Treatment method using BCN057 and BCN512

Abstract

This invention provides compounds and methods that can inhibit and / or control Wnt / β-catenin signaling. [Solution] This disclosure relates to methods for treating or improving various pathological conditions by administering 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 ducts. Furthermore, they can be used to treat fibrosis and various inflammatory conditions. Analogs of BCN057 and BCN512 are also described.

Description

[Technical Field]

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

[0002] This invention relates to novel small molecules and their therapeutic applications, more specifically to the therapeutic applications of the small molecules BCN057 and BCN512 and their analogues. [Background technology]

[0003] background Cancer can be defined as a group of diseases characterized by abnormal cell proliferation that can invade or spread to other parts of the body. Despite technological advancements, cancer remains a major cause of death and a source of immeasurable suffering. Cancer is the second most common cause of death in the United States.

[0004] Patients with cancer often have limited treatment options. Treatment 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 are often focused on early diagnosis of cancer, where treatment is more effective. However, the survival time gained from early diagnosis is only moderate. Recent research has offered new opportunities for cancer treatment, including the use of wingless (Wnt) pathway modulators.

[0005] The Wnt signaling pathway is a group of signaling pathways that begin with proteins that allow signals to pass into cells via cell surface receptors. Abnormal activation of the Wnt pathway is associated with human cancer, particularly gastrointestinal (GI) tract cancer. Inhibiting abnormal Wnt pathway activity in cancer cell lines can halt their growth, offering the potential for new therapeutic agents. Alternatively, activation of Wnt signaling and its downstream genes in cancer cells may induce apoptosis.

[0006] The Wnt signaling pathway is often divided into two categories: the standard pathway and the non-standard pathway. The standard pathway is typically called the β-catenin-dependent pathway. The non-standard pathway is independent of β-catenin and plays a role in regulating cell movement during morphogenesis. Both pathways are involved in cancer development, but the standard pathway is the most commonly recognized for its impact in gastrointestinal (GI) cancer.

[0007] There is a need for improved therapeutic approaches that can be achieved with Wnt signaling modulators. Wnt / β-catenin signaling modulators also have the potential to treat other diseases, including fibrosis, inflammatory conditions, bone growth, and alopecia. Therefore, compounds and methods capable of inhibiting and / or controlling Wnt / β-catenin signaling are needed. Specifically, effective Wnt pathway modulators are required. [Overview of the initiative]

[0008] Compound BCN057 disclosed herein was previously described in U.S. Patent Applications No. 13 / 813,923 and No. 14 / 889,719. The present invention provides novel analogues and novel uses. BCN057 (also known as YEL002), BCN512, and analogues of each compound are described below. The compounds of the present invention are particularly useful in the treatment of or prevention of inflammatory diseases and in the treatment of or prevention of cancer or other hyperproliferative conditions.

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

[0010] Another embodiment is a method for treating a disease in a subject, wherein the subject is given a therapeutically effective amount of formula B:

Chem.

[0011] A further embodiment provides 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, hematological cancer or testicular cancer. Treatment may comprise administering one or more additional agents to the subject and administering chemotherapy or radiation therapy.

[0012] Additional embodiments include a method 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 for 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 for treating fibrosis with compounds of formula B or analogs thereof. Fibrosis may be pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, noncystic fibrosis bronchiectasis, cirrhosis, hepatic fibrosis, endocardial myocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive nodular fibrosis, nephrogenic systemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloid condition, scleroderma / systemic sclerosis, arthralgia, Peyronie's disease, Dupuytren's contracture, oral submucosal fibrosis, hepatic fibrosis, gastrointestinal fibrosis, renal fibrosis due to nephrodialysis, and / or adhesive capsulitis.

[0014] Additional embodiments include methods for treating viral infections in subjects requiring such treatment with a compound of formula B or an analog thereof. The embodiments also include methods for treating depression with a compound of formula B or an analog thereof.

[0015] In one embodiment, a therapeutically effective amount of compound BCN057: [ka] A method for treating the subject is disclosed herein.

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

[0017] In another embodiment, the Disclosure provides a method for treating cancer in a subject requiring the treatment thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound or analog of BCN057. In another embodiment, the Disclosure provides a method for treating cancer in a subject requiring the treatment thereof, comprising the step of administering to the subject a combination of agents comprising a therapeutically effective amount of a compound or analog of BCN057.

[0018] In another embodiment, the Disclosure provides a method for treating adverse effects of chemotherapy or radiotherapy in a subject, comprising the step of administering a therapeutically effective dose of a compound or analog of BCN057 to the subject. In another embodiment, the Disclosure provides a method for treating radiation-induced gastrointestinal syndrome (RIGS) in a subject, comprising administering a therapeutically effective dose of a compound or analog of BCN057 to the subject.

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

[0020] In another embodiment, the present disclosure provides a method for modulating Wnt signaling in a subject, comprising administering a therapeutically effective dose of a BCN512 compound or analogue thereof.

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

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

[0023] In another embodiment, the Disclosure provides a method for treating fibrosis in a subject requiring such treatment, comprising administering a therapeutically effective amount of a compound or analog of BCN512 to the subject. In another embodiment, the fibrotic disease is pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, noncystic fibrosis bronchiectasis, cirrhosis, hepatic fibrosis (e.g., caused by chronic viral hepatitis B or C), endocardial myocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis (soft tissue of the mediastinum), myelofibrosis (bone marrow), retroperitoneal fibrosis, progressive nodular fibrosis, nephrogenic systemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloid condition, scleroderma / systemic sclerosis, arthral fibrosis, Peyronie's disease, Dupuytren's contracture, oral submucosal fibrosis, or adhesive capsulitis.

[0024] In another embodiment, the disclosure provides a method for treating bone density disorders or bone density deficiencies using BCN512 or an analogue thereof. Examples include osteoporosis, aging and bone density deficiencies, fractures or bone destruction.

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

[0026] In another embodiment, the present invention relates to formula I: [ka] (In the formula, A 5 is a secondary or tertiary amine (i.e., one that thereby forms a sulfonamide), and A 6 A is a substituted or unsubstituted aryl or heteroaryl group, preferably having at least one substituent, such as a substituted nitro located distal to the sulfonyl group. In a particular embodiment, A 5is a heterocyclic amine such as a piperidine, piperazine, or morpholine ring, but in other embodiments, the amine is acyclic, and / or the nitrogen atom bound to the sulfonyl is in A 5 not contained in any optional ring that may be present) provides a compound represented by or a pharmaceutically acceptable salt, ester or prodrug thereof.

[0027] Embodiments include a method of modulating Wnt activity for treating 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 disease may be radiation exposure, fibrosis, insulin sensitivity, cancer, osteoporosis, hair loss / hair growth, wound healing, low bone density and / or obesity. The disease may also be one or more side effects of chemotherapy or radiation therapy.

[0029] In another embodiment, the present invention provides Formula II

Chemical Formula

Chemical Formula

[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 (Selected from halogen-substituted phenyl groups, substituted or unsubstituted aryl groups (e.g., phenyl and heteroaryl groups), such as 4-fluorophenyl or 3-chlorophenyl.) It forms Y. 1 and Y 2 Each of these is ethyl. In a particular preferred embodiment, Y 1 and Y 2 These together form a piperazine ring. In certain preferred embodiments, Z is absent.

[0031] The embodiments include a method for 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 diseases may be radiation exposure, fibrosis, insulin sensitivity, cancer, osteoporosis, hair loss / hair growth, wound healing, low bone density, and obesity. The diseases may also be one or more side effects of chemotherapy or radiotherapy. Fibrosis can include pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, non-cystic fibrosis, bronchiectasis, cirrhosis, hepatic fibrosis, endocardial myocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive nodular fibrosis, nephrogenic systemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloid condition, scleroderma / systemic sclerosis, arthral fibrosis, Peyronie's disease, Dupuytren's contracture, submucosal fibrosis of the oral cavity, hepatic fibrosis, gastrointestinal fibrosis, renal fibrosis due to renal dialysis, or adhesive capsulitis.

[0032] Another embodiment is given by 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. It is a compound of or an analog thereof. The analogs may include compounds of formulas XXII, XXIII, XXIV, XXV, XXVI, and XXVII.

[0033] The embodiments also include a method for treating inflammation in a subject with a compound of formula C or an analog thereof. The analogs may be formulas XXII, XXIII, XXIV, XXV, XXVI, and / or XXVII.

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

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

[0036] In certain embodiments, the compounds of the present invention may be racemates. In certain embodiments, the compounds of the present invention may be enriched with one enantiomer. For example, the compounds of the present invention may have 30%ee, 40%ee, 50%ee, 60%ee, 70%ee, 80%ee, over 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 with 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 therapeutic methods using compounds of formulas Ia, IIa, A, B, and C, their analogues, and / or pharmaceutically acceptable salts. In certain embodiments, therapeutic preparations may be enriched to provide mainly one enantiomer of a compound (e.g., formula Ia, IIa, A, B, or C).

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

[0039] In certain embodiments, the present invention relates to a method of treatment with a compound of formula Ia, IIa, A, B, or C, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic preparation may be enriched to provide mainly 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 primarily one diastereomer of a compound (e.g., formula Ia, IIa, A, B, or C). In certain embodiments, the present invention provides a pharmaceutical formulation suitable for use in human patients, comprising any of the compounds described above (e.g., compounds of the present invention such as compounds of formula Ia, IIa, A, B, or C) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparation may be for use in treating or preventing the conditions or diseases described herein. In certain embodiments, the pharmaceutical preparation has sufficiently low pyrogen activity to be suitable for use in human patients. Any of the compounds of the above structures may be used in the manufacture of agents for the treatment of any disease or condition disclosed herein.

[0041] Various other purposes, characteristics, and associated advantages of the present invention will become more fully apparent when considered together with the accompanying drawings, in which similar reference letters designate the same or similar parts across several figures. [Brief explanation of the drawing]

[0042] [Figure 1] Figure 1 shows the effects of 5-FU and BCN057 on the survival rate of pancreatic cancer cell lines. [Figure 2A] Figure 2A shows dose-dependent annexin V apoptosis and necrosis assays in Panc-1 cells. [Figure 2B] Figure 2B shows the annexin V apoptosis and necrosis assays in Panc-1 cells over time. [Figure 3] Figures 3A to 3F show the effect of 10 μM BCN057 on the survival rate of pancreatic cancer cell lines. Figure 3A shows the pancreatic cancer cell lines at time 0, Figure 3B at 15 minutes, Figure 3C at 30 minutes, Figure 3D at 60 minutes, Figure 3E at 120 minutes, and Figure 3F at 240 minutes. [Figure 4A] Figure 4A is a graph showing the results of a survival assay in pancreatic cells. [Figure 4B] Figure 4B shows the data for each point in time. [Figure 5A] Figure 5A shows compound H. [Figure 5B] Figure 5B shows compound K. [Figure 6] Figure 6 is a graph showing fibrotic lesions in untreated lung tissue sections and sections treated with BCN512. [Figure 7] Figures 7A–7F show the histopathology of lung sections stained for TGFβ in C57M male mice that received no treatment (A), 14 Gy of thoracic irradiation (B), or irradiation and BCNB512 administration (C). Images D, E, and F show myocardial staining from the same animals with the same parameters. [Modes for carrying out the invention]

[0043] definition Any reference herein to “one embodiment / aspect” or “one embodiment / aspect” means that certain characteristics, structures, or features described in relation to an embodiment / aspect are included in at least one embodiment / aspect of this disclosure. The use of the phrases “one embodiment / aspect” or “another embodiment / aspect” in various places herein does not necessarily refer to the same embodiment / aspect, nor does it refer to separate or alternative embodiments / aspects, except for other embodiments / aspects. Furthermore, various characteristics are described that are shown in some embodiments / aspects but not in other embodiments. Similarly, various requirements are described that may be requirements for some embodiments / aspects but not for other embodiments / aspects. Embodiments and aspects may be used interchangeably in particular.

[0044] The terms used herein generally have their usual 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 herein to provide practitioners with additional guidance regarding the description of this disclosure. It will be understood that similar terms may be described in two or more ways.

[0045] As a result, alternative languages ​​and synonyms may be used for any one or more of the terms discussed herein. Furthermore, there is no particular importance as to whether a term is described in detail herein. Synonyms are provided for specific terms. Detailed explanation of one or more synonyms does not preclude the use of other synonyms. Any use of examples anywhere in this specification, including examples of any term discussed herein, is illustrative and not intended to further limit the scope and meaning of any exemplified term in this disclosure. Similarly, this disclosure is not limited to the various embodiments provided herein.

[0046] Without intending to further limit the scope of this disclosure, examples of apparatus, devices, methods, and their associated results according to embodiments of this disclosure are given below. Note that, for the convenience of the reader, titles or subtitles may be used as examples, although this should not be intended to limit the scope of this disclosure. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains. In case of any conflict, the definitions in this document shall prevail.

[0047] Unless otherwise indicated, all numbers representing features, items, quantities, parameters, properties, terms, etc., used herein and in the claims should be understood in all cases to be modified by the term “approximately.” The term “approximately” as used herein means that the feature, item, quantity, parameter, property, or term thus recognized encompasses a range of ±10% above or below the value of the stated feature, item, quantity, parameter, property, or term. Therefore, unless otherwise indicated, the numerical parameters described herein and in the appended claims are variable approximations. For example, a mass spectrometer may vary slightly in determining the mass of a given analyte, and the term “approximately” in the context of ion mass or ion mass / charge ratio refers to ±0.50 atomic mass units. At least, without attempting to limit the application of the doctrine of equivalents to the claims, each numerical representation should be interpreted by at least the reported significant digits and by the application of common rounding techniques.

[0048] With reference to an embodiment or aspect of an embodiment, the use of the terms “may” or “can” also carries the alternative meaning of “may not” or “cannot.” Thus, where this specification discloses that an embodiment or aspect of an embodiment is included, or may be included, as part of the subject matter of the invention, a negative limitation or exclusive condition is also expressly implied, meaning that the embodiment or aspect of an embodiment may not be included, or cannot be included, as part of the subject matter of the invention. Similarly, with reference to an embodiment or aspect of an embodiment, the use of the term “optionally” means that such an embodiment or aspect of an embodiment may or may not be included as part of the subject matter of the invention. Whether such a negative limitation or exclusive condition applies will depend on whether the negative limitation or exclusive condition is stated in the subject matter to which it is claimed.

[0049] Although the numerical ranges and values ​​describing the broad scope of this disclosure are approximations, the numerical ranges and values ​​described in specific examples are reported as accurately as possible. However, any numerical range or value inherently contains certain errors that inevitably arise from the standard deviation found in their respective test measurements. The description of numerical ranges of values ​​herein is intended merely as a shortened form of reference to each individual numerical value within the range. Unless otherwise specifically indicated herein, each individual value within a numerical range is incorporated herein as if it were described separately.

[0050] In the context described herein (particularly in the context of the following claims), the terms “a,” “an,” “it,” and similar references should be interpreted to encompass both singular and plural unless otherwise explicitly stated herein or the context expressly contradicts it. Furthermore, sequential indicators 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 position or order of such elements unless specifically stated herein. All methods described herein can be carried out in any suitable order unless otherwise explicitly stated herein or the context expressly contradicts it. Any and all examples or exemplary language provided herein (e.g., “such as”) are intended solely to facilitate a better understanding of this disclosure and do not limit the scope of the disclosure as specifically claimed. Language in this specification should not be interpreted as indicating any unclaimed elements essential to the implementation of this disclosure.

[0051] When used in the claims, whether as filed or added with each amendment, the unrestricted transitional term “comprising” (and its corresponding unrestricted transitional phrases such as “including,” “containing,” and “having”) encompasses all explicitly described elements, limitations, processes, and / or characteristics, either alone or in combination with undescribed subject matter; named elements, limitations, and / or characteristics are mandatory, but other unnamed elements, limitations, and / or characteristics may be added to further form a construct within the claims. The specific embodiments disclosed herein may be further limited in the claims by using the restrictive transitional phrases “consisting” or “essentially consisting of” instead of “comprising” or as a modification of “comprising.” When used in the claims, whether as filed or added with each amendment, the restrictive transitional phrase “consisting” excludes elements, limitations, processes, or characteristics not expressly described in the claims. The restrictive transitional clause “essentially consisting of” limits the claims to any other elements, restrictions, processes, and / or characteristics that do not substantially affect the elements, restrictions, processes, and / or characteristics that are explicitly described, as well as any other elements, restrictions, processes, and / or characteristics that do not substantially affect the basic and novel features of the claimed subject matter. Therefore, the meaning of the unrestrictive transitional clause “comprising” is defined as encompassing all elements, restrictions, processes, and / or characteristics that are specifically described, as well as any additional unspecified elements. The meaning of the restrictive transitional clause “consisting of” is defined as including only those elements, restrictions, processes, and / or characteristics that are specifically described in the claims, as well as any other elements, restrictions, processes, and / or characteristics that do not substantially affect the elements, restrictions, processes, and / or characteristics that are specifically described in the claims, as well as any other elements, restrictions, processes, and / or characteristics that do not substantially affect the basic and novel features of the claimed subject matter. Therefore, the unrestricted transitional phrase “comprising” (and its corresponding unrestricted transitional phrase) includes, in its limited sense, the claimed subject identified by the restricted transitional phrase “consisting of” or “essentially consisting of.”Such embodiments described herein, or claimed so in conjunction with the phrase “comprising,” are explicitly or essentially evident herein with respect to the phrases “essentially consisting of” and “consisting of.”

[0052] Where applicable, the terms “about” or “generally” used herein and in the claims mean a margin of ±20% unless otherwise specified. Also, where applicable, the term “substantially” used herein and in the claims means a margin of ±10% unless otherwise specified. It should be recognized that not all use of the above terms is quantifiable in such a way that the referenced scope may apply.

[0053] The term “activator” or “active ingredient” refers to a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect in the subject to which it is administered. In other words, an “activator” or “active ingredient” refers to a component or group of components of a composition to which all or part of the effect of the composition is attributable. An activator may be a primary activator, or in other words, a component(s) of a composition to which all or part of the effect of the composition is attributable. An activator may be a secondary agent, or in other words, a component(s) of a composition to which additional parts and / or other effects of the composition 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-Duvet 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, islet cell tumor, juvenile polyposis syndrome, kidney cancer, laryngeal cancer, leukemia - acute lymphoblastic leukemia, leukemia - acute lymphoblastic leukemia (ALL), leukemia - acute myeloid AML, leukemia - adult, leukemia - childhood, leukemia - chronic lymphocytic leukemia - This may include one or more of the following: CLL, leukemia-chronic myeloid-CML, liver cancer, lobular carcinoma, lung cancer, small cell lung cancer, lymphoma-Hodgkin lymphoma, lymphoma-non-Hodgkin lymphoma, malignant glioma, melanoma, meningioma, multiple myeloma, myelodysplastic syndrome (MDS), nasopharyngeal cancer, neuroendocrine tumor, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor, parathyroid cancer, penile cancer, peritoneal cancer, Peutz-Jeggers syndrome, pituitary tumor, polycythemia vera, prostate cancer, renal cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, sarcoma-Kaposi's sarcoma, skin cancer, small intestine cancer, gastric cancer, testicular cancer, thymoma, thyroid cancer, uterine (endometrial) cancer, vaginal cancer, and Wilms' tumor. The term "blood cancer" may include one or more of the following: leukemia, lymphoma, myeloma, myelodysplastic syndrome, and myeloproliferative neoplasm.

[0055] The term “derivative” may refer to any compound having the same or similar core structure as the compound but having at least one structural difference, including the substitution, deletion, and / or addition of one or more atoms or functional groups. The term “derivative” does not mean that the derivative is synthesized from the parent compound as either a starting material or an intermediate, although this may be the case. The term “derivative” may include prodrugs or metabolites of the parent compound. Derivatives include compounds in which a carboxyl group in the parent compound is derivatized to form methyl and ethyl esters, or other types of esters or hydrazides. Derivatives include compounds in which a hydroxyl group in the parent compound is derivatized to form O-acyl or O-alkyl derivatives. Derivatives include compounds in which a hydrogen bond donor group in the parent compound is substituted with another hydrogen bond donor group such as OH, NH, or SH. Derivatives include substituting a hydrogen bond acceptor group in the parent compound with another hydrogen bond acceptor group such as esters, ethers, ketones, carbonates, tertiary amines, imines, thions, sulfones, tertiary amides, and sulfides. Derivatives may also include salt forms, such as pharmaceutically acceptable salt forms of the parent compound or its derivative.

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

[0057] As used herein, “reduction” means reducing one or more negative symptoms of a condition in cells, organs, tissues, or organisms exhibiting an untreated condition or symptom for the same amount of time.

[0058] In some embodiments, contact of the compounds of the present invention with cells, organs, tissues, or organisms may include administering a therapeutically effective amount of the compound to the target. As used herein, “therapeutically effective amount” is an amount sufficient to alleviate a negative symptom or condition.

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

[0060] As used herein, the term “pharmaceutically acceptable carrier” refers to any solvent, dispersion medium, coating, isotonic agent, and absorption retarder, etc., that is suitable for pharmaceutically active substances. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0061] As used herein, the term “pharmaceutically acceptable composition” means a composition comprising at least one of the compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers.

[0062] As used herein, the term “pharmaceutically acceptable prodrug” refers to a prodrug of the compounds disclosed herein, which, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, is commensurate with a reasonable benefit / risk ratio, is effective for their intended use, and, where possible, is in the zwitterionic form of the compounds disclosed herein. The discussion is provided in Higuchi et al., “Prodrugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in 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 a salt of an acidic or basic group that may be present in the compounds used in the compositions of the present invention. Compounds included in the compositions of the present invention, which are essentially basic, can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include, but are not limited to, non-toxic acid addition salts, i.e., acids that form salts containing pharmacokinetically acceptable anions, including, but not limited to, sulfates, citrates, malates, acetates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, tartrates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, glucarons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the compositions of the present invention, which contain an amino portion, can form pharmaceutically acceptable salts with various amino acids, in addition to the acids described above. The inherently acidic compounds included in the compositions of the present invention can form basic salts having various pharmaceutically 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 anticancer drugs (i.e., chemotherapeutic agents). Chemotherapy may be administered for therapeutic purposes (typically a combination of drugs), or it may be used to prolong life or reduce symptoms (i.e., symptomatic chemotherapy). Conventional chemotherapeutic agents are cytotoxic by interfering with cell division (mitosis). Common side effects of chemotherapy include myelosuppression, mucositis (inflammation of the lining of the gastrointestinal tract), and alopecia.

[0065] The term "KRAS" refers to genes that act as "on / off" switches in cell signaling. When functioning normally, they control cell proliferation. They are allosterically activated and, along with other cell signaling receptors such as c-Raf and PI3-kinase, can recruit and activate proteins necessary for growth factor proliferation. Negative signaling can be disrupted when it mutates, causing cells to overgrow and develop into cancer.

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

[0067] The term "RIGS" or "radiation-induced gastrointestinal syndrome" arises from the combination of the direct cytodestructive effects of irradiation on intestinal crypt and stromal cells, loss of the mucosal barrier, and symptoms ranging from diarrhea and electrolyte imbalance to weight loss and death. A significant proportion of patients experience radiation-induced toxicity due to damage to normal tissue in the irradiation 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 "radiotherapy" generally refers to cancer treatment aimed at controlling or killing malignant cells. In part, it refers to treatment methods that use ionizing radiation. Radiation therapy is usually applied to cancerous tumors because of its ability to control cell proliferation. Ionizing radiation works by damaging the DNA of cancerous tissue, leading to cell death. The main side effects are fatigue and skin irritation. Acute side effects may include nausea and vomiting, damage to the epithelial surface, pain in the mouth, throat, and stomach, bloating, and intestinal discomfort. RIGS (Radiation-Induced Gastrointestinal Syndrome) is a common 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 (sFRPSs), which are a group of soluble frizzled-related proteins. sFRPSs 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 various 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 allow signals to pass into cells via cell surface receptors. The standard Wnt pathway results in the regulation of gene transcription.

[0071] The term “treating” or “treatment” means one or more of the following: (1) suppression of disease; for example, suppression of disease, disease, or disorder in an individual experiencing or exhibiting the pathology or total symptoms of disease, condition, or disorder (i.e., prevention of further development of the pathology and / or total symptoms); and (2) remission of disease; for example, remission of disease, condition, or disorder in an individual experiencing or exhibiting the pathology or total symptoms of disease, condition, or disorder (i.e., reversal of the pathology and / or total symptoms), such as a reduction in the severity of disease. Treatment may be prophylactic and / or therapeutic. The term “prophylactic or therapeutic” treatment is recognized in the art and includes administration of one or more of the compositions of the present invention to one or more hosts. If administered before the clinical manifestation of an undesirable condition (e.g., a disease or other undesirable state in the host animal), the treatment is prophylactic (i.e., it protects the host from the onset of the undesirable condition); however, if administered after the onset of the undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, alleviate, or stabilize the 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 contains a TCF / LEF luciferase reporter vector, which is a Wnt pathway response reporter.

[0073] As used herein, the terms “unit dosage form” or “unit” refer to physically separate units suitable as unit doses for human and animal subjects, each unit containing a predetermined amount of compound calculated in an amount sufficient to produce the desired effect when associated with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications of the novel unit dosage forms in this disclosure depend on the specific compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the subject.

[0074] The compounds of this 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 “stereoisomer” as used herein comprises all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbol “R” or “S” depending on the configuration of substituents around the chiral central carbon atom. This disclosure encompasses a variety of stereoisomers of these compounds and mixtures thereof. Stereoiomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be nominally designated as “(±)”, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center.

[0075] The individual stereoisomers of the compounds of this disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by resolution methods well known to those skilled in the art following the preparation of a racemic mixture. These resolution methods include (1) attachment of the enantiomer mixture to a chiral auxiliary, separation of the resulting diastereomer mixture by recrystallization or chromatography, and liberation of an optically pure product from the auxiliary, (2) salt formation using an optically active resolution agent, or (3) direct separation of the enantiomer mixture on a chiral chromatography column. The stereoisomer mixture can also be separated into the stereoisomers of its components 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 sterically pure intermediates, reagents, and catalysts by well known asymmetric synthesis methods.

[0076] Geometric isomers may also be present in the compounds of this disclosure. This disclosure encompasses a variety of geometric isomers and mixtures thereof arising from the arrangement of substituents around a carbon-carbon double bond or around a carbocyclic ring. The substituents around the carbon-carbon double bond are designated as being in a "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures exhibiting a double bond encompass both E and Z isomers.

[0077] Substituents around a carbon-carbon double bond are also often called "cis" or "trans," where "cis" refers to a substituent on the same side of the double bond, and "trans" refers to a substituent on the opposite side of the double bond. The arrangement of substituents around a carbon ring is named "cis" or "trans." The term "cis" refers to a substituent on the same side of the ring plane, and the term "trans" refers to a substituent on the opposite side of the ring plane. A mixture of compounds in which substituents are located on both the same and opposite sides of the ring plane is named "cis / trans."

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

[0079] The term "alkoxy" represents a chemical substituent of the 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, the 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 substituted with an alkoxy group, as defined herein. Exemplary unsubstituted alkoxyalkyl groups contain 2 to 12 carbon atoms. In some embodiments, each alkyl and alkoxy group may be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0081] The terms “alkyl,” “alkenyl,” and “alkynyl” include monovalent substituents in linear, branched, and cyclic structures containing only C and H when unsubstituted, as well as combinations thereof. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, etc. As used herein, the term “cycloalkyl” refers to a monovalent saturated or unsaturated non-aromatic cyclic alkyl group having 3 to 9 carbon atoms (e.g., C3-C9 cycloalkyl), unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, etc. When a cycloalkyl group contains one carbon-carbon double bond, it may be called a “cycloalkenyl” group. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, etc. Typically, alkyl, alkenyl, and alkynyl groups contain 1 to 12 carbon atoms (e.g., C1-C9). 12 Alkyl) or 2 to 12 carbon atoms (e.g., C2-C2) 12 Alkenyl or C2-C 12 The alkyl group includes an alkynyl group. 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. Furthermore, any hydrogen atom of one of these groups may be replaced with a substituent as described herein.

[0082] Heteroalkyl, heteroalkenyl, and heteroalkynyl groups are similarly defined, containing at least one carbon atom, but containing one or more O, S, or N heteroatoms or combinations thereof in the main chain residues, thereby replacing one carbon atom of the alkyl, alkenyl, or heteroalkynyl group to which the heteroform corresponds. In some embodiments, the heteroalkyl, heteroalkenyl, and heteroalkynyl groups have C at each end to which the group is attached to another group, and the present heteroatoms are not located at terminal positions. As understood in the art, these heteroforms do not contain four or more consecutive heteroatoms. In some embodiments, the heteroatoms are O or N. As used herein, the term “heterocyclyl” refers, unless otherwise specified, to a cyclic heteroalkyl or heteroalkenyl that is a 3, 4, 5, 6, or 7-membered ring containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example. Five-membered rings have 0 to 2 double bonds, while six-membered and seven-membered rings have 0 to 3 double bonds. The term "heterocyclyl" also refers to a heterocyclic compound having a bridging polycyclic structure in which one or more carbons 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 groups is fused with one, two, or three carbocyclic rings, such as an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, or another monocyclic heterocyclic group such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, or benzothienyl.

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

[0084] As used herein, the term "amino" represents -N(R)2, where each R is independently H, OH, NO2, N(R)2, SO2OR, SO2R, SOR, SO2N(R)2, SON(R)2, an N protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkylcycloalkyl, heterocyclyl (e.g., heteroaryl), alkylheterocyclyl (e.g., alkylheteroaryl), or two Rs bonded together to form a heterocyclyl or an N protecting group, where each R N2 R is independently H, alkyl, or aryl. In preferred embodiments, amino is -NH2 or -NHR, and R is independently OH, NO2, NH2, NR2, SO2OR, SO2R, SOR, SO2N(R)2, SON(R)2, alkyl, or aryl, where each R may be H, alkyl, or aryl. As used herein, the term "aminoalkyl" 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 alkyl and amino group may be further substituted with one, two, three, or four substituents as defined herein for each group. For example, the alkyl group may contain an oxo (=O) substituent.

[0085] The "aromatic" or "aryl" moiety refers to any monocyclic or fused bicyclic ring system that has aromatic characteristics in terms of electron distribution throughout the entire ring system and includes a monocyclic or fused bicyclic moiety such as phenyl or naphthyl. "Heteroaromatic" or "heteroaryl" also refers to such monocyclic or fused bicyclic ring systems that include one or more heteroatoms selected from O, S, and N. The inclusion of heteroatoms can also include five-membered and six-membered rings that are considered aromatic. Therefore, typical aromatic / heteroaromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, imidazolyl, etc. Phthalimide is also considered aromatic because tautomerism is theoretically possible. Typically, the ring system contains a 5- to 12-membered ring atom or a 6- to 10-membered ring atom. In some embodiments, the aromatic or heteroaromatic moiety is a 6-membered aromatic ring system containing optionally 1-2 nitrogen atoms. More particularly, the moiety is optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridadinyl, benzothiazolyl, or benzimimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzothiazolyl, or indolyl. Even more particularly, such a moiety is 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 residue via an oxygen atom. A typical example of an O-aryl is phenoxy. Similarly, “arylalkyl” refers to an aromatic or heteroaromatic system, including its heteroforms, typically bonded to another residue via a saturated or unsaturated carbon chain of C1-C2, C1-C6, or more particularly C1-C4 or C1-C3 when saturated, or C2-C8, C2-C6, C2-C4, or C2-C3 when unsaturated. For greater certainty, arylalkyl therefore includes the aryl or heteroaryl group defined above, bonded to the alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl moiety defined above.Typical arylalkyls are aryl(C6~C). 12 )alkyl (C1~C8), aryl (C6~C 12 ) Alkenyl (C2-C8), or aryl (C6-C8) 12 Alkynyl (C2-C8) and heteromorphs are also found. A typical example is phenylmethyl, commonly known as benzyl.

[0086] A halo can be a halogen atom, particularly F, Cl, Br, or I, and more particularly fluoro or chloro.

[0087] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, substituted with a halogen group (i.e., F, Cl, Br, or I). A haloalkyl group may be substituted with one, two, or three halogens, or, in the case of an alkyl group with two or more carbon atoms, with four halogens. Haloalkyl groups include perfluoroalkyl groups. In some embodiments, a haloalkyl group may be further substituted with one, two, three, or four substituents for the alkyl group as described herein.

[0088] As used herein, the term "hydroxy" refers to the -OH group.

[0089] As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined herein, substituted with one to three hydroxyl groups, however, one or fewer hydroxyl groups may be attached to a single carbon atom of the alkyl group, as exemplified by hydroxymethyl and dihydroxypropyl.

[0090] In general, substituents (e.g., alkyl, alkenyl, alkynyl, or aryl (including all heteroforms defined above)) may themselves be substituted by further substituents. The properties of these substituents are similar to those described for substituents on the basic structure above. Therefore, if the substituent embodiment is alkyl, this alkyl may be optionally substituted by the remaining substituents listed as chemically meaningful substituents, without impairing the size limit of the alkyl itself. For example, alkyls substituted with alkyl or alkenyl simply extend the carbon atom limit for these embodiments and are not included. For example, if a group is substituted, that group may be substituted with 1, 2, 3, 4, 5, or 6 substituents. Any 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), carboxylic acid ester(-CO2R'), carbamoyl(-OC(=O)NR'R'' or -NRC(=O)OR'), hydroxy(-OH), isocyano(-NC), sulfonate(-S(=OH) The substituents include, but are not limited to, OR, sulfonamide (-S(=OHNRR') or -NRS(=O)2R'), or sulfonyl (-S(=O)2R), and 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] Typical arbitrary 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 substituent may be an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, O-aryl, O-heteroaryl, and arylalkyl.

[0092] Other technical terms used herein have their usual meanings in the art in which they are used, as exemplified by various technical dictionaries. Specific values ​​and configurations discussed in these non-limiting examples are subject to change and are merely cited to illustrate at least one embodiment, and are not intended to limit their scope.

[0093] Detailed explanation It should be understood that both the general description above and the detailed description below are illustrative and descriptive, and are intended to provide a further description of the Art as described in the claims. Further features and advantages of the Art are described below, some of which are evident from the description or can be learned by practicing the Art. The advantages of the Art will be realized and achieved by the structures specifically pointed out in this specification and in its claims.

[0094] BCN057 and analogues BCN057, also known as YEL002, is represented by the following structural formula: [ka] It may also be described as (3-[(furan-2-ylmethyl)amino]-2-(7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)-6-methylimidazo[1,2-a]pyridine-1-ium). It will be understood that the present invention encompasses compounds of BCN057, their analogues and salts thereof. In one embodiment, the present invention relates to compounds of BCN057 in the form of a free base. In another embodiment, the present invention relates to compounds of BCN057 or pharmaceutically acceptable salts thereof.

[0095] For their potential use in pharmaceuticals, salts of the BCN057 compound may be preferred as pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts may include acid addition salts. By using the desired acid or base as appropriate, pharmaceutically acceptable salts can be readily prepared. The resulting salts can be precipitated from the solution and collected by filtration or recovered by evaporation of the solvent. The compound can exist as stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof. Several analogues of BCN057 are listed below.

[0096] The embodiment uses formula B for the therapeutically effective amount: [ka] (In the formula, R 1 is an alkyl, alkylamine, or ether; R 2 is H or CH3; and R 3 (is either H or OH) A method of treatment comprising administering a compound having the structure of [the given structure].

[0097] In some embodiments, the compound is an analog selected from formulas II to XIX, comprising compound H, compound K, compound BNB-1, compound BNB-2, compound BNB-3, compound BNB-4, and compound BNB-5. [Table 1] TIFF2026143504000015.tif225150 TIFF2026143504000016.tif225150 TIFF2026143504000017.tif225150 TIFF2026143504000018.tif225150 TIFF2026143504000019.tif225150

[0098] BCN512 and analogues The structure of 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 to XXVII. [Table 2] TIFF2026143504000022.tif225150 TIFF2026143504000023.tif78150

[0100] The compounds of formulas I to XXVIII disclosed herein, or their analogues, 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. Typical methods for producing the compounds are provided in U.S. Patent Applications 13 / 813,923 and 14 / 889,719, which are incorporated herein by reference. The compounds also include their pharmaceutically 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, while not bound by theory, are thought to exert their desired effects partly through their ability to modulate Wntβ-catenin signaling. The Wnt pathway is involved in tissue development in embryos and tissue maintenance in adults. It controls a specific set of genes that regulate 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 consequently, can promote cancer formation in a range of tissues, including the colon, skin, liver, and ovaries.

[0102] The Wnt signaling pathway is a group of signaling pathways that begin with proteins that allow signals to pass into cells via cell surface receptors. Abnormal activation of the Wnt pathway is associated with human cancer, particularly gastrointestinal (GI) tract cancer. Inhibiting abnormal Wnt pathway activity in cancer cell lines can block their proliferation, offering the potential for new therapeutic agents.

[0103] Wnt ligands bind to LRP5 / 6 and frizzled coreceptors present on epithelial crypt cells, leading to β-catenin stabilization and nuclear translocation, where they bind to the nuclear transcription factor TCF4, promoting gene expression programs that support stem cell maintenance, proliferation, and differentiation. Activation of Wnt / β-catenin signaling is also crucial for post-injury crypt regeneration. 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 signaling, the transcription activator β-catenin is actively degraded within the cell. Phosphorylated β-catenin is then recognized, ubiquitinated, and subjected to proteasomal degradation. As a result, levels of free β-catenin remain low, which allows DNA-binding T cell factor / lymphoid enhancer factor (Tcf / Lef) proteins to interact with transcriptional co-repressors to inhibit target gene expression in the nucleus.

[0105] In addition to cancer treatment, therapies that regulate Wnt / β-catenin signaling are promising in the treatment of other diseases, including fibrosis, inflammatory conditions, bone growth, wound healing, osteoporosis, alopecia (i.e., hair loss), depression, and viral infections. Therefore, compounds and methods that can inhibit and / or modulate Wnt / β-catenin signaling are needed.

[0106] BCN057 and its analogues - Cancer treatment and therapies The study demonstrated that the Wnt pathway is permanently activated in both hereditary familial adenomatous polyposis and spontaneous forms of colorectal cancer. Chronic activation of the Wnt pathway in these cells promotes their expansion into benign adenomas (also known as polyps), which often progress to invasive colorectal cancer. Approximately 90% of sporadic colorectal cancers exhibit abnormal Wnt signaling activity, usually as a result of mutations in APC.

[0107] BCN057 is an antineoplastic small molecule effective in the treatment of cancer, particularly pancreatic cancer and gastrointestinal (GI) cancer. It can function with a dual mechanism of action. Secondly, it can induce apoptosis in cancer cells. Secondly, it can promote the proliferation and survival of epithelial cells. BCN057 is particularly effective against pancreatic and gastrointestinal (GI) cancer. BCN057 has demonstrated an antitumor effect against "KRAS" cancer.

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

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

[0110] BCN512 and analogue-SFRP-mediated therapy Many colon cancers carry silent genes encoding secreted Fzd-related proteins (SFRPs) or members of the Wnt inhibitor (WIF) family, which act as natural brakes on the Wnt pathway. They can bind to 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, amplifying abnormal Wnt signaling activity initiated by mutations in APC, β-catenin, or Axin2. This abnormal Wnt pathway activation can lead to cancer.

[0111] Wnt signaling begins when the Wnt protein binds to the extracellular cysteine-rich domain at the N-terminus of Frizzled (Fzd) family receptors. When sfrp is inhibited or at low levels, wnt ligands can bind to Fzd receptors and transmit wnt-related gene expression. sfrp also has 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 kidney development, sFRPS inhibits tubule formation and bud growth in the metanephrine.

[0112] BCN512 can inhibit SFRP activity and disrupt its ability to bind to wnt ligands. SFRP acts as a negative regulator of wnt signaling by binding to wnt ligands via a domain similar to the fzd receptor domain that binds to wnt when standard wnt signaling is freely transmitted. This mechanism presents several therapeutic applications. BCN512 and its analogs can suppress histofibrosis via inhibitory SFRP containing SRFP1. BCN512 and its analogs can activate bone growth by inhibiting SRFP. BCN512 and its analogs can activate hair growth by inhibiting SRFP.

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

[0114] Further research has demonstrated that Wntβ-catenin signaling plays a crucial role in the restoration of the bronchial epithelial stem cell pool. Previous studies have shown that Wnt ligands are secreted and transported via exosomes. Exosomes derived from mouse exovivo lung organoids have been shown to contain Wnt ligands and exhibit Wnt activity in response to BCN512 treatment. Wnt activity has also been investigated in exosomes derived from human lung organoids.

[0115] To investigate the role of BCN512 in Wnt release from human lung epithelium, exosomes were purified from organoid-conditioned medium. The purified exosomes were tested for Wnt activity using the TOPFLASH assay. Exosome Wnt activity was observed to be several times higher in samples prepared from organoids treated with BCN512 and irradiated (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, plant photodermatitis, radiation dermatitis, and stasis dermatitis). Other inflammatory skin diseases include, but are not limited to, scleroderma, ulcers and erosions resulting from trauma, burns, blistering disorders, or ischemia of the skin or mucous membranes, several forms of ichthyosis, epidermolysis bullosa, hypertrophic scars, keloids, skin changes of endogenous aging, photoaging, blistering due to friction resulting from mechanical shear of the skin, and skin atrophy resulting from topical use of corticosteroids. Further inflammatory skin conditions include inflammation of 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), type 1 diabetes mellitus, and acute and chronic inflammation of the adrenal cortex. Inflammatory conditions of the cardiovascular system include, but are not limited to, coronary artery infarct injury, peripheral vascular disease, myocarditis, vasculitis, vascular regeneration of stenosis, atherosclerosis, and vascular diseases associated with type 2 diabetes mellitus.

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

[0119] Inflammatory conditions of the liver include hepatitis (resulting from viral infection, autoimmune response, drug treatment, toxins, environmental factors, or as a secondary consequence of primary injury), 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 Alzheimer's disease, Parkinson's disease, or dementia associated with HIV infection.

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

[0122] Treatment of viral infections Further embodiments include the use of BCN057 and analogues of BCN057 for the treatment of viral infections. Viral diseases and infections occur when pathogenic viruses enter 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 infection can destroy infected cells and lead to serious 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 hyperactivity of cytotoxic T cells. The 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, abnormal induction of the host immune response can trigger a flare release of cytokines known as a cytokine storm.

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

[0124] Treatment for depression Further embodiments include the use of BCN057 and analogues 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 similarly to treat depression. Lithium acts by inhibiting GSK3b in the Wnt downstream signaling pathway and by 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 decreased in the hippocampal CA3 and CA4 regions, while Wnt1 levels are increased in the hippocampal CA4 region of postmortem schizophrenic brains. Since lithium inhibits glycogen synthase kinase 3β (GSK3β), a component of the standard Wnt pathway, this pathway has been proposed as a specific target in the treatment of bipolar disorder. Therefore, BCN057 and its analogues 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 intended herein. These examples should not be construed as limiting any of the embodiments described herein, including those relating to compounds, pharmaceutical compositions, or methods and uses disclosed herein.

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

[0128] Figures 2A and 2B show the annexin V apoptosis and necrosis assay in Panc-1 cells. Panc-1 cells were exposed to serial dilutions of BCN057 in or without the 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 changes in fluorescence were observed during the same period. Apoptosis appeared to increase with increasing BCN057 concentration. 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 survival rate of pancreatic cancer cell lines. The images show pancreatic cancer cell lines at time 0 (Figure 3A), 15 minutes (Figure 3B), 30 minutes (Figure 3C), 60 minutes (Figure 3D), 120 minutes (Figure 3E), and 240 minutes (Figure 3F). Morphological changes and apoptosis are particularly evident at 240 minutes.

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

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

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

[0133] BCN512 for the treatment of fibrosis Fibrosis is generally defined as a pathological wound healing in which connective tissue is replaced to an unchecked extent by normal parenchymal tissue, 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 described herein (par. 095), any organ of the body can initiate a repair response that generally results in fibrotic lesions. Two examples are pulmonary fibrosis as a result of chronic obstructive pulmonary disease and hepatic fibrosis due to hepatic infection.

[0134] The inventors propose that type II alveolar cells function as progenitor cells that repair damaged alveolar epithelium. Furthermore, damaged epithelial cells are also a major source of inflammatory cytokines. Therefore, mitigating 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). At final autopsy and histological analysis of the lungs in C57BL mice, there was a significant reduction in pulmonary fibrosis in the BCN512 treatment (20×512) versus vehicle (20×V) group. Lesions are defined by local density in 5 mice per group evaluated at day 180. This effect is observed with non-radioactive induced stimuli such as LPS and cytotoxic agents.

[0136] Transforming growth factor β (TGF-β) is a central mediator of fibrosis. TGF-β is upregulated and activated in fibrotic diseases, regulating the phenotype and function of fibroblasts and inducing myofibroblast transdifferentiation while promoting matrix preservation. Figure 7 shows the histopathology of lung sections stained for TGFβ and evaluated at day 90 in C57M male mice receiving no administration (A), 14 Gy of thoracic irradiation (B), or irradiation and BCNB512 (C). TGFβ levels decrease when treated with 5 mg / kg of BCN512 for the first 20 days after irradiation. Images D-F show myocardial staining from the same animals under identical parameters. The inventors observed a significant decrease in staining for TGFβ. This indicates that TGF-β staining is lower in tissue from radiation damage when treated with BCN512. The inventors expect similar results using non-radioactive induced stimuli, including LPS and cytotoxic drugs.

[0137] These studies and observations are consistent with previous observations, specifically that WNT-catenin signaling promotes the autoregeneration and differentiation of LGR5+ epithelial (lung, oral, and 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 regulated. Along with a decrease in fibroblasts, the absence of late-stage fibrotic effects from animals with long-term irradiation (observed from long-term studies of whole-body irradiation studies) indicates that these drugs are effective in preventing fibrosis and inflammation from both irradiation and chemical means (LPS). Furthermore, fibroblast proliferation is macrophage-dependent, and BCN512 inhibits this macrophage function. In summary, the above results demonstrate that stem cells and progenitor cells can be preserved by administering the compound BCN512. This prevents connective tissue from being replaced by normal parenchymal tissue, and thus prevents fibrosis.

[0139] Pharmaceutical carriers and administration The methods of the present invention can 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 incidence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0140] The compositions and methods of this disclosure can be used to treat individuals in need. In certain embodiments, the individuals are mammals, such as humans or non-human mammals. When administered to animals such as humans, the compositions or compounds are preferably administered or used as a pharmaceutical composition comprising, for example, the compounds of this disclosure and a pharmaceutically acceptable carrier.

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

[0142] The pharmaceutical compositions disclosed herein may contain a therapeutic compound in an amount sufficient to enable a normal dose 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 the therapeutic compound. In certain embodiments, the pharmaceutical compositions disclosed herein may include, 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 the therapeutic compound. In yet another embodiment of this embodiment, the pharmaceutical compositions disclosed herein may include, for example, amounts 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 more specific embodiments, the pharmaceutical compositions disclosed herein include, for example, approximately 10 mg to approximately 250 mg, approximately 10 mg to approximately 500 mg, approximately 10 mg to approximately 750 mg, approximately 10 mg to approximately 1,000 mg, approximately 10 mg to approximately 1,500 mg, approximately 50 mg to approximately 250 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 750 mg, approximately 50 mg to approximately 1,000 mg, approximately 50 mg to approximately 1,500 mg, and approximately 100 mg. It may contain amounts in the range of approximately 250 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 750 mg, approximately 100 mg to approximately 1,000 mg, approximately 100 mg to approximately 1,500 mg, approximately 200 mg to approximately 500 mg, approximately 200 mg to approximately 750 mg, approximately 200 mg to approximately 1,000 mg, approximately 200 mg to approximately 1,500 mg, approximately 5 mg to approximately 1,500 mg, approximately 5 mg to approximately 1,000 mg, or approximately 5 mg to approximately 250 mg.

[0143] The pharmaceutical compositions disclosed herein may contain a solvent, emulsion, or other diluent in an amount sufficient to dissolve the therapeutic compound disclosed herein. In certain embodiments, the pharmaceutical compositions disclosed herein may contain, for example, a solvent, emulsion, or diluent in an amount 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 include, for example, about 1%(v / v) to 90%(v / v), about 1%(v / v) to 70%(v / v), about 1%(v / v) to 60%(v / v), about 1%(v / v) to 50%(v / v), about 1%(v / v) to 40%(v / v), about 1%(v / v) to 30%(v / v), and about 1%(v / 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), approximately 2% (v / v) ~ 20% (v / v), approximately 2% (v / v) ~ 10% (v / v), approximately 4% (v / v) ~ 50% (v / v), approximately 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 amounts ranging from 0% (v / v), approximately 8% (v / v) to 50% (v / v), approximately 8% (v / v) to 40% (v / v), approximately 8% (v / v) to 30% (v / v), approximately 8% (v / v) to 20% (v / v), approximately 8% (v / v) to 15% (v / v), or approximately 8% (v / v) to 12% (v / v).

[0144] The final concentration of the therapeutic compound disclosed herein in the pharmaceutical composition disclosed herein may be any appropriate concentration. In certain embodiments, the final concentration of the therapeutic compound in the pharmaceutical composition may be a therapeutically effective amount. In certain embodiments, the final concentration of the therapeutic compound in the pharmaceutical composition may 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 solution may 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 may 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, or 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 0.001 mg / mL, approximately 0.00001 mg / mL to approximately 0.001 mg / mL, approximately 0.00001 mg / mL to approximately 0.01 mg / mL, approximately 0.00001 mg / mL to approximately 0.1 mg / mL, approximately 0.00001 mg / mL to approximately 1 mg / mL, approximately 0.001 mg / mL to approximately 0.01 mg / mL, approximately 0.001 mg / mL to approximately 0.1 mg / mL, approximately 0.001 mg / mL to approximately 1 mg / mL, approximately 0.001 mg / mL to approximately 10 mg / mL, or approximately 0.001 mg / mL to approximately 100 mg / mL.

[0145] In certain embodiments, the therapeutically effective dose of the therapeutic compounds disclosed herein is generally in the range of about 0.001 mg / kg / day to about 100 mg / kg / day. In certain embodiments, the therapeutically effective dose of the therapeutic compounds disclosed herein may 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, the effective amount of the therapeutic compound disclosed herein is, 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, and about 0.001 mg / kg / day. 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 ~ approx. 200mg / kg / day, approx. 0.001mg / kg / day ~ approx. 250mg / kg / day, approx. 0.001mg / kg / day ~ approx. 300mg / kg / day, approx. 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 The dosage may be in the range of / kg / day, approximately 0.001mg / kg / day to approximately 550mg / kg / day, approximately 0.001mg / kg / day to approximately 600mg / kg / day, approximately 0.001mg / kg / day to approximately 650mg / kg / day, approximately 0.001mg / kg / day to approximately 700mg / kg / day, approximately 0.001mg / kg / day to approximately 750mg / kg / day, or approximately 0.001mg / kg / day to approximately 800mg / kg / day.In yet another embodiment of this embodiment, the effective amount of the therapeutic compound disclosed herein is, for example, about 0.01 mg / kg / day to about 10 mg / kg / day, about 0.01 mg / kg / day to about 15 mg / kg / day, about 0.01 mg / kg / day to about 20 mg / kg / day, about 0.01 mg / kg / day to about 25 mg / kg / day, about 0.01 mg / kg / day to about 30 mg / kg / day, 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 The dosage may be in the range of g / kg / day, approximately 0.01 mg / kg / day to approximately 550 mg / kg / day, approximately 0.01 mg / kg / day to approximately 600 mg / kg / day, approximately 0.01 mg / kg / day to approximately 650 mg / kg / day, approximately 0.01 mg / kg / day to approximately 700 mg / kg / day, approximately 0.01 mg / kg / day to approximately 750 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 800 mg / kg / day.In certain embodiments, the effective amount of the therapeutic compound disclosed herein is, 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, and about 0.1 mg / kg / day. 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 dosage may range from kg / day, approximately 0.1 mg / kg / day to approximately 550 mg / kg / day, approximately 0.1 mg / kg / day to approximately 600 mg / kg / day, approximately 0.1 mg / kg / day to approximately 650 mg / kg / day, approximately 0.1 mg / kg / day to approximately 700 mg / kg / day, approximately 0.1 mg / kg / day to approximately 750 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 800 mg / kg / day.In certain embodiments, the effective amount of the therapeutic compound disclosed herein is, 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 daily intake may range from 0 mg / kg / day, approximately 10 mg / kg / day to approximately 250 mg / kg / day, approximately 10 mg / kg / day to approximately 300 mg / kg / day, approximately 10 mg / kg / day to approximately 350 mg / kg / day, approximately 10 mg / kg / day to approximately 400 mg / kg / day, approximately 10 mg / kg / day to approximately 450 mg / kg / day, approximately 10 mg / kg / day to approximately 500 mg / kg / day, approximately 10 mg / kg / day to approximately 550 mg / kg / day, approximately 10 mg / kg / day to approximately 600 mg / kg / day, approximately 10 mg / kg / day to approximately 650 mg / kg / day, approximately 10 mg / kg / day to approximately 700 mg / kg / day, approximately 10 mg / kg / day to approximately 750 mg / kg / day, or approximately 10 mg / kg / day to approximately 800 mg / kg / day.

[0146] In other embodiments of this embodiment, the effective amount of the therapeutic compound disclosed herein may be, for example, in the range of 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, the effective amount of the therapeutic compound disclosed herein may be, for example, in the range of 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 semi-solid formulations, the concentrations of the therapeutic compounds disclosed herein may typically range from about 50 mg / mL to about 1,000 mg / mL. In certain embodiments, the therapeutically effective dose of the therapeutic agent disclosed herein may be, for example, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 50 mg / mL to about 700 mg / mL, about 50 mg / mL to about 800 mg / mL, about 50 mg / mL to about 900 mg / mL, about 50 mg / mL to about 1,000 mg / mL, and about 100 mg 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,It may be 000 mg / mL, approximately 600 mg / mL to approximately 700 mg / mL, approximately 600 mg / mL to approximately 800 mg / mL, approximately 600 mg / mL to approximately 900 mg / mL, or approximately 600 mg / mL to approximately 1,000 mg / mL.

[0148] The subjects may be humans, rats, mice, cats, dogs, horses, sheep, cattle, monkeys, birds, or amphibians. In another embodiment, the cells are in vivo or in vitro. Typical subjects to which the compounds of this disclosure may be administered are mammals, particularly primates, particularly humans. For veterinary use, a wide range of subjects would be suitable, e.g., livestock such as cattle, sheep, goats, and pigs; poultry such as chickens, ducks, geese, and turkeys; and domesticated animals, particularly pets such as dogs and cats. For diagnostic or research use, 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 use, the use of body fluid and cell samples of the above subjects is suitable, as are blood, urine, or tissue samples of mammals, particularly primates such as humans, or blood, urine, or tissue samples of the animals mentioned for veterinary use.

[0149] When administered to a living 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, for example, subcutaneously, parenterally, or intravenously.

[0150] In some embodiments, the compound may be administered in combination with other potential mitigating agents. In certain embodiments, the composition may be administered with growth factors, NSAIDs, chemotherapeutic agents, anti-inflammatory agents, antibiotics, metformin (such as Glucophage, Gourmetza), sulfonylureas, meglitinide, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, and / or insulin therapy for the treatment of the above-mentioned conditions. In one embodiment, 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 contain an effective amount of a regulatory factor and / or other pharmaceutically active agent in a physiologically acceptable carrier. The carrier may take a wide variety of forms depending on the desired formulation for a particular route of administration. Suitable carriers and their formulations are described, for example, in Remington's Pharmaceutical Sciences by E.W. Martin. In some embodiments, the compound may be contained in any suitable amount in any suitable carrier material, generally present in an amount of 1 to 95% by weight of the total weight of the composition. The composition may be provided in dosage forms suitable for parenteral (e.g., subcutaneous, intravenous, intramuscular, or intraperitoneal) or oral administration routes. Pharmaceutical compositions can be formulated according to conventional pharmaceutical practices (see, for example, Remington: The Science and Practice of Pharmacy (20th edition), ARGennaro, Lippincott Williams & Wilkins (eds.), 2000 and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and JCBoylan (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 permissible liquid vehicle. Permissible vehicles and solvents that may be used include water, water adjusted to a suitable pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable 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). In the case of parenterally administered formulations, the carrier usually contains sterile water, but other components, such as components to aid solubility or for preservation, may be included. Injectable solutions may also be prepared, if appropriate stabilizers are used. In one embodiment, the formulation contains at least one of the following vitamin E compounds: methanesulfonic acid, povidone, benzyl alcohol, n-methylpyrrolidone, ethanol, poloxamer 188, lactic acid, captisol (SBE-beta-CD), or TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate).

[0153] Formulations suitable for parenteral administration typically contain a sterile aqueous preparation of the compound (e.g., physiological saline) that can be isotonic with the recipient's blood. Such formulations may also contain suspensions and thickeners and liposomes, or other microparticle systems designed to target the compound to blood components or one or more organs. Formulations may be presented in single-dose or multi-dose forms.

[0154] Parenteral administration may include any suitable form of systemic or local delivery. Administration may be, for example, intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intra-abdominal (e.g., intraperitoneal), and may be carried out by an infusion pump (external or implantable) or any other suitable means suitable for the desired mode of administration.

[0155] In some embodiments, the composition may be in a form suitable for oral administration. For oral dosage forms, any of the usual pharmaceutical media may be used. For example, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavorings, preservatives, and colorants. For example, for solid oral preparations such as powders, capsules, and tablets, suitable carriers and additives include starch, sugars, diluents, granulators, lubricants, binders, and disintegrants. If desired, tablets may be sugar-coated or enterically 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 the active ingredient in powder or granule form. Optionally, suspensions in aqueous or non-aqueous liquids, such as syrups, elixirs, emulsions, or drafts, may be used. Formulations for oral use include tablets containing the active ingredient(s) in a mixture with pharmaceutically acceptable excipients. Such formulations are known to those skilled in the art. Excipients may include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch containing potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulators and disintegrants (e.g., cellulose derivatives containing microcrystalline cellulose, starch containing potato starch, croscarmellose sodium, alginate, 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, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow promoters, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other excipients that are acceptable as pharmaceuticals may include colorants, flavoring agents, plasticizers, wetting agents, and buffering agents.

[0157] The syrup can be prepared by adding a compound to a concentrated aqueous solution of sugar, such as sucrose, to which additional components may be added. Such additional components may include flavoring agents, suitable preservatives, agents that slow the crystallization of sugars, and agents that increase the solubility of any other components, such as polyhydroxy alcohols, e.g., glycerol or sorbitol.

[0158] In some embodiments, the composition may be in the form of a nasal or other mucosal spray formulation (e.g., an inhalable form). These formulations may contain a purified aqueous solution of an active compound having an antiseptic and an isotonic agent. Such formulations can be adjusted to a pH and isotonic state compatible with the nasal or other mucous membrane. Alternatively, they may be in the form of a finely divided solid powder suspended on a gaseous carrier. Such formulations can be delivered by any suitable means or method, such as a nebulizer, atomizer, or metered-dose inhaler.

[0159] In some embodiments, the composition may be in a form suitable for rectal administration. These formulations may be presented as suppositories having a suitable carrier such as cocoa butter, hydrogenated fat, or hydrogenated aliphatic carboxylic acid.

[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 into a thixotropic or gel-like carrier such as a cellulose medium, e.g., methylcellulose or hydroxyethylcellulose, and the resulting formulation is then filled into a transdermal device adapted to be fixed to the wearer's skin in skin contact.

[0161] In addition to the components described above, the compositions of this disclosure may further include one or more auxiliary components selected from capsules, diluents, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, and preservatives (including antioxidants).

[0162] In some embodiments, compositions 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, pharmaceutical compositions 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 controlled-release formulations, which include: (i) formulations that produce substantially constant concentrations of the drug in the body over a long period of time; (ii) formulations that produce substantially constant concentrations of the drug in the body over a long period of time after a predetermined delay; (iii) formulations that maintain an effect over a predetermined period of time by maintaining a relatively constant level of efficacy in the body while simultaneously minimizing undesirable side effects associated with fluctuations in plasma levels of the active substance (sawtooth kinetic patterns); (iv) formulations that localize the effect by spatially positioning the controlled-release composition adjacent to or within the central nervous system or cerebrospinal fluid, for example; (v) formulations that allow for convenient administration, such as once every one or two weeks; and (vi) formulations that target pathological sites. In some applications, controlled-release formulations eliminate the need for frequent administration to maintain a medically advantageous level of activity.

[0163] To obtain controlled release, where the release rate exceeds the metabolic rate of the compound in question, one of several strategies can be pursued. For example, controlled release can be achieved by appropriately selecting various formulation parameters and components, including, for example, various types of controlled release compositions and coatings. Thus, compounds are formulated with appropriate excipients into pharmaceutical compositions that release the compound in a controlled manner upon administration. Examples include single or multiple unit tablets or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes.

[0164] In some embodiments, the composition may include a "vectorized" form, such as by encapsulation of the compound in liposomes or other encapsulation media, or by immobilization of the compound on suitable biomolecules, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides, by covalent bonding, chelation, or association coordination.

[0165] In some embodiments, the composition may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, etc., for controlled release. Furthermore, the composition may include suspension agents, solubilizers, stabilizers, pH adjusters, tonicity adjusters, and / or dispersants. Alternatively, the compound may be incorporated into a biocompatible carrier, implant, or injection device.

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

[0167] In all embodiments, the compound or other active compound may exist as a pharmaceutically acceptable salt or other derivatives such as ether derivatives, ester derivatives, acid derivatives, and water-soluble modified derivatives of the active compound. Derivatives include all individual enantiomers, diastereomers, racemates, and other isomers of the compound. Derivatives also include all polymorphs and solvates, such as those formed in hydrates and organic solvents of the compound. Such isomers, polymorphs, and solvates can be prepared by methods known in the art, such as regioselective and / or enantioselective synthesis and resolution.

[0168] The ability to prepare salts depends on the acidity or basicity of the compound. Suitable salts of compounds include, but are not limited to, acid addition salts made from 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 from 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, cansilate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, and lactate. This includes, but is not limited to, tobionates, lauric acid, malates, maleates, mandelates, mesylates, methyl bromide, methyl nitrate, methyl sulfate, mucin, napsylate, nitrates, N-methylglucamine ammonium salts, oleates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, sulfates, acetates, succinates, tannates, tartrates, theocrates, tosylates, triethoidides, and valersates.

[0170] Pharmaceutically acceptable acid addition salts may exist as various solvates, such as water, methanol, ethanol, and dimethylformamide. Mixtures of such solvates can also be prepared. The source of such solvates may be derived from the crystallization solvent, which is inherent to or incidental to the solvent used for preparation or crystallization.

[0171] Wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.

[0172] Examples of antioxidants permitted as pharmaceuticals 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 otherwise specifically indicated by the context, the compositions of all embodiments may include various pharmaceutically acceptable salts or other derivatives described above.

[0174] Formulations and preparations of such compositions are well known to those skilled in the art of pharmaceutical manufacturing. These formulations can be found in Remington: The Science and Practice of Pharmacy.

[0175] The amount of compounds used in this disclosure varies depending on the disease state, patient / subject, and the severity of the disease.

[0176] All cited references (including references to documents, published patents, and published patent applications) made herein expressly incorporated by reference are expressly incorporated herein by reference. The present disclosure and the methods and processes for making and using it are described in such complete, clear, concise, and precise terms that it will enable those skilled in the art to make and use it.

[0177] The actual dosage levels of the active ingredient in a pharmaceutical composition may vary to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0178] The selected dosage level depends on the activity of the specific compound or combination of compounds used, or its ester, salt, or amide; the route of administration; the time of administration; the excretion rate of the specific compound(s) used; the duration of treatment; other drugs, compounds, and / or materials used in combination with the specific compound(s) used; the age, sex, weight, condition, general health, and medical history of the patient being treated; and similar factors well known in the medical field.

[0179] A physician or veterinarian with general skills in the art can easily determine and formulate the therapeutically effective dose of a required pharmaceutical composition. For example, a physician or veterinarian can start administration of a pharmaceutical composition or compound at a lower level than the amount required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. "Therapeutic dose" means a concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective dose of a compound varies depending on the subject's weight, sex, age, and medical history. Other factors influencing the effective dose 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 with the compound of this disclosure. A larger total dose can be delivered by administering the drug 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] Generally, an appropriate daily dose of the active compound used in the compositions and methods of this disclosure would be the amount of the compound that is the minimum dose effective in producing a therapeutic effect. Such an effective amount generally depends on the factors mentioned above.

[0181] Administration may be a single dose or cumulative (sequential), and this can be easily determined by those skilled in the art. For example, treatment may consist of a single dose of the effective dose of the pharmaceutical composition disclosed herein. Alternatively, treatment may consist of multiple doses of the effective dose of the pharmaceutical composition administered over a period of time, such as once daily, twice daily, three times daily, 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, the effective dose of the pharmaceutical composition disclosed herein can be administered to an individual irregularly once daily, or until the individual no longer requires treatment. Those skilled in the art will recognize that the individual's condition can be monitored throughout the course of treatment, and that the effective dose 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 one, two, three, four, five, or six or more subdoses, administered separately at appropriate intervals throughout the day, in unit dose forms as needed. In certain embodiments of this disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound is administered once daily.

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

[0184] Patients receiving this treatment include primates, especially humans, as well as other mammals such as horses, cattle, pigs, and sheep; and any animal that needs it, including poultry and pets in general.

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

[0186] Such combination products may use the compounds of the present disclosure or pharmaceutically acceptable salts thereof, within the above dosage range, and other pharmaceutically active agents within the approved dosage range.

[0187] In some embodiments, the compound may be administered after an attribute event, such as after exposure to ionizing radiation or after the commencement 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 yet another embodiment, the compound is administered 24 hours after exposure. In yet another embodiment, the compound is administered 24 hours after exposure. In yet another embodiment, the compound is administered 36 hours after exposure. In yet another embodiment, the compound is administered within 48 hours of exposure. In yet another embodiment, the compound is administered within 60 hours of exposure. In yet another embodiment, the compound is administered within 72 hours of exposure. In yet another embodiment, the compound is administered within 48 hours of exposure.

[0188] In certain embodiments or formulations, Yel002 / BCN057 was solubilized in aqueous solutions at a physiologically suitable 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 embodiments, 100 mM lactic acid was added to improve the solubility of these mixtures. In yet another embodiment, a formulation containing Yel002, 30% by weight of captisol (SBE-beta-CD), and 100 mM MSA showed excellent solubility at pH 4.1 or higher.

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

[0190] The present disclosure, which describes the entirety of this disclosure, is included solely to illustrate certain aspects and embodiments of this disclosure and is not intended to limit the disclosure, and can be more readily understood by referring to the following examples.

[0191] In other embodiments of this model, 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 embodiment of this embodiment, the fusion protein or chimeric molecule disclosed herein reduces the severity of the disease to, 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 90% Reduce by approximately 30% to 90%, 40% to 90%, 50% to 90%, 60% to 90%, 70% to 90%, 10% to 80%, 20% to 80%, 30% to 80%, 40% to 80%, 50% to 80%, or 60% to 80%, 10% to 70%, 20% to 70%, 30% to 70%, 40% to 70%, or 50% to 70%.

[0192] Finally, while aspects of this specification are emphasized by reference to specific embodiments, it should be understood that those skilled in the art will readily recognize that these disclosed embodiments merely illustrate the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is not limited to the specific compounds, compositions, articles, apparatus, methods, protocols, and / or reagents described herein unless otherwise explicitly stated. In addition, those skilled in the art will recognize that specific changes, modifications, substitutions, alterations, additions, subtractions, and subcombinations can be made in accordance with the teachings herein without departing from the spirit of this specification. Accordingly, the appended claims below and the following claims are intended to be construed as including all such changes, modifications, substitutions, alterations, additions, subtractions, and subcombinations as falling within their true spirit and scope.

[0193] Specific embodiments of the Disclosure, including the best mode known to the inventors for carrying out the Disclosure, are described herein. Of course, variations of these described embodiments will be obvious to those skilled in the art by reading the above description. The inventors expect that those skilled in the art will use such variations as appropriate, and the inventors intend to carry out the Disclosure in ways other than those specifically described herein. Accordingly, the Disclosure includes all modifications and equivalents of the subject matter described in the claims appended herein, as permitted by applicable rules. Furthermore, any combination of all possible variations of the above embodiments is incorporated herein unless it is specifically not shown herein or is clearly inconsistent with the context.

[0194] The grouping of other embodiments, elements, or processes of this disclosure should not be construed as limiting. Members of each group may be referred to and claimed individually or in any combination with members of other groups disclosed herein. For convenience and / or patentability reasons, it is anticipated that one or more members of a group may be included in or excluded from a group. In the event of such inclusion or exclusion, this specification shall be deemed to include the modified groups and thus satisfy all descriptions of Markush groups used in the appended claims.

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

[0196] Finally, the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of this disclosure as defined solely by the claims. Therefore, this disclosure is not limited to the precision illustrated and described.

Claims

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

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

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

4. The pharmaceutical composition according to 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 organ cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, rectal cancer, skin cancer, hematological cancer, or testicular cancer.

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

6. The pharmaceutical composition according to claim 5, wherein the one or more additional agents are chemotherapeutic agents or radiotherapy agents.

7. A pharmaceutical composition for use in the treatment of one or more side effects of chemotherapy or radiotherapy, comprising formula B: 【Chemistry 4】 It contains the compound, in the formula, R １ is an alkyl, alkylamine, or ether; R ２ is H or CH ３ And; R ３ is either H or OH; Pharmaceutical composition.

8. A pharmaceutical composition for use in the treatment of radiation-induced damage to epithelial cells in a subject, comprising formula B: 【Transformation 5】 It contains the compound, in the formula, R １ is an alkyl, alkylamine, or ether; R ２ is H or CH ３ And; R ３ is either H or OH; Pharmaceutical composition.

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

10. A pharmaceutical composition for use in the treatment of one or more side effects of chemotherapy or radiotherapy, comprising the compound described in claim 1.

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

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

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