an optionally substituted 5-6 membered cycloalkyl, an optionally substituted 5-6 membered cycloalkenyl, -N(R 1a )-(C1-C3)alkyl-, -(C1-C3)alkyl-N(R 1a )-, -(C1-C3)alkyl-N(R 1a )-(C1-C3)alkyl-, -O-(C1-C3)alkyl-, -(C1-C3)alkyl-O-, -N(R 1a )-C(O)-, -C(O)-N(R 1a )-, -N(R 1a )-C(O)-N(R 1a )-, -O-C(O)-N(R 1a )-, -N(R 1a )-C(O)-O-, -O-, -S- or -N(R 1a )-.

[0357] In a further embodiment, there is provided a compound of the above formula, wherein L 1 is selected from the group consisting of:

[0358]

[0359] In a further embodiment, there is provided a compound of the above formula, wherein L 2 is selected from the group consisting of:

[0360]

[0361] In another embodiment, the compounds of the present disclosure are compounds having Formula I, wherein: X is selected from the group consisting of:

[0362]

[0363]

[0364]

[0365]

[0366] In another embodiment, the compounds of the present disclosure are compounds having Formula I, wherein: Z is selected from:

[0367]

[0368]

[0369]

[0370]

[0371] Exemplary compounds for use in the compositions and formulations of the present invention include the following compounds shown in Tables 1 and 2.

[0372] Table 1: Novel Modulators of gp130 Signaling

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417] Table 2: Novel Modulators of gp130 Signaling

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442] In one embodiment, the modulator modulates the activity and / or expression of downstream molecules of gp130 signaling.

[0443] In another embodiment, the compounds of the present disclosure are direct gp130 agonists.

[0444] In another embodiment, the modulator directly interacts with gp130 signal transduction molecules.

[0445] In one aspect, the disclosed modulators have unique pro-regenerative and anti-inflammatory properties, wherein the modulator inhibits (i) the activation of p38, ERK1 / 2, and NF-kB by OSM, (ii) gp130 phosphorylation, (iii) the expression of MMP13 and ADAMTS4 induced by IL-6 family cytokines, and (iv) promotes or does not inhibit the activation of YAP and / or STAT3 by LIF, wherein the modulator is capable of increasing the expression of COL2 and ACAN in the presence of OSM.

[0446] In another aspect, the disclosed modulators have unique anti-inflammatory properties, wherein the modulator inhibits (i) the activation of p38, ERK1 / 2, NF-κb, and gp130 by IL-6 family cytokines, and (ii) the expression of MMP13 and ADAMTS4 induced by OSM.

[0447] In another aspect, the disclosed modulators have unique pro-regenerative properties, wherein the modulator enhances the activation of YAP and / or STAT3 by LIF and the modulator is capable of increasing the expression of COL2 and ACAN in the presence of OSM.

[0448] In certain embodiments, the disclosed modulators regulate the anti-inflammatory and / or pro-regenerative responses of cells by modulating gp130 activity.

[0449] In one embodiment, the compound modulates the activity of SRC, NF-κB, YAP, p38, ERK1 / 2, STAT3, or MYC, or a combination thereof.

[0450] In one embodiment, the disclosed compound modulates STAT3 and MYC signaling. In one embodiment, the compound does not stimulate STAT3 and MYC signaling. In another embodiment, the compound stimulates STAT3 and MYC signaling.

[0451] In one embodiment, the present invention also relates to stereoisomers, enantiomers, salts, solvates, polymorphs, multicomponent complexes, and liquid crystals of the compounds of formula (I) or (X-I) and their sub-formulas.

[0452] In one embodiment, the present invention also relates to polymorphs and crystal habits of the compounds of formula (I) or (X-I) and their sub-formulas, their prodrugs and isomers (including optical, geometric, and tautomeric isomers), and isotopically labeled compounds of formula (I) or (X-I) and their sub-formulas.

[0453] The compounds used in the formulations of the present invention may be in the form of pharmaceutically acceptable salts.

[0454] When the compounds disclosed herein contain acidic or basic moieties, they may also be disclosed as pharmaceutically acceptable salts (see, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use," edited by Stah and Wermuth; Wiley-VCH and VHCA, Zurich, 2002).

[0455] Suitable acids for preparing pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(IS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0456] Suitable bases for preparing pharmaceutically acceptable salts include, but are not limited to: inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases such as primary amines, secondary amines, tertiary amines, quaternary amines, aliphatic amines, and aromatic amines, including L-arginine, phenylethylbenzylamine, benzoxonium, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[0457] Compounds of formula (I) or (X-I) and the compounds of Tables 1 to 2 can be readily prepared. For example, a nucleophile (such as an amine, including a primary or secondary amine) can react with an acid or other reactive group under suitable conditions to link the various moieties of the compound. For example, the nucleophile can react with an acid (e.g., -C(=O)OH, -C(=O) halide such as -C(=O)Cl, -SO3H) or other reactive group in one or more solvents (including polar solvents such as dichloromethane, chloroform, etc.) at room temperature or elevated temperature for a time sufficient to effectively complete the reaction, which can be determined by chromatography or other analysis. The compounds formed can be further functionalized as needed, such as by one or more addition or coupling reactions. An exemplary preferred synthesis is shown in Example 7.

[0458] The present invention also generally encompasses all pharmaceutically acceptable prodrugs and precursors of the compounds of formula (I) or (X-I) and their sub-formulas.

[0459] In addition, in the presence of an alcohol group, pharmaceutically acceptable esters can be employed, such as acetate, maleate, pivaloyloxymethyl, etc., and those esters known in the art for altering solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

[0460] Prodrugs of the compounds described herein can be used in the methods of the present disclosure. Any compound that will be transformed in vivo to provide the biologically, pharmaceutically, or therapeutically active form of the compounds of the present disclosure is a prodrug. Various examples and forms of prodrugs are well known in the art. Examples of prodrugs can be found in particular in Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); Methods in Enzymology, volume 42, pages 309 - 396, edited by K. Widder, et al. (Academic Press, 1985); A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, chapter 5, "Design and Application of Prodrugs," H. Bundgaard, pages 113 - 191, 1991; H. Bundgaard, Advanced Drug Delivery Reviews, volume 8, pages 1 - 38 (1992); H. Bundgaard, et al., Journal of Pharmaceutical Sciences, volume 77, page 285 (1988); and Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388 - 392).

[0461] Prodrugs of the compounds disclosed herein can be prepared by methods known to those of skill in the art and their routine modifications, and / or by the procedures found in U.S. Patent No. 8,293,786 and the references cited therein and their routine modifications.

[0462] Pharmaceutical compositions

[0463] Also provided herein are pharmaceutical formulations. Accordingly, the present invention relates to a pharmaceutical composition comprising at least one modulator of the gp130 signaling pathway, a compound of any one of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) as described above, and at least one pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant.

[0464] In one embodiment, the pharmaceutical composition comprises at least one modulator of the gp130 signaling pathway selected from Tables 1 to 2 above and at least one pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant.

[0465] In an embodiment of the pharmaceutical composition, it comprises a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof.

[0466] The pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration.

[0467] Examples of routes of administration include parenteral, e.g., intra-articular injection, intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.

[0468] In one embodiment, the pharmaceutical composition of the present invention comprising a compound of formula (I) or (X-I) as described above is in a form suitable for administration to a subject. Such suitable forms of administration can be solid, semi-solid, or liquid. Such suitable forms of administration will be apparent to the person skilled in the art; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

[0469] Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate; and agents for adjusting tonicity, such as sodium chloride or glucose. The pH can be adjusted with an acid or a base (such as hydrochloric acid or sodium hydroxide). The parenteral preparation can be enclosed in an ampoule, a disposable syringe, or a multiple-dose vial made of glass or plastic. Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where the compound is water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM(BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid of such a degree as to be easily administrable by syringe. It must be stable under the conditions of preparation and storage and must be preserved from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using coatings such as lecithin, in the case of dispersions by maintaining the required particle size and by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include in the composition isotonic agents, for example, sugars, polyols such as mannitol, sorbitol, sodium chloride. The absorption of injectable compositions can be prolonged by including in the composition agents that delay absorption, for example, aluminum monostearate and gelatin.

[0470] Sterile injectable solutions can be prepared as follows: The active compound, for example, a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) disclosed herein, is added in the required amount to a suitable solvent containing a combination of one or more of the ingredients listed above as required, and then filtered through a bacteria-retaining filter. Generally, dispersions are prepared by adding the active compound to a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the method of preparation is vacuum drying and freeze drying, which yields a powder of the active ingredient plus any additional required ingredients from its previously sterile-filtered solution.

[0471] In a particular embodiment, one or more compounds of the present disclosure are prepared with a carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, which includes implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art. Such materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions, including liposomes targeted to cells with monoclonal antibodies, can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0472] In certain embodiments, a pharmaceutical composition comprising a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) is administered in solid form. Some preferred, but non-limiting, examples of such forms include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) and a solid carrier. The solid carrier can be one or more substances that also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like.

[0473] In a powder, the carrier can be a finely divided solid that is mixed with the finely divided active ingredient. In a tablet, the active ingredient can be mixed with a carrier having the necessary binding properties in suitable proportions and compressed into the desired shape and size.

[0474] The powders and tablets preferably contain from 1% to 70% of the active compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII).

[0475] To prepare a suppository, first a low melting wax (such as a mixture of fatty acid glycerides or cocoa butter) is melted, and the active ingredient is uniformly dispersed therein, such as by stirring. Then the melted homogeneous mixture is poured into a convenient pre-sized mold, allowed to cool, and thereby solidified.

[0476] The pharmaceutical composition can be intended for intravenous application. Pharmaceutically acceptable excipients can include buffers to adjust the pH to the desired range for intravenous application. Many buffers are known, including salts of inorganic acids such as phosphates, borates, and sulfates.

[0477] In one aspect, the pharmaceutical compositions described herein are formulated to be compatible with topical administration. In one embodiment, the pharmaceutical composition is formulated as a topical preparation.

[0478] The topical formulation can be applied to a skin area in a suitable dosage and treatment regimen. The dosage and administration regimen of the described method depend on the nature and condition to be treated, the age and condition of the patient, and any prior or concurrent treatment.

[0479] In certain cases, the topical formulation can be administered once a week, every other day, once a day, twice a day, three times a day, or four times a day over a suitable period of time. Treatment can be terminated when the skin area has healed. Treatment can be resumed if necessary, for example, if a skin area requires additional treatment.

[0480] According to the present invention, the topical formulation can be topically administered in the form of a cream, gel, or liquid. The topical administration delivers the stabilized formulation directly to the skin, preferably using a dermatologically acceptable carrier. Although the carrier can consist of a relatively simple solvent or dispersant (such as an oil), it is generally preferred that the carrier contains materials that are more conducive to topical application, particularly materials that will form a film or layer on the skin to which it is applied. This localizes the application and provides some resistance to sweating and / or aids in transdermal delivery and penetration of the active ingredient into the lipid layer. Many such compositions are known in the art and can be in the form of creams, gels, ointments, hydrogels, pastes, or plasters, and liquid dosage forms such as solutions, emulsions, particularly oil-in-water emulsions, suspensions, such as lotions, etc., or even solid sticks. Liposomes or microspheres can also be used. In certain embodiments, the topical formulation can be administered using devices or methods designed to more easily breach the skin barrier and enable the agents in the topical formulation to cross the stratum corneum in a faster or more efficient manner. These include, for example, sonotherapy or ultrasound, oxygen nebulizers, and nanobody mists in combination with iontophoresis. In certain embodiments, a nebulizer or atomizer can be used to generate a nanobody mist. In one embodiment, a microelectronic cosmetic delivery mechanism described as can be used to deliver the topical formulation to the skin. This method can be used to deliver ionizable compounds to the skin and aids in the penetration of small molecules through the stratum corneum.

[0481] In one embodiment, a low-intensity ultrasound delivery system described as OZ Inside TM can be used to deliver the topical formulation to the skin. PCT / US2011 / 041787 and PCT / US2014 / 043951 are hereby incorporated by reference for using such a delivery system to administer the topical formulations of the present disclosure.

[0482] The subject to be treated by the topical formulation can be a human or non-human mammal.

[0483] In certain embodiments, a pharmaceutical composition comprising a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII) or (VIII) can be administered orally in solid form. Some preferred, but non-limiting examples of such forms include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.

[0484] In one aspect, a pharmaceutical composition comprising a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII) or (VIII) can be formulated for use in an implant coating.

[0485] In certain embodiments, the implant coating is used to coat an implantable device.

[0486] In certain embodiments, the implant coating can be used for the sustained release of a pharmaceutical composition comprising a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII) or (VIII).

[0487] In certain embodiments, the implantable device is a member selected from the group consisting of bone substitutes, joint prostheses, dental implants, maxillofacial implants, spinal surgery aids and percutaneous devices.

[0488] Other ingredients

[0489] The pharmaceutical composition of the present invention can optionally comprise one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants. Such suitable carriers, diluents, excipients and / or adjuvants for preparing the dosage forms will be apparent to those skilled in the art; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

[0490] In particular, the pharmaceutical composition of the present invention can optionally contain inactive substances commonly used in pharmaceutical formulations, such as cosolvents, antioxidants, surfactants, wetting agents, emulsifiers, buffers, pH regulators, preservatives (or conserving agents), isotonic agents, stabilizers, granulating agents or binders, precipitation inhibitors, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersants, suspending agents, fillers, demolding agents, sweeteners, flavoring agents, etc.

[0491] According to one embodiment, the pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable inactive ingredients selected from: caprylic acid, polyethylene glycol, propylene glycol, ethanol, glycerol, dimethyl sulfoxide, dimethylacetamide, isosorbide dimethyl ether, cellulose derivatives (including hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, and hypromellose acetate succinate), cremophor RH40 (polyoxyethylene 40 hydrogenated castor oil), cremophor EL (polyoxyethylene 35 hydrogenated castor oil), polysorbate 20 (polyoxyethylene sorbitan monolaurate), polysorbate 80 (polyoxyethylene sorbitan monooleate), poloxamer 188 (polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol), poloxamer 407 (polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol), vitamin E TPGS (vitamin E polyethylene glycol succinate), solutol HS15 (polyoxylated 12-hydroxystearic acid), caprylic / capric polyethylene glycol glyceride (caprylic / capric polyoxyl-8 glyceride), labrafil M1944 (oleoyl polyoxyl-6 glyceride), polyvinylpyrrolidone (also known as povidone, preferably polyvinylpyrrolidone K17, K19, K29-K32, K90), polyvinylpyrrolidone polyvinyl acetate copolymer, carboxymethyl cellulose (Na / Ca), polyethylene glycol methyl ether-block-poly(D-L-lactide) copolymer, sodium lauryl sulfate, sodium docusate, propylene glycol monolaurate, propylene glycol dilaurate, propylene glycol monocaprylate, polyethylene glycol 660 12-monostearate, poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, sodium lauryl sulfate.

[0492] In a preferred embodiment, the pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable co-solvents. Preferably, the co-solvents are selected from caprylic acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethyl sulfoxide, dimethylacetamide, isosorbide dimethyl ether, and mixtures thereof. In a specific embodiment, the pharmaceutical composition of the present invention comprises caprylic acid and / or PEG. Advantageously, when the composition comprises PEG as a co-solvent, PEG has a low molecular weight, preferably PEG is PEG 400. In an alternative embodiment, when the composition comprises PEG, it has a medium molecular weight, preferably PEG2000.

[0493] In one embodiment, the pharmaceutical composition of the present invention further comprises one or more antioxidants; preferably, the antioxidants are selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, sodium metabisulfite, ascorbic acid, methionine, and vitamin E; more preferably, the antioxidant is BHT.

[0494] In certain embodiments, surfactants are added, such as polyethylene glycol, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, sodium docusate, sodium lauryl sulfate, polysorbates (20, 80, etc.), poloxamers (188, 407, etc.), pluronic polyols, polyoxyethylene sorbitan monoethers ( etc.), vitamin E TPGS (vitamin E polyethylene glycol succinate), cremophor RH40 (polyoxyethylene 40 hydrogenated castor oil), cremophor EL (polyoxyethylene 35 hydrogenated castor oil), polyethylene glycol 660 12-monostearate, solutol HS15 (polyoxethylated 12-hydroxystearic acid), caprylic / capric polyethylene glycol glyceride (caprylic / capric polyoxyethylene-8 glyceride), labrafil M1944 (oleoyl polyoxyl-6 glyceride).

[0495] In certain embodiments, wetting agents are added, such as sodium lauryl sulfate, vitamin E TPGS, sodium docusate, polysorbate 80, poloxamer 407. A preferred wetting agent is sodium lauryl sulfate.

[0496] In certain embodiments, emulsifiers are added, such as carbomer, carrageenan, lanolin, lecithin, mineral oil, oleic acid, oleyl alcohol, pectin, poloxamer, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, triethanolamine, propylene glycol monolaurate, propylene glycol dilaurate, propylene glycol monocaprylate. Preferred emulsifiers are, for example, poloxamer, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprylate.

[0497] In certain embodiments, a buffering agent is used to help maintain the pH within a range close to physiological conditions. Suitable buffering agents include organic and inorganic acids and their salts, such as citrate buffers (e.g., sodium citrate monobasic - disodium citrate mixture, citric acid - trisodium citrate mixture, citric acid - sodium citrate monobasic mixture, etc.), succinate buffers (e.g., succinic acid - sodium succinate monobasic mixture, succinic acid - sodium hydroxide mixture, succinic acid - disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid - sodium tartrate mixture, tartaric acid - potassium tartrate mixture, tartaric acid - sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumaric acid - sodium fumarate monobasic mixture, fumaric acid - disodium fumarate mixture, sodium fumarate monobasic - disodium fumarate mixture, etc.), gluconate buffers (e.g., gluconic acid - sodium gluconate mixture, gluconic acid - sodium hydroxide mixture, gluconic acid - potassium gluconate mixture, etc.), oxalate buffers (e.g., oxalic acid - sodium oxalate mixture, oxalic acid - sodium hydroxide mixture, oxalic acid - potassium oxalate mixture, etc.), lactate buffers (e.g., lactic acid - sodium lactate mixture, lactic acid - sodium hydroxide mixture, lactic acid - potassium lactate mixture, etc.), and acetate buffers (e.g., acetic acid - sodium acetate mixture, acetic acid - sodium hydroxide mixture, etc.). Additionally, phosphate buffers, histidine buffers, and trimethylamine salts such as Tris can be used.

[0498] In certain embodiments, a pH regulator is added, such as sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, meglumine, sodium carbonate, citric acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, and malic acid.

[0499] In certain embodiments, a preservative is added to prevent microbial growth. Preservatives suitable for the present disclosure include phenol, benzyl alcohol, m - cresol, methyl paraben, propyl paraben, octadecyl dimethyl benzyl ammonium chloride, benzalkonium halides (e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkyl parabens such as methyl paraben or propyl paraben, catechol, resorcinol, cyclohexanol, and 3 - pentanol.

[0500] In certain embodiments, an isosmotic agent sometimes referred to as a "stabilizer" is added, and the isosmotic agent includes polyhydric sugar alcohols, such as sugar alcohols of three or more hydroxyl groups, such as glycerol, erythritol, arabitol, xylitol, sorbitol, and mannitol. Stabilizers represent a broad class of excipients whose functional range can span from fillers to additives that dissolve the therapeutic agent, or help prevent denaturation or adhesion to the container wall, or help inhibit precipitation, particle growth, or aggregation of the active ingredient. Typical stabilizers can be polyhydric sugar alcohols (listed above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, etc., including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur-containing reducing agents, such as urea, glutathione, lipoic acid, sodium thioglycolate, thioglycerol, α-monothioglycerol, and sodium thiosulfate; low molecular weight polypeptides (e.g., peptides of 10 or fewer residues); proteins such as human serum albumin, bovine serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, or hydroxypropylmethylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); monosaccharides, such as xylose, mannose, fructose, glucose; disaccharides such as lactose, maltose, sucrose, and trisaccharides such as raffinose; polysaccharides such as dextran; poly(ethylene glycol methyl ether)-block-poly(D-L-lactide) copolymer; poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1.

[0501] Preferred stabilizers are, for example, glycerol; polyethylene glycol; polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, or hydroxypropylmethylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); poly(ethylene glycol methyl ether)-block-poly(D-L-lactide) copolymer; and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1.

[0502] In certain embodiments, a granulating agent / binder is added, such as starch, gums (including natural, semi-synthetic, and synthetic), microcrystalline cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, liquid glucose polymers such as polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, etc. Preferred granulating agents are, for example, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone vinyl acetate copolymer.

[0503] In certain embodiments, a precipitation inhibitor is added, such as water-soluble derivatives of cellulose, including hydroxypropyl methylcellulose and methylcellulose, and water-soluble polymers, such as polyvinylpyrrolidone or polyvinylpyrrolidone-vinyl acetate copolymer. A preferred precipitation inhibitor is hydroxypropyl methylcellulose.

[0504] In certain embodiments, a lubricant is added, such as magnesium stearate, glycerides, behenoyl polyoxyl-8 glyceride Nf (Compritol HD5 ATO), sodium stearyl fumarate, and the like.

[0505] In certain embodiments, a disintegrant is added, such as synthetic compounds like sodium starch glycolate, crospovidone, croscarmellose sodium, kollidon CL, and natural sources such as locust bean gum.

[0506] In certain embodiments, a glidant is added, such as talc, magnesium stearate, colloidal silicon dioxide, starch, and the like.

[0507] In certain embodiments, a diluent (or filler) is added, such as dextrose, lactose, mannitol, microcrystalline cellulose, sorbitol, sucrose, calcium hydrogen phosphate, anhydrous calcium sulfate, starch, and the like.

[0508] In certain embodiments, an adsorbent is added, such as silica, purified aluminum silicate, and the like.

[0509] In certain embodiments, the pharmaceutical composition of the present invention is in the form of a tablet and a tableting excipient is added, such as a granulating agent, a binder, a lubricant, a disintegrant, a glidant, a diluent, an adsorbent, and the like.

[0510] In certain embodiments, the pharmaceutical composition of the present invention is in the form of a capsule, wherein the capsule shell is composed of gelatin or a non-animal-derived product (such as cellulose and its derivatives such as hydroxypropyl methylcellulose). Other components may be included in the capsule shell, such as polyethylene glycol used as a plasticizer; pigments such as titanium dioxide or iron oxide for providing opacity and color differentiation; lubricants such as carnauba wax; gelling agents such as carrageenan; and wetting agents such as sodium lauryl sulfate. In one embodiment, the pharmaceutical composition of the present invention is formulated as a capsule, wherein the capsule shell is composed of gelatin and wherein additional components, such as polyethylene glycol and sodium lauryl sulfate, are optionally included in the capsule shell.

[0511] Dosage and unit dosage

[0512] Data obtained from cell culture assays and animal studies can be used in formulating the dosage range for human use. The dosage of such a compound lies within the range of circulating concentrations that includes the ED50 with little or no toxicity. Depending on the dosage form used and the route of administration employed, the dosage can vary within this range. For any compound used in the methods of the present disclosure, a therapeutically effective dosage can be initially estimated from cell culture assays. Dosages can be formulated in animal models to achieve a range of circulating plasma concentrations that includes the IC50 determined in cell culture (e.g., the concentration of the test compound at which half-maximal inhibition of symptoms is achieved). Such information can be used to more accurately determine the dosage useful in humans. For example, by high performance liquid chromatography, the levels in plasma can be measured.

[0513] The pharmaceutical composition is preferably in unit dosage form. In such form, the composition is subdivided into unit dosages containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged composition, the package containing discrete quantities of the composition, such as packeted tablets, capsules, and powders in vials or ampoules.

[0514] In addition, the unit dosage form can be the capsule, tablet, cachet or lozenge itself, or it can be any of these in packaged form in appropriate quantities.

[0515] The quantity of a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII) or (VIII) in a unit dosage composition can vary or be adjusted according to the particular use and the potency of the active ingredient. In one embodiment, the dosage comprises an amount of the compound from about 0.1 mg to about 10000 mg. In another embodiment, the dosage comprises an amount of the compound from about 1 mg to about 1000 mg. In another embodiment, the dosage comprises an amount of the compound from about 1 mg to about 400 mg. In another embodiment, the dosage comprises an amount of the compound from about 1 mg to about 100 mg. In another embodiment, the dosage comprises an amount of the compound from about 1 mg to about 10 mg.

[0516] If desired, the composition may also contain other compatible therapeutic agents. Some of the compounds of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII) or (VIII) may have limited solubility in water and may therefore require a surfactant or other suitable cosolvent in the composition. Such cosolvents include: polysorbates 20, 60 and 80; Pluronic F-68, F-84 and P-103; cyclodextrins; and polyoxyethylene 35 castor oil. Such cosolvents are typically used at levels between about 0.01% and about 2% by weight. A viscosity greater than that of a simple aqueous solution may be required to reduce variability during administration of the formulation, reduce physical separation of the components of the formulation suspension or emulsion and / or otherwise improve the formulation. Such viscosity builders include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically used at levels between about 0.01% and about 2% by weight.

[0517] In one embodiment, the pharmaceutical composition of the invention is administered as a daily dose such that it corresponds to administering to the subject about 1 mg to about 400 mg of the above-mentioned compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII) or (VIII) per day.

[0518] In certain embodiments, the daily dose is administered in the form of 2, 3, 4 or 6 equal unit doses administered independently throughout the day.

[0519] In another embodiment, the daily dose is administered as a single unit dose.

[0520] In certain embodiments, each unit dose is administered in the form of 1, 2, 3 or 4 tablets, suspensions, granules or capsules.

[0521] The pharmaceutical composition of the invention can also be formulated to provide rapid, sustained or delayed release of the above-mentioned modulators contained therein.

[0522] Additional therapeutic agents and methods

[0523] The compositions and formulations of one or more gp130 signaling pathway modulators disclosed herein can be used in combination with other active agents to treat disorders or diseases in a subject.

[0524] It should be understood that administering an additional therapeutic agent together with a compound of the present disclosure encompasses co-administering these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients or in multiple separate capsules for each active ingredient. Additionally, co-administering an additional therapeutic agent with a compound disclosed herein also encompasses using each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the disorders described herein.

[0525] In a further embodiment, the compounds disclosed herein can be combined with one or more classes of therapeutic agents, including but not limited to alkylating agents, cancer immunotherapy monoclonal antibodies, antimetabolites, mitotic inhibitors, antitumor antibiotics, topoisomerase inhibitors, photosensitizers, tyrosine kinase inhibitors, anticancer agents, chemotherapeutic agents, anti-migraine therapeutics, antitussives, mucolytics, decongestants, anti-allergy non-steroidals, expectorants, antihistamine therapeutics, antiretrovirals, CYP3A inhibitors, CYP3A inducers, protease inhibitors, adrenergic agonists, anticholinergics, mast cell stabilizers, xanthines, leukotriene antagonists, glucocorticoid therapeutics, antibacterial agents, antifungal agents, sepsis therapeutics, steroids, local or general anesthetics, NSAIDS, NRI, DARI, SNRI, sedatives, NDRI, SNDRI, monoamine oxidase inhibitors, hypothalamic phospholipids, antiemetics, ECE inhibitors, opioids, thromboxane receptor antagonists, potassium channel openers, thrombin inhibitors, growth factor inhibitors, antiplatelet agents, P2Y(AC) antagonists, anticoagulants, low molecular weight heparins, factor Via inhibitors, factor Xa inhibitors, renin inhibitors, NEP inhibitors, vasopeptidase inhibitors, squalene synthase inhibitors, anti-atherosclerotic agents, MTP inhibitors, calcium channel blockers, potassium channel activators, α-muscarinic agents, β-muscarinic agents, antiarrhythmics, diuretics, thrombolytics, antidiabetic agents, mineralocorticoid receptor antagonists, growth hormone secretagogues, aP2 inhibitors, phosphodiesterase inhibitors, anti-inflammatory agents, antiproliferatives, antibiotics, farnesyl-protein transferase inhibitors, hormone agents, plant-derived products, etoposide, taxanes, geranylgeranyl-protein transferase inhibitors, anti-TNF antibodies and soluble TNF receptors, cyclooxygenase-2 inhibitors and other agents.

[0526] It should be understood that administering an additional therapeutic agent together with a compound of the present disclosure encompasses co-administering these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple separate capsules of each active ingredient. Additionally, co-administering an additional therapeutic agent with a compound disclosed herein also encompasses using each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the disorders described herein.

[0527] Kit

[0528] For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits can include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, test tubes, etc., each container containing one of the separate elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic.

[0529] For example, the container can contain one or more of the compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container optionally has a sterile access port (e.g., the container can be an intravenous solution bag or a vial having a stopper that can be pierced by a hypodermic needle). Such kits optionally contain a compound having an identifying description or label or instructions associated with its use in the methods described herein.

[0530] The kit will generally include one or more additional containers, each having one or more of the various materials (such as reagents, optionally in concentrated form, and / or devices) required for using the compounds described herein from a commercial and user standpoint. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vials, and / or test tube labels (listing contents and / or instructions for use), as well as package inserts having instructions for use. A set of instructions will generally also be included.

[0531] The label can be on the container or accompany the container. The label can be on the container when the letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself; the label can accompany the container when it is present in a holder or carrier that also holds the container (such as a package insert). The label can be used to indicate that the contents will be used for a specific therapeutic application. The label can also indicate instructions for using the contents, such as in the methods described herein. For example, these other therapeutic agents can be used in the amounts indicated in the Physicians' Desk Reference (PDR) or otherwise determined by one of ordinary skill in the art.

[0532] Topical formulation

[0533] The present invention also generally encompasses novel topical formulations of all provided small molecule modulators of gp130 signaling or derivatives thereof for improving the skin appearance of normal and aged human skin.

[0534] In one embodiment, the topical formulation has the appearance of an opaque and viscous lotion.

[0535] In another embodiment, the topical formulation has a color ranging from off-white to straw-colored.

[0536] In another embodiment, the topical formulation has a citrus odor.

[0537] In another embodiment, the topical formulation has a specific gravity at 25 °C.

[0538] In another embodiment, the topical formulation has a pH in the range of 4.5 - 5.5 at 25 °C.

[0539] In another embodiment, the topical formulation has a total solids percentage in the range of 17.5% to 21.5%.

[0540] In another embodiment, the topical formulation has a viscosity in the range of 18,000 centipoise (cps) to 40,000 cps at 25 °C.

[0541] In one embodiment, excipients commonly used in skin care compositions can be utilized, such as emollients, skin conditioners, emulsifiers, humectants, preservatives, antioxidants, fragrances, chelating agents, buffering agents, etc., provided that they are physically and chemically compatible with the other components in the formulation.

[0542] In one embodiment, the topical formulation contains:

[0543] a. A first part, which contains a mixture of a first component, a second component, a third component, a fourth component, a fifth component, and a sixth component;

[0544] b. A second part, which contains a mixture of two components, namely a seventh component and an eighth component; and

[0545] c. A third part, which contains a mixture of a ninth component, a tenth component, an eleventh component, a twelfth component, a thirteenth component, a fourteenth component, a fifteenth component, a sixteenth component, a seventeenth component, and an eighteenth component, wherein the formulation contains a combination of the first part, the second part, and the third part.

[0546] In one embodiment, the topical formulation comprises cross-linked hyaluronic acid. In one embodiment, the cross-linked hyaluronic acid is an aqueous combination of pentylene glycol, ethylhexylglycerin, sodium hyaluronate, and a cross-linking polymer (e.g., EG10 (CAS# 105524-32-1, available from Vantage Specialty Ingredients)). In one embodiment, the topical formulation comprises about 1% W / W of cross-linked hyaluronic acid. In one embodiment, the topical formulation comprises about 1% W / W of cross-linked hyaluronic acid.

[0547] In one embodiment, the topical formulation comprises a self-emulsifying elastomeric dispersion. In one embodiment, the self-emulsifying elastomeric dispersion is a combination of polydimethylsiloxane, polysiloxane-11, isododecane, ammonium polyacryloyldimethyltaurate, tocopheryl acetate, polysorbate 80, and polysorbate 20, e.g., Gransil ORB-5CS (available from Grant Industries). In one embodiment, the topical formulation comprises about 25% W / W of the self-emulsifying elastomeric dispersion. In one embodiment, the topical formulation comprises about 25% W / W of the self-emulsifying elastomeric dispersion.

[0548] In one embodiment, the topical formulation comprises a branched aliphatic hydrocarbon softener. In one embodiment, the branched aliphatic hydrocarbon softener is isododecane, e.g., Armesii 12C (CAS# 93685-81-5, #31807-55-3, #13475-82-6, available from Argan Co.). In one embodiment, the topical formulation comprises about 8% W / W of the branched aliphatic hydrocarbon softener. In one embodiment, the topical formulation comprises about 8% W / W of the branched aliphatic hydrocarbon softener.

[0549] In one embodiment, the topical formulation comprises a stable and oil-soluble form of vitamin C. In one embodiment, the stable and oil-soluble form of vitamin C is tetrahexyldecyl ascorbate, e.g., BV-OSC (CAS# 183476-82-6, available from Barnet Products Corporation). In one embodiment, the topical formulation comprises about 0.5% W / W of the stable and oil-soluble form of vitamin C. In one embodiment, the topical formulation comprises about 0.5% W / W of the stable and oil-soluble form of vitamin C.

[0550] In one embodiment, the topical formulation comprises an active cooling ingredient. In one embodiment, the active cooling ingredient is menthyl ethylamido oxalate, e.g., X-Cool (available from Symrise). In one embodiment, the topical formulation comprises a stable and oil-soluble form of vitamin C at about 0.1% W / W. In one embodiment, the topical formulation comprises an active cooling ingredient at about 0.1% W / W.

[0551] In one embodiment, the topical formulation comprises an orange essential oil mixture. In one embodiment, the orange essential oil mixture is a combination of limonene, sweet orange (Aurantium dulcis) (orange) peel oil, and tangerine (Citrus tangerina) (mandarin) peel oil, e.g., Frag. orange essential oil mixture (#CE-188609, available from Harris). In one embodiment, the topical formulation comprises a stable and oil-soluble form of vitamin C at about 0.2% W / W. In one embodiment, the topical formulation comprises the orange essential oil mixture at about 0.2% W / W.

[0552] In one embodiment, the topical formulation comprises a viscous oil. In one embodiment, the viscous oil is tocopherol, e.g., DL-α-tocopherol (available from DSM). In one embodiment, the topical formulation comprises the viscous oil at about 0.1% W / W. In one embodiment, the topical formulation comprises the viscous oil at about 0.1% W / W.

[0553] In one embodiment, the topical formulation comprises a softening agent. In one embodiment, the softening agent is butylene glycol, e.g., 1,3-butylene glycol (available from Univar). In one embodiment, the topical formulation comprises the softening agent at about 4% W / W. In one embodiment, the topical formulation comprises the softening agent at about 4% W / W.

[0554] In one embodiment, the topical formulation comprises a polymeric thickener and stabilizer. In one embodiment, the polymeric thickener and stabilizer is a combination of isododecane, ammonium polyacryldimethyltaurate, and polysorbate 80, e.g., Granthix APP (available from Grant Industries). In one embodiment, the topical formulation comprises the polymeric thickener and stabilizer at about 2.5% W / W. In one embodiment, the topical formulation comprises the polymeric thickener and stabilizer at about 2.5% W / W.

[0555] In one embodiment, the topical formulation comprises sustainable pentylene glycol. In one embodiment, the sustainable pentylene glycol is 5 Green (available from Symrise). In one embodiment, the topical formulation comprises about 1% W / W of sustainable pentylene glycol. In one embodiment, the topical formulation comprises about 1% W / W of sustainable pentylene glycol.

[0556] In one embodiment, the topical formulation comprises lipopeptides. In one embodiment, the lipopeptides are a combination of water (aqueous solution), pentylene glycol, caprylyl glycol, and N-prolyl palmitoyl tripeptide-56 acetate, e.g., Morphemics TM (available from Sederma). In one embodiment, the topical formulation comprises about 2% W / W of lipopeptides. In one embodiment, the topical formulation comprises about 2% W / W of lipopeptides.

[0557] In one embodiment, the topical formulation comprises a stress oxidation inhibitor. In one embodiment, the stress oxidation inhibitor is a combination of glycerol and Acer rubrum extract, e.g., Borealine Expert (available from Lucas Meyer). In one embodiment, the topical formulation comprises about 0.1% W / W of lipopeptides. In one embodiment, the topical formulation comprises about 0.1% W / W of the stress oxidation inhibitor.

[0558] In one embodiment, the topical formulation comprises a tropical fruit extract standardized in terms of carbohydrates and total alpha hydroxy acids (AHAs). In one embodiment, the tropical fruit extract is a combination of water (aqueous solution), Spondias mombin pulp extract, Mangifera indica (mango) pulp extract, Musa sapientum (banana) pulp extract, benzyl alcohol, and potassium sorbate, e.g., Exfo-Bio (available from ChemyUnion). In one embodiment, the topical formulation comprises about 2% W / W of the tropical fruit extract. In one embodiment, the topical formulation comprises about 2% W / W of the tropical fruit extract standardized in terms of carbohydrates and total alpha hydroxy acids (AHAs).

[0559] In one embodiment, the topical formulation comprises a mixture of multifunctional ingredients with self-preserving properties. In one embodiment, the mixture of multifunctional ingredients comprises a combination of glyceryl caprylate, glycerol, and octyl hydroxamic acid, e.g., Spectrastat TM G2N (available from Inolex). In one embodiment, the topical formulation comprises about 1.2% W / W of the mixture of multifunctional ingredients. In one embodiment, the topical formulation comprises about 1.2% W / W of the mixture of multifunctional ingredients with self-preserving properties.

[0560] In one embodiment, the topical formulation comprises at least one chelating agent. As used herein, the term "chelating agent" refers to any known pharmaceutically acceptable chelating agent. Suitable chelating agents can include, but are not limited to, any one or more of the following: ethylenediaminetetraacetic acid (EDTA) and its derivatives, ethylene glycol-bis-(2-aminoethyl)-N,N,N′,N′-tetraacetic acid (EGTA) and its derivatives, cyclohexanediaminetetraacetic acid (CDTA) and its derivatives, hydroxyethylethylenediaminetriacetic acid (HEDTA) and its derivatives, diethylenetriaminepentaacetic acid (DTPA) and its derivatives, dimercaptopropanesulfonic acid (DMPS) and its derivatives, dimercaptosuccinic acid (DMSA) and its derivatives, aminotrimethylenephosphonic acid (ATPA) and its derivatives, N,N-bis(carboxymethyl)glycine (NTA) and its derivatives, nitrilotriacetic acid and its derivatives, citric acid and its derivatives, nicotinamide and its derivatives, sodium deoxycholate and its derivatives, sodium phytate and its derivatives, trisodium ethylenediaminedisuccinate and its derivatives, polyphosphates; porphine; and any pharmaceutically acceptable salts thereof.

[0561] The described chelating agent can be present in the described topical pharmaceutical composition in amounts such as, for example: from about 0.001% to about 10% by weight; from about 0.005% to about 5% by weight; from about 0.005% to about 0.5% by weight; from about 0.001% to about 1% by weight; from about 0.01 to about 5% by weight; from about 0.006% to about 0.04% by weight; from about 0.007% to about 0.035% by weight; from about 0.008% to about 0.035% by weight; from about 0.009% to about 0.035% by weight; from about 0.01% to about 0.03% by weight; from about 0.015% to about 0.025% by weight; from about 0.018% to about 0.022% by weight; from about 0.019% to about 0.021% by weight; about 0.019% by weight; about 0.02% by weight; or about 0.021% by weight of chelating agent.

[0562] In one embodiment, the topical formulation is stable at room temperature. The optimal storage conditions are between 15°C and 25°C, in a dry environment, and away from ultraviolet light and heat.

[0563] Handle according to good practice. Avoid elevated temperatures.

[0564] Kit for promoting skin health and reducing the effects of aging

[0565] The present disclosure also provides a kit for promoting skin health and reducing the effects of aging. Such a kit can include one or more containers that contain the topical formulations described herein, including but not limited to one or more compounds of formula (I) or (X-I) and the compounds of Tables 1 to 2 above.

[0566] In certain embodiments, the kit can contain instructions for use according to any of the methods described herein. The included instructions can contain a description of administering the topical formulation according to any of the methods described herein to promote skin health and reduce the effects of aging. The kit can further contain a description of selecting a suitable individual for treatment based on identifying whether the individual is in need of treatment. Instructions related to the use of the topical formulation generally include information about the dosage, dosing regimen, and route of administration for the intended treatment. The containers can be unit dose, bulk pack (e.g., multi-dose pack), or sub-unit dose. The instructions provided in the kits of the present invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0567] The label or package insert indicates that the composition is for promoting skin health and reducing the effects of aging. Instructions for practicing any of the methods described herein can be provided.

[0568] The kits of the present invention are in a suitable package. Suitable packages include but are not limited to vials, bottles, jars, flexible packages (e.g., sealed Mylar or plastic bags), etc. At least one active agent in the composition is an active agent selected from the group consisting of the compounds of Tables 1 to 2.

[0569] The kit can optionally provide additional ingredients such as explanatory information. Generally, the kit contains the container and a label or package insert on or accompanying the container. In certain embodiments, the present invention provides a finished product containing the contents of the above-described kit.

[0570] Method of Use - Promoting Skin Health and Preventing or Reducing Inflammaging

[0571] "Inflammaging" as described herein refers to inflammation, particularly skin inflammation, as a biological response of body tissues to environmental challenges such as sunlight and wind, as well as internal drivers such as diet, alcohol, and smoking, and other potentially harmful stimuli, which promotes harmful biological responses that lead to visible signs of aging such as the appearance of fine lines and wrinkles, hyperpigmentation, and increased laxity. The harmful stimuli can include, but are not limited to, pathogens, bacteria, viruses, fungi, damaged cells, and other irritants known to those skilled in the art. Inflammation can be a protective immune response, which can involve, for example, immune cells, white blood cells, blood vessels, molecular mediators, and other small molecules. Signs of inflammation can include, but are not limited to, pain, fever, swelling, and / or loss of function. Inflammation can be acute or chronic.

[0572] In certain embodiments described herein, a preparation for treating inflammaging is provided. The preparation can include cells prepared by the methods described herein.

[0573] In certain embodiments, the subject suffers from inflammaging in one or more skin regions or is at risk of developing inflammaging in one or more skin regions.

[0574] In certain embodiments, the inflammation is on the skin, scalp, nasal cavity, oral cavity, nail area (such as the stratum corneum), eye, vaginal area, or perineal area.

[0575] Any topical preparation described herein can be used to promote skin health and reduce the effects of aging in a subject in need of treatment. The topical preparation can be applied to a skin region in accordance with a suitable dosage and treatment regimen. The dosage and administration regimen of the described method depend on the nature and condition of the wound to be treated, the age and condition of the patient, and any prior or concurrent treatments.

[0576] In certain cases, the topical preparation can be administered once a week, every other day, once a day, twice a day, three times a day, or four times a day for a suitable period of time. When the skin region has recovered, the treatment can be terminated. The treatment can be resumed if necessary, for example, if a particular skin region requires additional treatment.

[0577] According to the present invention, the topical formulation may be topically administered in the form of a cream, gel, or liquid. The topical administration delivers the stabilized formulation directly to the skin, preferably using a dermatologically acceptable carrier. Although the carrier may consist of a relatively simple solvent or dispersant (such as an oil), it is generally preferred that the carrier comprises materials that are more conducive to topical application, particularly materials that will form a film or layer on the skin to which it is applied. This localizes the application and provides some resistance to sweating and / or aids in transdermal delivery and penetration of the active ingredient into the lipid layer. Many such compositions are known in the art and may take the form of creams, gels, ointments, hydrogels, pastes or plasters, and liquid dosage forms such as solutions, emulsions, particularly oil-in-water emulsions, suspensions, such as lotions, etc., or even solid sticks. Liposomes or microspheres may also be used.

[0578] In certain embodiments, the topical formulation may be administered using a device or method designed to more easily breach the skin barrier and enable the agent in the topical formulation to cross the stratum corneum in a faster or more efficient manner. These include, for example, sonotherapy or ultrasound, oxygen nebulizers, and nanobody mists in combination with iontophoresis. In certain embodiments, a nebulizer or atomizer may be used to generate a nanobody mist. In one embodiment, a microelectronic cosmetic delivery mechanism described as may be used to deliver the topical formulation to the skin. This method can be used to deliver ionizable compounds to the skin and aids in the penetration of small molecules through the stratum corneum.

[0579] In one embodiment, a low-intensity ultrasound delivery system described as OZ Inside TM may be used to deliver the topical formulation to the skin. PCT / US2011 / 041787 and PCT / US2014 / 043951 are hereby incorporated by reference for using such delivery systems to administer the topical formulations of the present disclosure.

[0580] The subject treated by the topical formulation may be a human or non-human mammal.

[0581] In certain embodiments, the subject is a human patient who would benefit from an improvement in skin health, promotion of the skin self-renewal process, and protection of the skin from oxidative damage.

[0582] In certain embodiments, methods are provided for treating a subject suffering from a skin disorder. The method may include providing a cell of any of the embodiments described herein or a topical formulation of any of the embodiments described herein, and applying the topical formulation to the subject, wherein the topical formulation is applied to the skin.

[0583] In certain embodiments, the skin disorder is selected from the group consisting of psoriasis, skin cancer, acne, hair loss, carbuncle, dermatitis, eczema, atopic dermatitis, contact dermatitis, seborrheic dermatitis, cradle cap, perioral dermatitis, herpes zoster, ringworm, melisma, and impetigo.

[0584] In certain embodiments, the skin disorder is derived from an autoimmune or inflammatory disorder.

[0585] In certain embodiments, the autoimmune or inflammatory disorder is alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa acquisita, erythema nodosum, herpes gestationis, hidradenitis suppurativa, lichen planus, lichen sclerosus, linear IgA disease, morphea, pemphigus vulgaris, pityriasis lichenoides et varioliformis acuta, Sweet's disease, psoriasis, systemic sclerosis, or vitiligo. In certain embodiments, skin diseases and skin disorders can include summer acne (Mallorca acne), acne conglobata, acne cosmetica, acne fulminans, acne keloidalis nuchae, adult forehead with scattered red papules, acne vulgaris, acne mechanica, acne medicamentosa, acne necrotica miliaris, acne vulgaris, acne with facial edema, chalazion, acne rosacea erythematotelangiectatica, acne excoriée, acne glandularis, gnathophyma, acne rosacea gram-negative, granulomatous facial dermatitis, adult male with large, red, bulbous nose, acne rosacea hypertrophica, granulomatous perioral dermatitis, acne halogena, hidradenitis suppurativa, idiopathic facial aseptic granuloma, acne neonatorum, acne rosacea lupoides, lupus miliaris disseminatus faciei, metophyma, neonatal acne, occupational acne, acne sebacea, acne rosacea ophthalmica, otophyma, perioral dermatitis, persistent acne rosacea edema, acne rosacea hyperplastica, acne pomade, acne rosacea papulopustulosa, perifolliculitis capitis abscedens et suffodiens, perioral dermatitis, periorbital dermatitis, facial pyoderma, acne rosacea hypertrophica, acne rosacea, acne rosacea conglobata, synovitis-acne-pustulosis-hyperostosis-osteomyelitis syndrome (SAPHO syndrome), acne rosacea steroid, acne tar, skin cancer, and tropical acne.

[0586] Method of Use

[0587] The present invention provides methods for treating a disease or disorder in a subject, the methods comprising administering to the subject a therapeutically effective amount of a gp130 receptor modulator. In certain embodiments, the present invention provides methods for treating a disease or disorder in a subject, the methods comprising administering to the subject a therapeutically effective amount of a gp130 receptor agonist or an effective amount of a modulator of the gp130 signaling pathway described herein.

[0588] The present invention provides methods for repairing joint surface damage in a subject, the methods comprising administering to the subject a therapeutically effective amount of a binding site 1 gp130 receptor agonist or an effective amount of a modulator of the gp130 signaling pathway described herein.

[0589] Method of use - proliferative disorders

[0590] The present invention provides methods for treating a proliferative disorder in a subject, the methods comprising administering to the subject a therapeutically effective amount of a gp130 receptor modulator. In certain embodiments, the proliferative disorder is cancer. In certain embodiments, the cancer is a cancer that is mediated in part by the gp130 receptor. In certain embodiments, the cancer is a cancer that responds to inhibition of the gp130 receptor.

[0591] In certain embodiments, the cancer is skin cancer. In certain embodiments, the skin cancer is melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, or sebaceous gland carcinoma.

[0592] Merkel cell carcinoma, sebaceous gland carcinoma.

[0593] Method of Use - Cartilage

[0594] The present invention also provides methods for treating a cartilage degenerative disease in a subject in need thereof. The methods comprise administering to the subject a therapeutically effective amount of a binding site 1 gp130 receptor agonist or an effective amount of a modulator described herein. In an embodiment, the disorder is arthritis. In an embodiment, the disorder is osteoarthritis. In an embodiment, the disorder is rheumatoid arthritis.

[0595] The present invention further provides methods for increasing the secretion of cartilage matrix in cartilage, the methods comprising contacting the gp130 receptor with a gp130 receptor agonist or an effective amount of a modulator described herein. In an embodiment, the method for increasing the secretion of cartilage matrix in cartilage comprises contacting the gp130 receptor with a binding site 1 gp130 receptor agonist or an effective amount of a modulator described herein.

[0596] In an embodiment, the cartilage matrix is in articular cartilage. In an embodiment, the cartilage matrix comprises collagen and proteoglycan.

[0597] Method of Use - Modulating the Activity of the gp130 Receptor

[0598] Provided herein are methods of modulating the activity of the gp130 receptor in a cell.

[0599] The method comprises contacting the cell with a binding site 1 gp130 receptor agonist or an effective amount of a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein.

[0600] In an embodiment, the activity of the gp130 receptor is increased. In an embodiment, the activity of the gp130 receptor is decreased or inhibited. In an embodiment, the activity is heterodimerization.

[0601] Also provided herein are methods of converting mature adult cells into progenitor cells, the method comprising contacting the cell with a binding site 1 gp130 receptor agonist or an effective amount of a modulator described herein.

[0602] In an embodiment, the cell is a human cell. In an embodiment, the cell is a chondrocyte. In certain embodiments, the chondrocyte is an adult chondrocyte. In certain embodiments, the binding site 1 cgp130 receptor agonist is a compound described herein, e.g., a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein.

[0603] Provided herein are methods of modulating chondrocyte activation, maturation, and / or differentiation, the method comprising contacting the chondrocyte with a modulator described herein.

[0604] Also provided herein are methods of regenerating or repairing tissue in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a modulator described herein. Preferably, the tissue is cartilage.

[0605] Further provided herein are methods of modulating the expression of COL2 and ACAN in the presence of an IL-6 family cytokine.

[0606] Further provided herein are methods of modulating the expression of MMP13 and ADAMTS4 in the presence of an IL-6 family cytokine.

[0607] The present disclosure further provides methods for modulating the activity of SRC, NF-κB, STAT3, p38, ERK1 / 2, YAP, or MYC, or combinations thereof, in cells.

[0608] In one aspect, the method comprises contacting the cell with a binding site 1 gp130 receptor agonist or an effective amount of a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein.

[0609] The contacting can be carried out in vitro. The contacting can be carried out in vivo.

[0610] The present disclosure provides methods for modulating chondrocyte activation, maturation, and / or differentiation. In certain aspects, the method comprises contacting chondrocytes with a binding site 1 gp130 receptor agonist or an effective amount of a modulator described herein.

[0611] In certain embodiments, the chondrocyte activation comprises an increase in proliferation, migration, metabolism, or any combination thereof.

[0612] The present disclosure also provides methods for treating inflammatory diseases or disorders or cell proliferative diseases and disorders, the method comprising contacting a subject with a compound as described herein and above. In one embodiment, the inflammatory disease or disorder or cell proliferative disease and disorder is selected from the group consisting of: stroke; heart disease; cartilage degeneration; hair loss; wound healing; arthritis; fibrosis; neurodegenerative disorders; aging; diseases known to be associated with low-grade chronic inflammation; immune disorders, including psoriasis, rosacea, lupus, rheumatoid arthritis, inflammatory bowel disease; cytokine release syndrome; and cancer.

[0613] In certain embodiments, the present disclosure provides methods for modulating inflammation and / or the production or induction of inflammatory cytokines, the method comprising contacting a cell or a subject with a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein. In certain embodiments, the cell is a chondrocyte.

[0614] The present disclosure also provides methods for modulating IL-6-mediated inflammatory responses in cells, the method comprising contacting the cell with a compound as described herein and above. In one embodiment, the cell is a chondrocyte.

[0615] The present disclosure also provides a composition comprising a pharmaceutically acceptable carrier and a compound of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein and above.

[0616] The present disclosure also provides a method of treating an acute or chronic inflammatory condition, the method comprising contacting a subject with a compound or a medicament of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein and above.

[0617] The present disclosure also provides a method of reducing an activated inflammatory pathway in a cell, the method comprising contacting the cell with a compound or a medicament of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein and above.

[0618] The present disclosure provides a method of inhibiting the production or induction of a pro-inflammatory gene, cytokine, or mediator, the method comprising contacting a cell or a subject with a compound or a medicament of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein and above.

[0619] The present disclosure provides a method of inhibiting the production or induction of an extracellular matrix degrading enzyme, the method comprising contacting a cell or a subject with a compound or a medicament of formula (I), (X-I), (X-I-A), (X-I-B), (II), (III), (IV), (V), (V-a-j), (VI), (VIa-f), (VII), or (VIII) described herein and above.

[0620] The present disclosure also provides a method of treating an acute or chronic inflammatory condition, the method comprising contacting a subject with a compound of formula (I).

[0621] The present disclosure further provides a method of reducing an activated inflammatory pathway in a cell, the method comprising contacting the cell with a compound of formula (I).

[0622] The present disclosure provides methods for inhibiting the production or induction of pro-inflammatory genes, cytokines or mediators, the methods comprising contacting a cell or a subject with a compound of formula (I).

[0623] The present disclosure also provides methods for treating skin disorders, the methods comprising contacting a subject with a modulator described herein and above. In one embodiment

[0624] In certain embodiments, the subject is a human patient who would benefit from an improvement in skin health, a promotion of the skin self-renewal process and protection of the skin from oxidative damage.

[0625] In certain embodiments, methods for treating a subject suffering from a skin disorder are provided. The methods can comprise providing a cell of any of the embodiments described herein or a topical formulation of any of the embodiments described herein, and applying the topical formulation to the subject, wherein the topical formulation is applied to the skin.

[0626] In certain embodiments, the skin disorder is selected from the group consisting of: psoriasis, skin cancer, acne, alopecia, carbuncle, dermatitis, eczema, atopic dermatitis, contact dermatitis, seborrheic dermatitis, cradle cap, perioral dermatitis, herpes zoster, tinea, melisma, vitiligo and impetigo.

[0627] In certain embodiments, the skin disorder results from an autoimmune or inflammatory disorder.

[0628] In certain embodiments, the autoimmune or inflammatory disorder is alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa acquisita, erythema nodosum, pemphigoid gestationis, hidradenitis suppurativa, lichen planus, lichen sclerosus, linear IgA disease, morphea, pemphigus vulgaris, pityriasis lichenoides et varioliformis acuta, Sweet's disease, psoriasis, systemic sclerosis, or vitiligo. In certain embodiments, skin diseases and skin disorders can include summer acne (Mallorca acne), acne conglobata, cosmetic acne (cosmetica acne), acne fulminans (acute febrile ulcerative acne), acne keloidalis nuchae (keloid acne, papular dermatitis of the nape, keloid folliculitis, keloid folliculitis of the nape, keloid acne of the nape), adult forehead with scattered red papules, acne vulgaris, mechanical acne, drug-induced acne, acne necrotica miliaris (acne varioliformis), acne vulgaris, acne with facial edema (solid facial edema), chalazion, erythematotelangiectatic rosacea (erythematovascular rosacea, vascular erythematous rosacea), exfoliative acne (juvenile artificial acne, juvenile factitial acne), glandular erythematous acne, gnathophyma, gram-negative folliculitis, granulomatous facial dermatitis, adult male with large, red, bulbous nose, hypertrophic rosacea, granulomatous perioral dermatitis, halogen acne, hidradenitis suppurativa (acne inversa, pyoderma fistulans, Verneuil's disease), idiopathic facial aseptic granuloma, infantile acne, lupus erythematosus-like rosacea (granulomatous erythematous acne, micropapular tuberculid, Lewandowsky's rosacea-like tuberculid), miliary lupus erythematosus disseminatus faciei, metophyma, neonatal acne (infantile acne, neonatal acne, neonatal cephalic pustulosis), occupational acne, oily acne, ophthalmic rosacea (ophthalmic erythematous rosacea, ocular erythematous rosacea), otophyma, perioral dermatitis, persistent erythematous rosacea edema (chronic upper facial erythema edema, Morbihan's disease, erythematous lymphangiectasis), proliferative rosacea, pomade acne, papulopustular erythematous rosacea (inflammatory erythematous rosacea), perifolliculitis capitis abscedens et suffodiens (scalp dissecting cellulitis, dissecting folliculitis, Hoffman's perifolliculitis capitis abscedens et suffodiens), perioral dermatitis, periorbital dermatitis (periocular dermatitis), facial pyoderma (fulminant erythematous rosacea), hypertrophic rosacea, rosacea, rosacea conglobata, synovitis-acne-pustulosis-hyperostosis-osteomyelitis syndrome (SAPHO syndrome), steroid rosacea, tar acne, skin cancer, and tropical acne.

[0629] Also provided herein are methods of treating or improving inflammatory aging.

[0630] In one aspect, the method of treating or ameliorating inflammaging comprises contacting a subject's cells with an effective amount of a modulator described herein.

[0631] In certain embodiments, the subject has inflammaging in one or more skin regions or is at risk of developing inflammaging in one or more skin regions.

[0632] In certain embodiments, the inflammation is on the skin, scalp, nasal cavity, oral cavity, nail region (such as the stratum corneum), eye, vaginal region, or perineal region.

[0633] In one embodiment, a modulator of the gp130 signaling pathway described herein can be used to promote skin health and reduce the effects of aging in a subject in need of treatment.

[0634] In one embodiment, a modulator of the gp130 signaling pathway described herein can be used to promote hair growth in a subject in need of treatment.

[0635] In one embodiment, a modulator of the gp130 signaling pathway described herein can be used to treat or ameliorate muscular dystrophy.

[0636] The present invention further provides a method for treating or ameliorating a pain disorder in a subject in need thereof, wherein the pain disorder is selected from the group consisting of neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, musculoskeletal pain, craniofacial pain, other somatic forms of pain, and referred pain.

[0637] In certain embodiments, the inflammatory pain is selected from pain associated with an inflammatory disorder, the inflammatory disorder being selected from the group consisting of: arthritis disorders; autoimmune diseases; connective tissue disorders; injury; infection; neuritis; and joint inflammation.

[0638] In certain embodiments, the somatic pain is selected from the group consisting of excessive muscle tension; repetitive motion disorders; muscle disorders; myalgia; infection; and drugs.

[0639] The method comprises administering to the subject a therapeutically effective amount of a binding site 1 gp130 receptor agonist or an effective amount of a modulator described herein.

[0640] In another aspect, the present invention provides a method for treating or ameliorating a disorder of a plurality of syndromes including those selected from septic shock and cytokine storm.

[0641] IL-6 / gp130 axis

[0642] The pathogenesis of osteoarthritis (OA) typically begins with damage to articular cartilage, which forms a chronic low-grade inflammation mediated by interleukin-6 / glycoprotein 130 (IL-6 / gp130) and other factors that, over time, promote matrix degradation and ultimately lead to cartilage destruction. IL-6 signaling through IL-6R / gp130 inhibits chondrocyte proliferation, promotes mineralization in articular cartilage, downregulates matrix proteins, and increases the expression of matrix-degrading proteases. In addition, in vivo blockade of IL-6 in OA mouse models has been shown to have a chondroprotective effect. Importantly, higher serum levels of IL-6 have been associated with the development of OA in humans, and monoclonal antibodies against IL-6R are currently in phase III clinical trials for the treatment of hand OA (NCT02477059).

[0643] Signaling downstream of IL-6 / gp130 is mediated by multiple pathways, including signal transducer and activator of transcription 3 (STAT3). STAT3 has been shown to have pleiotropic effects during chondrogenesis and in articular chondrocytes. During the chondrogenic differentiation of multipotent mesenchymal stem cells, IL-6 / STAT3 signaling promotes chondrocyte specification and matrix production. Similarly, deletion of STAT3 during limb formation results in increased hypertrophy, premature ossification, and reduced expression of SOX9, a master regulator of chondrocyte identity. Conversely, inhibition of STAT3 downstream of IL-6 in adult articular chondrocytes has a chondroprotective effect, reducing the severity of OA-like pathology in mouse models. Collectively, these data suggest that IL-6 / STAT3 signaling can drive matrix loss and the development of OA in mouse models and humans.

[0644] Recent studies have shown that bone morphogenetic protein receptor IB (BMPR1B) marks superficial chondrocytes in human ontogeny and in rodent joints. As described herein, these cells can also be identified by their high levels of expression and activity of the IL-6 coreceptor gp130. Based on the known role of IL-6 / gp130 signaling in hypertrophy and OA pathogenesis, a small molecule screen was performed to identify potential agents that manipulate gp130 signaling. These studies revealed regulator of cartilage growth and differentiation 423 (RCGD 423), a small molecule modulator of gp130 (see, e.g., PCT / US2016 / 020126, which is incorporated herein by reference for all purposes).

[0645] In vitro studies confirmed that RCGD 423 signals through gp130 and interacts with the extracellular region of gp130.

[0646] Further elucidation of the mechanism of RCGD 423 confirmed that it promotes the formation of active, ligand-independent gp130 homodimers, thereby distinguishing its activity from that of IL-6 family cytokines; this is reflected in key differences in the downstream molecular events stimulated by IL-6 family cytokines and RCGD 423. In addition, RCGD 423 actively competes with signal transduction by pro-inflammatory IL-6 family cytokines by blocking the formation of gp130 heterodimers with IL-6R. Finally, in a rat model of OA, the molecule exhibited a significant ability to prevent cartilage degradation.

[0647] Approximate analogs of RCGD 423 have been shown to stimulate the hair cycle in mice through stabilization of the MYC protein, thus validating the mechanism of action of the compound in a completely independent system. However, despite these positive results, increases in pSTAT3 and MYC levels may be harmful in the context of clinical OA pathology, based on potential pro-degenerative and carcinogenic concerns, respectively.

[0648] RCGD 423 provides information on a specific regulatory pocket / cleft in gp130. Using this information, modeling and basic research will lead to the identification of other small molecules that interact with the gp130 pocket / cleft. For example, one such molecule, CX-011 (also referred to herein as "B8") and related analogs have been shown to be effective inhibitors of catabolic signaling mediated by IL-6 family cytokines and do not affect the levels of pSTAT3 or MYC proteins (see, for example, PCT / US2019 / 020058, which is incorporated herein by reference for all purposes).

[0649] It is predicted that CX-011 will bind gp130 in the same binding pocket as RCGD 423 and is hypothesized to stabilize the inactive conformation. In vitro results suggest that small molecule inhibitors of pro-inflammatory, catabolic signaling mediated by IL-6 family cytokines through gp130 are of great clinical importance. Although a biologic agent targeting IL-6R is currently being tested as a therapeutic agent for OA, this therapy will not block the actions of oncostatin M (OSM) and LIF, two other IL-6 family members that have catabolic consequences for articular cartilage. Thus, small molecule gp130 inhibitors such as CX-011 and its analogs can be used for post-traumatic OA and have a different mode of action. It is speculated that broad modulation of IL-6 family cytokine signaling will interrupt the pro-inflammatory, catabolic environment that exists after injury.

[0650] Nonetheless, the physicochemical properties (e.g., solubility, potency, functional groups) and metabolically labile sites ("hot spots") of RCGD 423, CX-01, and their derivatives still need to be improved to ensure successful clinical outcomes. A significant improvement in these properties may result in a first-in-class drug for the treatment of post-traumatic OA. Accordingly, the present disclosure provides small molecule modulators of the gp130 signaling pathway with improved properties. Specifically, these compounds can be used to treat or improve inflammatory disorders or conditions, neoplasms, and cell proliferative disorders.

[0651] Examples

[0652] The present disclosure is described in further detail by reference to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise indicated. Accordingly, the present disclosure should in no way be construed as limited to the following examples, but rather should be construed to cover any and all variations that become apparent from the teachings provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the foregoing description and the following exemplary examples, make and utilize the compounds of the present invention and practice the methods claimed in the claims. The following working examples specifically point out various aspects of the present invention and should not be construed as limiting the remainder of the present disclosure in any way.

[0653] Example 1: Creation of a library of small molecule gp130 signaling pathway modulators with improved properties

[0654] A library of structural variants based on the RCGD 423 and CX-011 (B805) scaffolds was generated, and they have improved physical properties. The compounds of formula (I) were found to have different molecular features that modulate different gp130 signaling pathways.

[0655] The compounds of formula (I) or (X-I) include, but are not limited to, the compounds shown in Tables 1 to 2. The compounds of formula (I) or (X-I) can be synthesized by suitable synthetic methods known in the art. The synthetic methods can follow any organic synthetic pathway or biocatalytic pathway.

[0656] Example 2: Selection of gp130 signaling pathway modulators

[0657] The gp130 co-receptor LIFR is expressed on subsets of superficial chondrocytes during human ontogeny. Based on these data, it was hypothesized that gp130 would also be expressed on these cells, and indeed it was. Given the known effects (and mostly detrimental effects) of IL-6 family cytokines on articular chondrocytes, a high-throughput screen was performed to identify small molecules that could modulate gp130 signaling. In adult mice, IL-6 / gp130 signaling drives Col10a1 expression and hypertrophy, which has been strongly associated with OA progression; thus, compounds were screened for their ability to prevent the increase in Col10-mCherry fluorescence in mouse limb mesenchymal cells stimulated with BMP-4 (a strong driver of hypertrophy). After secondary screening, certain compounds were found to prevent the increase in alkaline phosphatase (a marker of hypertrophy) in fetal articular chondrocytes.

[0658] Based on these data, three classes of compounds were identified:

[0659] Class 1: Pro-regenerative, anti-inflammatory. Inhibits the activation of p38, ERK1 / 2, and NF-kB by OSM, as well as gp130 phosphorylation. At the same time, antagonizes the activation of YAP by LIF while allowing the activation of STAT3 by LIF. It potently inhibits the expression of MMP13 and ADAMTS4 induced by OSM.

[0660] Class 2: Primarily pro-regenerative. Mildly inhibits the activation of p38 by OSM, has little or no effect on ERK1 / 2 and NF-kB, and gp130 phosphorylation. At the same time, strongly antagonizes the activation of YAP by LIF. In the presence of OSM, it increases the expression of COL2 and ACAN while inhibiting the expression of MMP13 induced by OSM, but does not inhibit the expression of ADAMTS4.

[0661] Class 3: Primarily anti-inflammatory. Potently inhibits the activation of p38, ERK1 / 2, and gp13 by OSM, with relatively low NF-kB. At the same time, inhibits the activation of YAP and STAT3 by LIF. It inhibits the expression of MMP13 and ADAMTS4 induced by OSM.

[0662] The mRNA expression of COL2, ACAN, MMP13, and ADAMTS4 was evaluated using PCR.

[0663] These data identify distinct molecular signatures that affect the gp130 signaling pathway. This supports the use of the modulators of the present invention for the treatment or amelioration of a variety of diseases, conditions, or disorders associated with gp130 signaling.

[0664] Example 3: Preparation method of formulated compounds

[0665] The compounds disclosed herein are formulated according to cGMP requirements as follows.

[0666] · Weighing procedure: Wipe the lid of the bucket and / or the bag to avoid contamination by dust and debris. All ingredients are weighed and measured and checked into separate, clean, properly labeled, appropriately sized tare containers.

[0667] · Mixing procedure: All equipment is cleaned and disinfected, and all product-contact tools are likewise so before use. All components are completely dry. Then the materials are staged to the main mixing area.

[0668] In Phase A, the first mixture is produced as follows. Item #1 according to Table 2 is added to the main processing tank equipped with a propeller mixer and side sweepers, and medium-speed mixing is started. Then items #2 to #6 are added in the given order, and mixed well after each addition. The first mixture is mixed until completely homogeneous.

[0669] In Phase B, in a separate container, items #7 and #8 are premixed. Once item #8 has dissolved, the premix is slowly added to the first container processing tank and mixed until completely homogeneous.

[0670] In Phase C, item #9 is added to a separate container and medium-speed mixing is started. Items #10 to #18 are added to the Phase 3 container in the given order and mixed after each addition. The formulation is mixed until homogeneous. Once homogeneous, the contents of the Phase C container are slowly added to the main processing tank and mixed until completely homogeneous.

[0671] In Phase D, using a clean container, sufficient samples and complete batch records are taken to the laboratory for testing and approval.

[0672] Table 2. Master formulation

[0673]

[0674]

[0675]

[0676] Example 4: Clinical evaluation of a cosmetic skin care preparation - Patient selection

[0677] A single-center clinical trial was conducted to evaluate the efficacy of the compounds and formulations disclosed herein in women and men with mild to moderate facial photoaging when used for 8 weeks. The study evaluated any statistically significant improvement in the efficacy parameter clinical grading score compared to the baseline score during the 8-week use. In skin samples collected from the subgroup, changes in any biomarkers related to photoaging were recorded.

[0678] 1. Study Endpoints and Patient Randomization

[0679] The study endpoints are as follows:

[0680] · Clinical grading of potency parameters at baseline, and at weeks 4 and 8.

[0681] · VISIA imaging procedures at baseline and week 8.

[0682] · Antera imaging procedures at baseline, and at weeks 4 and 8, and image analysis of mean roughness (Ra), mean melanin level, and wrinkles (indentation index and maximum depth) using images from baseline, and at weeks 4 and 8 at the end of the study. · For a subgroup of at least 3 subjects, 2-mm biopsies are taken (1 at baseline and 1 at week 8; 2 in total per subject) and sent to the sponsor for histological evaluation.

[0683] · Monitoring of adverse events (AEs) during the study

[0684] 2. Monitoring of Adverse Events (AEs) During the Study

[0685] Subjects are consecutively numbered in the order of their eligibility to participate in the study. All subjects use the test materials as instructed. Randomization is generated to determine the location of all Antera imaging (cheek and crow's feet) to the right or left side of the face.

[0686] 3. Number of Subjects

[0687] It is expected that at least 25 eligible subjects will complete participation in the clinical trial, with at least 3 subjects in the biopsy subgroup.

[0688] Eligibility Criteria: Inclusion Criteria

[0689] Individuals meeting all of the following criteria are eligible to participate in the study. Such individuals are:

[0690] · Female or male, aged 30 to 65 years.

[0691] · According to self-report of the subject, in good general health (physical, mental, and social health, and not just the absence of disease / infirmity).

[0692] · Having Fitzpatrick skin type I-V.

[0693] Fitzpatrick skin classification is based on the unprotected response of the skin to the first 30 to 45 minutes of sunlight exposure after no sunlight exposure in winter. The classification of skin types is shown in Table 3.

[0694] Table 3. Skin Type Classification

[0695]

[0696] · Have mild to moderate (scored 3 - 6 according to the modified Griffiths scale, where 0 = none and 9 = severe) photodamage across the entire face.

[0697] · Have used a sunscreen with SPF ≥ 30 for at least 30 days without any incident before the start of the study and be willing to continue using the sunscreen during the study.

[0698] · Be willing to provide written informed consent and be able to read, speak, write, and understand English.

[0699] · Be willing to sign a photography authorization form.

[0700] · Have not had any facial treatments in the past 6 months and be willing to discontinue all facial treatments during the study, including facial massage, facial peel, intense pulsed light, laser treatment, dermabrasion, botulinum toxin injection - filling treatment, intense pulsed light (IPL), acid treatment, tightening treatment, facial plastic surgery, or any other treatment administered by a physician or skin - care professional aimed at improving the appearance or firmness of the facial skin. Waxing and threading for hair removal are allowed, but facial laser hair removal is not allowed.

[0701] · Men who shave regularly (at least 3 times a week). Subjects are allowed to have a mustache or goatee as long as most of the facial hair is shaved off.

[0702] · Be willing to cooperate and participate in the study during the study period, comply with the study requirements (including those outlined in Example 3), and immediately report any changes in health status or symptoms or reactions to medications, AEs. The following additional inclusion criteria apply only to potential subjects in the biopsy subgroup who meet the following conditions:

[0703] · Be willing to undergo two 2 - mm punch biopsies on the face.

[0704] · Be willing to have blood drawn for screening for blood - borne pathogens, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV).

[0705] Eligibility Criteria: Exclusion Criteria

[0706] Individuals meeting any of the following criteria are not eligible to participate in the study, including such individuals:

[0707] · Have been diagnosed with a known allergy to facial skin - care products;

[0708] · Breastfeeding, pregnant, or planning to become pregnant during the study period, as reported by the subject;

[0709] · History of skin cancer within the past 5 years;

[0710] · Currently using or having used any of the following medications within the specified time frame before the start of the study:

[0711] 1. Oral isotretinoin within 6 months before the start of the study

[0712] 2. Retin-A within 3 months before the start of the study or

[0713] 3. Prescription-strength skin lightening products within 3 months before the start of the study (e.g., hydroquinone, retinoids, alpha / beta / polyhydroxy acids, 4-methoxyphenol, etc., used alone or in combination with retinoids);

[0714] 4. Any anti-wrinkle products, skin lightening products, or other products or topical or systemic medications known to affect skin aging or skin discoloration within 2 weeks before the start of the study (e.g., containing alpha / beta / polyhydroxy acids, emblica extract, Gigawhite TM [, hydroquinone, lemon juice extract [topical], Q-10, soy, whole or licorice extract [topical], Cosmo C250, products with vitamin C);

[0715] · Having health problems and / or pre-existing or latent skin diseases on the face (e.g., psoriasis, rosacea, acne [severe acne, conglobata acne, nodules or cysts], eczema, seborrheic dermatitis, severe epidermal exfoliation), which are considered by the researcher or designee as not suitable for participation or may interfere with the study results;

[0716] · Having observable sunburn, sun tan, scar, mole, hirsutism, tattoo, or other skin conditions at the test site, which are considered by the researcher or designee as possibly affecting the test results;

[0717] · History of immunosuppression / immunodeficiency disorders (including HIV infection, AIDS, multiple sclerosis, Crohn's disease, rheumatoid arthritis), organ transplantation (heart, kidney, etc.), or currently using oral or systemic immunosuppressive medications and biologics (e.g., azathioprine, belimumab, cyclophosphamide, cyclosporine, mycophenolate mofetil, methotrexate, Prednisone, Siliq TM , ) and / or are receiving radiation or chemotherapy;

[0718] · Currently using or have regularly used corticosteroids (systemic or topical, non-nasal or ocular) (including but not limited to betamethasone, clobetasol, desoximetasone, diflorasone, fluocinonide, fluticasone, mometasone, halcinonide, and halobetasol) within the past 4 weeks;

[0719] · Have a condition such as asthma, diabetes, epilepsy, hypertension, hyperthyroidism, or hypothyroidism that cannot be controlled by diet or medication. Individuals with multiple health conditions may also be excluded from participation, even if the conditions are controlled by diet, medication, etc.;

[0720] · Have started long-term medication within 2 months before the start of the study;

[0721] · Have any planned surgery or invasive medical procedure during the course of the study. The investigator or designee will review the impact of non-invasive medical procedures or surgery on the study results and acceptability;

[0722] · Are currently participating in any other clinical trial at the same clinical site, other research institution, or physician's office;

[0723] · Have participated in any clinical trial involving the trial area at the same clinical site, other research institution, or physician's office within 2 weeks before inclusion in the study.

[0724] · Have started hormone replacement therapy (HRT) or contraceptive hormones less than 3 months before the start of the study, or plan to start, stop, or change the dose of HRT or contraceptive hormones during the study; or

[0725] · Have started prescription testosterone therapy less than 3 months before the start of the study, or plan to start, stop, or change the dose of testosterone therapy (e.g., testosterone cypionate, testosterone enanthate, testosterone undecanoate, and testosterone pellets) during the study, or use testosterone boosters or prescription testosterone (e.g., DHEA, tribulus, testosterone cypionate, testosterone enanthate, Sustanon (testosterone blend), testosterone propionate, testosterone phenylpropionate, or Omnadren).

[0726] The following additional exclusions apply only to potential subjects in the biopsy subgroup who:

[0727] · A medical history of allergy, hypersensitivity, or any severe reaction to topical antibiotics or antiseptics, or topical anesthesia, and having received any treatment that may affect blood coagulation and hemostasis (anticoagulant medications, including Coumadin, Heparin, Plavix, long-term use of NSAIDs, etc.).

[0728] · A history of developing abnormal pigmentation responses (skin color changes) such as hyperpigmentation or hypopigmentation resulting from medical procedures such as surgical incisions and skin biopsies, or a history of healing defects such as hypertrophy or keloids;

[0729] · Currently using or frequently using anti-inflammatory medications to treat specific medical conditions. Low-dose aspirin (≤81 mg / day) is acceptable;

[0730] · A history of systemic granulomatous disease (active or inactive) (e.g., sarcoidosis, Wegener's granulomatosis, or tuberculosis) or connective tissue disease (e.g., lupus or dermatomyositis); or

[0731] · Having been diagnosed with hepatitis or acute or chronic renal insufficiency.

[0732] Example 5: Clinical evaluation of a skin care preparation - Treatment protocol

[0733] Assign each subject a 3-digit number that, when combined with the clinical study number, can uniquely identify each subject in the study. This number shall accompany the subject throughout the study and shall be used in all references to an individual in this study. Once the study has started, the number will not be re-assigned.

[0734] Subjects shall follow the following instructions during the study:

[0735] The pre-study instructions are to avoid using facial moisturizers for at least 7 days prior to Visit 1 and to avoid using any facial anti-wrinkle products, skin whitening products, or other products or topical medications or treatments known to affect skin aging or skin discoloration for at least 14 days prior to Visit 1.

[0736] Instructions for using the test material include the following: Apply the test material 2 times each morning and evening before applying sunscreen; use a quarter-sized amount each time so that there is a complete layer on the skin; cover the entire face, including under and around the eyes (avoiding the upper eyelids), around the mouth, along the jawline, and near the ears; and wait 15 minutes before applying any other products on top of the essence.

[0737] Instructions for the subjects attending the study visits include the following: Use the test material as scheduled on the evening before each clinical visit after baseline. If the appointment is in the morning (before noon), apply the test material in the morning and clean the face at least 30 minutes before the on-site visit; Wash the face and / or remove all cosmetics at least 30 minutes before each scheduled clinic visit. Do not apply other topical products to the face or eye area until the study visit is completed. If the makeup has not been removed before coming to the study site, it needs to be removed at the clinic, and there is a 20-minute waiting period before the test procedure.

[0738] General study instructions include the following: During the study, the subjects use their sunscreen with SPF≥30 every day. During the study, avoid prolonged sun exposure and use all sun beds and sunless tanning products. Take extra care, wear protective clothing and sunglasses, and avoid sun exposure between 10 am and 3 pm; Use the designated test material as instructed; The subjects continue to use all regular brands of makeup and makeup removers and use the designated test material during the study. The subjects stop using any anti-aging products and do not start using any new facial products other than the designated test material.

[0739] Efficacy is evaluated by clinical grading at baseline and at 4 weeks and 8 weeks. VISIA imaging is performed at baseline and 8 weeks. Antera digital imaging is performed at baseline and at 4 weeks and 8 weeks, and image analysis is performed on the images at all time points at the end of the study. A subgroup of subjects had 2-mm punch biopsies performed between the outer canthus and the hairline (1 time at baseline and 1 time at 8 weeks; a total of 2 times for each biopsy subject). Table 4 shows an overview of the procedure.

[0740] Table 4: Overview of the clinical procedures

[0741]

[0742] Regarding the test material and / or daily diary: D = Dispense, C = Collect, R = Review, W = Weigh, and I = Inspect (visually).

[0743] a A subgroup of subjects who will participate in the biopsy procedure attend the screening visit.

[0744] b After the study is completed, image analysis of the Antera images at baseline and at 4 weeks and 8 weeks is performed for roughness, mean melanin, and wrinkles.

[0745] Once at each specified time point, a 2-mm punch biopsy was performed on each subject in a subgroup of subjects (at least 3) who tested negative for BBP, and the samples were sent to the sponsor for histological evaluation after the study was completed.

[0746] Screening of potential biopsy subjects: Visit 1

[0747] Before participating in any study procedures, each potential subject will be given an IRB-approved informed consent form (ICF) that complies with the requirements of Title 21 of the Federal Administrative Code (CFR) 50.25. Potential subjects will be given sufficient time to read the ICF and will have the opportunity to have all of their study-related questions satisfactorily answered before signing the ICF. If there are additional questions, potential subjects will be given sufficient time during the first visit to have the study personnel, sub-investigators, or study coordinators answer questions about the study and / or the ICF before signing. The original signed ICF for each subject participating in the study is retained in the study files, and each subject will receive a copy of the signed ICF. Without a signed ICF, potential subjects will not be eligible to participate in the study.

[0748] Potential biopsy subjects will receive an IRB-approved ICF for reading and signing. The study personnel or designated staff will answer all of their study-related questions, and if they agree, they will sign the ICF. They will receive a copy of the signed ICF, and the original signed ICF will be retained in the study files.

[0749] Candidate subjects who sign the ICF will be assigned a screening number and acclimated to the environmental temperature and humidity conditions for at least 15 minutes.

[0750] Candidate subjects are to complete a qualification and health questionnaire, and the qualification criteria are screened by the study personnel or designated personnel.

[0751] Blood samples are drawn from candidate subjects (at least 3) who may undergo a biopsy to screen for blood-borne pathogens, including HIV, HBV, and HCV.

[0752] Baseline of potential biopsy subjects: Visit 2

[0753] The clinician records the concomitant medications and asks the candidate subject if there have been any changes in their health status since the last visit. If an AE is reported, the study personnel will be notified and an AE form will be completed.

[0754] Candidate subjects who meet the criteria for biopsy sample collection have negative BBP results, including HIV, HBV, and HCV. Eligible subjects are enrolled in the study and assigned subject numbers.

[0755] The biopsy subject is acclimated to the environmental temperature and humidity conditions for at least 15 minutes. The applicable room is maintained at a temperature of 68° - 75°F and the relative humidity is maintained in the range of 35% - 65%. After acclimation, the candidate subject participates in the following procedures: clinical grading of potency parameters; imaging procedures and Antera imaging procedures. For eligible subjects, a biopsy will be performed.

[0756] Each subject is provided with a pre-weighed unit of test material and support materials, as well as oral and written instructions for use. The subject is provided with a daily diary to record test material application and comments.

[0757] Baseline, Visit 2: Non-biopsy subjects

[0758] Potential subjects who sign the ICF are assigned a screening number and acclimated to the environmental temperature and humidity conditions for at least 15 minutes. The applicable room is maintained at a temperature of 68° - 75°F and the relative humidity is in the range of 35% - 65%.

[0759] Potential subjects complete an eligibility and health questionnaire and are screened for eligibility criteria by the researcher or designated personnel.

[0760] All potency parameters are graded for candidate subjects. Subjects meeting the eligibility requirements are enrolled in the study and assigned a subject number. Subjects participate in the VISIA imaging procedures and Antera imaging procedures. Each subject is provided with a pre-weighed unit of test material and support materials, as well as oral and written instructions for use.

[0761] Subject mid-visit: Visit 3 (Week 4 ± 3 days):

[0762] The clinician records concomitant medications and asks the candidate subject if there have been any changes in their health status since the last visit. If an AE is reported, the researcher will be notified and an AE form will be completed. The daily diaries are collected and reviewed and compliance is reviewed. Non-compliant subjects will be informed that if they continue to be non-compliant, they will be withdrawn from the study. The diaries are retained by the trial site and new diaries are distributed to the subjects. A visual inspection and weighing of the test material units is performed to verify use compliance. The test material units are returned to the subject.

[0763] The subject is acclimated to the environmental temperature and humidity conditions for at least 15 minutes. The applicable room is maintained at a temperature of 68° - 75°F and the relative humidity is in the range of 35% - 65%. After acclimation, the subject participates in the clinical grading of potency parameters and Antera imaging procedures.

[0764] Final study visit: Visit 4 (Week 8 ± 3 days)

[0765] The clinician records concomitant medications and asks the candidate subject if there have been any changes in their health status since the last visit. If an AE is reported, the investigator is notified and an AE form is completed. Refer to the reporting procedures based on the AE section below.

[0766] The trial site collects daily diaries, reviews compliance, and retains the diaries. Subjects with non-compliance may be withdrawn from the study. Visual inspection and weighing of the trial material units are performed to verify use compliance. The trial material units are retained by the trial site. Then, the subject acclimates to the environmental temperature and humidity conditions for at least 15 minutes. The applicable room is maintained at a temperature of 68° - 75°F and the relative humidity is in the range of 35% - 65%. After acclimation, the subject participates in the following procedures: clinical grading of efficacy parameters, imaging procedures and Antera imaging procedures. Subjects in the biopsy subgroup have biopsies collected.

[0767] Example 6: Clinical grading of potency parameters

[0768] Clinical grading of efficacy parameters is performed at baseline and at Weeks 4 and 8. The overall facial efficacy parameters of each subject are evaluated using the modified Griffiths 10 - point scale (Griffiths CE, Wang TS, Hamilton TA, Voorhees JJ, Ellis CN. A photonumeric scale for the assessment of cutaneous photodamage. Arch Dermatol. 1992;128(3):347 - 351) according to the following numerical definitions (half - point scores may be used when necessary to more accurately describe the skin condition):

[0769] · 0 = None (best possible condition)

[0770] · 1 to 3 = Mild

[0771] · 4 to 6 = Moderate

[0772] · 7 to 9 = Severe (worst possible condition)

[0773] The following parameters are evaluated using the scale anchors shown in Table 5.

[0774] Table 5: Scale anchors for evaluating images using the Griffiths 10 - point scale

[0775]

[0776] 1. Digital imaging procedure

[0777] Before the imaging procedure, the clinical staff ensures that the subject's face is clean and free of makeup, as described in the study protocol. The subject removes all jewelry from the area to be photographed and acclimates to the environmental conditions within the clinic for at least 15 minutes prior to any photography. A black or gray matte headband is provided to the subject to keep the hair away from the face, and a black or gray matte cloth is placed over the subject's clothing.

[0778] The subject is asked to maintain a neutral, non-smiling expression, gently close their eyes, and be carefully positioned for each photograph.

[0779] 2. Imaging procedure

[0780] The VISIA imaging procedure is performed at baseline and week 8. A total of 3 full-face digital images (left, middle, and right views) of each subject's face are taken using a VISIA CR photographic station (Canfield Imaging Systems, Fairfield, New Jersey) and a Canon Mark II digital SLR camera (Canon Incorporated, Tokyo, Japan) under the following lighting conditions:

[0781] · Standard illumination 1: Visible (bright)

[0782] · Standard illumination 2: Visible standard illumination 3

[0783] · Cross-polarized parallel polarization

[0784] 3D imaging procedure

[0785] The Antera 3D imaging procedure is performed at baseline and weeks 4 and 8 in the cheek and crow's feet regions (either the left or right side of the face is selected according to the randomization procedure generated by Stephens). A total of 2 images are taken of each subject at each time point. Each image is labeled with the study number, subject number, and site code.

[0786] Photography is performed using Antera 3D imaging (Miravex Limited, Dublin, Ireland). Antera 3D relies on multi-directional illumination and computer-aided skin surface reconstruction, illuminating the surface using light-emitting diodes (LEDs) of different wavelengths that shine from different angles, and reconstructing the surface in three dimensions using the differences between these images. The field of view is 56 x 56 mm, the lateral resolution is 0.1 mm, and the vertical resolution is 0.01 mm.

[0787] Evaluate the images according to the selected parameters, where the data of 30 patients show the average change in the clinical grading scores of the specified parameters at week 4 and week 8.

[0788] 3. Biopsy procedure (only for subgroup)

[0789] At baseline and week 8, a subgroup of subjects (at least 3) participated in the biopsy procedure after all other procedures. Each selected subject underwent a 2-mm punch biopsy between the lateral canthus and the hairline on one side of the face at baseline, where Antera 3D imaging was performed. At week 8, a biopsy was performed between the lateral canthus and the hairline on the other side of the face.

[0790] After local anesthesia in the dermis, the biopsy was obtained using standard aseptic techniques and could be treated with topical antibiotics and sterile dressings in a conventional manner. The test site could be marked with surgical markers for reference.

[0791] The biopsy samples were immediately transferred into 10% formalin solution and stored at room temperature for 12 - 16 hours, rinsed with tap water, and stored and transported in 70% ethanol. The collected biopsy samples were sent to the sponsor for histological evaluation by FedEx with the following name and address. The biopsy sample list contains the subject number, product information, total number of collected biopsy samples, and any other relevant information required to identify the samples after analysis.

[0792] Example 7: Synthesis of compounds

[0793] Preparation of N-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-ethyl-1H-pyrazole-3-carboxamide (Compound 7)

[0794]

[0795] To a solution of 5-cyclopropyl-1,3,4-oxadiazol-2-amine 1a (100 mg, 0.80 mmol) and 1-ethylpyrazole-3-carboxylic acid (123 mg, 0.88 mmol) in ACN (10 mL) was added TCFH (336 mg, 1.20 mmol) and NMI (197 mg, 2.40 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated and purified on a Biotage IsoleraOne (C 18 column, eluted with 5% to 95% MeCN / H2O containing 0.1% formic acid) and by preparative HPLC (column: Gemini 5um C 18150 * 21.2 mm, mobile phase: MeCN / H2O containing 0.1% formic acid, gradient: 5% to 50%) was purified to obtain N-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-ethyl-1H-pyrazole-3-carboxamide (Compound 7) as an off-white solid (41.40 mg, 99% purity, 20.75% yield). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 11.34 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H), 2.28 - 2.07 (m, 1H), 1.43 (t, J = 7.6 Hz, 3H), 1.16 - 0.92 (m, 4H). C 11 H 14 N5O2[M + H] + The calculated value of LCMS (ESI) for m / z is 248.26, and the measured value is 248.05

[0796] Preparation of 1-methyl-N-(thiazolo[5,4-b]pyridin-2-yl)-1H-pyrazole-3-carboxamide (Compound 2)

[0797]

[0798] To a solution of thiazolo[5,4-b]pyridin-2-amine 1 (200 mg, 1.32 mmol) and 1-methylpyrazole-3-carboxylic acid (184 mg, 1.46 mmol) in ACN (10 mL) was added TCFH (557 mg, 1.98 mmol) and NMI (326 mg, 3.97 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated and purified on a Biotage Isolera One (C 18 column, eluting with 5% to 95% MeCN / H2O containing 0.1% formic acid) to obtain 1-methyl-N-(thiazolo[5,4-b]pyridin-2-yl)-1H-pyrazole-3-carboxamide (Compound 2) as an off-white solid (133.42 mg, 98% purity, 38.12% yield). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 12.51 (s, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 8.14 (dd, J = 8.0, 1.6 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.0, 4.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 3.99 (s, 3H). C 11 H 10N5OS[M+H] + Calculated LCMS (ESI) value of m / z 260.06, measured value 260.15.

[0799] Incorporated by reference

[0800] The entire disclosure of all patents and non - patent disclosures cited herein are hereby incorporated by reference in their entirety for all purposes.

[0801] Other embodiments

[0802] The above - described present disclosure may cover a plurality of different disclosures having independent utilities. The specific embodiments disclosed and illustrated herein should not be considered in a limiting sense, as various modifications are possible. The subject matter of the present disclosure includes all novel and non - obvious combinations and sub - combinations of the various elements, features, functions, and / or properties disclosed herein. The following claims particularly point out certain combinations and sub - combinations that are regarded as novel and non - obvious. The disclosures embodied in other combinations and sub - combinations of features, functions, elements, and / or properties may be claimed in this application, in an application claiming priority to this application, or in a related application. Such claims, whether directed to different disclosures or the same disclosure, and whether their scope is broader, narrower, equivalent, or different compared to the original claims, are also regarded as included in the subject matter of the disclosure of the present disclosure.

Claims

1. A compound having the structure of formula (X-I): Wherein: A is O or S; X is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl or an optionally substituted aryl; Y is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl or an optionally substituted aryl, or is absent; Z is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted heteroaryl or an optionally substituted aryl or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl; L 1 is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -O-, -S- or -N(R 1a )-, or is absent; L 2 is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -O-, -S- or -N(R 1a ), or is absent; L 3 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, -C(O)-, NH-C(O)-, -C(O)-NH-, -O-, -S- or -N(R 1a ), or is absent; R 1 is H or a C1-C6 alkyl group; Each R 1a is H or a C1-C6 alkyl group; Or Its pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein the compound has the structure of formula (X-I-A):

3. The compound according to claim 1, wherein the compound has the structure of formula (X-I-B):

4. The compound according to claim 1, wherein X is And Y is Or is absent; Wherein, X 1 to X 18 each independently is -C(R 2 )=, -N=, -O- or -S-; X 19 and X 20 each independently is -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-; Y 1 , Y 2 , Y 3 and Y 4 Each is independently -C(R 2 )=or-N=; Y 5 and Y 8 each independently is -C(R 2 )(R 3 )-, -N(R 4 )-, -O- or -S-; Y 6 and Y 7 each independently is -C(R 2 )- or N; R 2 and R 3 are independently H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, R 1a and R 2a each independently is H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkenyl, (C1-C3) alkynyl or (C1-C3) alkoxy, (C3-C6) branched alkyl, (C3-C6) branched haloalkyl, (C3-C6) branched alkenyl, (C3-C6) branched alkynyl or (C3-C6) branched alkoxy; v is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5.

5. The compound according to claim 1, wherein Z is or does not exist; Z 1 from Z to 9 each independently is -C(R 2 )=, -N=, -O- or -S-; Z 10 is -C(R 2 )- or N; Z 11 , Z 12 and Z 13 Each is independently -C(R 2 )(R 3 )-、-N(R 4 )-, -O-, or -S-; R 2 and R 3 are independently H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, R 4 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, (C1-C3)alkoxy, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, R 1a and R 2a each independently is H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkenyl, (C1-C3) alkynyl, (C1-C3) alkoxy, (C3-C6) branched alkyl, (C3-C6) branched haloalkyl, (C3-C6) branched alkenyl, (C3-C6) branched alkynyl or (C3-C6) branched alkoxy; and n is 0, 1, 2, 3, 4 or 5.

6. The compound according to claim 1, wherein the compound has the structure of formula (II): Wherein, X 8 to X 15 each independently is -C(R 2 )=, -N=, -O- or -S-, and R 2 independently is H, D, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl, halogen, cyano, hydroxy, nitro, mercapto, amino, (C1-C3)alkoxy, -S(O)2N(H)(C1-C3)alkyl, -S(O)2N(H)CH3, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl, (C3-C6)branched alkoxy, -S(O)2N(H)(C3-C6)branched alkyl, and R 1a and R 2a each independently is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkenyl, (C1-C3)alkynyl or (C1-C3)alkoxy, (C3-C6)branched alkyl, (C3-C6)branched haloalkyl, (C3-C6)branched alkenyl, (C3-C6)branched alkynyl or (C3-C6)branched alkoxy.

7. The compound according to claim 1, wherein the compound has the structure of formula (IIa):

8. The compound according to claim 1, wherein the compound has the structure of formula (III):

9. The compound according to claim 1, wherein the compound has the structure of formula (IIIa):

10. The compound according to claim 1, wherein the compound has the structure of formula (IV):

11. The compound according to claim 1, wherein the compound has the structure of formula (IVa):

12. The compound according to claim 1, wherein L 1 is absent.

13. The compound according to claim 1, wherein L 1 is optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkenyl, (C1-C3) alkynyl, optionally substituted 5-6 membered cycloalkyl, optionally substituted 5-6 membered cycloalkenyl, -O-, -S- or -N(R 1a ).

14. The compound according to claim 1, wherein L 2 is absent.

15. The compound according to claim 1, wherein L 2 is optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkenyl, (C1-C3) alkynyl, optionally substituted 5-6 membered cycloalkyl, optionally substituted 5-6 membered cycloalkenyl, -O-, -S- or -N(R 1a )-.

16. The compound according to claim 1, wherein X is selected from the group consisting of:

17. The compound according to claim 1, wherein Z is selected from the group consisting of:

18. The compound according to claim 1, wherein the compound is selected from the compounds in Tables 1 to 2.

19. A pharmaceutical composition comprising one or more of the compounds according to any one of claims 1 to 18.

20. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to any one of claims 19 to 20, wherein the pharmaceutical composition comprises one or more of the compounds according to any one of claims 1 to 16, and the amount of the compound is effective for treating inflammation, relieving joint pain, preventing joint degeneration or promoting cartilage regeneration.

22. The pharmaceutical composition according to any one of claims 19 to 21, wherein the pharmaceutical composition comprises an amount of one or more compounds of formula (X-I) effective for treating cancer.

23. The pharmaceutical composition according to claim 22, wherein the cancer is skin cancer.

24. The pharmaceutical composition according to any one of claims 19 to 23, wherein the compound regulates the expression or activity of gp130, SRC, NF-κB, YAP, p38, ERK1 / 2, STAT3, MYC, MMP13, ADAMTS4, COL2, and / or ACAN.

25. The pharmaceutical composition according to any one of claims 19 to 24, which is formulated to be effective after administration to a human subject suffering from osteoarthritis.

26. The pharmaceutical composition according to any one of claims 19 to 25, which is formulated for administration by intravenous injection, intra-articular injection, intramuscular injection, oral administration, or topical delivery.

27. The pharmaceutical composition according to any one of claims 19 to 26, which further comprises an additional therapeutic compound selected from the group consisting of, but not limited to, alkylating agents, cancer immunotherapy monoclonal antibodies, antimetabolites, mitotic inhibitors, antitumor antibiotics, topoisomerase inhibitors, photosensitizers, tyrosine kinase inhibitors, anticancer agents, chemotherapeutic agents, antimigraine therapeutic agents, antitussives, mucolytics, decongestants, anti-allergy non-steroids, expectorants, antihistamine therapeutic agents, antiretroviral agents, CYP3A inhibitors, CYP3A inducers, protease inhibitors, adrenergic agonists, anticholinergics, mast cell stabilizers, xanthines, leukotriene antagonists, glucocorticoid therapeutic agents, antibacterial agents, antifungal agents, sepsis therapeutic agents, steroids, local or general anesthetics, NSAIDs, NRI, DARI, SNRI, sedatives, NDRI, SNDRI, monoamine oxidase inhibitors, hypothalamic phospholipids, antiemetics, ECE inhibitors, opioids, thromboxane receptor antagonists, potassium channel openers, thrombin inhibitors, growth factor inhibitors, antiplatelet agents, P2Y(AC) antagonists, anticoagulants, low molecular weight heparins, factor Via inhibitors, factor Xa inhibitors, renin inhibitors, NEP inhibitors, vasopeptidase inhibitors, squalene synthase inhibitors, anti-atherosclerotic agents, MTP inhibitors, calcium channel blockers, potassium channel activators, α-muscarinic agents, β-muscarinic agents, antiarrhythmic agents, diuretics, thrombolytics, antidiabetic agents, mineralocorticoid receptor antagonists, growth hormone secretagogues, aP2 inhibitors, phosphodiesterase inhibitors, anti-inflammatory agents, antiproliferatives, antibiotics, farnesyl-protein transferase inhibitors, hormonal agents, plant-derived products, etoposide, taxanes, geranylgeranyl-protein transferase inhibitors, anti-TNF antibodies and soluble TNF receptors, cyclooxygenase-2 inhibitors, and other agents.

28. The pharmaceutical composition according to any one of claims 19 to 27, which further comprises microspheres, wherein the composition is formulated for sustained release delivery.

29. A topical formulation comprising the compound according to any one of claims 1 to 18.

30. The topical formulation according to claim 29, wherein the compound is present in an amount effective to modulate the activity of members of the gp130 signaling pathway in a target population of human skin cells.

31. The topical formulation according to claim 30, wherein the compound directly interacts with a gp130 signal transduction molecule.

32. The topical formulation according to claim 30, wherein the compound modulates the activity and / or expression of molecules downstream of gp130 signaling.

33. The topical formulation according to claim 30, wherein the compound significantly increases the expression of (i) the STAT3 gene and / or (ii) the level and / or activity of the STAT3 polypeptide in a target population of human skin cells.

34. The topical formulation according to claim 30, wherein the compound does not increase NF-κB activation in the target cell population.

35. The topical formulation according to claim 30, wherein the topical formulation is formulated for topical administration to a skin surface selected from the group consisting essentially of the face, hands, and neck.

36. The topical formulation according to claim 30, wherein the compound is present at a concentration from about 100 nM to about 500 μM.

37. The topical formulation according to claim 30, the topical formulation comprising from about 0.1 mg to about 10,000 mg of the compound.

38. The topical formulation according to claim 30, the topical formulation comprising from about 1 mg to about 100 mg of the compound.

39. The topical formulation according to claim 30, the topical formulation further comprising DL-α-tocopherol, BV-OSC, sodium hyaluronate cross-linked polymer, N-prolyl palmitoyl tripeptide-56 acetate.

40. The topical formulation according to claim 30, wherein the formulation comprises DL-α-tocopherol at a concentration of from about 0.095% WT / WT to about 0.105% WT / WT, BV-OSC at a concentration of from about 0.475% WT / WT to about 0.525 WT / WT, sodium hyaluronate cross-linked polymer at a concentration of from about 0.95% WT / WT to about 1.05% WT / WT, and N-prolyl palmitoyl tripeptide-56 acetate at a concentration of from about 1.9% WT / WT to about 2.1% WT / WT.

41. The topical formulation according to claim 30, wherein the topical formulation is formulated for dermal or subdermal delivery of the compound.

42. The topical formulation according to claim 30, wherein the topical formulation is formulated as a liquid, gel, cream, or ointment.

43. The topical formulation according to claim 30, wherein the formulation is stable at room temperature.

44. The topical formulation according to claim 30, wherein the formulation is a sterically stabilized oil-in-water (o / w) emulsion.

45. A method of reducing or preventing inflammaging in a target tissue of a human subject in need thereof, the method comprising the step of contacting the target tissue with an effective amount of the topical formulation according to any one of claims 30 to 44.

46. A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt or solvate thereof, wherein the subject has an inflammatory disorder.

47. A method of treating inflammation, an inflammatory disease or disorder, alleviating joint pain, preventing joint degeneration or promoting cartilage regeneration in a human subject over 25 years of age in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 to 44.

48. The method of claim 47, wherein the inflammatory disease or disorder is enhanced by gp130 activation and is selected from the group consisting of stroke, heart disease, cartilage degeneration, hair loss, arthritis, neurodegenerative disorders, aging, psoriasis, rosacea, lupus, rheumatoid arthritis, inflammatory bowel disease, fibrosis, inflammaging and / or chronic inflammation.

49. A method of treating cell proliferative diseases and disorders enhanced by gp130 activation in a human subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 to 44.

50. A method of treating or improving a pain condition enhanced by gp130 activation in a human subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 to 44, wherein the pain condition is selected from the group consisting of neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, musculoskeletal pain, craniofacial pain, other somatic forms of pain and referred pain.

51. A method of modulating an IL-6 family cytokine-mediated inflammatory response in a cell, the method comprising contacting the cell with a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 to 44.

52. The method of claim 51, wherein the cell is a chondrocyte or a synoviocyte.

53. A method of treating an acute or chronic inflammatory state, the method comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 - 44.

54. A method of reducing an activated inflammatory pathway in a cell, the method comprising contacting the cell with a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 to 44.

55. A method of inhibiting the production or induction of a pro-inflammatory gene, cytokine or mediator, the method comprising contacting a cell or a subject with a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 to 44.

56. A method for inhibiting the production or induction of extracellular matrix degrading enzymes, the method comprising contacting a cell or a subject with a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 to 44.

57. A method for modulating the level of STAT3 and / or MYC in a cell, the method comprising contacting the cell with a compound according to any one of claims 1 to 18 or a composition according to any one of claims 19 to 44.

58. The method according to claim 57, wherein the cell is a chondrocyte, a stem cell or progenitor cell, a macrophage, a fibroblast or a T-cell.

59. A method for preparing a topical formulation of a compound, the amount of the compound being effective to significantly modulate the activity or expression of members of the gp130 signaling pathway in a target population of human skin cells, the method comprising: a. Forming a first part, wherein the steps include: i. Adding a first component to a main processing tank, the first component comprising a mixture of polydimethylsiloxane, polysiloxane-11, isododecane, ammonium polyacryloyldimethyltaurate, tocopheryl acetate, polysorbate 80 and polysorbate 20, the first component being added to a processing tank equipped with a propeller mixer and a side sweeper; ii. Adding a second component comprising isododecane and mixing well; iii. Adding a third component comprising polysorbate 20 and mixing well; iv. Adding a fourth component comprising tetrahexyl decyl ascorbate and mixing well; v. Adding a fifth component comprising menthyl ethylamido oxalate and mixing well; and vi. Adding a sixth component comprising an aromatic additive; wherein the first part of the formulation is mixed until completely homogeneous; b. Forming a second part in a separate container, wherein the steps include: i. Forming a premix by combining tocopherol with the compounds of Tables 1 to 2; and ii. Ensuring that the compounds are completely dissolved; wherein then the second part is added to the first part in the main processing tank and mixed until the combination of the first part and the second part is completely homogeneous; and c. Forming a third part in a separate container, wherein the steps include: i. Adding deionized water and starting medium-speed mixing; ii. Adding disodium EDTA and / or sodium phytate and / or trisodium ethylenediaminedisuccinate and mixing well; iii. Adding butylene glycol and mixing well; iv. Adding a mixture comprising isododecane, ammonium polyacryloyldimethyltaurate and polysorbate 80 and mixing well; v. Adding pentylene glycol and mixing well; vi. Adding a mixture comprising water, pentylene glycol, ethylhexylglycerin and a cross-linked hyaluronic acid sodium polymer and mixing well; vii. Adding a mixture comprising water, pentylene glycol, caprylyl glycol and N-prolyl palmitoyl tripeptide-56 acetate and mixing well; viii. Adding a mixture comprising glycerin and Acer rubrum extract and mixing well; ix. Add a mixture comprising water, Spondias mombin pulp extract, mango pulp extract, glycerol, Musa sapientum pulp extract, benzyl alcohol, and potassium sorbate and mix well; and add a mixture of glyceryl caprylate, glycerol, and octylohydroxamic acid and mix well until the preparation is homogeneous; and d. Slowly add the third portion from the third container into the main treatment tank and mix until completely homogeneous.

60. The method of claim 59, wherein the topical preparation comprises a compound according to any one of claims 1 to 16.

61. The method of claim 60, wherein the compound is present in the topical preparation in an amount effective to significantly increase the expression of (i) the STAT3 gene and / or (ii) the level and / or activity of the STAT3 polypeptide in a target population of human skin cells.

62. A method of treating a subject having a skin disorder, the method comprising administering to the subject a topical preparation, the amount of the topical preparation being effective to modulate gp130 signaling in a target population of human skin cells.

63. The method of claim 62, wherein the topical preparation comprises a compound according to any one of claims 1 to 18.

64. The method according to any one of claims 62 to 63, wherein the compound directly interacts with a gp130 signal transduction molecule.

65. The method according to any one of claims 62 to 63, wherein the topical preparation comprises a compound according to claims 1 to 16, the compound modulating the activity or expression of a downstream molecule of gp130 signaling.

66. The method according to any one of claims 62 to 63, the topical preparation comprising a compound that significantly increases the expression of (i) the STAT3 gene and / or (ii) the level and / or activity of the STAT3 polypeptide in a target population of human skin cells.

67. The method according to any one of claims 62 to 63, wherein the topical preparation comprises a compound that does not increase NF-κB activation in the target cell population.

68. The method of claim 62 to 63, wherein the skin disorder comprises skin conditions and skin diseases.

69. The method of claim 68, wherein the skin disorder comprises the effects of aging, increased skin roughness, loss of skin elasticity, increased skin transparency, skin fragility, increased frequency of abrasions, the macroscopic appearance of skin wrinkles and folds, and hypopigmentation of the skin.

70. A method for cosmetic use, the method comprising administering a topical preparation comprising one or more compounds according to any one of claims 1 to 18 to a skin area of a subject.

71. The method of claim 70, wherein the compound is present in the topical preparation in an amount effective to modulate gp130 signaling in a target population of human skin cells.

72. The method of claim 70, wherein the compound directly interacts with a gp130 signal transduction molecule.

73. The method according to any one of claims 70 to 72, wherein the compound modulates the activity or expression of downstream molecules of gp130 signaling.

74. The method according to any one of claims 70 to 73, wherein the compound significantly increases the expression of (i) the STAT3 gene and / or (ii) the level and / or activity of the STAT3 polypeptide in a target population of human skin cells.

75. The method according to any one of claims 70 to 74, wherein the compound does not increase NF-κB activity in the target cell population.

76. The method according to any one of claims 70 to 75, the method further comprising administering a therapeutically effective amount of a second therapeutic agent useful for treating cancer.

77. The method according to claim 76, wherein the cancer is skin cancer.

78. The method according to claim 77, wherein the skin cancer is melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma or sebaceous gland carcinoma.

79. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating an inflammatory disorder.

80. A method for modulating the expression or activity of gp130, SRC, NF-κB, YAP, p38, ERK1 / 2, STAT3, MYC, MMP13, ADAMTS4, COL2 and / or ACAN, the method comprising contacting a cell with a compound according to any one of claims 1 to 18.

81. A kit comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound or a pharmaceutically acceptable salt thereof to a subject having an inflammatory disorder.

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