Methods of treatment using BCN057 and BCN512

Abstract

To provide therapeutic applications of small molecules BCN057 and BCN512 and analogs thereof which are useful for treating or preventing inflammatory disease and for treating or preventing cancer or other hyperproliferative conditions.SOLUTION: The present disclosure is directed to methods of treating or ameliorating various conditions by the administration of BCN057, BCN512 or analogs of these compounds. The compounds can be used to reduce tumor burden in cancers, including pancreatic cancer and gastrointestinal (GI) cancer. The compounds can also be used to protect against chemotherapy-induced toxicity to the GI tract. Further, they can be used to treat fibrosis and various inflammatory conditions. Analogs of BCN057 and BCN512 are also described.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 891,338, filed Aug. 24, 2019, the contents of which are incorporated herein by reference.

[0002] The present invention relates to novel small molecules and their therapeutic uses, and more particularly to the therapeutic uses of the small molecules BCN057 and BCN512 and their analogs. [Background technology]

[0003] background Cancer may be defined as a group of diseases involving abnormal cell growth that can invade or spread to other parts of the body. Despite technological advances, cancer remains a significant cause of death and immense suffering. Cancer is the second most common cause of death in the United States.

[0004] Patients with cancer often have limited treatment options. Treatments may include a combination of surgery, radiation therapy, chemotherapy, and targeted therapy. Despite advances in research, these treatments have remained relatively unchanged for the past few decades. Efforts have often focused on early diagnosis of cancer, when treatments are more effective. However, early diagnosis provides only modest survival times. Recent research has provided new opportunities for cancer treatment, including the use of Wingless-type (Wnt) pathway modulators.

[0005] The Wnt signaling pathway is a group of signaling pathways that begin with proteins that pass signals into cells through cell surface receptors. Aberrant activation of the Wnt pathway has been implicated in human cancers, particularly those of the gastrointestinal (GI) tract. Inhibition of aberrant Wnt pathway activity in cancer cell lines can block their growth, presenting a potential new therapeutic agent. Alternatively, activation of Wnt signaling and its downstream genes in cancers can induce apoptosis in cancer cells.

[0006] Wnt signaling pathways are often divided into two categories: canonical and non-canonical. The canonical pathway is typically referred to as the β-catenin-dependent pathway. The non-canonical pathway is independent of β-catenin and is responsible for controlling cell movement during morphogenesis. Although both pathways have been implicated in cancer development, the canonical pathway is most commonly recognized for its influence in gastrointestinal (GI) cancers.

[0007] There is a need for improved therapeutic methods that can be achieved by Wnt signal modulators.Modulators of Wnt / β-catenin signaling also have the potential to treat other diseases, including fibrosis, inflammatory conditions, bone growth and alopecia.Therefore, compounds and methods that can inhibit and / or control Wnt / β-catenin signaling are needed.In particular, effective Wnt pathway modulators are needed. Summary of the Invention

[0008] The compound BCN057 disclosed herein was previously described in U.S. Patent Application Nos. 13 / 813,923 and 14 / 889,719. The present invention provides new analogs and new methods of use. BCN057 (also called YEL002), BCN512 and analogs of each compound are described below. The compounds of the present invention are useful for treating or preventing inflammatory diseases, and treating or preventing cancer or other hyperproliferative conditions, among other therapeutic methods.

[0009] One embodiment is a compound of formula A or an analog thereof: [ka] (Wherein, R1 is CH3 or H, and R2 is [ka] It is one of the.)

[0010] Another embodiment is a method of treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula B: [ka] (In the formula: R 1 is an alkyl, alkylamine, or ether; R 2 is H or CH3; and R 3 is H or OH) The method includes administering a compound having the structure: The analogs of Formula B may include those of Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, and Formula XIX as described herein.

[0011] A further embodiment is a method of treating cancer in a subject with a therapeutically effective amount of a compound of formula B or an analog thereof. The cancer can be bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, rectal cancer, skin cancer, blood cancer or testicular cancer. Treatment can include administering one or more additional agents to the subject and administering chemotherapy or radiation therapy.

[0012] Additional embodiments include methods of treating a subject having one or more side effects of chemotherapy or radiation therapy with a compound of formula B or an analog thereof. Yet another embodiment is a method of preventing or treating radiation-induced damage to epithelial cells by administering a therapeutically effective amount of a compound of formula B or an analog thereof. Radiation-induced damage to epithelial cells can be identified as radiation-induced gastrointestinal syndrome (RIGS), radiation-induced mucositis, radiation-induced oral mucositis, radiation-induced proctitis, and / or radiation-induced enteritis.

[0013] Further embodiments include methods of treating fibrosis with a compound of formula B or an analog thereof. The fibrosis can be pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, non-cystic fibrosis bronchiectasis, liver cirrhosis, hepatic fibrosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloid conditions, scleroderma / systemic sclerosis, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, oral submucous fibrosis, hepatic fibrosis, gastrointestinal fibrosis, renal fibrosis due to renal dialysis, and / or adhesive capsulitis.

[0014] Additional embodiments include methods of treating a viral infection in a subject in need thereof with a compound of formula B or an analog thereof. Embodiments also include methods of treating depression with a compound of formula B or an analog thereof.

[0015] In one embodiment, a therapeutically effective amount of the compound BCN057: [ka] Disclosed herein are methods of treating a subject with

[0016] BCN057 may also be referred to by its structural name: (3-[(furan-2-ylmethyl)amino]-2-(7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)-6-methylimidazo[1,2-a]pyridin-1-ium).

[0017] In another embodiment, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound BCN057 or an analog thereof.In another embodiment, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination comprising the compound BCN057 or an analog thereof.

[0018] In another embodiment, the disclosure provides a method of treating a side effect of chemotherapy or radiation therapy in a subject, comprising administering to the subject a therapeutically effective amount of the compound BCN057 or an analog thereof.In another embodiment, the disclosure provides a method of treating radiation-induced gastrointestinal syndrome (RIGS) in a subject, comprising administering to the subject a therapeutically effective amount of the compound BCN057 or an analog thereof.

[0019] In one aspect, disclosed herein is a method of treating a subject with a therapeutically effective amount of the compound BCN512. The structure of the compound BCN512 is shown below, and it is also known as 1-[(4-nitrobenzene)sulfonyl]-4-phenylpiperazine. Analogs include BCN512A1 and BCN512B. [ka]

[0020] In another embodiment, the disclosure provides a method of modulating Wnt signaling in a subject, comprising administering a therapeutically effective amount of a compound of BCN512 or an analog thereof.

[0021] In another embodiment, the disclosure provides a method of treating a subject having fibrosis, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination comprising a compound of BCN512 or an analog thereof.

[0022] In another embodiment, the disclosure provides a method for inhibiting SFRP activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of BCN512 or an analog thereof.

[0023] In another embodiment, the disclosure provides a method of treating fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of BCN512 or an analog thereof. In another embodiment, the fibrotic disease is pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, non-cystic fibrosis bronchiectasis, liver cirrhosis, liver fibrosis (e.g., caused by chronic viral hepatitis B or C), endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis (soft tissue of the mediastinum), myelofibrosis (bone marrow), retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloid conditions, scleroderma / systemic sclerosis, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, oral submucous fibrosis, or adhesive capsulitis.

[0024] In another embodiment, the present disclosure provides a method of treating bone density disorders or lack of bone density using BCN512 or an analog thereof. Examples include osteoporosis, aging and lack of bone density, bone fracture or destruction of bone.

[0025] In another embodiment, the disclosure provides a method of treating lack of hair growth or hair loss with BCN512 or an analog thereof. Examples include alopecia, age-related hair loss or patterned alopecia.

[0026] In another embodiment, the present invention provides a compound of formula I: [ka] (In the formula, A 5 is a secondary or tertiary amine (i.e., thereby forming a sulfonamide), and A 6 is a substituted or unsubstituted aryl or heteroaryl group, preferably the aryl or heteroaryl group has at least one substituent that is substituted, e.g., including a nitro located in a position distal to the sulfonyl. 5is a heterocyclic amine such as a piperidine, piperazine, or morpholine ring, while in other embodiments the amine is acyclic and / or the nitrogen atom attached to the sulfonyl is A 5 (not included in any ring that may exist in or a pharma- ceutically acceptable salt, ester or prodrug thereof.

[0027] Embodiments include a method of modulating Wnt activity to treat a disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound having the structure of Formula Ia.

[0028] The condition may be radiation exposure, fibrosis, insulin sensitivity, cancer, osteoporosis, hair loss / regrowth, wound healing, low bone density, and / or obesity. The condition may also be one or more side effects of chemotherapy or radiation therapy.

[0029] In another embodiment, the present invention provides a compound of formula II [ka] (In formula; X is N or -CH-, preferably N; Y 1 and Y 2 are each independently a lower alkyl group; or Y 1 and Y 2 With X, [ka] (In the formula, X is N, C or CH; G is N, C or CH; Z is absent or selected from substituted or unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl; and R 4 is hydrogen or is selected from substituted or unsubstituted aryl (e.g., phenyl) and heteroaryl; and R5 and R 6 are each independently absent or lower alkyl. forming a heterocyclyl ring system such as or a pharma- ceutically acceptable salt, ester or prodrug thereof.

[0030] In other embodiments, X, Y 1 and Y 2 Both are ring systems [ka] (In the formula, X is -C(H)-, and R 4 is selected from halogen substituted phenyl groups, substituted or unsubstituted aryl (e.g., phenyl) and heteroaryl, such as 4-fluorophenyl or 3-chlorophenyl; In certain embodiments, Y 1 and Y 2 are each ethyl. In certain preferred embodiments, Y 1 and Y 2 together form a piperazine ring. In certain preferred embodiments, Z is absent.

[0031] An embodiment includes a method of modulating Wnt activity to treat a disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound having the structure of formula IIa. The disease can be radiation exposure, fibrosis, insulin sensitivity, cancer, osteoporosis, hair loss / hair growth, wound healing, low bone density, and obesity. The disease can also be one or more side effects of chemotherapy or radiation therapy. The fibrosis may be pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, non-cystic fibrosis bronchiectasis, liver cirrhosis, hepatic fibrosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloid conditions, scleroderma / systemic sclerosis, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, oral submucous fibrosis, hepatic fibrosis, gastrointestinal fibrosis, renal fibrosis due to kidney dialysis, or adhesive capsulitis.

[0032] Another embodiment is a compound of formula C [ka] (In the formula, R1 = halogen, N, OH, CH3, OH, (CH2)n-CH3 or substituted or unsubstituted aryl; R2 = halogen, N, OH, CH3, OH, (CH2)n-CH3 or substituted or unsubstituted aryl; R3 = halogen, N, OH, CH3, OH, (CH2)n-CH3 or substituted or unsubstituted aryl; R4 = halogen, N, OH, CH3, OH, (CH2)n-CH3 or substituted or unsubstituted aryl or an analog thereof. The analogs can include compounds of formula XXII, formula XXIII, formula XXIV, formula XXV, formula XXVI, and formula XXVII.

[0033]

[0023] Embodiments also include methods of treating inflammation in a subject with a compound of Formula C or an analog thereof. The analog can be of Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, and / or Formula XXVII.

[0034] The embodiments also include a method of modulating Wnt activity to treat a disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula XXI or an analog thereof. The analog can be of formula XXII, formula XXIII, formula XXIV, formula XXV, formula XXVI, and / or formula XXVII. The disease can be radiation exposure, fibrosis, insulin sensitivity, cancer, osteoporosis, hair loss / growth, wound healing, low bone density, and / or obesity. The fibrosis may be pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, non-cystic fibrosis bronchiectasis, liver cirrhosis, hepatic fibrosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloid conditions, scleroderma / systemic sclerosis, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, oral submucous fibrosis, hepatic fibrosis, gastrointestinal fibrosis, renal fibrosis due to kidney dialysis, or adhesive capsulitis.

[0035] In certain embodiments, the compounds of the invention may be prodrugs of compounds of formula I or II, for example, where a hydroxyl in the parent compound is presented as an ester or carbonate, or a carboxylic acid present in the parent compound is presented as an ester. In certain such embodiments, the prodrug is metabolized in vivo to the active parent compound (e.g., an ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).

[0036] In certain embodiments, the compounds of the present invention may be racemic. In certain embodiments, the compounds of the present invention may be enriched in one enantiomer. For example, the compounds of the present invention may have 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, more than 90% ee, or even 95% or more ee. In certain embodiments, the compounds of the present invention may have two or more stereocenters. In certain such embodiments, the compounds of the present invention may be enriched in one or more diastereomers. For example, the compounds of the present invention may have 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or 95% or more de.

[0037] In certain embodiments, the present invention relates to methods of treatment with compounds of Formula Ia, IIa, A, B, C, analogs and / or pharma- ceutically acceptable salts thereof, hi certain embodiments, therapeutic preparations may be enriched to provide predominantly one enantiomer of the compound (e.g., Formula Ia, IIa, A, B or C).

[0038] In certain embodiments, a therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula Ia, IIa, A, B, or C). A diastereomerically enriched mixture may, for example, contain at least 60 mole %, or more preferably at least 75, 90, 95, or even 99 mole % of one diastereomer.

[0039] In certain embodiments, the present invention relates to methods of treatment with a compound of Formula Ia, IIa, A, B or C, or a pharma- ceutically acceptable salt thereof, in certain embodiments, a therapeutic preparation may be enriched to provide predominantly one enantiomer of the compound (e.g., Formula Ia, IIa, A, B or C).

[0040] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of the compound (e.g., Formula Ia, IIa, A, B, or C). In certain embodiments, the present invention provides a pharmaceutical formulation suitable for use in a human patient, comprising any of the compounds set forth above (e.g., a compound of the present invention, such as a compound of Formula Ia, IIa, A, B, or C), and one or more pharma- ceutically acceptable excipients. In certain embodiments, the pharmaceutical preparation may be for use in treating or preventing a condition or disease described herein. In certain embodiments, the pharmaceutical preparation has sufficiently low pyrogen activity to be suitable for use in a human patient. Any compound of the above structure may be used in the manufacture of a medicament for the treatment of any disease or condition disclosed herein.

[0041] Various other objects, features and attendant advantages of the present invention will become more fully appreciated as the same becomes better understood when considered in conjunction with the accompanying drawings, in which like reference characters designate the same or similar parts throughout the several views. [Brief description of the drawings]

[0042] [Figure 1] FIG. 1 shows the effect of 5-FU and BCN057 on the viability of pancreatic cancer cell lines. [Figure 2A] FIG. 2A shows Annexin V apoptosis and necrosis assays in Panc-1 cells in a dose-dependent manner. [Figure 2B] FIG. 2B shows Annexin V apoptosis and necrosis assays in Panc-1 cells over time. [Diagram 3] Figures 3A-3F show the effect of 10 μM BCN057 on the viability of pancreatic cancer cell lines at time 0 (Figure 3A), 15 min (Figure 3B), 30 min (Figure 3C), 60 min (Figure 3D), 120 min (Figure 3E), and 240 min (Figure 3F). [Figure 4A] FIG. 4A is a graph showing the results of a survival assay in pancreatic cells. [Figure 4B] FIG. 4B shows the data for each time point. [Figure 5A] FIG. 5A shows compound H. [Figure 5B] FIG. 5B shows compound K. [Figure 6] FIG. 6 is a graph showing fibrotic lesions in untreated lung tissue sections and sections treated with BCN512. [Figure 7] Figures 7A-7F show histopathology of lung sections stained for TGFβ in C57M male mice that received nothing (A), 14 Gy of thoracic irradiation (B) or irradiation and BCNB512 treatment (C). Images D, E and F are myocardial staining with the same parameters from the same animals. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] definition Reference herein to "one embodiment / aspect" or "one embodiment / aspect" means that a particular feature, structure, or characteristic described in connection with the embodiment / aspect is included in at least one embodiment / aspect of the present disclosure. Use of the phrase "one embodiment / aspect" or "another embodiment / aspect" in various places herein does not necessarily refer all to the same embodiment / aspect, nor does it refer to embodiments / aspects separate or alternative to one another, except for other embodiments / aspects. Furthermore, various characteristics are described that are exhibited by some embodiments / aspects and may not be exhibited by other embodiments. Similarly, various requirements are described that may be requirements for some embodiments / aspects but not other embodiments / aspects. Embodiments and aspects may be used interchangeably in certain cases.

[0044] The terms used in this specification generally have their ordinary meanings in the art, within the context of this disclosure, and in the specific context in which each term is used.Specific terms used to describe this disclosure are discussed below or elsewhere in this specification to provide the practitioner with additional guidance regarding the description of this disclosure.It will be understood that the same thing can be described in more than one way.

[0045] As a result, alternative language and synonyms may be used for any one or more of the terms discussed herein. Also, there is no particular importance to whether a term is detailed herein or not. Synonyms for certain terms are provided. The detailed description of one or more synonyms does not preclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any term discussed herein, is merely illustrative and is not intended to further limit the scope and meaning of the disclosure or of any exemplified term. Similarly, the disclosure is not limited to the various embodiments provided herein.

[0046] Without intending to further limit the scope of the present disclosure, examples of instruments, devices, methods and their related results according to the embodiments of the present disclosure are given below. It should be noted that titles or subtitles may be used in the examples for the convenience of the reader, but should not limit the scope of the present disclosure in any way. Unless otherwise limited, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present disclosure belongs. In case of conflict, the present document, including definitions, shall prevail.

[0047] Unless otherwise indicated, all numbers expressing features, items, quantities, parameters, characteristics, terms, etc. used in the present specification and claims should be understood in all cases to be modified by the term "about". As used herein, the term "about" means that the feature, item, quantity, parameter, characteristic, or term so qualified encompasses a range of ±10% above or below the value of the stated feature, item, quantity, parameter, characteristic, or term. Thus, unless indicated to the contrary, the numerical parameters described in this specification and the appended claims are approximations that may vary. For example, mass spectrometry instruments may vary slightly in determining the mass of a given analyte, and the term "about" in the context of the mass of an ion or the mass / charge ratio of an ion refers to ±0.50 atomic mass units. At the very least, and without any attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical designation should be construed at least by the number of significant digits reported and by applying ordinary rounding techniques.

[0048] The use of the terms "may" or "can" with reference to an embodiment or an aspect of an embodiment also carries with it the alternative meaning of "may not" or "can not." Thus, when the specification discloses that an embodiment or an aspect of an embodiment is or may be included as part of the inventive subject matter, a negative limitation or exclusionary condition is also expressly implied, meaning that an embodiment or an aspect of an embodiment may not or cannot be included as part of the inventive subject matter. Similarly, the use of the term "optionally" with reference to an embodiment or an aspect of an embodiment means that such embodiment or aspect of an embodiment may or may not be included as part of the inventive subject matter. Whether such a negative limitation or exclusionary condition applies will be based on whether the negative limitation or exclusionary condition is recited in the claimed subject matter.

[0049] Although the numerical ranges and values ​​describing the broad scope of the present disclosure are approximate, the numerical ranges and values ​​described in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The description of numerical ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value in a numerical range is incorporated herein as if it were individually described herein.

[0050] The terms "a," "an," "the," and similar references as used in the context of the present disclosure (particularly in the context of the claims below) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Furthermore, order designations such as first, second, third, etc. are used to distinguish between elements, and do not indicate or imply a required or limited number of such elements, nor do they indicate a particular location or order of such elements, unless otherwise specifically stated. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to provide a better understanding of the disclosure, and does not limit the scope of the disclosure as specifically claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.

[0051] When used in the claims, whether as filed or added per amendment, the open-ended transitional term "comprising" (and its corresponding open-ended transitional phrases such as including, containing, and having) includes all explicitly recited elements, limitations, steps, and / or features, either alone or in combination with unrecited subject matter; the named elements, limitations, and / or features are essential, but other unnamed elements, limitations, and / or features may be added to form further constructs within the scope of the claim. Specific embodiments disclosed herein may be further limited in the claims using the open-ended transitional phrases "consisting of" or "consisting essentially of" in place of or as a modification of "comprising." When used in the claims, whether as filed or added per amendment, the open-ended transitional phrase "consisting of" excludes any element, limitation, step, or feature not expressly recited in the claim. The closed transitional phrase "consisting essentially of" limits the scope of the claim to those elements, limitations, steps, and / or characteristics specifically recited, as well as any other elements, limitations, steps, and / or characteristics that do not materially affect the basic and novel characteristic(s) of the claimed subject matter. As such, the meaning of the open transitional phrase "comprising" is defined as including all of the specifically recited elements, limitations, steps, and / or characteristics, as well as any additional unspecified ones. The meaning of the closed transitional phrase "consisting of" is defined as including only those elements, limitations, steps, and / or characteristics specifically recited in the claim, while the meaning of the closed transitional phrase "consisting essentially of" is defined as including only those elements, limitations, steps, and / or characteristics specifically recited in the claim, as well as those elements, limitations, steps, and / or characteristics that do not materially affect the basic and novel characteristic(s) of the claimed subject matter. Thus, the open-ended transitional phrase "comprising" (and its corresponding open-ended transitional phrase) includes within its meaning, in limited cases, the claimed subject matter identified by the open-ended transitional phrase "consisting of" or "consisting essentially of."Such embodiments described herein or so claimed with the phrase "comprising" are expressly or essentially expressly described, enabled and supported herein by the phrases "consisting essentially of" and "consisting of."

[0052] The terms "about" or "generally" as used herein and in the claims, where applicable, mean a margin of ±20% unless otherwise indicated. Also, the term "substantially" as used herein and in the claims, where applicable, mean a margin of ±10% unless otherwise indicated. It should be recognized that not all uses of the above terms are quantifiable such that a referenced range may be applicable.

[0053] The term "active agent" or "active ingredient" refers to a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect in a subject to which it is administered. In other words, "active agent" or "active ingredient" refers to the component or components of a composition to which all or part of the composition's effect is attributable. The active agent may be a primary active agent, or in other words, the component(s) of the composition to which all or part of the composition's effect is attributable. The active agent may be a secondary agent, or in other words, the component(s) of the composition to which additional portions of the composition and / or other effects are attributable.

[0054] The term "cancer" includes adenoid cystic carcinoma, adrenal carcinoma, amyloidosis, anal cancer, ataxia telangiectasia, atypical mole syndrome, basal cell carcinoma, cholangiocarcinoma, Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer, brain tumor, breast cancer, male breast cancer, carcinoid tumor, cervical cancer, colorectal cancer, ductal carcinoma in situ, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), HER2 positive breast cancer, pancreatic islet cell tumor, juvenile polyposis syndrome, kidney cancer, laryngeal cancer, leukemia - acute lymphoblastic leukemia, leukemia - acute lymphoblastic (ALL), leukemia - acute myeloid AML, leukemia - adult, leukemia - childhood, leukemia - chronic lymphocytic leukemia - The cancer may include one or more of CLL, leukemia-chronic myeloid-CML, liver cancer, lobular carcinoma, lung cancer, lung cancer-small cell, lymphoma-Hodgkin's lymphoma, lymphoma-non-Hodgkin's lymphoma, malignant glioma, melanoma, meningioma, multiple myeloma, myelodysplastic syndromes (MDS), nasopharyngeal carcinoma, neuroendocrine tumors, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, parathyroid cancer, penile cancer, peritoneal cancer, Peutz-Jeghers syndrome, pituitary tumors, polycythemia vera, prostate cancer, renal cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, sarcoma-Kaposi's sarcoma, skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma, thyroid cancer, uterine (endometrial) cancer, vaginal cancer, and Wilms' tumor. The term "hematological cancer" may include one or more of leukemia, lymphoma, myeloma, myelodysplastic syndrome, and myeloproliferative neoplasm.

[0055] The term "derivative" may refer to any compound that has the same or similar core structure as the compound, but has at least one structural difference, including substitution, deletion, and / or addition of one or more atoms or functional groups. The term "derivative" does not imply that the derivative is synthesized from the parent compound, either as a starting material or intermediate, although this may be the case. The term "derivative" may include prodrugs or metabolites of the parent compound. Derivatives include compounds in which carboxyl groups in the parent compound are derivatized to form methyl and ethyl esters, or other types of esters or hydrazides. Derivatives include compounds in which hydroxyl groups in the parent compound are derivatized to form O-acyl or O-alkyl derivatives. Derivatives include compounds in which a hydrogen bond donor group in the parent compound is replaced with another hydrogen bond donor group, such as OH, NH, or SH. Derivatives include replacing a hydrogen bond acceptor group in the parent compound with another hydrogen bond acceptor group, such as an ester, ether, ketone, carbonate, tertiary amine, imine, thione, sulfone, tertiary amide, and sulfide. Derivatives may also include salt forms, such as pharma- ceutically acceptable salt forms of the parent compound or its derivatives.

[0056] The term "fibrosis" refers to a condition involving the formation of excess fibrous connective tissue in an organ or tissue in a repair or reactive process, which can be a reactive, benign or pathological condition.

[0057] As used herein, "amelioration" means a decrease in one or more negative symptoms of a condition, relative to a cell, organ, tissue, or organism that exhibits an untreated symptom or condition, but for the same amount of time.

[0058] In some embodiments, contacting a compound of the invention with a cell, organ, tissue, or organism can include administering a therapeutically effective amount of the compound to the subject. As used herein, a "therapeutically effective amount" is an amount sufficient to alleviate a negative symptom or condition.

[0059] The term "subject" or "patient" refers to any single animal, more preferably a mammal (including, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human animals such as non-human primates), for which treatment is desired. Most preferably, the patient herein is a human.

[0060] The term "pharmaceutical acceptable carrier" as used herein refers to any solvent, dispersion medium, coating, isotonicity agent, absorption delaying agent, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0061] As used herein, the term "pharmaceutical acceptable composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable carriers.

[0062] The term "pharmaceutical acceptable prodrug" as used herein refers to a prodrug of a compound of the present disclosure, which, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, commensurate with a reasonable benefit / risk ratio, and is effective for their intended use, and, to the extent possible, is a zwitterionic form of the compound of the present disclosure. Discussions are provided in Higuchi et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Roche, EB, (ed.). Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0063] The term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. Compounds included in the compositions of the present invention that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids which may be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, tartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in the compositions of the present invention that contain an amino moiety can form pharma- ceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds contained in the compositions of the present invention that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0064] The term "chemotherapy" refers to a type of cancer treatment that uses one or more anti-cancer drugs (i.e., chemotherapeutic agents). Chemotherapy can be given for curative purposes (typically a combination of drugs) or it can be used to extend life or reduce symptoms (i.e., palliative chemotherapy). Traditional chemotherapy agents are cytotoxic by means of interfering with cell division (mitosis). Common side effects of chemotherapy include bone marrow suppression, mucositis (inflammation of the lining of the digestive tract), and alopecia.

[0065] The term "KRAS" refers to a gene that acts as an "on / off" switch in cell signaling. When it functions normally, it controls cell proliferation. It can be activated allosterically and, together with other cell signaling receptors such as c-Raf and PI3-kinase, can recruit and activate proteins required for growth factors proliferation. Negative signaling can be disrupted when it mutates, causing cells to hyperproliferate and develop into cancer.

[0066] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. These terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of a corresponding naturally occurring amino acid, as well as to naturally occurring and non-naturally occurring amino acid polymers. Methods for obtaining (e.g., generating, isolating, purifying, synthesizing, and recombinantly producing) polypeptides are well known to those of skill in the art.

[0067] The term "RIGS" or "Radiation-Induced Gastrointestinal Syndrome" arises from the direct cytocidal effects of irradiation on intestinal crypt and stromal cells, combined with loss of mucosal barrier and symptoms ranging from diarrhea, electrolyte imbalance, weight loss and death. A significant proportion of patients experience radiation-induced toxicity due to damage to normal tissues in the radiation field. The use of chemical or biological approaches aimed at reducing or preventing normal tissue toxicity induced by radiation treatment has been a long-standing goal.

[0068] The term "radiation therapy" or "radio therapy" generally refers to treatments that use ionizing radiation as part of cancer treatment to control or kill malignant cells. Radiation therapy is usually applied to cancerous tumors for its ability to control cell proliferation. Ionizing radiation works by damaging the DNA of cancerous tissues leading to cell death. The main side effects are fatigue and skin irritation. Acute side effects may include nausea and vomiting, damage to epithelial surfaces, mouth, throat and stomach pain, swelling, and intestinal discomfort. RIGS (Radiation Induced Gastrointestinal Syndrome) is a general term used to describe side effects related to the gastrointestinal system.

[0069] The term "SFRP" or "secreted frizzled-related protein" refers to Wnt signaling pathway inhibitors (sFRPS), which are part of the soluble frizzled-related proteins. sFRPS function as modulators of Wnt signaling through direct interaction with Wnts. Five mammalian sFRPs have been identified (sFRP-1, sFRP-2, sFRP-3, sFRP-4, and sFRP-5). These proteins consist of approximately 300 amino acids, including a signal sequence, a frizzled-like cysteine-rich domain (CRD), and a small hydrophilic C-terminal domain. As a group, sFRPs are expressed in a variety of embryonic and adult tissues, suggesting a common mechanism for inhibiting Wnt signaling. However, individual family members have specific spatial and temporal expression patterns.

[0070] The term "Wnt signaling pathway" refers to a group of signaling pathways that begin with proteins that pass signals into cells through cell surface receptors. The canonical Wnt pathway results in the regulation of gene transcription.

[0071] The term "treating" or "treatment" refers to one or more of: (1) suppression of a disease; e.g., suppression of a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., prevention of further development of the pathology and / or symptomology); and (2) amelioration of a disease; e.g., amelioration of a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., reversal of the pathology and / or symptomology), such as reduction in the severity of the disease. Treatment can be prophylactic and / or therapeutic. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to a host of one or more of the compositions of the invention. If it is administered prior to the clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is prophylactic (i.e., it protects the host from the onset of the undesirable condition), whereas if it is administered after the onset of the undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects).

[0072] The term "TOPFLASH" or "TCF / LEF reporter kit" refers to a kit for monitoring the activity of the Wnt / β-catenin signaling pathway in cultured cells. The kit typically includes a TCF / LEF luciferase reporter vector, which is a Wnt pathway responsive reporter.

[0073] The term "unit dosage form" or "unit" as used herein refers to physically discrete units suitable as unitary doses for human and animal subjects, each unit containing a predetermined amount of compound calculated to be in an amount sufficient to produce a desired effect in association with a pharma- ceutically acceptable diluent, carrier, or vehicle. The specifications for the novel unit dosage forms of the present disclosure depend on the particular compound employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the subject.

[0074] The compounds of the present disclosure may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term "stereoisomers" as used herein consists of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R" or "S" depending on the configuration of the substituents around the asymmetric center carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be named "(±)" in the nomenclature, but one of skill in the art will recognize that the structure may implicitly show chiral centers.

[0075] Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of the mixture of enantiomers to a chiral auxiliary, separation of the resulting diastereomeric mixture by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary, (2) salt formation with an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereopure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0076] Geometric isomers may also exist in the compounds of the present disclosure. The present disclosure encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbon ring. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both E and Z isomers.

[0077] Substituents around a carbon-carbon double bond may also be referred to as "cis" or "trans", with "cis" referring to substituents on the same side of the double bond and "trans" referring to substituents on opposite sides of the double bond. The arrangement of substituents around a carbon ring is named as "cis" or "trans". The term "cis" refers to substituents on the same side of the plane of the ring and the term "trans" refers to substituents on opposite sides of the plane of the ring. Mixtures of compounds in which substituents are located on both the same and opposite sides of the plane of the ring are named "cis / trans".

[0078] The compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended to be encompassed within the scope of the disclosure even if only one tautomeric structure is shown.

[0079] The term "alkoxy" refers to a chemical substituent of formula -OR, where R is an optionally substituted C1-C6 alkyl group, unless otherwise specified. In some embodiments, the alkyl group may be substituted, for example, an alkoxy group may have 1, 2, 3, 4, 5, or 6 substituents as defined herein.

[0080] The term "alkoxyalkyl" refers to a heteroalkyl group, described as an alkyl group, as defined herein, substituted with an alkoxy group. Exemplary unsubstituted alkoxyalkyl groups contain 2-12 carbons. In some embodiments, each of the alkyl and alkoxy can be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0081] The terms "alkyl", "alkenyl" and "alkynyl" include linear, branched and cyclic monovalent substituents containing only C and H when unsubstituted, and combinations thereof. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. The term "cycloalkyl", as used herein, unless otherwise specified, refers to a monovalent saturated or unsaturated non-aromatic cyclic alkyl group having 3 to 9 carbons (e.g., C3-C9 cycloalkyl), exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and the like. When a cycloalkyl group contains one carbon-carbon double bond, the cycloalkyl group can be referred to as a "cycloalkenyl" group. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, and the like. Typically, alkyl, alkenyl and alkynyl groups are 1 to 12 carbons (e.g., C1 to C9 cycloalkyl). 12 alkyl) or 2 to 12 carbons (e.g., C2 to C 12 Alkenyl or C2-C 12 In some embodiments, the alkyl group is a C1-C8, C1-C6, C1-C4, C1-C3, or C1-C2 alkyl group; or a C2-C8, C2-C6, C2-C4, or C2-C3 alkenyl or alkynyl group. Additionally, any hydrogen atom on either of these groups may be replaced with a substituent described herein.

[0082] Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly defined and contain at least one carbon atom, but one or more O, S or N heteroatoms or combinations thereof within the backbone residue, whereby each heteroatom in the heteroalkyl, heteroalkenyl or heteroalkynyl group replaces one carbon atom of the corresponding alkyl, alkenyl or alkynyl group in the heteroform. In some embodiments, the heteroalkyl, heteroalkenyl and heteroalkynyl groups have a C at each end where the group is attached to another group, and the heteroatom(s) present are not located at the terminal position. As understood in the art, these heteroforms do not contain four or more consecutive heteroatoms. In some embodiments, the heteroatom is O or N. The term "heterocyclyl" as used herein refers to a cyclic heteroalkyl or heteroalkenyl that is a 3-, 4-, 5-, 6- or 7-membered ring, containing, for example, 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, unless otherwise specified. The 5-membered ring has 0-2 double bonds, and the 6- and 7-membered rings have 0-3 double bonds. The term "heterocyclyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbon and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as a quinuclidinyl group. The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings are fused with one, two, or three carbocyclic rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, and the like.

[0083] The term "alkylsulfonyl" as used herein refers to a heteroalkyl group, as described herein as an optionally substituted alkyl group, containing an -S(O)2- group.

[0084] The term "amino" as used herein refers to -N(R), where each R is independently H, OH, NO, N(R), SOOR, SOR, SOR, SON(R), SON(R), an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkylcycloalkyl, heterocyclyl (e.g., heteroaryl), alkylheterocyclyl (e.g., alkylheteroaryl), or two R joined together to form a heterocyclyl or an N-protecting group, and each R N2 is independently H, alkyl, or aryl. In a preferred embodiment, amino is -NH2 or -NHR, and R is independently OH, NO2, NH2, NR2, SO2OR, SO2R, SOR, SON(R)2, SON(R), alkyl, or aryl, and each R can be H, alkyl, or aryl. The term "aminoalkyl" as used herein refers to a heteroalkyl group, as defined herein, described as an alkyl group, as defined herein, substituted with an amino group, as defined herein. Each of the alkyl and amino can be further substituted with 1, 2, 3, or 4 substituents, as described herein for each group. For example, the alkyl moiety can include an oxo (=O) substituent.

[0085] An "aromatic" or "aryl" moiety refers to any monocyclic or fused bicyclic ring system that has the characteristics of aromaticity in terms of electron distribution throughout the ring system, and includes monocyclic or fused bicyclic moieties such as phenyl or naphthyl. A "heteroaromatic" or "heteroaryl" also refers to such monocyclic or fused bicyclic ring systems that contain one or more heteroatoms selected from O, S, and N. The inclusion of heteroatoms may also include 5- and 6-membered rings that are considered aromatic. Thus, typical aromatic / heteroaromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzisoxazolyl, imidazolyl, and the like. Phthalimide is also considered aromatic, since tautomers are theoretically possible. Typically, the ring system contains 5-12 ring atoms or 6-10 ring atoms. In some embodiments, the aromatic or heteroaromatic moiety is a 6-membered aromatic ring system, optionally containing 1-2 nitrogen atoms. More particularly, the moiety is optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl or benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzothiazolyl, indolyl. Even more particularly, such moieties are phenyl, pyridyl, or pyrimidyl, and even more particularly, phenyl. "O-aryl" or "O-heteroaryl" refers to an aromatic or heteroaromatic system that is bonded to another moiety via an oxygen atom. A typical example of an O-aryl is phenoxy. Similarly, "arylalkyl" refers to an aromatic or heteroaromatic system, including heteroforms thereof, that is bonded to another residue via a saturated or unsaturated carbon chain, typically C1-C2, C1-C6, or more particularly C1-C4 or C1-C3 when saturated, and C2-C8, C2-C6, C2-C4, or C2-C3 when unsaturated. For greater certainty, arylalkyl thus includes an aryl or heteroaryl group as defined above bonded to an alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl moiety as defined above.Typical arylalkyls are aryl (C6-C. 12 ) Alkyl (C1-C8), Aryl (C6-C 12 ) alkenyl (C2-C8) or aryl (C6-C 12 ) alkynyl (C2-C8), and heteroforms. A typical example is phenylmethyl, commonly called benzyl.

[0086] Halo may be a halogen atom, in particular F, Cl, Br or I, more in particular fluoro or chloro.

[0087] The term "haloalkyl" as used herein refers to an alkyl, as defined herein, substituted with a halogen group (i.e., F, Cl, Br, or I). Haloalkyl can be substituted with 1, 2, 3 halogens, or in the case of alkyls of 2 or more carbons, 4 halogens. Haloalkyl groups include perfluoroalkyl. In some embodiments, haloalkyl groups can be further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups.

[0088] The term "hydroxy" as used herein refers to an --OH group.

[0089] The term "hydroxyalkyl," as used herein, refers to an alkyl, as defined herein, substituted with one, two, three, or more hydroxy groups, provided that not more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by hydroxymethyl, dihydroxypropyl, and the like.

[0090] In general, a substituent (e.g., alkyl, alkenyl, alkynyl, or aryl (including all hetero forms defined above) may itself be substituted by further substituents. The nature of these substituents is similar to that described for the substituents on the base structure above. Thus, when a substituent embodiment is an alkyl, the alkyl may be optionally substituted by the remaining substituents listed as chemically meaningful substituents without violating the size limit of the alkyl itself. For example, an alkyl substituted by an alkyl or alkenyl merely extends the upper carbon atom limit for these embodiments and is not included. For example, when a group is substituted, the group may be substituted with 1, 2, 3, 4, 5, or 6 substituents. Optional substituents include C1-C6 alkyl or heteroaryl, C2-C6 alkenyl or heteroalkenyl, C2-C6 alkynyl or heteroalkynyl, halogen; aryl, heteroaryl, azide. (-N3), nitro (-NO2), cyano (-CN), acyloxy (-OC(=O)R'), acyl (-C(=O)R'), alkoxy (-OR'), amide (-NR'C(=O)R" or -C(=O)NR'R"), amino (-NR'R"), carboxylic acid (-CO2H), carboxylate (-CO2R'), carbamoyl (-OC(=O)NR'R" or -NRC(=O)OR'), hydroxy (-OH), isocyano (-NC), sulfonate (-S(=OH OR), sulfonamide (-S(=OHNRR') or -NRS(=O)2R'), or sulfonyl (-S(=O)2R), where each R or R' is independently selected from H, C1-C6 alkyl or heteroaryl, C2-C6 alkenyl or heteroalkenyl, C2-C6 alkynyl or heteroalkynyl, aryl, or heteroaryl. The substituents may have, for example, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents.

[0091] Exemplary optional substituents are independently halo, CN, NO2, CF3, OCF3, COOR, CONR Y2, OR, SR, SOR, SO2R, NR2, NR(CO)R, NRC(O)OR, NRC(O)NR2, NRSO2NR2, or NRSO2R, where each R is independently H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and aryl, all as defined above; or the substituents can be optionally substituted groups selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, O-aryl, O-heteroaryl, and arylalkyl.

[0092] Other technical terms used herein have their ordinary meaning in the art in which they are used, as exemplified by various technical dictionaries. The specific values ​​and configurations discussed in these non-limiting examples may vary and are cited merely to illustrate at least one embodiment and are not intended to limit the scope thereof.

[0093] Detailed Description It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the present technology as claimed. Additional features and advantages of the present technology will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the present technology. The advantages of the present technology will be realized and attained by the structure particularly pointed out in the description and claims hereof.

[0094] BCN057 and Analogs BCN057, also known as YEL002, has the following structural formula: [ka] It may also be described as (3-[(furan-2-ylmethyl)amino]-2-(7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)-6-methylimidazo[1,2-a]pyridin-1-ium). It will be understood that the present invention encompasses the compound BCN057, its analogs and salts thereof. In one embodiment, the present invention relates to the compound BCN057 in the form of the free base. In another embodiment, the present invention relates to the compound BCN057 or a pharma- ceutically acceptable salt thereof.

[0095] Due to their potential use in medicine, salts of compounds of BCN057 may be preferred as pharma- ceutically acceptable salts. Suitable pharma-ceutically acceptable salts may include acid addition salts. By using a desired acid or base appropriately, pharma-ceutically acceptable salts can be easily prepared. The resulting salts can be precipitated from the solution and collected by filtration or recovered by evaporation of the solvent. Compounds can exist as stereoisomers, tautomers, pharma-ceutically acceptable salts, or hydrates thereof. Some analogs of BCN057 are shown below.

[0096] An embodiment is a therapeutically effective amount of a compound of formula B: [ka] (In the formula, R 1 is an alkyl, alkylamine, or ether; R 2 is H or CH3; and R 3 is H or OH) The present invention also includes a method of treatment comprising administering a compound having the structure:

[0097] In some embodiments, the compound is an analog selected from Formulas II-XIX, including Compound H, Compound K, Compound BNB-1, Compound BNB-2, Compound BNB-3, Compound BNB-4, and Compound BNB-5. [Table 1] TIFF2025032222000015.tif242162TIFF2025032222000016.tif242162TIFF20250322220 00017.tif242162TIFF2025032222000018.tif242162TIFF2025032222000019.tif242162

[0098] BCN512 and Analogs The structure of the compound BCN512 is shown below as formula XXI, and is also known as 1-[(4-nitrobenzene)sulfonyl]-4-phenylpiperazine. [ka]

[0099] In some embodiments, the compound is an analog selected from Formulas XXII-XXVII. [Table 2] TIFF2025032222000022.tif242162TIFF2025032222000023.tif84162

[0100] The compounds of formulas I-XXVIII disclosed herein or analogs thereof can be prepared according to methods established in the field of organic synthesis. General methods for synthesizing the compounds can be found, for example, in Stuart Warren and Paul Wyatt, Workbook for Organic Synthesis: The Disconnection Approach, 2nd Edition, Wiley, 2010. Exemplary methods for preparing the compounds are provided in U.S. Patent Application No. 13 / 813,923 and U.S. Patent Application No. 14 / 889,719, which are incorporated herein by reference. The compounds also include their pharma- ceutical acceptable salts, their prodrugs, their hydrates, their solvates and their polymorphic crystals. The compounds can be administered as pharmaceutical compositions.

[0101] Usefulness and Administration The compounds described herein are useful in the methods of the present invention, and are believed to exert their desired effects in part through their ability to regulate Wnt β-catenin signaling, without being bound by theory. The Wnt pathway is involved in tissue development in embryos and tissue maintenance in adults. It controls a specific set of genes that control cell growth, migration and cell survival. Chronic activation of these genes and abnormal activation of the Wnt pathway can lead to uncontrolled cell proliferation and survival, and can ultimately promote the formation of cancer in a range of tissues, including colon, skin, liver and ovary.

[0102] The Wnt signaling pathway is a group of signal transduction pathways that begin with proteins that pass signals into the cell through cell surface receptors. Aberrant activation of the Wnt pathway has been implicated in human cancers, particularly those of the gastrointestinal (GI) tract. Inhibition of aberrant Wnt pathway activity in cancer cell lines can block their proliferation, presenting a potential new therapeutic agent.

[0103] Wnt ligands bind to LRP5 / 6 and frizzled co-receptors present on epithelial crypt cells, resulting in β-catenin stabilization and nuclear translocation, where it binds to the nuclear transcription factor TCF4 to promote gene expression programs that support stem cell maintenance, proliferation and differentiation. Activation of Wnt / β-catenin signaling is also important for crypt regeneration after injury. Studies have demonstrated that respondin 1 (RSPO1), ISC growth factor and LGR5 receptor agonists activate the Wnt / β-catenin pathway to repair and regenerate the intestine after chemoradiation-induced injury. DKK1, a negative regulator of the Wnt / β-catenin pathway, impairs RSPO1-induced intestinal regeneration.

[0104] In the absence of Wnt signals, the transcriptional activator β-catenin is actively degraded in cells. Phosphorylated β-catenin is then recognized and ubiquitinated, leading to its proteasomal degradation. As a result, the levels of free β-catenin are kept low, which allows DNA-binding T-cell factor / lymphoid enhancer factor (Tcf / Lef) proteins to interact with transcriptional corepressors to block target gene expression in the nucleus.

[0105] In addition to treating cancer, therapies that regulate Wnt / β-catenin signaling also hold promise for treating other diseases, including fibrosis, inflammatory conditions, bone growth, wound healing, osteoporosis, alopecia (i.e., hair loss), depression, and viral infections. Thus, there is a need for compounds and methods that can inhibit and / or modulate Wnt / β-catenin signaling.

[0106] BCN057 and Analogs - Cancer Treatment and Therapeutics Studies have demonstrated that the Wnt pathway is permanently activated in both hereditary familial coli polyposis and spontaneous forms of colon cancer. Chronic activation of the Wnt pathway in these cells promotes their expansion into benign adenomas (also called polyps), which often progress to invasive colon cancer. Approximately 90% of sporadic colon cancers exhibit aberrant Wnt signaling activity, usually as a result of mutations in APC.

[0107] BCN057 is an anti-neoplastic small molecule that is effective in the treatment of cancer, particularly pancreatic and gastrointestinal (GI) cancers. It can function with a dual effect: it induces apoptosis in cancer cells. Secondly, it can promote epithelial cell proliferation and survival. BCN057 is particularly effective against pancreatic and gastrointestinal (GI) cancers. BCN057 has demonstrated anti-tumor effects against "KRAS" cancers.

[0108] Radiation / chemotherapy-related uses BCN057 is effective in treating cancer, particularly pancreatic and gastrointestinal (GI) cancer. In one aspect, disclosed herein is a method of treating radiation-induced gastrointestinal syndrome (RIGS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of BCN057 or an analog of BCN057. The analog can be one or more of the compounds of formulas II-XIX. BCN057 can alleviate RIGS and improve the therapeutic ratio for abdominal radiotherapy. Additionally, BCN057 alleviates radiation-induced mucositis, including oral mucositis, GI mucositis, e.g., throat, stomach and intestines, enteritis and mastitis. Additionally, it can prevent and treat epithelial tissue damage from radiation and chemotherapy. These compounds are also useful for treating or preventing these radiation syndromes associated with radiation therapy.

[0109] Combination therapy Combination therapy is particularly effective with drugs that act by different mechanisms, thereby reducing the possibility of developing resistant cancer cells. When drugs with different effects are combined, each drug can be used at an optimal dose without producing unacceptable side effects. BCN057 and a second drug can be combined for therapeutic effect. The second drug can have a different mechanism. Alternatively, it can use the same mechanism as BCN057 for therapeutic effect. This combination can act through synergistic effects. Combination therapy can also include additional (e.g., third, fourth, fifth, etc.) drugs. BCN512 can be used in combination therapy as well.

[0110] BCN512 and Analogs - SFRP-Mediated Therapy Many colon cancers carry silent genes encoding secreted Fzd-related proteins (SFRPs) or members of the Wnt inhibitory factor (WIF) family, which act as natural brakes on the Wnt pathway. They can bind Wnt ligands and block pathway activation at the cell surface. Without this inhibition, Wnt ligands produced by cancer cells can activate the pathway at the membrane and amplify aberrant Wnt signaling activity initiated by mutations in APC, β-catenin, or Axin2. This aberrant Wnt pathway activation can lead to cancer.

[0111] Wnt signaling is initiated when Wnt proteins bind to the N-terminal extracellular cysteine-rich domain of Frizzled (Fzd) family receptors. When sfrps are inhibited or at low levels, wnt ligands can bind to Fzd receptors and mediate wnt-related gene expression. sfrps also have antiproliferative effects on vascular cells in vitro and in vivo. In the vascular cell cycle, they delay the G1 phase and enter the S phase. In renal development, sFRPS inhibit tubule formation and blastema growth in the metanephros.

[0112] BCN512 can inhibit SFRP activity and destroy their ability to bind wnt ligands. SFRPs act as negative regulators of wnt signaling by binding to wnt ligands through domains similar to the fzd receptor domain that binds to wnt when free to transmit canonical wnt signaling. This mechanism presents several therapeutic applications. BCN512 and its analogs can suppress tissue fibrosis through inhibiting SFRPs, including SRFP1. BCN512 and its analogs can activate bone growth by inhibiting SRFPs. BCN512 and its analogs can activate hair growth by inhibiting SRFPs.

[0113] If BCN512 and related structures inhibit the activity of SRFP, BCN512 can free Wnt ligands from epithelial cells more. The free Wnt ligands are transported and secreted via exosomes. To determine the role of BCN512 in Wnt release from lung epithelia, exosomes were purified from organoid-conditioned medium. Purified exosomes were tested for Wnt activity by TOPFLASH assay. Exosomal Wnt activity was observed to be several-fold higher in samples prepared from BCN512-treated and irradiated organoids compared to irradiated controls. These results suggest that BCN512 also induces endogenous Wnt release.

[0114] Further studies demonstrated that Wnt β-catenin signaling plays an important role in restoring the bronchial epithelial stem cell pool. Previous studies demonstrated that Wnt ligands were secreted and transported through exosomes. It was demonstrated that exosomes derived from mouse ex vivo lung organoids contained Wnt ligands and exhibited Wnt activity in response to BCN512 treatment. Wnt activity has also been examined in exosomes derived from human lung organoids.

[0115] Regarding the role of BCN512 in Wnt release from human lung epithelium, exosomes were purified from organoid-conditioned medium. Purified exosomes were tested for Wnt activity by TOPFLASH assay. Exosomal Wnt activity was observed to be several-fold higher in samples prepared from BCN512-treated and irradiated organoids (4–6 Gy) compared to irradiated controls. These results suggest that BCN512 also induces endogenous Wnt release from human lung epithelium.

[0116] inflammatory diseases BCN512 can be used to treat inflammatory diseases or conditions. Inflammatory skin diseases include conditions associated with cell proliferation, such as psoriasis, eczema, and dermatitis (e.g., eczematous dermatitis, topical and seborrheic dermatitis, allergic or irritant contact dermatitis, fissured eczema, photoallergic dermatitis, phototoxic dermatitis, phytophotodermatitis, radiation dermatitis, and stasis dermatitis). Other inflammatory skin diseases include, but are not limited to, scleroderma, ulcers and erosions caused by trauma, burns, bullous lesions, or ischemia of the skin or mucous membranes, some forms of ichthyosis, epidermolysis bullosa, hypertrophic scars, keloids, skin changes of intrinsic aging, photoaging, friction blisters caused by mechanical shearing of the skin, and skin atrophy caused by topical use of corticosteroids. Further inflammatory skin conditions include inflammation of the mucous membranes, such as cheilitis, chapped lips, nasal inflammation, mucositis, and vulvovaginitis.

[0117] Inflammatory disorders of the endocrine system include, but are not limited to, autoimmune thyroiditis (Hashimoto's disease), diabetes mellitus type I, and acute and chronic inflammation of the adrenal cortex. Inflammatory conditions of the cardiovascular system include, but are not limited to, vascular disease associated with coronary infarction injury, peripheral vascular disease, myocarditis, vasculitis, revascularization of stenosis, atherosclerosis, and diabetes mellitus type II.

[0118] Renal inflammatory conditions include glomerulonephritis, interstitial nephritis, lupus nephritis, nephritis secondary to Wegener's disease, acute renal failure secondary to acute nephritis, Goodpasture's syndrome, post-obstructive syndrome, tubular ischemia, irritable bowel disorder, or inflammation-induced colonic malignancy.

[0119] Inflammatory conditions of the liver include hepatitis (arising from viral infection, autoimmune response, drug treatment, toxins, environmental factors, or as a secondary consequence of a primary insult), biliary atresia, primary biliary cirrhosis, and primary sclerosing cholangitis.

[0120] Inflammatory conditions of the central nervous system include neurodegenerative diseases such as multiple sclerosis and dementia associated with Alzheimer's disease, Parkinson's disease, or HIV infection.

[0121] Other inflammatory conditions include periodontal disease, tissue necrosis in chronic inflammation, endotoxic shock, smooth muscle proliferation disorders, graft-versus-host disease, tissue damage following ischemia-reperfusion injury, idiopathic pulmonary fibrosis, and tissue rejection following transplant surgery.

[0122] Treating viral infections Further embodiments include the use of BCN057 and analogs of BCN057 for the treatment of viral infections. Viral disease infections occur when a pathogenic virus invades the body and infectious viral particles attach to and invade susceptible cells. The host immune response can mediate disease and excessive inflammation. Stimulation of the innate and adaptive immune systems in response to viral infections can destroy infected cells, resulting in severe pathological consequences for the host (i.e., virus-induced immunopathology). Specifically, immunopathology is caused by excessive release of antibodies, interferons and inflammatory cytokines, activation of the complement system, or overactivity of cytotoxic T cells. Secretion of interferons and other cytokines can cause cell damage, fever, and flu-like symptoms. In severe cases of certain viral infections, such as the 2005 avian H5N1 influenza, aberrant induction of the host immune response can trigger a flare release of cytokines known as a cytokine storm.

[0123] Wnt signaling is important for the innate immune response to viruses. Pathogenic viruses suppress the downstream expression of β-catenin of important genes to evade the first line of defense in the immune system. β-catenin is essential for the expression of IFN-α / β and the subsequent transcriptional activation of interferon-stimulated genes. IFN-β induces autocrine and paracrine expression of antiviral genes. Therefore, BCN057 and analogs of BCN057 can prevent pathological outcomes such as virus-induced immunopathology.

[0124] Treating depression Further embodiments include the use of BCN057 and analogs of BCN057 for the treatment of depression. Wnt signaling is also important in treating depression. Since the 1950s, lithium carbonate and other salts have been used to treat depression as well. Lithium acts by inhibiting GSK3b in the wnt downstream signal pathway and transcribing β-catenin downstream genes.

[0125] Recent studies have demonstrated that altered Wnt signaling may play a role in the pathophysiology of mood disorders. β-catenin levels are reduced in the CA3 and CA4 regions of the hippocampus, and Wnt1 levels are increased in the CA4 region of the hippocampus in postmortem schizophrenic brains. Lithium inhibits glycogen synthase kinase 3β (GSK3β), a component of the canonical Wnt pathway, and this pathway has been proposed as a specific target in the treatment of bipolar disorder. Therefore, BCN057 and analogs of BCN057 may be used to treat depression and mood disorders. EXAMPLES

[0126] The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of the representative embodiments contemplated herein, and are not to be construed as limiting any of the embodiments described herein, including with respect to the compounds, pharmaceutical compositions, or methods and uses disclosed herein.

[0127] BCN057 for the treatment of pancreatic cancer Figure 1 shows the effect of 5-FU and BCN057 on the viability of pancreatic cancer cell lines. The effect of 5-FU and BCN057 on the viability of pancreatic cancer cell lines was evaluated by ATP Lite assay (Perkin Elmer). 50uM 5Fu (5Fu, n=5), 50uM 5Fu and 2, 5, 10, and 20uM BCN057 (5Fu+BCN057, n=5), or 2, 5, 10, and 20uM CN057 (CN057, n=5). Control cells (V, n=5). Phosphorylation rates were calculated by dividing the average value of each condition by the average value of control cells (V) at each time point.

[0128] Figures 2A and 2B show Annexin V apoptosis and necrosis assays in Panc-1 cells. Panc-1 cells were exposed to serial dilutions of 057 in the presence or absence of RealTime-Glo™ Annexin V Apoptosis and Necrosis Assay Reagent. Plates were incubated at 37°C / 5% CO2 and luminescence (Annexin V binding) was measured over 6 hours. No change in fluorescence was observed over the same period. Apoptosis appeared to increase with increasing concentrations of BCN057. Figure 2A shows apoptosis observed at 10 minutes (dose dependent). Figure 2B shows apoptosis observed at 10 minutes, 30 minutes, 1 hour and 6 hours.

[0129] Figure 3 shows the effect of 10 μM BCN057 on the viability of pancreatic cancer cell lines. Images show pancreatic cancer cell lines at time 0 (Figure 3A), 15 min (Figure 3B), 30 min (Figure 3C), 60 min (Figure 3D), 120 min (Figure 3E), and 240 min (Figure 3F). Morphological changes and apoptosis are particularly evident at 240 min.

[0130] Figures 4A and 4B show the results of a viability assay for Compound H, Compound K, and pancreatic cells. The graph (Figure 4A) shows the effect on Panc-1 cancer cell viability over 24, 48, and 72 hours in the presence of 10 μM BCN057, Compound H, or K. Each replicate (n=3) is shown as a percentage of its vehicle control (a% of control). Numerical data is also included (Figure 4B). Figure 5A shows Compound H and Figure 5B shows Compound K.

[0131] The results demonstrate that BCN057 has potent antitumor activity and inhibits the proliferation of tumor cell lines, an activity that is complementary to chemotherapy such as 5-fluorouracil.

[0132] This study also demonstrates that BCN057 restores apoptosis in pancreatic cancer cells. Conversely, BCN057 allows stem cell survival and thus prevents damage from chemotherapy-induced damage to the epithelial tissue lining the digestive canal and digestive tract.

[0133] BCN512 for the treatment of fibrosis Fibrosis is generally defined as a pathological wound healing in which connective tissue replaces normal parenchymal tissue unchecked, resulting in significant tissue remodeling and the formation of permanent scar tissue. Pulmonary fibrosis is a lung disease that occurs when lung tissue is damaged and scarred. As explained herein (par.095), any organ in the body can mount a repair response that generally results in fibrotic lesions. Pulmonary fibrosis as a result of chronic obstructive pulmonary disease and liver fibrosis due to hepatitis infection are two examples.

[0134] We propose that type II pneumocytes function as progenitor cells to repair damaged alveolar epithelium. Moreover, damaged epithelial cells are also the main source of inflammatory cytokines. Therefore, reducing epithelial damage and progenitor / stem-related remodeling is important for preventing or treating fibrosis.

[0135] Figure 6 shows the number of fibrotic lesions in lung sections (untreated and treated with BCN512). Upon terminal necropsy and histological analysis of the lungs in C57BL mice, there was a significant reduction in pulmonary fibrosis with BCN512 treatment (20x512) vs. vehicle (20xV). Lesions are defined by regional density with 5 mice per group evaluated at day 180. This effect is observed with non-radioactive inducing stimuli such as LPS and cytotoxic drugs.

[0136] Transforming growth factor beta (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases, regulating fibroblast phenotype and function, and inducing myofibroblast transdifferentiation while promoting matrix preservation. Figure 7 shows the histopathology of lung sections stained for TGFβ in C57M male mice receiving nothing (A), 14 Gy of thoracic irradiation (B), or irradiation and BCNB512 (C), each assessed at day 90. TGFβ is reduced when treated with 5 mg / kg BCN512 for the first 20 days after irradiation. Images D-F are myocardial staining under the same parameters from the same animals. We observed a significant reduction in staining for TGFβ. This indicates that TGF-β staining is lower in tissues from radiation injury when treated with BCN512. We expect the same results using non-radioactive inducer stimuli including LPS and cytotoxic drugs.

[0137] These studies and observations are consistent with previous observations, specifically that WNT-catenin signaling promotes self-renewal and differentiation of LGR5+ epithelial (lung, oral, intestinal) stem cells. Standard WNT activity was measured in HEK293 cells with a TCF / LEF luciferase reporter construct. Luciferase activity was measured after 24 hours. BCN512 treatment significantly increased luciferase activity in HEK293 cells compared to vehicle-treated cells.

[0138] The regulation of macrophage function is also modulated. The absence of late effects of fibrosis from chronically irradiated animals (observations from long-term studies of total body irradiation studies) along with the reduction of fibroblasts indicates that these drugs are effective in preventing fibrosis and inflammation from both irradiation or chemical means (LPS). Furthermore, fibroblast proliferation is macrophage-dependent, and BCN512 inhibits this macrophage function. Taken together, the above results demonstrate that the compound BCN512 can be administered to preserve stem and progenitor cells. This prevents connective tissue from replacing normal parenchymal tissue, thus preventing fibrosis.

[0139] Pharmaceutical Carriers and Administration The methods of the invention may prevent a disease or condition, or one or more symptoms of a disease or condition. As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

[0140] The compositions and methods of the present disclosure can be utilized to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered or used as a pharmaceutical composition, for example comprising a compound of the present disclosure and a pharma- ceutical acceptable carrier.

[0141] Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or saline, or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to delay release of the drug or to selectively target one or more cells, tissues, or organs. Pharmaceutical compositions can be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized for reconstitution, powders, solutions, syrups, suppositories, injections, and the like. The compositions can be present in transdermal delivery systems, for example, skin patches.

[0142] The pharmaceutical compositions disclosed herein may contain a therapeutic compound in an amount sufficient to allow for normal administration to an individual. In certain embodiments, the pharmaceutical compositions disclosed herein may contain, for example, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeutic compound. In certain embodiments, a pharmaceutical composition disclosed herein may contain, for example, at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a therapeutic compound. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein may contain, for example, in the range of about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg.In further specific embodiments, the pharmaceutical compositions disclosed herein may be administered in a dose range of, for example, about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg.

[0143] The pharmaceutical compositions disclosed herein may include a solvent, emulsion, or other diluent in an amount sufficient to dissolve the therapeutic compounds disclosed herein. In certain embodiments, the pharmaceutical compositions disclosed herein may include a solvent, emulsion, or diluent in an amount of, for example, less than about 90% (v / v), less than about 80% (v / v), less than about 70% (v / v), less than about 65% (v / v), less than about 60% (v / v), less than about 55% (v / v), less than about 50% (v / v), less than about 45% (v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v), less than about 25% (v / v), less than about 20% (v / v), less than about 15% (v / v), less than about 10% (v / v), less than about 5% (v / v), or less than about 1% (v / v). In certain embodiments, the pharmaceutical compositions disclosed herein may be, for example, from about 1% (v / v) to 90% (v / v), from about 1% (v / v) to 70% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 40% (v / v), from about 1% (v / v) to 30% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 70% (v / v), from about 1% (v / v) to 80% (v / v), from about 1% (v / v) to 90% (v / v), from about 1% (v / v) to 100% (v / v), from about 1% (v / v) to 150% (v / v), from about 1% (v / v) to 20% (v / v), from about 1% (v / v) to 25% (v / v), from about 1% (v / v) to 30% (v / v), from about 1% (v / v) to 40% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 70% (v / v), from about 1% (v / v) to 80% (v / v), from about 1% (v / v) to 15% (v / v), from about 1% (v / v) to 25% (v / v), from about 1% (v / v) to 30 v) ~ 20% (v / v), approximately 1% (v / v) ~ 10% (v / v), approximately 2% (v / v) ~ 50% (v / v), approximately 2% (v / v) ~ 40% (v / v), approximately 2% (v / v) )~30%(v / v), approx. 2%(v / v)~20%(v / v), approx. 2%(v / v)~10%(v / v), approx. 4%(v / v)~50%(v / v), approx. 4%(v / v) ~40%(v / v), approx. 4%(v / v)~30%(v / v), approx. 4%(v / v)~20%(v / v), approx. 4%(v / v)~10%(v / v), approx. 6%(v / v)~ 50%(v / v), approx. 6%(v / v)~40%(v / v), approx. 6%(v / v)~30%(v / v), approx. 6%(v / v)~20%(v / v), approx. 6%(v / v)~1 It may contain a solvent, emulsion or other diluent in an amount ranging from 0% (v / v), about 8% (v / v) to 50% (v / v), about 8% (v / v) to 40% (v / v), about 8% (v / v) to 30% (v / v), about 8% (v / v) to 20% (v / v), about 8% (v / v) to 15% (v / v), or about 8% (v / v) to 12% (v / v).

[0144] The final concentration of the therapeutic compound disclosed herein in the pharmaceutical composition disclosed herein can be any suitable concentration. In certain embodiments, the final concentration of the therapeutic compound in the pharmaceutical composition can be a therapeutically effective amount. In certain embodiments, the final concentration of the therapeutic compound in the pharmaceutical composition can be, for example, at least 0.00001 mg / mL, at least 0.0001 mg / mL, at least 0.001 mg / mL, at least 0.01 mg / mL, at least 0.1 mg / mL, at least 1 mg / mL, at least 10 mg / mL, at least 25 mg / mL, at least 50 mg / mL, at least 100 mg / mL, at least 200 mg / mL, at least 500 mg / mL, at least 700 mg / mL, at least 1,000 mg / mL, or at least 1,200 mg / mL. In certain embodiments, the concentration of the therapeutic compound disclosed herein in the solution can be, for example, up to 1,000 mg / mL, up to 1,100 mg / mL, up to 1,200 mg / mL, up to 1,300 mg / mL, up to 1,400 mg / mL, up to 1,500 mg / mL, up to 2,000 mg / mL, up to 2,000 mg / mL, or up to 3,000 mg / mL. In certain embodiments, the final concentration of the therapeutic compound in the pharmaceutical composition can be, for example, about 0.00001 mg / mL to about 3,000 mg / mL, about 0.0001 mg / mL to about 3,000 mg / mL, about 0.01 mg / mL to about 3,000 mg / mL, about 0.1mg / mL to approx. 3,000mg / mL, approx. 1mg / mL to approx. 3,000mg / mL, approx. 250mg / mL to approx. 3,000mg / mL, approx. 500mg / mL to approx. 3,000mg / mL, approx. 750mg / mL to approx. 3,000mg / mL, approx. 1,000 mg / mL ~ approx. 3,000 mg / mL, approx. 100 mg / mL ~ approx. 2,000 mg / mL, approx. 250 mg / mL ~ approx. 2,000 mg / mL, approx. 500 mg / mL ~ approx. 2,000 mg / mL, approx. 750 mg / mL ~ approx. 2,000 mg / mL, approx. 1,000 mg / mL ~ approx. 2,000 mg / mL, approx. 100 mg / mL ~ approx. 1,500 mg / mL, approx. 250 mg / mL ~ approx. 1,500 mg / mL, approx. 500 mg / mL ~ approx. 1,500 mg / mL, approx. 750 mg / mL ~ approx. 1,500 mg / mL, approx. 1,000 mg / mL ~ approx. 1,500 mg / mL, approx. 100 mg / mL ~ approx. 1,200 mg / mL, approx. 250 mg / mL ~ approx. 1,200 mg / mL, approx. 500 mg / mL ~ approx. 1,200 mg / mL, approx. 750 mg / mL ~ approx. 1,200 mg / mL, approx. 1000 m g / mL~about 1,200mg / mL, about 100mg / mL~about 1,000mg / mL, about 250mg / mL~about 1,000mg / mL, about 500mg / mL~about 1,000mg / mL, about 750mg / mL~about 1,000mg / mL, about 100mg / mL mL ~ approx. 750 mg / mL, approx. 250 mg / mL ~ approx. 750 mg / mL, approx. 500 mg / mL ~ approx. 750 mg / mL, approx. 100 mg / mL ~ approx. 500 mg / mL, approx. 250 mg / mL ~ approx. 500 mg / mL, approx. 0.00.001 mg / mL ~ approx. 0.0 The concentration may be in the range of about 0.001 mg / mL, about 0.00001 mg / mL to about 0.001 mg / mL, about 0.00001 mg / mL to about 0.01 mg / mL, about 0.00001 mg / mL to about 0.1 mg / mL, about 0.00001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 10 mg / mL, or about 0.001 mg / mL to about 100 mg / mL.

[0145] In certain embodiments, a therapeutically effective amount of a therapeutic compound disclosed herein generally ranges from about 0.001 mg / kg / day to about 100 mg / kg / day. In certain embodiments, an effective amount of a therapeutic compound disclosed herein can be, for example, at least 0.001 mg / kg / day, at least 0.01 mg / kg / day, at least 0.1 mg / kg / day, at least 1.0 mg / kg / day, at least 5.0 mg / kg / day, at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, at least 35 mg / kg / day, at least 40 mg / kg / day, at least 45 mg / kg / day, or at least 50 mg / kg / day.In certain embodiments, an effective amount of a therapeutic compound disclosed herein can be, for example, about 0.001 mg / kg / day to about 10 mg / kg / day, about 0.001 mg / kg / day to about 15 mg / kg / day, about 0.001 mg / kg / day to about 20 mg / kg / day, about 0.001 mg / kg / day to about 25 mg / kg / day, about 0.001 mg / kg / day to about 30 mg / kg / day, about 0.001 mg / kg / day to about 35 mg / kg / day, about 0.001 mg / kg / day to about 40 mg / kg / day, about 0.001 mg / kg / day to about 50 mg / kg / day, about 0.001 mg / kg / day to about 60 mg / kg / day, about 0.001 mg / kg / day to about 70 mg / kg / day, about 0.001 mg / kg / day to about 80 mg / kg / day, about 0.001 mg / kg / day to about 100 mg / kg / day, about 0.001 mg / kg / day to about 150 mg / kg / day, about 0.001 mg / kg / day to about 20 mg / kg / day, about 0.001 mg / kg / day to about 25 mg / kg / day, about 0.001 mg / kg / day to about 30 mg / kg / day, about 0.001 mg / kg / day to about 150 mg / kg / day, about 0.001 mg / kg / day to about 150 mg / kg / day, about 0.001 mg / kg / day to about 20 mg / kg / day, about 0.001 mg / kg / day to about 35 mg / kg / day, about 0.001 mg / kg / day to about 150 mg / kg / day, about 0. g / day ~ approx. 35 mg / kg / day, approx. 0.001 mg / kg / day ~ approx. 40 mg / kg / day, approx. 0.001 mg / kg / day ~ approx. 45 mg / kg / day, approx. 0.001 mg / kg / day ~ approx. 50 mg / k g / day, about 0.001mg / kg / day to about 75mg / kg / day, about 0.001mg / kg / day to about 100mg / kg / day, about 0.001mg / kg / day to about 150mg / kg / day, about 0.00 1mg / kg / day to about 200mg / kg / day, about 0.001mg / kg / day to about 250mg / kg / day, about 0.001mg / kg / day to about 300mg / kg / day, about 0.001mg / kg / day ~350mg / kg / day, approx. 0.001mg / kg / day ~ approx. 400mg / kg / day, approx. 0.001mg / kg / day ~ approx. 450mg / kg / day, approx. 0.001mg / kg / day ~ approx. 500mg / kg / day, about 0.001 mg / kg / day to about 550 mg / kg / day, about 0.001 mg / kg / day to about 600 mg / kg / day, about 0.001 mg / kg / day to about 650 mg / kg / day, about 0.001 mg / kg / day to about 700 mg / kg / day, about 0.001 mg / kg / day to about 750 mg / kg / day, or about 0.001 mg / kg / day to about 800 mg / kg / day.In yet other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein can be, for example, from about 0.01 mg / kg / day to about 10 mg / kg / day, from about 0.01 mg / kg / day to about 15 mg / kg / day, from about 0.01 mg / kg / day to about 20 mg / kg / day, from about 0.01 mg / kg / day to about 25 mg / kg / day, from about 0.01 mg / kg / day to about 30 mg / kg / day, from about 0.0 1mg / kg / day ~ approx. 35mg / kg / day, approx. 0.01mg / kg / day ~ approx. 40mg / kg / day, approx. 0.01mg / kg / day ~ approx. 45mg / kg / day, approx. 0.01mg / kg / day ~ approx. 5 0mg / kg / day, about 0.01mg / kg / day to about 75mg / kg / day, about 0.01mg / kg / day to about 100mg / kg / day, about 0.01mg / kg / day to about 150mg / kg / day, about 0.01mg / kg / day ~ approx. 200mg / kg / day, approx. 0.01mg / kg / day ~ approx. 250mg / kg / day, approx. 0.01mg / kg / day ~ approx. 300mg / kg / day, approx. 0.01mg / k g / day ~ approx. 350 mg / kg / day, approx. 0.01 mg / kg / day ~ approx. 400 mg / kg / day, approx. 0.01 mg / kg / day ~ approx. 450 mg / kg / day, approx. 0.01 mg / kg / day ~ approx. 500 m g / kg / day, about 0.01 mg / kg / day to about 550 mg / kg / day, about 0.01 mg / kg / day to about 600 mg / kg / day, about 0.01 mg / kg / day to about 650 mg / kg / day, about 0.01 mg / kg / day to about 700 mg / kg / day, about 0.01 mg / kg / day to about 750 mg / kg / day, or about 0.01 mg / kg / day to about 800 mg / kg / day.In certain embodiments, an effective amount of a therapeutic compound disclosed herein can be, for example, about 0.1 mg / kg / day to about 10 mg / kg / day, about 0.1 mg / kg / day to about 15 mg / kg / day, about 0.1 mg / kg / day to about 20 mg / kg / day, about 0.1 mg / kg / day to about 25 mg / kg / day, about 0.1 mg / kg / day to about 30 mg / kg / day, about 0.1 mg / kg / day to about 35 mg / kg / day, about 0.1 mg / kg / day to about 40 mg / kg / day, about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.1 mg / kg / day to about 60 mg / kg / day, about 0.1 mg / kg / day to about 70 mg / kg / day, about 0.1 mg / kg / day to about 80 mg / kg / day, about 0.1 mg / kg / day to about 90 mg / kg / day, about 0.1 mg / kg / day to about 100 mg / kg / day, about 0.1 mg / kg / day to about 150 mg / kg / day, about 0.1 mg / kg / day to about 20 mg / kg / day, about 0.1 mg / kg / day to about 25 mg / kg / day, about 0.1 mg / kg / day to about 30 mg / kg / day, about 0.1 mg / kg / day to about 15 ... g / day ~ approx. 35 mg / kg / day, approx. 0.1 mg / kg / day ~ approx. 40 mg / kg / day, approx. 0.1 mg / kg / day ~ approx. 45 mg / kg / day, approx. 0.1 mg / kg / day ~ approx. 50 mg / day kg / day, about 0.1 mg / kg / day to about 75 mg / kg / day, about 0.1 mg / kg / day to about 100 mg / kg / day, about 0.1 mg / kg / day to about 150 mg / kg / day, about 0.1 mg / kg / day ~ approx. 200 mg / kg / day, approx. 0.1 mg / kg / day ~ approx. 250 mg / kg / day, approx. 0.1 mg / kg / day ~ approx. 300 mg / kg / day, approx. 0.1 mg / kg / day ~350mg / kg / day, approx. 0.1mg / kg / day ~ approx. 400mg / kg / day, approx. 0.1mg / kg / day ~ approx. 450mg / kg / day, approx. 0.1mg / kg / day ~ approx. 500mg / day The dose may be in the range of about 0.1 mg / kg / day to about 550 mg / kg / day, about 0.1 mg / kg / day to about 600 mg / kg / day, about 0.1 mg / kg / day to about 650 mg / kg / day, about 0.1 mg / kg / day to about 700 mg / kg / day, about 0.1 mg / kg / day to about 750 mg / kg / day, or about 0.1 mg / kg / day to about 800 mg / kg / day.In certain embodiments, an effective amount of a therapeutic compound disclosed herein can be, for example, about 10 mg / kg / day to about 15 mg / kg / day, about 10 mg / kg / day to about 20 mg / kg / day, about 10 mg / kg / day to about 25 mg / kg / day, about 10 mg / kg / day to about 30 mg / kg / day, about 10 mg / kg / day to about 35 mg / kg / day, about 10 mg / kg / day to about 40 mg / kg / day, about 10 mg / kg / day to about 45 mg / kg / day, about 10 mg / kg / day to about 50 mg / kg / day, about 10 mg / kg / day to about 75 mg / kg / day, about 10 mg / kg / day to about 100 mg / kg / day, about 10 mg / kg / day to about 150 mg / kg / day, about 10 mg / kg / day to about 20 The dose may be in the range of about 0 mg / kg / day, about 10 mg / kg / day to about 250 mg / kg / day, about 10 mg / kg / day to about 300 mg / kg / day, about 10 mg / kg / day to about 350 mg / kg / day, about 10 mg / kg / day to about 400 mg / kg / day, about 10 mg / kg / day to about 450 mg / kg / day, about 10 mg / kg / day to about 500 mg / kg / day, about 10 mg / kg / day to about 550 mg / kg / day, about 10 mg / kg / day to about 600 mg / kg / day, about 10 mg / kg / day to about 650 mg / kg / day, about 10 mg / kg / day to about 700 mg / kg / day, about 10 mg / kg / day to about 750 mg / kg / day, or about 10 mg / kg / day to about 800 mg / kg / day.

[0146] In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein can be in the range of, for example, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 15 mg / kg / day, about 1 mg / kg / day to about 20 mg / kg / day, about 1 mg / kg / day to about 25 mg / kg / day, about 1 mg / kg / day to about 30 mg / kg / day, about 1 mg / kg / day to about 35 mg / kg / day, about 1 mg / kg / day to about 40 mg / kg / day, about 1 mg / kg / day to about 45 mg / kg / day, about 1 mg / kg / day to about 50 mg / kg / day, about 1 mg / kg / day to about 75 mg / kg / day, or about 1 mg / kg / day to about 100 mg / kg / day. In certain embodiments, an effective amount of a therapeutic compound disclosed herein can be in the range of, for example, about 5 mg / kg / day to about 10 mg / kg / day, about 5 mg / kg / day to about 15 mg / kg / day, about 5 mg / kg / day to about 20 mg / kg / day, about 5 mg / kg / day to about 25 mg / kg / day, about 5 mg / kg / day to about 30 mg / kg / day, about 5 mg / kg / day to about 35 mg / kg / day, about 5 mg / kg / day to about 40 mg / kg / day, about 5 mg / kg / day to about 45 mg / kg / day, about 5 mg / kg / day to about 50 mg / kg / day, about 5 mg / kg / day to about 75 mg / kg / day, or about 5 mg / kg / day to about 100 mg / kg / day.

[0147] In liquid and semisolid formulations, the concentration of the therapeutic compounds disclosed herein can typically be from about 50 mg / mL to about 1,000 mg / mL. In certain embodiments, the therapeutically effective amount of a therapeutic agent disclosed herein can be, for example, from about 50 mg / mL to about 100 mg / mL, from about 50 mg / mL to about 200 mg / mL, from about 50 mg / mL to about 300 mg / mL, from about 50 mg / mL to about 400 mg / mL, from about 50 mg / mL to about 500 mg / mL, from about 50 mg / mL to about 600 mg / mL, from about 50 mg / mL to about 700 mg / mL, from about 50 mg / mL to about 800 mg / mL, from about 50 mg / mL to about 900 mg / mL, from about 50 mg / mL to about 1,000 mg / mL, or from about 100 mg / mL. g / mL~about 200mg / mL, about 100mg / mL~about 300mg / mL, about 100mg / mL~about 400mg / mL, about 100mg / mL~about 500mg / mL, about 100mg / mL~about 600mg / mL, about 100mg / mL~about 700mg / mL, about 100mg / mL to approx. 800mg / mL, approx. 100mg / mL to approx. 900mg / mL, approx. 100mg / mL to approx. 1,000mg / mL, approx. 200mg / mL to approx. 300mg / mL, approx. 200mg / mL to approx. 400mg / mL, approx. 200mg / mL to approx. 500m g / mL, approximately 200 mg / mL to approximately 600 mg / mL, approximately 200 mg / mL to approximately 700 mg / mL, approximately 200 mg / mL to approximately 800 mg / mL, approximately 200 mg / mL to approximately 900 mg / mL, approximately 200 mg / mL to approximately 1,000 mg / mL, approximately 300 mg / mL ~400mg / mL, 300mg / mL~500mg / mL, 300mg / mL~600mg / mL, 300mg / mL~700mg / mL, 300mg / mL~800mg / mL, 300mg / mL~900mg / mL, 300m g / mL~about 1,000mg / mL, about 400mg / mL~about 500mg / mL, about 400mg / mL~about 600mg / mL, about 400mg / mL~about 700mg / mL, about 400mg / mL~about 800mg / mL, about 400mg / mL~about 900mg / mL , about 400mg / mL to about 1,000mg / mL, about 500mg / mL to about 600mg / mL, about 500mg / mL to about 700mg / mL, about 500mg / mL to about 800mg / mL, about 500mg / mL to about 900mg / mL, about 500mg / mL to about 1,The concentration may be about 600 mg / mL to about 700 mg / mL, about 600 mg / mL to about 800 mg / mL, about 600 mg / mL to about 900 mg / mL, or about 600 mg / mL to about 1,000 mg / mL.

[0148] The subject may be a human, rat, mouse, cat, dog, horse, sheep, cow, monkey, bird, or amphibian. In another embodiment, the cell is in vivo or in vitro. Typical subjects to which the compounds of the present disclosure may be administered are mammals, particularly primates, especially humans. For veterinary applications, a wide range of subjects would be suitable, such as livestock animals, such as cows, sheep, goats, cattle, pigs; poultry, such as chickens, ducks, geese, turkeys; and domesticated animals, especially pets, such as dogs and cats. For diagnostic or research applications, a wide range of mammals are suitable subjects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and pigs, such as inbred pigs. Furthermore, for in vitro applications, such as in vitro diagnostic and research applications, body fluids and cell samples of the above subjects are suitable for use, such as mammals, particularly primates, such as humans, blood, urine, or tissue samples, or blood, urine, or tissue samples of the animals mentioned for veterinary applications.

[0149] When administered to an organism, the compound may be administered by any suitable means. In some embodiments, the compound or formulation is administered orally. In some embodiments, the compound or formulation is administered by injection, e.g., subcutaneous, parenteral, or intravenous injection.

[0150] In some embodiments, the compound may be administered in combination with other potential alleviators. In certain embodiments, the composition may be administered with growth factors, NSAIDs, chemotherapeutic agents, anti-inflammatory agents, antibiotics, metformin (Glucophage, Glumetza, etc.), sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, and / or insulin therapy for the treatment of the above conditions. In one aspect, the growth factor may be G-CSF (also known as filgrastim, NEUPOGEN®) or erythropoietin (also known as EPOGEN®).

[0151] In other embodiments, the composition may include an effective amount of the modulator and / or other pharma- ceutical active agent in a physiologically acceptable carrier. The carrier may take a wide variety of forms, depending on the preparation form desired for a particular route of administration. Suitable carriers and their formulations are described, for example, in Remington's Pharmaceutical Sciences by EW Martin. In some embodiments, the compound may be contained in any suitable amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form suitable for parenteral (e.g., subcutaneous, intravenous, intramuscular, or intraperitoneal) or oral administration routes. Pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), A. R. Gennaro, Lippincott Williams & Wilkins (eds.), 2000 and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J. C. Boylan (eds.), 1988-1999, Marcel Dekker, New York).

[0152] In some embodiments, the composition may be in a form suitable for administration by sterile injection. In one example, to prepare such a composition, the composition(s) are dissolved or suspended in a parenterally acceptable liquid vehicle. Acceptable vehicles and solvents that may be used are water, water adjusted to an appropriate pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide or an appropriate buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution and dextrose solution. Aqueous formulations may also contain one or more preservatives (e.g., methyl, ethyl, or n-propyl p-hydroxybenzoate). For parenteral formulations, the carrier usually comprises sterile water, although other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared, where appropriate stabilizers may be used. In one embodiment, the formulation includes at least one of the following vitamin E salts: methanesulfonic acid, povidone, benzyl alcohol, n-methylpyrrolidone, ethanol, poloxamer 188, lactic acid, Captisol (SBE-beta-CD), or TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate).

[0153] Formulations suitable for parenteral administration usually include a sterile aqueous preparation of the compound (e.g., physiological saline), which may be isotonic with the blood of the recipient. Such formulations may include suspending agents and thickening agents, and liposomes or other microparticulate systems designed to target the compound to blood components or one or more organs. Formulations may be presented in unit dose form or multi-dose form.

[0154] Parenteral administration can include any suitable form of systemic or localized delivery. Administration can be, for example, intravenous, intraarterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and can be performed by an infusion pump (external or implantable) or any other suitable means appropriate for the desired mode of administration.

[0155] In some embodiments, the composition may be in a form suitable for oral administration. For the composition in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations, such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. For solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. If desired, tablets may be sugar-coated or enteric-coated by standard techniques.

[0156] Compositions suitable for oral administration may be presented as separate units, such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of active ingredient as powder or granules. Optionally, suspensions in aqueous or non-aqueous liquids, such as syrups, elixirs, emulsions, or draughts, may be used. Formulations for oral use include tablets containing the active ingredient(s) in a mixture with pharma-ceutically acceptable excipients. Such formulations are known to those skilled in the art. Excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils, or talc). Other pharma- ceutical acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0157] Syrups can be made by adding the compound to a concentrated aqueous solution of a sugar, for example sucrose, to which accessory ingredient(s) may also be added, which may include flavourings, suitable preservatives, agents to retard sugar crystallization, and agents to increase the solubility of any other ingredients, such as polyhydroxy alcohols, for example glycerol or sorbitol.

[0158] In some embodiments, the compositions may be in the form of a nasal or other mucosal spray formulation (e.g., inhalable form). These formulations may include purified aqueous solutions of active compounds with preservatives and isotonicity agents. Such formulations may be adjusted to a pH and isotonic state compatible with nasal or other mucosal membranes. Alternatively, they may be in the form of a finely divided solid powder suspended in a gaseous carrier. Such formulations may be delivered by any suitable means or method, such as a nebulizer, atomizer, metered dose inhaler, etc.

[0159] In some embodiments, the compositions may be in a form suitable for rectal administration. These preparations may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.

[0160] In some embodiments, the composition may be in a form suitable for transdermal administration. These formulations may be prepared, for example, by incorporating the active compound in a thixotropic or gel-like carrier, such as a cellulose medium, e.g., methylcellulose or hydroxyethylcellulose, and the resulting formulation is then loaded into a transdermal device adapted to be fixed in skin contact to the skin of the wearer.

[0161] In addition to the aforementioned components, the compositions of the present disclosure may further comprise one or more accessory ingredient(s) selected from encapsulants, diluents, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like.

[0162] In some embodiments, the composition may be formulated for immediate release, sustained release, delayed onset release, or any other release profile known to those skilled in the art. In some embodiments, the pharmaceutical composition may be formulated to release the active compound substantially immediately after administration or at any predetermined time or period after administration. The latter type of composition is generally known as a controlled release formulation, which includes: (i) a formulation that produces a substantially constant concentration of drug in the body for an extended period of time; (ii) a formulation that produces a substantially constant concentration of drug in the body for an extended period of time after a predetermined delay time; (iii) a formulation that maintains action for a predetermined period of time by maintaining a relatively constant effective level in the body while simultaneously minimizing undesirable side effects associated with fluctuations in the plasma level of the active substance (sawtooth kinetic pattern); (iv) a formulation that localizes action, for example, by spatially placing the controlled release composition adjacent to or within the central nervous system or cerebrospinal fluid; (v) a formulation that allows for convenient administration, such as a dose administered once every week or two weeks; and (vi) a formulation that targets the pathological site. In some applications, controlled release formulations eliminate the need for frequent administration to maintain activity at medically beneficial levels.

[0163] In order to obtain controlled release, in which the release rate exceeds the metabolism rate of the compound in question, any of several strategies can be pursued.In one example, controlled release is obtained by appropriately selecting various formulation parameters and ingredients, including, for example, various types of controlled release compositions and coating agents.Therefore, the compound is formulated with suitable excipients into a pharmaceutical composition that releases the compound in a controlled manner upon administration.Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes.

[0164] In some embodiments, the compositions may be in a "vectorized" form, such as by encapsulation of the compound in a liposome or other encapsulation vehicle, or by immobilization of the compound, e.g., by covalent bonding, chelation, or associated coordination, on a suitable biomolecule, such as, for example, one selected from proteins, lipoproteins, glycoproteins, and polysaccharides.

[0165] In some embodiments, the compositions may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, etc. for controlled release. Additionally, the compositions may include suspending agents, solubilizing agents, stabilizing agents, pH adjusting agents, tonicity adjusting agents, and / or dispersing agents. Alternatively, the compounds may be incorporated into biocompatible carriers, implants, or infusion devices.

[0166] Materials for use in preparing microspheres and / or microcapsules are, for example, biodegradable / bioerodible polymers such as polygalactin, poly(isobutylcyanoacrylate), poly(2-hydroxyethyl-L-glutamine), and poly(lactic acid). Biocompatible carriers that can be used in formulating controlled release parenteral formulations are carbohydrates (e.g., dextran), proteins (e.g., albumin), lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable (e.g., polydimethylsiloxane) or biodegradable (e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid), or poly(orthoesters), or combinations thereof).

[0167] In all embodiments, the compounds or other active compounds may be present as pharma- ceutically acceptable salts or other derivatives, such as ether, ester, acid, and water-soluble modified derivatives of the active compounds. Derivatives include all individual enantiomers, diastereomers, racemates, and other isomers of the compounds. Derivatives also include all polymorphs and solvates, such as hydrates and those formed with organic solvents, of the compounds. Such isomers, polymorphs, and solvates may be prepared by methods known in the art, such as regiospecific and / or enantioselective synthesis and resolution.

[0168] The ability to prepare salts depends on the acidity or basicity of the compound. Suitable salts of the compound include, but are not limited to, acid addition salts such as those made with hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, carbonic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; and salts formed with organic or inorganic ligands such as quaternary ammonium salts.

[0169] Additional suitable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsenate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate ... These include, but are not limited to, tobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, acetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate salts.

[0170] Pharmaceutically acceptable acid addition salts may exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may come from the solvent of crystallization, either inherent in or adventitious to the solvent of preparation or crystallization.

[0171] Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0172] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0173] Unless the context clearly indicates otherwise, the compositions of all embodiments may include various pharma- ceutically acceptable salts, or other derivatives of the above.

[0174] The formulation and preparation of such compositions are well known to those skilled in the pharmaceutical art and can be found in Remington: The Science and Practice of Pharmacy.

[0175] The dosage of the compounds used in this disclosure will vary depending on the condition, the patient / subject, and the severity of the condition.

[0176] The contents of all cited references (including literature references, issued patents, and published patent applications) cited throughout this application are expressly incorporated herein by reference. This disclosure and the methods and processes of making and using it are described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use it.

[0177] Actual dosage levels of the active ingredient in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0178] The selected dosage level will depend upon the activity of the particular compound or combination of compounds, or esters, salts or amides thereof, used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0179] A physician or veterinarian of ordinary skill in the art can easily determine and formulate the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of a compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered together with the compound of the present disclosure. A larger total dose can be delivered by administering the agent multiple times. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th Edition, 1814-1882, incorporated herein by reference).

[0180] In general, a suitable daily dose of an active compound used in the compositions and methods of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective amount will generally depend upon the factors described above.

[0181] Administration may be a single dose or cumulative (continuous administration), which can be easily determined by one skilled in the art. For example, treatment may include a single administration of an effective dose of the pharmaceutical composition disclosed herein. Alternatively, treatment may include multiple administrations of an effective dose of the pharmaceutical composition administered over a range of time periods, such as, for example, once a day, twice a day, three times a day, once every few days, or once a week. The timing of administration may vary from individual to individual, depending on factors such as the severity of the individual's symptoms. For example, an effective amount of the pharmaceutical composition disclosed herein may be administered to an individual once a day on an irregular basis, or until the individual no longer requires treatment. One skilled in the art will recognize that an individual's condition can be monitored throughout the course of treatment, and the effective amount of the pharmaceutical composition disclosed herein administered can be adjusted accordingly.

[0182] If desired, the effective daily dose of the active compound may be administered as 1, 2, 3, 4, 5, 6 or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the present disclosure, the active compound may be administered two or three times daily. In a preferred embodiment, the active compound is administered once daily.

[0183] In certain embodiments, the administration period of the therapeutic compound is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In certain embodiments, a treatment regimen may include a period during which administration is suspended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0184] The patients receiving this treatment may be any animal in need thereof, including primates, particularly humans, and other mammals such as horses, cattle, pigs, and sheep; and generally poultry and pets.

[0185] In other embodiments, the compounds described herein may be provided in a kit with one or more additional therapeutic agents, either in a single container or in separate containers, e.g., as separate pharmaceutical formulations that can be used together in the conjoint therapy disclosed herein. In some particular such embodiments, the kit may further include instructions for conjoint administration of the pharmaceutical formulations, e.g., to treat or prevent any of the above-mentioned conditions.

[0186] Such combination products may employ the compounds of the present disclosure, or a pharma- ceutically acceptable salt thereof, within the dosage ranges described above, and the other pharma- ceutical active agent within its approved dosage range.

[0187] In some embodiments, the compound may be administered after an attributing event, such as after exposure to ionizing radiation or after the onset of exposure to radiation, including accidental or therapeutic irradiation. In one embodiment, the compound is administered immediately after exposure. In another embodiment, the compound is administered within 12 hours after exposure. In another embodiment, the compound is administered within 24 hours after exposure. In another embodiment, the compound is administered 24 hours after exposure. In another embodiment, the compound is administered 24 hours after exposure. In another embodiment, the compound is administered 36 hours after exposure. In another embodiment, the compound is administered within 48 hours after exposure. In another embodiment, the compound is administered within 60 hours after exposure. In another embodiment, the compound is administered within 72 hours after exposure. In another embodiment, the compound is administered within 48 hours after exposure.

[0188] In certain embodiments or formulations, Yel002 / BCN057 was solubilized in aqueous solution at physiologically compatible pH using 100 mM methanesulfonic acid (MSA) / 10% povidone (PVP); 100 mM MSA / 2% benzyl alcohol / 2% N-methylpyrrolidone (NMP); and 100 mM MSA / 10% ethanol / 1% poloxamer 188. In further aspects, 100 mM lactic acid was added to also improve the solubility of these mixtures. In yet another embodiment, a formulation comprising Yel002 and 30% by weight Captisol (SBE-beta-CD) and 100 mM MSA showed excellent solubility at pH 4.1 and above.

[0189] In another embodiment, formulations for intravenous, subcutaneous and oral delivery of therapeutic levels of Yel002 / BCN057 were developed containing 30% by weight Captisol (SBE-β-CD) and 100 mM MSA at pH 4.1 or higher (adjusted with 1.0 N NaOH).

[0190] The present disclosure, as now generally described, may be more readily understood by reference to the following examples, which are included solely to illustrate certain aspects and embodiments of the disclosure and are not intended to be limiting of the disclosure.

[0191] In other aspects of this embodiment, the molecules disclosed herein reduce the severity of the disease by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet another aspect of this embodiment, the fusion protein or chimeric molecule disclosed herein reduces disease severity by, for example, about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 9 ... %, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0192] Finally, although aspects of the present specification are highlighted by reference to specific embodiments, it should be understood that those skilled in the art will readily recognize that these disclosed embodiments merely exemplify the principles of the subject matter disclosed herein. Thus, it should be understood that the disclosed subject matter is not limited to the specific compounds, compositions, articles, devices, methods, protocols, and / or reagents, etc., described herein, unless expressly stated as such. In addition, those skilled in the art will recognize that certain changes, modifications, substitutions, alterations, additions, subtractions, and subcombinations thereof can be made in accordance with the teachings of the present specification without departing from the spirit of the present specification. Accordingly, it is intended that the following appended claims and the following claims be construed to include all such changes, modifications, substitutions, alterations, additions, subtractions, and subcombinations as are within the true spirit and scope of the present specification.

[0193] Certain embodiments of the present disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the above description. The inventors expect that such variations will be utilized by those skilled in the art as appropriate, and the inventors intend to carry out the present disclosure in ways other than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of all possible variations of the above-described embodiments is encompassed in the present disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0194] The grouping of alternative embodiments, elements, or steps of the present disclosure should not be construed as limiting. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or removed from, a group for reasons of convenience and / or patentability. When such inclusion or removal occurs, the specification is deemed to include the modified group, and therefore satisfies the description of all Markush groups used in the appended claims.

[0195] All patents, patent publications, and other publications referenced or identified in this specification are individually and expressly incorporated herein by reference in their entirety, for example to describe and disclose the compositions and methodologies described in such publications that may be used in connection with the present disclosure. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors do not antedate such disclosure by prior disclosure or for any other reason. All statements as to the date or expression of the contents of these documents are based on the information available to the applicants and do not constitute an admission as to the accuracy of the dates or contents of these documents.

[0196] Finally, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosure, which is defined solely by the claims. Thus, the disclosure is not limited to be precisely as shown and described.

Claims

1. Formula A: 【Chemistry 1】 A compound of the formula: R ３ is O-CH ３ and R ２ is CH ３ or H, R １ teeth, 【Chemistry 2】 One of the compound.

2. 1. A pharmaceutical composition for use in treating cancer, a viral infection, or depression in a subject, comprising a compound of formula C: 【Chemistry 3】 The compound includes a compound having the structure: R １ is an alkyl, alkylamine, or ether; R ２ is H or CH ３ and R ３ is H or OH; R ４ is H; Pharmaceutical compositions.

3. 13. A pharmaceutical composition comprising a compound of claim 1 for use in the treatment of cancer, a viral infection, or depression.

4. 4. The pharmaceutical composition of claim 2 or 3, wherein the cancer is at least one of bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, reproductive cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, rectal cancer, skin cancer, blood cancer or testicular cancer.

5. The pharmaceutical composition of any one of claims 2 to 4, further comprising one or more additional pharmaceutical agents.

6. The pharmaceutical composition of claim 5 , wherein the one or more additional agents are a chemotherapeutic agent or a radiotherapeutic agent.

7. 1. A pharmaceutical composition for use in treating one or more side effects of chemotherapy or radiation therapy, comprising a compound of formula B: 【Chemistry 4】 wherein R １ is an alkyl, alkylamine, or ether; R ２ is H or CH ３ and R ３ is H or OH; Pharmaceutical compositions.

8. 1. A pharmaceutical composition for use in treating radiation-induced damage to epithelial cells in a subject, comprising a compound of formula B: 【Chemistry 5】 wherein R １ is an alkyl, alkylamine, or ether; R ２ is H or CH ３ and R ３ is H or OH; Pharmaceutical compositions.

9. 9. The pharmaceutical composition of claim 8, wherein the radiation-induced damage to epithelial cells is identified as one or more of radiation-induced gastrointestinal syndrome (RIGS), radiation-induced mucositis, radiation-induced oral mucositis, radiation-induced proctitis, or radiation-induced enteritis.

10. 13. A pharmaceutical composition for use in treating one or more side effects of chemotherapy or radiation therapy, comprising a compound according to claim 1.

11. 13. A pharmaceutical composition for use in the treatment of radiation-induced damage to epithelial cells, comprising a compound according to claim 1.

12. 12. The pharmaceutical composition of claim 11, wherein the radiation-induced damage to epithelial cells is identified as one or more of radiation-induced gastrointestinal syndrome (RIGS), radiation-induced mucositis, radiation-induced oral mucositis, radiation-induced proctitis, or radiation-induced enteritis.

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