Composition for use in inhibiting Src kinase and in treating and preventing related disorders.

Abstract

This provides a method for regulating Src kinase. [Solution] A method comprising administering the following structure or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereoisomer, racemate, or stereoisomer mixture thereof. JPEG2026048692000026.jpg48153

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 901,540, filed September 17, 2019, which is incorporated herein by reference in its entirety.

[0002] Technical field The present invention encompasses compounds and compositions that inhibit Src kinase, as well as methods for treating or preventing related disorders. In some embodiments, the present invention encompasses compositions and combinations of agents that act synergistically to inhibit the proliferation of cancer cells, and in particular, such compositions and combinations can be used to treat cancer. [Background technology]

[0003] The U.S. National Cancer Institute estimates that one in three people in the United States alone will develop cancer during their lifetime. The widespread incidence of this disease highlights the need for improvements in anti-cancer regimens to treat malignant lesions.

[0004] Vernonia cinerea (Asteraceae family), also commonly known as purple bellflower, is a native species of tropical Asia and Africa. This branched herb grows to a height of approximately 0.5 to 3 feet and is found throughout India. Various parts of the plant, including stems, seeds, leaves, roots, and flowers, have been described in ancient texts and alternative medicines. Several studies from the Asian subcontinent have reported the use of purple bellflower as an anthelmintic, antibacterial, antiviral, antifungal, anti-inflammatory, diuretic, and stomach medicine.

[0005] Phytochemical screening of the whole plant extract revealed the presence of triterpene compounds such as beta-amyrin acetate and lupeol acetate; and sterols such as beta-sitosterol, stigmasterol, alpha-spinasterol, and phenol resins. Recently, the antitumor activity of this plant extract has also been established. However, the identity of the biologically active compound(s) responsible for this antitumor activity remains unknown.

[0006] The inventors identified active compounds responsible for antitumor activity and certain specific derivatives from a crude extract of Erigeron annuus by utilizing various extraction and biochemical analysis tools. [Overview of the project]

[0007] The present invention generally encompasses compounds that inhibit specific tyrosine kinases (i.e., Src kinases), compositions containing such compounds, and furthermore, combinations of such compositions with known anticancer drugs for treating and preventing cancer.

[0008] In another embodiment, the present invention encompasses methods of using compositions comprising active compounds or derivatives and metabolites in any medical condition involving Src tyrosine kinase or Src family kinase (SFK) activity, such as, but not limited to, the development, maintenance, progression, and metastatic propagation of cancer.

[0009] In certain embodiments, the compounds and compositions include, but are not limited to, those associated with chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), breast cancer (e.g., triple-negative, HER2-positive, etc.), and colon cancer. It is effective against human cancer and tumor cells.

[0010] In one embodiment, the compound of the present invention is a compound having the following structure: [ka] [wherein, X is O or S; R1 is hydrogen, or, but not limited to, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m R7, (CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH) n -S-(CH2) m -R7, a substituted or unsubstituted substituent containing each of R2 to R6 is independently hydrogen, hydroxyl, halogen, lower alkyl, lower alkenyl, lower alkynyl, amino, nitro, azide, sulfate, sulfonate, sulfonamide, -(CH2) m R7, (CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, --(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R7, R7, in each occurrence, represents hydrogen, hydroxyl, or substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, benzyl, cycloalkyl, cycloalkenyl, or heterocycle; and each occurrence of m is independently an integer in the range of 1 to 9, and each occurrence of n is independently an integer in the range of 1 to 9.][[ID=S5]] Or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereoisomer, racemate or mixture of stereoisomers thereof is included.

[0011] In another embodiment, the compound of the present invention is a compound having the following structure: [ka] [In the formula, X is either O or S; R1 is hydrogen, or not limited to, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m R7, (CH2) m -OH,-(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R7 is a substituted or unsubstituted substituent, Each of R2 to R6 can independently be hydrogen, hydroxyl, halogen, lower alkyl, lower alkenyl, lower alkynyl, amino, nitro, azide, sulfate, sulfonate, sulfonamide, or -(CH2) m R7, (CH2) m -OH,-(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, --(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R7, R7, R8, and R9 each independently represent, in each occurrence, hydrogen, hydroxyl, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, benzyl, cycloalkyl, cycloalkenyl, or heterocycle; and Each occurrence of m and n is a separate and independent integer in the range of 1 to 9, and each occurrence of z is an independent integer in the range of 1 to 9. This may include pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereoisomers, racemates, or mixtures of stereoisomers thereof.

[0012] In another embodiment, the compound of the present invention is a compound having the following structure: [ka] [In the formula, R1 is hydrogen, or not limited to, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m R7, -(CH2) m -OH,-(CH2) m (=X)XR7, -(CH2) m (=X)R7, -(CH2) m -X-Lower alkyl, -(CH2) m -X-lower alkenyl, -(CH2) n -X-(CH2) m -R7, -(CH2) m -XR7 is a substituted or unsubstituted substituent, X is either O or S; Each of R2, R5, and R6 is independently hydrogen, hydroxyl, halogen, lower alkyl, lower alkenyl, lower alkynyl, amino, nitro, azide, sulfate, sulfonate, sulfonamide, -(CH2) m R7, (CH2) m -OH,-(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, --(CH2)m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R7, R'7, in each occurrence, is hydrogen, hydroxyl, or substituted or unsubstituted alkyl, acetyl Represents a aryl, alkenyl, aryl, aralkyl, benzyl, cycloalkyl, cycloalkenyl, or heterocycle; and Each occurrence of m is an integer in the range of 1 to 9, and each occurrence of n is an integer in the range of 1 to 9. This may include pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereoisomers, racemates, or mixtures of stereoisomers thereof.

[0013] In one particular embodiment, R1 is a linear or branched alkyl having six or fewer carbon atoms (e.g., C1-C6 in a linear chain, C3-C6 in a branched chain), and in another embodiment, the linear or branched alkyl has four or fewer carbon atoms.

[0014] The present invention relates to a method for treating or preventing cancer by administering a composition comprising a compound of formula (I), (II), or (III), a pharmaceutically acceptable salt thereof, a prodrug, a metabolite, a polymorph, or a solvate thereof to a subject requiring such treatment, wherein the administration of the composition of the present invention, or a pharmaceutically acceptable salt thereof, a prodrug, a metabolite, a polymorph, or a solvate thereof, results in one or more of the following: inhibition of cancer cell proliferation by accumulation of cells in one or more phases of the cell cycle (e.g., G1, G1 / S, G2 / M), induction of cellular senescence, or promotion of tumor cell differentiation; promotion of cell death in cancer cells by cytotoxicity, necrosis, or apoptosis without significant cell death in normal cells; and antitumor activity in animals having at least two therapeutic indices. As used herein, “therapeutic index” is the maximum tolerated dose divided by the effective dose.

[0015] In a particular embodiment, the present invention has the following structure: [ka] [In the formula, X is either O or S; R1 is hydrogen, or not limited to, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m R7, (CH2) m -OH,-(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R7 is a substituted or unsubstituted substituent, Each of R2 to R6 can independently be hydrogen, hydroxyl, halogen, lower alkyl, lower alkenyl, lower alkynyl, amino, nitro, azide, sulfate, sulfonate, sulfonamide, or -(CH2) m R7, (CH2) m -OH,-(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, --(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R7, R7, R8, and R9 are each independently represented by hydrogen, hydroxyl, or substitution in each occurrence. or representing an unsubstituted alkyl, alkenyl, aryl, aralkyl, benzyl, cycloalkyl, cycloalkenyl, or heterocycle; and Each occurrence of m and n is a separate and independent integer in the range of 1 to 9, and each occurrence of z is an independent integer in the range of 1 to 9. This includes methods for modulating Src kinase, including administering a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereoisomer, racemic mixture, or stereoisomer mixture thereof.

[0016] In a particular embodiment, R3 and R4 are each -OH.

[0017] In a particular embodiment, R2 and R3 are each -OH.

[0018] In a particular embodiment, z is 2, and R8 and R9 are each -H.

[0019] In a particular embodiment, z is 2; R1, R2, R5, R6, R8, and R9 are each -H; and R3 and R4 are each -OH.

[0020] In a particular embodiment, X is O.

[0021] In a particular embodiment, R1, R2, R3, R6, R8, and R9 are each -H; R4 and R5 are both -OH; X is O; and Z is 2.

[0022] In a particular embodiment, the compound of formula II has the following structure: [ka] It may also have pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereoisomers, racemates, or mixtures of stereoisomers thereof.

[0023] In certain embodiments, the compound of Formula II is a prodrug of the following structure: [Chemical formula] [wherein, R1 is an ester including an ethyl ester, a morpholinoethanol ester, an acetate ester, a dialkylaminoacetate ester, a formate ester, a phosphate ester, a sulfate ester, and a benzoic acid derivative; a carbamate including N,N-dimethylaminocarbonyl of a hydroxy functional group, and an N-acyl derivative].

[0024] The present invention also provides a prodrug of the following formula: [Chemical formula] [wherein, R1 is an ester including an ethyl ester, a morpholinoethanol ester, an acetate ester, a dialkylaminoacetate ester, a formate ester, a phosphate ester, a sulfate ester, and a benzoic acid derivative; a carbamate including N,N-dimethylaminocarbonyl of a hydroxy functional group, and an N-acyl derivative].

[0025] In other embodiments, the present invention provides a method for treating cancers including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), breast cancer, and colon cancer, having the following structure: [Chemical formula] [wherein, X is O or S; R1 is hydrogen, or, but not limited to, lower alkyl, lower alkenyl, lower alkynyl, -(CH2)[[ID=​​​​​​​​​​m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -A substituted or unsubstituted substituent containing -R7, [[ID=IO]] [[ID=II]]Each of Rl to R6 is independently hydrogen, hydroxyl, halogen, lower alkyl, lower alkenyl, lower alkynyl, amino, nitro, azide, sulfate, sulfonate, sulfonamide, -(CH2) s<000OO98>R7, (CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m [[ID=I9]]-O-lower alkenyl, -(CH2) n -O-(CH2)<OO00103>-R7, --(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R7, R7, R8, and R9 are each independently, in each occurrence, hydrogen, hydroxyl, or represent substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, benzyl, cycloalkyl, cycloalkenyl, or heterocycle; and Each occurrence of m and n is separately and independently an integer in the range from 1 to 9, and each occurrence of z is independently an integer in the range from 1 to 9] Or administering a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereoisomer, racemate or mixture of stereoisomers thereof, including the above method.

[0026] In certain embodiments, R3 and R4 are each -OH.

[0027] In certain embodiments, R2 and R3 are each -OH.

[0028] In a particular embodiment, z is 2, and R8 and R9 are each -H.

[0029] In a particular embodiment, z is 2; R1, R2, R5, R6, R8, and R9 are each -H; and R3 and R4 are each -OH.

[0030] In a particular embodiment, X is O.

[0031] In a particular embodiment, R1, R2, R3, R6, R8, and R9 are each -H; R4 and R5 are both -OH; X is O; and Z is 2.

[0032] In a particular embodiment, the compound of formula II has the following structure: [ka] It may also have pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereoisomers, racemates, or mixtures of stereoisomers thereof.

[0033] In a particular embodiment, the compound of formula II is a prodrug with the following structure: [ka] [In the formula, R1 is an ester comprising ethyl esters, morpholinoethanol esters, acetate esters, dialkylaminoacetic acid esters, formic acid esters, phosphate esters, sulfate esters, and benzoic acid derivatives; a carbamate comprising the hydroxyl functional group N,N-dimethylaminocarbonyl, and an N-acyl derivative.]

[0034] In certain embodiments, the present invention further includes the administration of one or more additional therapeutic agents, including anticancer drugs or chemotherapeutic agents.

[0035] Those skilled in the art can refer to general references for detailed descriptions of known technologies or equivalent technologies discussed herein. These references include Ausubel et al., *Current Protocols in Molecular*. Biology, John Wiley and Sons, Inc. (2005);Sambrook et al., Molecular Cloning, A Laboratory Manual (3.sup.th edition), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000);Coligan et al., Current Protocols in Immunology, John Wiley & S. ons, NY; Enna et al., Current Protocols This includes *in Pharmacology*, John Wiley & Sons, NY; Fingl et al., *The Pharmacological Basis of Therapeutics* (1975), *Remington's Pharmaceutical Sciences*, Mack Publishing Co., Easton, Pa., 18th sup.th edition (1990). These documents can, of course, be referenced when creating or using embodiments of the present invention.

[0036] This invention provides an effective therapeutic method for regulating tumor growth or metastasis, using a combination of drugs. The method offers advantages such as greater overall efficacy when achieving synergistic effects or avoiding antagonistic effects, and, if desired, allows for a reduction in the amount of one or more of the individual drugs used, while simultaneously reducing side effects. Furthermore, even when the treated tumor does not respond optimally to a given anticancer drug, the use of this combination therapy can yield effective treatment.

[0037] As used herein, the term “effective amount” of a compound or pharmaceutical composition means, but is not limited to, an amount sufficient to modulate tumor growth or metastasis in animals, particularly humans, including prophylactic administration, to reduce tumor growth or size, or to prevent the formation of tumor growth in animals that do not have any tumors prior to administration.

[0038] As used herein, the terms “tumor,” “tumor growth,” or “tumor tissue” may be used interchangeably and refer to abnormal growth of tissue resulting from uncontrolled progressive proliferation of cells and a lack of physiological function. Solid tumors can be malignant, life-threatening, or benign, for example, with a tendency to metastasize. Examples of solid tumors that can be treated or prevented by the methods of the present invention include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphoendothelial sarcoma, synoviomas, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma This includes sarcomas and carcinomas such as medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, liver metastasis, cholangiocarcinoma, choriocarcinoma, seminomas, embryonic carcinoma, and anaplastic thyroid carcinoma; Wilms' tumor, cervical carcinoma, testicular carcinoma, lung carcinomas such as small cell lung carcinoma and non-small cell lung carcinoma; bladder carcinoma; epithelial carcinoma; glioma, gliosclerocytoma, medulloblastoma, craniopharyngioma, ependymal cell carcinoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0039] Furthermore, tumors involving abnormal proliferative changes (such as metaplasia and dysplasia) can be treated or prevented in epithelial tissues, such as those in the cervix, colon, esophagus, and lungs, using the pharmaceutical compositions or methods of the present invention. Thus, the present invention provides treatment for conditions known or suspected to be precursors to neoplasia or cancer when non-neoplastic cell proliferation, consisting more specifically of hyperplasia, metaplasia, or most specifically of dysplasia, occurs (see Robbins and Angell, 1976, Basic Pathology, 2d Ed., WB Saunders Co., Philadelphia, pp. 68 to 79, for an overview of such abnormal proliferative conditions). Hyperplasia is a form of controlled cell proliferation involving an increase in the number of cells in a tissue or organ without significant structural or functional alteration. For example, endometrial hyperplasia often precedes endometrial cancer. Metaplasia is a form of controlled cell proliferation in which one type of mature or fully differentiated cell is replaced by another type of mature cell. Metaplasia can occur in epithelial or connective tissue cells. Atypical metaplasia is related to somewhat disordered metaplastic epithelial cells. Dysplasia is often a precursor to cancer and is mainly found in epithelium; this is non-neoplastic cell proliferation. Dysplasia is the most disordered form of dysplasia, characterized by a loss of individual cell uniformity and cellular architectural orientation. Dysplasia often has abnormally large deep chromosomal nuclei and exhibits pleomorphism. Dysplasia is characteristically found in areas where chronic irritation or inflammation is present, and is frequently found in the cervix, respiratory tract, oral cavity, and gallbladder. For an overview of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., JB Lippincott Co., Philadelphia.

[0040] This invention encompasses treating and / or preventing various types of leukemia. Leukemia is a cancer of early hematopoietic cells. Most often, leukemia is a cancer of white blood cells, but some leukemias begin in other blood cell types. There are several types of leukemia, which are mainly classified based on whether the leukemia is acute (rapid growth) or chronic (slow growth) and whether it begins in myeloid cells or lymphoid cells. Different types of leukemia have different treatment options and prospects. Acute lymphoblastic (or lymphoblastic) leukemia is sometimes called ALL. It begins in the bone marrow where blood cells are made. It is more common in children than in adults. Acute myeloid leukemia is also called acute myeloid leukemia, acute granulocytic leukemia, acute non-lymphoblastic leukemia, or sometimes just AML. It is most common in older adults. Chronic lymphocytic leukemia (CLL) is a type of cancer that originates in the white blood cells (called lymphocytes) of the bone marrow. CLL mainly affects older adults and accounts for about one-third of all leukemias. Chronic myeloid leukemia (CML), also known as chronic myeloid leukemia, is a type of cancer that originates in the hematopoietic cells of the bone marrow and invades the bloodstream. CML accounts for about 15% of leukemias in adults. Chronic myeloid monocytic leukemia (CMML) is a type of cancer that originates in the hematopoietic cells of the bone marrow and invades the bloodstream. This mainly affects older adults.

[0041] This method can be carried out, for example, using a single pharmaceutical composition containing both an Aur-A inhibitor and a Src inhibitor (dasatinib) (when administration should be simultaneous), or using two or more pharmaceutical compositions containing the Src inhibitor and dasatinib separately (when administration should be simultaneous or sequential). The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that, when administered to humans, are physiologically acceptable and preferably do not cause allergic or similar adverse reactions such as acute gastric motility or dizziness.

[0042] The pharmaceutical compositions of the present invention can be administered by any suitable route, for example, by injection, orally, pulmonaryly, intranasally, or by other forms of administration. Generally, pharmaceutical compositions intended to be within the scope of the present invention particularly include pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, and / or carriers. Such compositions may include various buffering agents (e.g., Tris-HCl, acetates, phosphates), diluents of pH and ionic strength; additives such as surfactants and solubilizers (e.g., Tween 80, Polysorbate 80), antioxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., thimerosal, benzyl alcohol), and bulking agents (e.g., lactose, mannitol); and the introduction of substances into particulate formulations or liposomes of polymer compounds such as polylactic acid and polyglycolic acid. Such compositions may affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the components of the pharmaceutical compositions of the present invention. For example, see Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042), pages 1435-1712, which is incorporated herein by reference. The pharmaceutical compositions of the present invention may be prepared, for example, in liquid form or in dry powder form, such as lyophilized form. Specific methods for administering such compositions are described below.

[0043] The present invention relates to an Aur-A inhibitor, such as those listed above, and at least one Src inhibitor. The present invention relates to methods for regulating tumor growth and metastasis, including administration of a drug, preferably with dasatinib. The drugs of the present invention may be administered separately (e.g., formulated and administered separately) or in combination as a pharmaceutical composition of the present invention. Administration may be achieved by any suitable route, such as parenteral, transmucosal, e.g., oral, transnasal, or rectal, or transdermal. Preferably, administration is parenteral, e.g., via intravenous injection. Alternative means of administration, but not limited to these, may also include intra-arterial, intramuscular, intradermal, subcutaneous, perivascular, intraventricular, and intracranial administration, or injection into or into the tumor(s) being treated or the tissue surrounding the tumor(s).

[0044] In another embodiment, the pharmaceutical composition of the present invention can be delivered in a controlled-release system, such as by intravenous infusion, implantable osmotic pump, transdermal patch, liposome, or other administration methods. In certain embodiments, a pump can be used [Langer, cited above; Sefton, CRC Crit. Ref. Biomed. Eng.]. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980);Saudek et al., N. Engl. J. See Med. 321:574 (1989). In another embodiment, polymer materials can be used [see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press: Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley: New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and also Howard et al., J. Neurosurg. 71:105 (1989)]. In another embodiment, the controlled-release system can be placed near the target tissue of the animal so that only a portion of the systemic dose is required [see, for example, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)]. In particular, the controlled-release device can be introduced into the animal near the site of inappropriate immune activation or tumor. Other controlled-release systems are discussed in the overview by Langer [Science 249:1527-1533 (1990)]. [Brief explanation of the drawing]

[0045] [Figure 1] An exemplary embodiment of the chromatographic profile of the fraction identified in the initial capture step is illustrated. [Figure 2] An exemplary embodiment of the chromatographic profile of the fraction identified in the intermediate step is illustrated. [Figure 3]An exemplary embodiment of the chromatographic profile of the fraction identified in the polishing step is illustrated. [Figure 4] An exemplary embodiment of the chromatographic profile of the fraction identified in the desalting step is illustrated. [Figure 5] An exemplary embodiment of the proton (1H) NMR profile of purified compound E05 is illustrated. [Figure 6] An exemplary embodiment of the carbon (13C) NMR profile of purified compound E05 is illustrated. [Figure 7] An exemplary embodiment of the strain-free signal-enhanced (DEPT) profile of purified compound E05 due to polarization shift is illustrated. [Figure 8] An exemplary embodiment of the infrared (IR) profile of purified compound E05 is illustrated. [Figure 9A] An exemplary embodiment of the LC-MS spectrum of purified compound E05 is illustrated. [Figure 9B] An exemplary embodiment of the MS spectrum of purified compound E05 is illustrated. [Figure 10] An exemplary embodiment of the ORTEP diagram of compound E05 (3-(3,4-dihydroxyphenyl)propanoic acid) showing an atomic numbering scheme is illustrated, where the substitution ellipsoid is depicted at a 50% probability level, and H atoms are shown as small spheres with arbitrary radii. [Figure 11] Exemplary embodiments of the water-soluble fraction-induced antiproliferative activity of Erigeron annuus in various cell lines are illustrated. [Figure 12] This illustration shows an exemplary embodiment of the antiproliferative activity of the pure compound (E05) in the colon cancer cell line, HCT116. A dose-dependent response may be observed with treatment with the pure compound. [Figure 13] Exemplary embodiments of the antiproliferative activity of the pure compound (E05) in breast cancer cells, BT-474, are illustrated. A dose-dependent response may be observed with treatment with the pure compound. [Figure 14]An exemplary embodiment of the comparison of IC50 values ​​between synthetic E05 and the SRC kinase inhibitor bosutinib in F-36E cells is illustrated. [Figure 15] This figure illustrates an exemplary embodiment of the IC50 value of synthetic E05 in the trinegative breast cancer cell line, MDA-MB-468. [Figure 16] This figure illustrates an exemplary embodiment of the comparison of antiproliferative activity between synthetic E05 and lapatinib in the trinegative breast cancer cell line, MDA-MB-468. [Figure 17] This illustration shows an exemplary embodiment of the efficacy of exemplary compound E05 in a mouse xenograft model of trinegative breast cancer. [Figure 18] This illustration shows an exemplary embodiment of the mean plasma concentration-time profile of a low molecular weight formulation after forced oral administration (dose: 10 mg / kg; G3) of the low molecular weight formulation in male Sprague Dawley rats. [Modes for carrying out the invention]

[0046] As used herein, the term "cycloalkyl" refers to a group of atoms with 3 to 30 carbon atoms (e.g., C3-C3). 10The term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic hydrocarbon monocyclic or polycyclic (e.g., condensed, bridged, or spirocyclic) system having an optionally substituted heteroatom (such as O, N, S, or Se). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl. Unless otherwise specified, the term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (condensed, bridged, or spirocyclic), or 11- to 14-membered tricyclic system (condensed, bridged, or spirocyclic) having one or more heteroatoms (such as O, N, S, or Se). Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, oxyranyl, azetidinyl, oxetanyl, thietanyl, and 1,2,3,6-tetrahydropyridinyl. These include tetrahydropyranil, dihydropyranil, pyranil, morpholinil, 1,4-diazepanil, 1,4-oxaazepanil, 2-oxa-5-azabicyclo[2.2.1]heptanil, 2,5-diazabicyclo[2.2.1]heptanil, 2-oxa-6-azaspiro[3.3]heptanil, 2,6-diazaspiro[3.3]heptanil, and 1,4-dioxa-8-azaspiro[4.5]decanil.

[0047] The term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0048] The "arylalkyl" or "aralkyl" portion is an alkyl group substituted with an aryl group (e.g., phenylmethyl(benzyl)). The "alkylaryl" portion is an aryl group substituted with an alkyl group (e.g., methylphenyl).

[0049] The term "alkenyl" includes unsaturated aliphatic groups that are similar in length to the alkyl groups mentioned above, are substituted, and contain at least one double bond. For example, the term "alkenyl" includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, linear or branched alkenyl groups have six or fewer carbon atoms in their skeleton (e.g., C1-C6 for linear groups, C3-C6 for branched groups). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

[0050] The term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0051] "Alkynyl" includes unsaturated aliphatic groups that are similar in length to the alkyl groups mentioned above, are substituted, and contain at least one triple bond. For example, "Alkynyl" includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl) and branched alkynyl groups. In certain embodiments, the linear or branched alkynyl group has six or fewer carbon atoms in its skeleton. It has atoms (for example, C2-C6 in a straight chain, C3-C6 in a branched chain). The term "C2-C6" includes alkynyl groups containing 2-6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3-6 carbon atoms. The term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0052] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moieties) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0053] The term "aryl" includes aromatic groups that are "conjugated" or polycyclic systems containing at least one aromatic ring and no heteroatoms in the ring structure. Examples include phenyl, benzyl, and 1,2,3,4-tetrahydronaphthalenyl.

[0054] A "heteroaryl" group is an aryl group as defined above, except that it has 1 to 4 heteroatoms in its ring structure, and may also be called an "aryl heterocyclic" or "heteroaromatic." As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocyclic ring consisting of a carbon atom and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N → O and S(O)p, where p = 1 or 2). Note that the total number of S and O atoms in an aromatic heterocycle is 1 or less. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0055] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic and bicyclic groups, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, and benzo It contains furan, purine, benzofuran, deazapurine, and indolinidine.

[0056] In the case of polycyclic aromatic rings, all rings may be aromatic (e.g., quinoline), but it is also necessary that at least one of the rings be aromatic (e.g., 2,3-dihydroindole). The second ring may be condensed or cross-linked.

[0057] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have substituents at one or more ring positions (e.g., heteroatoms such as ring-forming carbon or N), such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, They may be substituted with minocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. The aryl and heteroaryl groups may be condensed or crosslinked with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl).

[0058] As used herein, “carbocyclic ring” or “carbocyclic ring” is intended to include any stable monocyclic, bicyclic, or tricyclic ring having a specified number of carbon atoms, which may be saturated, unsaturated, or aromatic. Carbocyclic rings include cycloalkyl and aryl rings. For example, C3-C 14A carbocyclic ring is intended to include monocyclic, bicyclic, or tricyclic rings having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. Examples of carbocyclic rings, but not limited to these, include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. Crosslinked rings are also included in the definition of a carbocyclic ring, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, and [2.2.2]bicyclooctane. A crosslinked ring is formed when one or more carbon atoms bond to two non-adjacent carbon atoms. In one embodiment, the bridging ring is one or two carbon atoms. Note that the bridge always converts a monocyclic ring to a tricyclic ring. When a ring is bridging, the substituents listed for the ring may be present on the bridge. Condensations (e.g., naphthyl, tetrahydronaphthyl) and spirorings are also included.

[0059] As used herein, “heterocycle” or “heterocyclic group” includes any ring structure (saturated, unsaturated, or aromatic) containing at least one ring heteroatom (e.g., N, O, or S). Heterocycles include heterocycloalkyls and heteroaryls. Examples of heterocycles, but not limited to, include morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran. Examples of heterocyclic groups, but not limited to, include acridinyl, azosinyl, benzimidazolyl, benzofuranil, and benzothiofuranil. benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carborinyl, chromanil, clomenil, cinolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinyl, dihydrofloflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl Indolidinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranil, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthilidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazole 5(4H)-one, oxazolidinyl, oxazolyl Oxoindolyl, pyrimidinyl, phenanthrolinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperadinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, prinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrrolyl, quinazolinyl, quinolinyl Lu, 4H-Quinolidinyl, Quinoxalinyl, Quinuclidinyl, Tetrahydrofuranil, Tetrahydroisoquinolinyl, Tetrahydroquinolinyl, Tetrazolyl, 6H-1,2,5-Thiadianizinyl, 1,2,3-Thiadianzolyl, 1,2,4-Thiadianzolyl, 1,2,5-Thiadianzolyl, 1,3,4-Thiadianzolyl, Thiantrenyl, Thiazolyl, Thienyl, Thienothiazolyl, Thienooxazolyl, Thienoimidazolyl, Thiophenyl, Triazinyl, 1,2,3-Triazolyl, 1,2,4-Triazolyl, 1,2,5-Triazolyl, 1,3,It contains 4-triazolyl and xanthenyl.

[0060] If any variant (e.g., R2) appears more than once in any component or formula for a compound, its definition is independent of any other appearances. Therefore, for example, if a group is indicated to be substituted with 0 to 2 R1 moieties, that group may be optionally substituted with up to 2 R1 moieties, and each R1 is independently selected from the definition of R1. Furthermore, combinations of substituents and / or variants are permissible, but only if such combinations result in a stable compound.

[0061] The terms "hydroxy" or "hydroxyl" include groups containing --OH.

[0062] As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodine. The term "perhalogenated" generally refers to a moiety in which all hydrogen atoms are replaced by halogen atoms. The terms "haloalkyl" or "haloalkoxyl" refer to an alkyl or alkoxyl that is substituted with one or more halogen atoms.

[0063] The term "carbonyl" includes compounds and parts containing a carbon atom linked to an oxygen atom by a double bond. Examples of carbonyl-containing parts include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, and anhydrides.

[0064] The term "carboxyl" refers to --COOH or its C1-C6 alkyl ester.

[0065] The term "acyl" includes a moiety containing an acyl radical (R--C(O)--) or a carbonyl group. "Substituting acyls" include acyl groups in which one or more hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogens, hydroxyls, alkylcarbonyloxys, arylcarbonyloxys, alkoxycarbonyloxys, carboxylates, alkylcarbonyls, arylcarbonyls, alkoxycarbonyls, aminocarbonyls, alkylaminocarbonyls, dialkylaminocarbonyls, alkylthiocarbonyls, alkoxyls, phosphates, phosphonatos, phosphinatos, aminos (including alkylaminos, dialkylaminos, arylaminos, diarylaminos, and alkylarylaminos), acylaminos (including alkylcarbonylaminos, arylcarbonylaminos, carbamoyls, and ureidos), amidinos, iminos, sulfhydryls, alkylthios, arylthios, thiocarboxylates, sulfates, alkylsulfinyls, sulfonates, sulfamoyls, sulfonamides, nitros, trifluoromethyls, cyanos, azides, heterocyclyls, alkylaryls, or aromatic or heteroaromatic moieties. The terms "alkoxy" or "alkoxyl" include substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups.The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0066] The terms "ether" or "alkoxy" include compounds or moieties that contain oxygen bonded to two carbon atoms or heteroatoms. For example, the terms include "alkoxyalkyl," which refers to an alkyl, alkenyl, or alkynyl group that is covalently bonded to an oxygen atom, or to an alkyl group.

[0067] The term "ester" includes compounds or parts that contain a carbon or heteroatom bonded to an oxygen atom bonded to a carbon in a carbonyl group. The term "ester" also includes alkoxycarboxyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and pentoxycarbonyl.

[0068] As used herein, “amine” or “amino” refers to an unsubstituted or substituted -NH2 group. “Alkylamino” includes a group of compounds in which the nitrogen of the -NH2 group is bonded to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, and phenethylamino. “Dialkylamino” includes groups in which the nitrogen of the -NH2 group is bonded to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. This includes: "Arylamino" and "diarylamino" groups, which each contain a nitrogen atom bonded to at least one or two aryl groups. "Aminoaryl" and "aminoaryloxy" refer to aryl and aryloxy groups that are substituted with aminos. "Alkylarylamino," "alkylaminoaryl," or "arylaminoalkyl" refer to an amino group bonded to at least one alkyl group and at least one aryl group. "Alkyaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bonded to a nitrogen atom that is also bonded to an alkyl group. "Acylamino" groups, which include a nitrogen atom bonded to an acyl group. Examples of acylaminos, but not limited to these, include alkylcarbonylaminos, arylcarbonylaminos, carbamoyl, and ureido groups.

[0069] The terms “amide” or “aminocarboxy” include compounds or moieties containing a nitrogen atom bonded to the carbonyl or thiocarbonyl group. This term includes the “alkylaminocarboxy” group, which contains an alkyl, alkenyl, or alkynyl group bonded to an amino group bonded to the carbonyl or thiocarbonyl group. This also includes the “arylaminocarboxy” group, which contains an aryl or heteroaryl moiety bonded to an amino group bonded to the carbonyl or thiocarbonyl group. The terms “alkylaminocarboxy,” “alkenylaminocarboxy,” “alkynylaminocarboxy,” and “arylaminocarboxy” include moieties in which the alkyl, alkenyl, alkynyl, and aryl moieties are bonded to a nitrogen atom further bonded to the carbonyl group, respectively. Amides may be substituted with substituents such as linear alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic groups. Substituents on the amide group may be further substituted.

[0070] Other compounds of the present invention can be obtained by converting nitrogen-containing compounds to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and / or hydrogen peroxide). Therefore, all nitrogen-containing compounds shown and claimed are, where permitted by valence and structure, the compounds as shown and their N-oxide derivatives (N → O or N + -O ーIt is thought to include both (which can be expressed as ). Furthermore, in other cases, the nitrogen in the compounds of the present invention can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidizing the parent amine with an oxidizing agent such as m-CPBA. All nitrogen-containing compounds shown and claimed are also thought to cover both the compounds as shown and their N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, where R is a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-14 membered carbon ring or 3-14 membered heterocycle) derivatives, where permitted by valence and structure.

[0071] In this specification, the structural formulas of compounds of formula (I) or (II) may, in some cases, represent specific isomers for convenience, but the present invention includes all isomers, including geometric isomers, optical isomers based on chiral carbons, stereoisomers, and tautomers. In addition, crystalline polymorphisms may exist for compounds represented by formula. Note that any crystalline form, mixture of crystalline forms, or their anhydrous or hydrate is within the scope of the present invention. Furthermore, so-called metabolites produced by the in vivo degradation of this compound are also within the scope of the present invention.

[0072] It should be understood that the structures and other compounds discussed in this invention include all of their atropisomers. “Atropisomer” is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. The existence of atropisomers is due to restricted rotation resulting from the obstruction of the rotation of the larger group around the central bond. Such atropisomers typically exist as a mixture, but Recent advances in chromatographic techniques have made it possible to separate a mixture of two atrop isomers when carefully selected.

[0073] A "tautomer" is one of two or more structural isomers that exist in equilibrium and readily convert from one isomer to the other. This conversion results in a formal transfer of hydrogen atoms, which occurs with the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer sets in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be exchanged through tautomerization is called tautomerism.

[0074] The terms "crystalline polymorphism," "polymorphism," or "crystalline form" refer to the crystalline structures in which a compound (or its salt or solvate) can crystallize in different crystalline packing arrangements (all having the same elemental composition). Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may favor one crystalline form. Crystallographic polymorphisms of a compound can be prepared by crystallizing under different conditions.

[0075] The term “compounds of the present invention” includes the compounds of formula (I), (II), (III), or (IV) disclosed herein, including the compounds themselves, and, where appropriate, their salts, their esters, their solvates, and their prodrugs.

[0076] Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on an aryl- or heteroaryl-substituted benzene compound. Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, glutamates, glucuronates, glutarates, malatates, maleates, succinates, fumarates, tarlatates, tosylates, salicylates, lactates, naphthalenesulfonates, and acetates (e.g., trifluoroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can be formed between a cation and a negatively charged group (e.g., carboxylate) on an aryl- or heteroaryl-substituted benzene compound. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions. Aryl- or heteroaryl-substituted benzene compounds also include salts containing quaternary nitrogen atoms. In salt form, it is understood that the ratio of the compound to the cation or anion in the salt may be 1:1, or any other ratio, such as 3:1, 2:1, 1:2, or 1:3.

[0077] Examples of prodrugs include esters and other pharmaceutically acceptable derivatives that, when administered to a subject, may yield active aryl- or heteroaryl-substituted benzene compounds.

[0078] In addition, the compounds of the present invention, for example, salts of the compounds, may exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvate, acetone solvate, etc.

[0079] A "solvate" refers to a solvated form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates by trapping a certain molar ratio of solvent molecules in their crystalline solid state. When the solvent is water, the resulting solvate is a hydrate. When the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one molecule of a substance, in which case the water retains its molecular state as H2O.

[0080] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but has a slightly different composition (for example, by substitution of one atom with an atom of a different element, or by the presence of a particular functional group, or by substitution of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but does not have the same structure or origin.

[0081] As defined herein, the term “derivative” refers to a compound having a common core structure and being substituted with various groups as described herein. For example, all compounds represented by formulas (I) and (II) are aryl- or heteroaryl-substituted benzene compounds and have formulas (I) and (II) as a common core.

[0082] The term "biological equivalent" refers to a compound resulting from the exchange of one atom or group of atoms for another, broadly speaking, similar atom or group of atoms. The purpose of biological equivalent substitution is to create a new compound that has similar biological properties to the parent compound. Biological equivalent substitution may be based on physical chemistry or topology. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0083] The present invention is intended to include all isotopes of an atom occurring in the compound. Isotopes include atoms that have the same atomic number but different mass numbers. Common examples, but not limited to, include tritium and deuterium as isotopes of hydrogen, and C-13 and C-14 as isotopes of carbon.

[0084] Inhibition is a measurable inhibition compared to a suitable control. In one embodiment, inhibition is at least 10 percent inhibition compared to a suitable control; that is, the percentage of enzyme activity or the amount of product when the inhibitor is used is 90 percent or less of the corresponding percentage or amount that would occur without the inhibitor. In various other embodiments, inhibition is at least 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, or 95 percent inhibition compared to a suitable control. In one embodiment, inhibition is at least 99 percent inhibition compared to a suitable control; that is, the percentage of enzyme activity or the amount of product when the inhibitor is used is 1 percent or less of the corresponding percentage or amount that would occur without the inhibitor.

[0085] The term "composition of the present invention" includes, where appropriate, compounds of formula (I) or (II), (III) or (IV), or pharmaceutically acceptable salts thereof, as well as esters thereof, solvates thereof, and prodrugs thereof.

[0086] The present invention provides a combination of a compound of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents or pharmaceutically acceptable salts thereof, as a co-formulation or separate formulation, wherein the formulations are administered simultaneously, sequentially, or alternately. In certain embodiments, the other therapeutic agent may be an agent recognized in the art as useful for treating the disease or condition treated by the composition of the present invention. In other embodiments, the other therapeutic agent may be an agent recognized in the art as useful for treating the disease or condition treated by the composition of the present invention. In one embodiment, the other therapeutic agent may be an agent that contributes favorably to the composition of the present invention (e.g., an agent that affects the viscosity of the composition). Favorable contributions to the composition of the present invention are not limited to these. The pharmacokinetic or pharmacodynamic concurrent effects are not defined but include those resulting from a combination of a compound of formula (I), (II), (III), or (IV) with one or more other therapeutic agents. For example, one or more other therapeutic agents may be anticancer drugs or chemotherapeutic agents. For example, one or more other therapeutic agents may be glucocorticoids. For example, one or more other therapeutic agents may be selected from prednisone, prednisolone, cyclophosphamide, vincristine, doxorubicin, maphosphamide, cisplatin, AraC, everolimus, decitabine, dexamethasone, or their functional analogs, derivatives, prodrugs, and metabolites. In another embodiment, the other therapeutic agent may be prednisone or its active metabolite, prednisolone.

[0087] Combination of the present invention The compositions of the present invention comprise a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0088] The present invention provides administration of a compound of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents or pharmaceutically acceptable salts thereof, as a co-formulation or separate formulation, wherein the formulations are administered simultaneously, sequentially, or alternately. In certain embodiments, the other therapeutic agent may be an agent recognized in the art as useful for treating the disease or condition treated by the composition of the present invention. In other embodiments, the other therapeutic agent may be an agent recognized in the art as useful for treating the disease or condition treated by the composition of the present invention. In one embodiment, the other therapeutic agent may be an agent that contributes favorably to the composition of the present invention (e.g., an agent that affects the viscosity of the composition). Favorable contributions to the composition of the present invention include, but are not limited to, pharmacokinetic or pharmacodynamic concurrent actions resulting from the combination of a compound of formula (I), (II), (III), or (IV) and one or more other therapeutic agents. For example, one or more other therapeutic agents may be anticancer agents or chemotherapeutic agents. For example, one or more other therapeutic agents may be glucocorticoids. For example, one or more other therapeutic agents may be selected from prednisone, prednisolone, cyclophosphamide, vincristine, doxorubicin, maphosphamide, cisplatin, AraC, everolimus, decitabine, dexamethasone, or their functional analogs, derivatives, prodrugs, and metabolites. In another embodiment, the other therapeutic agent may be prednisone or its active metabolite, prednisolone.

[0089] The therapeutic agents listed below are illustrative and not intended to be limiting. The present invention includes at least one other therapeutic agent selected from the list below. The present invention may include more than one other therapeutic agent, for example, two, three, four, or five other therapeutic agents, so that the composition of the present invention performs its intended function.

[0090] In one embodiment, the other therapeutic agent is an anticancer drug.

[0091] In one embodiment, the anticancer drug is a chemotherapeutic agent (2CdA, 5-FU, 6-Mercaptopurine, 6-TG, Abraxane®, Accutane®, Actinomycin-D, Adriamycin®, Alimta®, all-trans retinoic acid, ametopterin, Ara-C, Azacitadine, BCNU, Blenoxane®, Camptosar®, CeeNU®, Clofarabine, Clolar®, Cytoxan®, daunorubicin hydrochloride, DaunoXome®, Dacogen®, DIC, Doxil®, Ellence®, Eloxatin®, Emcyt®, etoposide phosphate, Fl udara(registered trademark), FUDR(registered trademark), Gemzar(registered trademark), Gleevec(registered trademark), Hexamethylmelamine, Hycamtin(registered trademark), Hydrea(registered trademark), Idamycin(registered trademark), Ifex(registered trademark), Ixabepyrone, Ixempra(registered trademark), L-asparaginase, Leukeran(registered trademark), Liposome Ara-C, L-PAM, Lysodren, Matulane(registered trademark), Mitracin, Mitomycin-C, Myleran(registered trademark), Navelbine(registered trademark), Neutrexin(registered trademark), Nilotinib, Nipent(registered trademark), Nitrogen Mustard, Novantrone®, Oncaspar®, Panretin®, Paraplatin®, Platinol®, Prolifeprospan 20 with carmustine implant, Sandostatin®, Targretin®, Tasigna®, Taxotere®, Temodar®, TESPA, Trisenox®, Valstar®, Velban®, Vidaza®, Vincristine sulfate, VM26, Xeloda® and Zanosar®, etc.; Biologics (alpha interferon, Bacillus Calmette-Guerin, Bexxar®, Campath®, Ergamisol®, Erlotinib, Herceptin®, Interleukin-2, Iressa®, Lenalidomide, Mylotarg®, Ontak®, Pegasys®, Revlimid®, Rituxan®, Tarceva®, Thalomid®, Tykerb®, Velcade®, and Zevalin®, etc.; Corticosteroids (dexamethasone sodium phosphate, DeltaSone®, and Delta-Cortef®, etc.);Hormone therapy drugs (Arimidex®, Aromasin®, Casodex®, Cytadren®, Eligard®, Eulexin®, Evista®, Faslodex®, Femara®, Halotestin®, Megace®, Nilandron®, Nolvadex®, Plenaxis®, and Zoladex®, etc.); and radiopharmaceuticals (Iodotope®, Metastron®, Phosphocol®, and Samarium); It is selected from a group consisting of (SM-153, etc.).

[0092] In another embodiment, other therapeutic agents are chemotherapeutic agents (also referred to as antitumor agents or antiproliferative agents) selected from the group including alkylating agents; antibiotics; antimetabolites; antidotes; interferons; polyclonal or monoclonal antibodies; EGFR inhibitors; HER2 inhibitors; histone deacetylase inhibitors; hormones; mitotic inhibitors; MTOR inhibitors; multikinase inhibitors; serine / threonine kinase inhibitors; tyrosine kinase inhibitors; VEGF / VEGFR inhibitors; taxanes or taxane derivatives; aromatase inhibitors; anthracyclines; microtubule-targeting agents; topoisomerase toxins; inhibitors of molecular targets or enzymes (e.g., kinases or protein methyltransferases); cytidine analogs or any other chemotherapeutic agents, including antineoplastic or antiproliferative agents listed at www.cancer.org / docroot / cdg / cdg_0.asp.

[0093] Exemplary alkylating agents include, but are not limited to, cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leukeran); melphalan (Alkeran); carmustine (BiCNU); busulfan (Busulfex); lomustine (CeeNU); dacarbazine (DTIC-Dome); oxaliplatin (Eloxatin); carmustine (Gliadel); ifosfamide (Ifex); mechloretamine (Mustargen); busulfan (Myleran); and carboplatin. (Paraplatin); cisplatin (CDDP; Platinol); temozolomide (Temodar); sub-thiotepa (Thioplex); sub-bendamustine (Treanda); or sub-streptozocin (Zanosar).

[0094] Examples of antimetabolites include, but are not limited to, fluorouracil (Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine (Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nerarabine (Arranon); cladribine (Cladribine Novaplus); clofarabine (Clolar); cytarabine (Cytosar-U); decitabine (Dacogen); cytarabine liposome (DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); phloxuridine (FUDR); gemcitabine (Gemzar); cladribine (Leustatin); fludarabine (Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall); thioguanine (Tabloid); TS-1 or cytarabine (Tarabine PFS).

[0095] Examples of antidotes include, but are not limited to, amiphostine (Ethyol) or sub-mesna (Mesnex).

[0096] Examples of interferons include, but are not limited to, interferon alpha-2b (Intron A) or interferon alpha-2a (Roferon A).

[0097] Examples of polyclonal or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab (Avastin); rituximab (Rituxan); cetuximab (Erbitux); panitumumab (Vectibix); tositumomab / iodine-131 tositumomab (Bexxar); alemtuzumab (Campath); ibritumomab (Zevalin; In-111; Y-90 Zevalin); sub-gemtuzumab (Mylotarg); sub-eculizumab (Soliris) or denosumab.

[0098] Examples of EGFR inhibitors include, but are not limited to, gefitinib (Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva); panitumumab (Vectibix); PKI-166; canertinib (CI-1033); matsuzumab (Emd7200); or EKB-569.

[0099] Examples of HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin); lapatinib (Tykerb); or AC-480.

[0100] Histone deacetylase inhibitors include, but are not limited to, vorinostat (Zolinza).

[0101] Exemplary hormones include, but are not limited to, tamoxifen (Soltamox; Nolvadex); raloxifen (Evista); megestrol (Megace); leuprolide (Lupron; Lupron Depot; Eligard; Viadur); fulvestrant (Faslodex); letrozole (Femara); triptorelin (Trelstar LA; Trelstar Depot); exemestane (Aromasin); goserelin (Zoladex); bicalutamide (Casodex); anastrozole (Arimidex); and fluoxymesterone (Andro). This includes xy; Halotestin; medroxyprogesterone (Provera; Depo-Provera); estramustine (Emcyt); flutamide (Eulexin); toremifene (Fareston); sub. degarelix (Firmagon); sub. niltamide (Nilandron), sub. abarelix (Plenaxis); or testolactone (Teslac).

[0102] Exemplary mitotic inhibitors include, but are not limited to, paclitaxel (Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin; Vincasar PFS); vinblastine (Velban); etoposide (Toposar; Etopophos; VePesid); teniposide (Vumon); isabepyrone (Ixempra); nocodazole; epotilone; sub. vinorelbine (Navelbine); camptothecin (CPT); sub. irinotecan (Camptosar); topotecan (Hycamtin); amsacrine or lamellarin D (LAM-D).

[0103] Examples of MTOR inhibitors include, but are not limited to, everolimus (Afinitor) or temsirolimus (Torisel); rapamune, lidaforolimus; or AP23573.

[0104] Examples of VEGFNEGFR inhibitors include, but are not limited to, bevacizumab (Avastin); sub-sorafenib (Nexavar); sub-sunitinib (Sutent); ranibizumab; pegaptanib; or vandetinib.

[0105] Examples of microtubule-targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristine, vinblastine, nocodazole, epotilon, and navelbine.

[0106] Examples of topoisomerase poisons include, but are not limited to, teniposide, etoposide, adriamycin, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrin, epirubicin, and idarubicin.

[0107] Exemplary taxanes or taxane derivatives include, but are not limited to, paclitaxel and docetaxol.

[0108] Examples of general chemotherapeutic drugs, antineoplastic agents, and antiproliferative agents include, but are not limited to, altretamine (Hexalen); isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin (Vesanoid); azacitidine (Vidaza); bortezomib (Velcade); asparaginase (Elspar); levamisole (Ergamisol); mitotane (Lysodren); and procarbazine (Matulane). ); Pegaspar gauze (Oncaspar); Denileukin difutitox (Ontak), porfimer (Photofrin); sub-Aldesleukin (Proleukin); Lenalidomide (Rebrimid); Bexarotene (Targretin); Thalidomide (Thalomid); Temsirolimus (Torisel); Arsenic trioxide (Trisenox); Verteporfin (Visudyne); Mimosine (Leucenol); (1M tegafur-0.4M 5-chloro-2,4-dihydroxypyrimidine-1M potassium oxonate), or lovastatin.

[0109] In another embodiment, the other therapeutic agent is a chemotherapy drug or a cytokine such as G-CSF (granulocyte colony-stimulating factor).

[0110] In another embodiment, other therapeutic agents include, but are not limited to, CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), CAF (cyclophosphamide, adriamycin, and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and paclitaxel), rituximab, Xeloda (capecitabine), cisplatin (CDDP), carboplatin, and TS-1 (in a molar ratio of 1:0.4:1). This may be a combination of standard chemotherapeutic agents such as tegafur, gimesat and otastat potassium potassium, Camptothecin-11 (CPT-11, Irinotecan or Camptosar®), CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone or prednisolone), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone or prednisolone), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

[0111] In another embodiment, the other therapeutic agent may be an enzyme inhibitor, such as a receptor or non-receptor kinase. Receptor and non-receptor kinases are, for example, tyrosine kinase or serine / threonine kinase. The kinase inhibitors described herein are small molecules, polynucleic acids, polypeptides, or antibodies.

[0112] Examples of kinase inhibitors include, but are not limited to, Bevacizumab (targeting VEGF), BIBW2992 (targeting EGFR and Erb2), Cetuximab / Erbitux (targeting Erb1), Imatinib / Gleevic (targeting Bcr-Abl), Trastuzumab (targeting Erb2), Gefitinib / Iressa (targeting EGFR), Ranibizumab (targeting VEGF), Pegaptanib (targeting VEGF), Erlotinib / Tarceva (targets Erb1), Nilotinib (targets Bcr-Abl), Lapatinib (targets Erb1 and Erb2 / Her2), GW-572016 / Lapatinib ditosylate (targets HER2 / Erb2), Panitumumab / Vectibix (targets EGFR), Vandetinib (targets RET / VEGFR), E7080 (multiple targets including RET and VEGFR), Herceptin (targets HER2 / Erb2), PKI-166 (targets EGFR) Canertinib / CI-1033 (target: EGFR), Sunitinib / SU-11464 / Sutent (target: EGFR and FLT3), Matuzumab / Emd7200 (target: EGFR), EKB-569 (target: EGFR), Zd6474 (target: EGFR and VEGFR), PKC-412 (target: VEGR and FLT3), Vatalanib / Ptk787 / ZK222584 (target: VEGR), CEP-701 (target: FLT3), SU5614 (target: FLT 3) MLN518 (target FLT3), XL999 (target FLT3), VX-322 (target FLT3), Azd0530 (target SRC), BMS-354825 (target SRC), SKI-606 (target SRC), CP-690 (target JAK), AG-490 (target JAK), WHI-P154 (target JAK), WHI-P131 (target JAK), sorafenib / Nexavar (target RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-beta).These include KIT, FLT-3, and RET, Dasatinib / Sprycel (BCR / ABL and Src), AC-220 (targeting Flt3), AC-480 (targeting all HER proteins, "panHER"), motesanib diphosphate (targeting VEGF1-3, PDGFR, and c-kit), Denosumab (targeting RANKL, inhibiting SRC), AMG888 (targeting HER3), and AP24534 (multiple targets including Flt3).

[0113] Examples of serine / threonine kinase inhibitors include, but are not limited to, Rapa mune (target mTOR / FRAP1), Defolimus (target mTOR), Certican / Everolimus (target mTOR / FRAP1), AP23573 (target mTOR / FRAP1), Eril / Fasudil hydrochloride (target RHO), Flavopiridol (target CDK), Seliciclib / CYC202 / Roscovitrine (target CDK), SNS-032 / BMS-387032 (target CDK), Rubocistaurin (target PKC), Pkc412 (target PKC), Bryostatin (target PKC), KAI-9803 (target PKC), SF1126 (target PI3K), VX-680 (target Aurora kinase), Azd1152 (target Aurora This includes kinases Arry-142886 / AZD-6244 (targeting MAP / MEK), SCIO-469 (targeting MAP / MEK), GW681323 (targeting MAP / MEK), CC-401 (targeting JNK), CEP-1347 (targeting JNK), and PD332991 (targeting CDK).

[0114] Examples of tyrosine kinase inhibitors include, but are not limited to, erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); and everolimus (Af). initor); includes alemtuzumab (Campath), gemtuzumab (Mylotarg), temsirolimus (Torisel), pazopanib (Votrient), dasatinib (Sprycel), nilotinib (Tasigna), batalanib (Ptk787; ZK222584); CEP-701; SU5614; MLN518, XL999; VX-322; Azd0530; BMS-354825; SKI-606; CP-690; AG-490; WHI-P154; WHI-P131; AC-220; or AMG888.

[0115] The present invention provides a method for combination therapy, in which a composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents is administered to a subject requiring treatment for a disease or cancer. Combination therapy may also be administered to cancer cells to inhibit proliferation or induce cell death. In one embodiment, a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is administered before administration of the composition of the present invention comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. In one embodiment, a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is administered before administration of one or more therapeutic agents, and the other therapeutic agents are administered in a single composition or in two or more compositions, for example, simultaneously, sequentially, or alternately.

[0116] In one embodiment, the composition of the present invention comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and one or more anticancer drugs, for example, CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisone or prednisolone) or R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone or prednisolone). In one embodiment, the composition of the present invention comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and prednisone or prednisolone. The method of the present invention comprises combination therapy in which a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is administered, along with an anticancer drug which is CHOP, R-CHOP, prednisone, or prednisolone.

[0117] In certain embodiments, "combination therapy" involves administering these therapeutic agents in a sequential manner, where each therapeutic agent is administered at different times, and furthermore, a small portion of these therapeutic agents, or a small portion of the therapeutic agents. It is intended to include administering at least two drugs simultaneously or substantially simultaneously. Simultaneous administration can be achieved, for example, by administering to the subject a single capsule containing each therapeutic agent in a fixed ratio, or by administering each therapeutic agent in multiple single capsules. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption via mucosal tissue. Therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of a selected combination may be administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. Therapeutic agents may be administered alternately.

[0118] In certain embodiments of the present invention, the combination therapies featured herein may produce synergistic effects in the treatment of a disease or cancer. “Synergistic effect” is defined as the efficacy of a combination of therapeutic agents being greater than the sum of the effects of any one agent given individually. A synergistic effect may also be an effect that could not be achieved by administering either the compound or any other therapeutic agent individually. Synergistic effects may include, but are not limited to, effects that treat cancer by reducing tumor size, inhibiting tumor growth, or extending the survival of the subject. Synergistic effects may also include reducing cancer cell viability, inducing cancer cell death, and inhibiting or delaying cancer cell growth.

[0119] In certain aspects of the present invention, “combination therapy” also includes the administration of the therapeutic agent as described above in further combination with other biologically active ingredients and non-pharmacological treatments (e.g., surgery or radiotherapy). If the combination therapy further includes non-pharmacological treatment, the non-pharmacological treatment may be performed at any appropriate time, as long as beneficial effects are achieved from the simultaneous action of the combination of the therapeutic agent and the non-pharmacological treatment. For example, where appropriate, further beneficial effects may be achieved by temporarily removing the non-pharmacological treatment from the administration of the therapeutic agent, perhaps for several days or weeks.

[0120] In another embodiment, the compositions of the present invention, or pharmaceutically acceptable salts, prodrugs, metabolites, analogs, or derivatives thereof, may be administered in combination with radiotherapy. Radiotherapy may also be administered in combination with the compositions of the present invention and other chemotherapeutic agents described herein as part of a plurality of drug therapies.

[0121] Composition of the present invention The present invention also provides pharmaceutical compositions comprising a compound of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically appropriate carrier or additive(s), in a dose for treating or preventing a disease or condition as described herein. In one embodiment, the present invention also provides pharmaceutical compositions comprising any compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically appropriate carrier or additive(s), in a dose for treating or preventing a disease or condition as described herein. In another embodiment, the present invention also provides pharmaceutical compositions comprising a compound of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically appropriate carrier or additive(s), in a dose for treating or preventing a disease or condition as described herein. The pharmaceutical compositions of the present invention may also be administered simultaneously, sequentially, or alternately in combination with other therapeutic or therapeutic modalities.

[0122] A mixture of the compositions of the present invention may be administered to a patient as a single mixture or in a suitable formulated pharmaceutical composition. For example, one aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective dose of an SRC inhibitor of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt, hydrate, enantiomer, or stereoisomer thereof; one or more other therapeutic agents; and a pharmaceutically acceptable diluent or carrier.

[0123] A "pharmaceutical composition" is a formulation containing a compound of formula (I), (II), (III), or (IV) in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage forms. Unit dosage forms are any of various forms, including, for example, capsules, IV bags, tablets, single pumps or vials of aerosol inhalers. The amount of the active ingredient (e.g., a formulation of the compound disclosed or its salt, hydrate, solvate, or isomer) in a unit dose of the composition is an effective amount and varies according to the specific treatment in question. Those skilled in the art will know that it is sometimes necessary to routinely vary the dosage according to the patient's age and condition. The dosage should also depend on the route of administration. Various routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, perivascular, inhalation, buccal, sublingual, intrapleural, intrathecal, and intranasal. Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, liquids, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0124] As used herein, the term “pharmaceutically acceptable” means a compound, anion, cation, material, composition, carrier, and / or dosage form that is appropriate for use in contact with human and animal tissues, within the bounds of good medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, in proportion to a reasonable benefit-to-risk ratio.

[0125] "Pharmacovigilantly acceptable additives" generally means additives that are safe, non-toxic, and not particularly undesirable biologically in the preparation of pharmaceutical compositions, and include additives that are acceptable for veterinary use and even for human pharmaceutical use. As used herein and in the claims, "pharmacovigilantly acceptable additives" include one and one or more such additives.

[0126] The pharmaceutical compositions of the present invention are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral administration, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Liquids or suspensions used for parenteral, intradermal, or subcutaneous applications may contain the following components: sterile diluents such as water for injection, physiological saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and agents for adjusting tonicity such as sodium chloride or dextrose. The pH can be adjusted using acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials.

[0127] The compositions of the present invention can be administered to a subject by many of the well-known methods currently used for chemotherapy treatments. For example, in the treatment of cancer, the compounds of the present invention can be injected directly into the tumor, into the bloodstream or body cavity, administered orally, or applied via the skin in the form of a transdermal patch. The selected dose should be sufficient to constitute an effective treatment, but should not be so high as to cause unacceptable side effects. The patient's medical condition (e.g., cancer, precancerous conditions) and health status should preferably be closely monitored during and for a reasonable period after the treatment.

[0128] When used herein, the term "therapeutic dose" means the amount that treats, relieves, or prevents an identified disease or condition, or that produces a detectable therapeutic or inhibitory effect. This refers to the amount of the drug indicated. Its effect can be detected by any assay method known in the art. The exact effective dose for a subject will depend on the subject's weight, build, and health; the nature and degree of the condition; and the treatment or combination of treatments selected for administration. The therapeutically effective dose for a given situation can be determined by routine experiments, which are within the scope of the clinician's skill and judgment. In a preferred embodiment, the disease or condition being treated is cancer. In another embodiment, the disease or condition being treated is a cytoproliferative disorder.

[0129] In certain embodiments, the therapeutically effective dose of each drug used in a combination is lower when used in combination compared to monotherapy using each drug alone. Such lower therapeutic doses may result in lower toxicity of the treatment regimen.

[0130] For any compound, the therapeutically effective dose can initially be estimated, for example, in a cell culture assay of newly formed cells or in an animal model, usually a rat, mouse, rabbit, dog, or pig. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine effective doses and routes of administration in humans. Standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED 50 (Therapeutic dose effective in 50% of the population) and LD 50 The therapeutic / preventive efficacy and toxicity can be determined by the dose (lethal dose for 50% of the population). The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, which is the ratio LD50. 50 / ED 50 It can be expressed as follows. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0131] The dosage and administration should be adjusted to supply an adequate level of the active drug(s) or to maintain the desired effect. Factors to consider include the severity of the condition, the patient's overall health, age, weight, and sex, diet, administration time and frequency, drug(s) combination(s), sensitivity to response, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, or every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0132] Pharmaceutical compositions containing the active compound of the present invention can be manufactured by generally known methods, for example, by conventional mixing, dissolution, granulation, sugar formulation, levigating, emulsification, encapsulation, encapsulation, or freeze-drying processes. The pharmaceutical compositions can be formulated by conventional methods using one or more pharmaceutically acceptable carriers containing additives and / or auxiliaries that facilitate the processing of the active compound into a pharmaceutically usable formulation. Of course, the appropriate formulation depends on the chosen route of administration.

[0133] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if water-soluble) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersants. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid insofar as it allows for easy passage through the injection needle. It must be stable under manufacturing and storage conditions and protected against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersants, and by the use of surfactants. Prevention of microbial activity can be achieved with various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, isotonic agents, such as sugars and mannitol, are also used. It is preferable that the composition also contains polyalcohols such as sorbitol, and sodium chloride. By including absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition, the injectable composition can be absorbed for a longer period of time.

[0134] A sterile injection solution can be prepared by incorporating the required amount of the active compound into a suitable solvent, along with one or a combination of the components listed above, if necessary, and then sterilizing by filtration. Generally, dispersants are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other components required from those listed above. In the case of sterile powders for preparing sterile injection solutions, the preparation method is vacuum drying and freeze-drying, which yield a powder of the active ingredient and any additional desired components from a pre-sterilized and filtered solution.

[0135] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food-grade carrier. These can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with additives and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is orally administered and spread throughout the mouth, then either spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; additives such as starch or lactose, disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; fluidity enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring agents.

[0136] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, such as a gas like carbon dioxide.

[0137] Systemic administration may be by mucosal or transdermal means. For mucosal or transdermal administration, a penetrating agent suitable for the barrier to be penetrated is used in the formulation. Such penetrating agents are generally known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives for mucosal administration. Mucosal administration can be achieved by the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, topical preparations, gels, or creams as is generally known in the art.

[0138] The active compound can be prepared on a pharmaceutically acceptable carrier that protects the compound from rapid excretion from the body, such as a controlled-release formulation including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be obvious to those skilled in the art. These materials are Alza They can also be commercially obtained from the Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (containing liposomes targeted to infected cells using monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared, for example, according to methods known to those skilled in the art, as described in U.S. Patent No. 4,522,811.

[0139] For ease of administration and uniformity of dosage, oral or parenteral compositions are available in dosage unit form. Formulation is particularly advantageous. The dosing unit forms used herein refer to physically distinct units adapted as unit doses for the subject being treated; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier. The specifications for the dosing unit forms of the present invention are determined by and directly depend upon the inherent characteristics of the active compound and the specific therapeutic effect to be achieved.

[0140] In therapeutic applications, the dosage of the SRC inhibitor compounds of formula (I), (II), (III), or (IV) described herein used in the present invention, other therapeutic agents described herein, compositions comprising the compounds of formula (I), (II), (III), or (IV) and optionally one or more other therapeutic agents, or pharmaceutical compositions, will vary depending on the drug, the age, weight, and clinical condition of the recipient patient, as well as the experience and judgment of the clinician or practitioner administering the treatment, among other factors that influence the selected dosage. Generally, the dosage should be sufficient to slow, preferably regress, tumor growth and preferably also induce complete regression of the cancer. The dosage may range from about 0.01 mg / kg to about 5000 mg / kg per day. In a preferred embodiment, the dosage may range from about 1 mg / kg to about 1000 mg / kg per day. In one embodiment, the dose would be in the range of approximately 0.1 mg / day to approximately 50 g / day; approximately 0.1 mg / day to approximately 25 g / day; approximately 0.1 mg / day to approximately 10 g / day; approximately 0.1 mg to approximately 3 g / day; or approximately 0.1 mg to approximately 1 g / day, in single, divided, or continuous doses (this dose depends on the patient's body weight (kg) and body surface area (m²). 2 (and can be adjusted with age). The effective dose of a drug is the one that produces an objectively identifiable improvement as noted by a clinician or other qualified observer. For example, tumor regression in a patient can be measured in terms of tumor diameter. A reduction in tumor diameter indicates regression. Regression is also indicated by the fact that the tumor does not recur after treatment has been discontinued. As used herein, the term “effective dose” refers to the amount of the active compound that produces the desired biological effect in the subject or cells.

[0141] The pharmaceutical composition can be placed in a container, pack, or dispenser along with a dosage instruction sheet.

[0142] The compositions of the present invention can further form salts. The compositions of the present invention can form more than one salt per molecule, for example, monosalts, disalts, and trisalts. All of these forms are intended to fall within the scope of the present invention as described in the claims.

[0143] As used herein, “pharmaceutically acceptable salt” refers to a derivative of the compound of the present invention in which the parent compound is modified by the preparation of an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmacochemically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyarsanilic acid, hexylresorcinic acid, hydrabum (hydra) bamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and general This includes amine acids present in the environment, such as inorganic acids and organic acids selected from glycine, alanine, phenylalanine, arginine, etc.

[0144] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-octo-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present invention also includes salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when it is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine.

[0145] It should be understood that all references to pharmaceutically acceptable salts include the same salt in either a solvated form (solvate) or a crystalline form (polymorph) as defined herein.

[0146] The compositions of the present invention can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, the carboxylic acid functional group in the compounds of formula (I), (II), (III), or (IV) can be converted to its corresponding ester, such as methyl, ethyl, or other esters. Furthermore, the alcohol group in the compounds can be converted to its corresponding ester, such as acetate, propionic acid, or other esters.

[0147] The compositions of the present invention may also be prepared as prodrugs, for example, pharmaceutically acceptable prodrugs. The terms “prodrug” and “prodrug” are used interchangeably herein and refer to any compound that releases the active parent drug in vivo. Since prodrugs are known to enhance many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacture, etc.), the compounds of the present invention can be delivered in prodrug form. Accordingly, the present invention is intended to encompass prodrugs of the currently claimed compounds, methods for delivering them, and compositions containing them. “Prodrug” is intended to include any covalently bonded carrier that, when such a prodrug is administered to a subject, releases the active parent drug of the present invention in vivo. Prodrugs in the present invention are prepared by modifying functional groups present in the compound, such that the modification is cleaved either in a routine operation or in vivo to obtain the parent compound. The prodrugs include compounds of the present invention in which a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group is cleaved in vivo and bonded to any group that can form a free hydroxyl, free amino, free sulfhydryl, free carboxyl, or free carbonyl group, respectively.

[0148] Examples of prodrugs, but not limited to those mentioned above, include esters of hydroxyl functional groups in the compounds of the present invention (e.g., acetate esters, dialkylaminoacetic acid esters, formic acid esters, phosphate esters, sulfate esters, and benzoic acid derivatives) and carbamic acid esters (e.g., N,N-dimethylaminocarbonyl), esters of carboxyl functional groups (e.g., ethyl esters, morpholinoethanol esters), N-acyl derivatives of amino functional groups (e.g., N-acetyl), N-Mannich bases, Schiff bases, and enaminones, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups. See Bundegaard, H., Design of Prodrugs, pp. 1-92, Elesevier, New York-Oxford (1985).

[0149] The composition, or a pharmaceutically acceptable salt, ester, or prodrug thereof, is administered orally, nasally, transdermally, transpulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0150] Administration regimens utilizing compounds are selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof used. A physician or veterinarian with the usual skills can easily determine and prescribe the effective dose of drug needed to prevent, counteract, or halt the progression of a condition.

[0151] The techniques for formulation and administration of the compounds of the present invention disclosed herein are published in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA This can be found in (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid extenders or diluents and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0152] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present invention are evident from various examples. The provided examples illustrate various components and methodologies useful in practicing the present invention. The examples do not limit the claimed invention. Based on this disclosure, those skilled in the art can identify and utilize other components and methodologies useful in practicing the present disclosure.

[0153] The present invention provides compositions and methods for treating conditions and diseases in which the methylation state of histones or other proteins can be regulated to influence their course, and in which such methylation states are at least partially mediated by SRC activity. The regulation of the histone methylation state can then affect the expression levels of target genes that are activated by methylation and / or repressed by methylation. The method comprises administering a therapeutically effective amount of the composition of the present invention or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof to a subject requiring such treatment.

[0154] Based on the fact that abnormal histone methylation has been found to be associated with certain cancers and precancerous conditions, a method for treating a cancer or precancerous condition with mutated SRCs in a subject comprises administering a therapeutically effective dose of a compound that inhibits methylation to the subject in need. In one embodiment, a method for treating a cancer or precancerous condition in a subject comprises administering a therapeutically effective dose of a compound that inhibits the conversion of unmethylated H3-K27 to monomethylated H3-K27 (H3-K27me1) to the subject in need. In one embodiment, a method for treating a cancer or precancerous condition in a subject comprises administering a therapeutically effective dose of a compound that inhibits the conversion of monomethylated H3-K27 (H3-K27me1) to dimethylated H3-K27 (H3-K27me2) to the subject in need. In one embodiment, a method for treating cancer or a precancerous condition in a subject comprises administering to the subject in need a therapeutically effective dose of a compound that inhibits the conversion of H3-K27me2 to trimethylated H3-K27 (H3-K27me3). In one embodiment, a method for treating cancer or a precancerous condition in a subject comprises administering to the subject in need a therapeutically effective dose of a compound that inhibits both the conversion of H3-K27me1 to H3-K27me2 and the conversion of H3-K27me2 to H3-K27me3. This includes administering inhibitory compounds. It is important to note that disease-specific increases in methylation can occur in chromatin at key genomic loci in the absence of a general increase in histone or protein methylation at the cellular level. For example, abnormal hypermethylation at significant disease-related genes may occur against a background of general histone or protein hypomethylation.

[0155] Methylation modifiers can generally be used to regulate cell proliferation. For example, in some cases, excessive proliferation can be reduced with drugs that decrease methylation, while insufficient proliferation can be stimulated with drugs that increase methylation. Therefore, diseases that can be treated include hyperproliferative disorders such as benign and malignant cell proliferation (cancer).

[0156] Disorders in which SRC-mediated protein methylation plays a role may include cancer, proliferative disorders, or precancerous conditions. The present invention further provides the use of compositions of the present invention, or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, for preparing pharmaceuticals useful for treating cancer in subjects requiring such treatment. Exemplary cancers that can be treated include lymphomas, including non-Hodgkin lymphoma, follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL); melanoma; and leukemia, including CML. Exemplary precancerous conditions include myelodysplastic syndrome (MDS; formerly known as preleukemia).

[0157] Generally, compounds that are methylation modifiers can be used to regulate cell proliferation. For example, in some cases, excessive proliferation can be reduced with agents that decrease methylation, while insufficient proliferation can be stimulated with agents that increase methylation. Therefore, diseases that can be treated with the compounds of the present invention include hyperproliferative disorders such as benign and malignant cell proliferation.

[0158] As used herein, “subjects requiring it” are subjects having a disorder in which SRC-mediated proteins play a role, or subjects at increased risk of developing such a disorder compared to the general population. Subjects requiring it may have a precancerous condition. Preferably, subjects requiring it have cancer. “Subjects” include mammals. Mammals may be, for example, any mammal, e.g., human, primate, bird, mouse, rat, chicken, dog, cat, cow, horse, goat, camel, sheep, or pig. Preferably, the mammal is human.

[0159] The present invention is applicable to any human subject who has been diagnosed with cancer or a precancerous condition, has symptoms thereof, or is at risk of developing such conditions. The present invention is applicable to any human subject expressing a mutant SRC. For example, a mutant SRC comprises one or more mutations, where the mutation is a substitution, point mutation, nonsense mutation, missense mutation, deletion, or insertion as described herein, or any other SRC mutation.

[0160] Subjects requiring this treatment may have refractory or resistant cancer. "Refractory or resistant cancer" means cancer that does not respond to treatment. The cancer may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, subjects requiring this treatment have experienced a recurrence of cancer after remission with the most recent treatment. In some embodiments, subjects requiring this treatment have been administered all known effective treatments for cancer treatment and have failed. In some embodiments, subjects requiring this treatment have received at least one prior treatment. In certain embodiments, the prior treatment is monotherapy. In certain embodiments, the prior treatment is combination therapy.

[0161] In some embodiments, the subject requiring this may have secondary cancer as a result of prior treatment. "Secondary cancer" means cancer that arises as a result of or as a consequence of prior carcinogenic treatment such as chemotherapy.

[0162] The subjects may exhibit resistance to SRC histone methyltransferase inhibitors or other therapeutic agents.

[0163] The present invention also features a method for selecting a combination therapy for a subject having cancer. The method comprises the steps of: detecting one or more SRC mutations described herein in a sample from the subject; and selecting a combination therapy for treating the cancer based on the presence of one or more SRC mutations. In one embodiment, the therapy comprises administering to the subject a composition of the present invention. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of the composition of the present invention. The SRC mutations can be detected using any suitable method known in the art. Further methods are described in U.S. Patent Application Publication No. 20130040906, which is incorporated herein by reference in whole.

[0164] The methods and uses described herein may include the step of detecting one or more SRC mutations described herein in a sample from a subject requiring administration of a composition of the present invention (for example, a composition comprising a compound of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents) to the subject. The presence of one or more SRC mutations described herein in a test sample indicates a response to the combination therapy of the present invention.

[0165] The present invention provides personalized medicines, treatments, and / or cancer management for subjects by genetically screening them for one or more SRC mutations described herein. For example, the present invention provides a method for treating or alleviating symptoms of cancer or a precancerous condition in a subject in need by determining the responsiveness of a subject to combination therapy and, if the subject is responsive to combination therapy, administering the composition of the present invention to the subject. Responsiveness is determined by obtaining a sample from the subject and detecting one or more SRC mutations described herein, the presence of such one or more SRC mutations described herein indicates that the subject is responsive to the composition of the present invention. Once the responsiveness of the subject has been determined, a therapeutically effective amount of the composition, for example, a compound of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents can be administered. The therapeutically effective amount of the composition can be determined by those skilled in the art.

[0166] As used herein, the term “responsive” is interchangeable with the terms “responsive,” “sensitive,” and “sensitive,” and means that a subject exhibits a therapeutic response when administered with the composition of the present invention, for example, that the tumor cells or tumor tissue of the subject undergo apoptosis and / or necrosis and / or show proliferation, differentiation, or decreased growth. The term also means that a subject would or would have a higher probability of exhibiting a therapeutic response when administered with the composition of the present invention compared to the general population, for example, that the tumor cells or tumor tissue of the subject undergo apoptosis and / or necrosis and / or show proliferation, differentiation, or decreased growth.

[0167] In the term "sample," any biological sample derived from the subject includes, but is not limited to, cells, tissues, samples, body fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), tumor cells, and tumor tissue. Preferably, the sample is selected from bone marrow, peripheral blood cells, blood, plasma, and serum. The sample can be obtained by the subject under treatment or testing. Alternatively, the sample can be obtained by a physician in accordance with routine practices in the art.

[0168] Conditions, disorders, or diseases that can be treated or prevented by the compounds, compositions, and combinations of the present invention As used herein, the term “hypoproliferative disorder” refers to a condition in which uncontrolled or abnormal proliferation of cells, or both, can lead to the development of an undesirable condition or disease, which may or may not be cancerous. Exemplary hypoproliferative disorders of the present invention encompass a variety of conditions in which cell division is deregulated. Exemplary hypoproliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, in situ tumors, inclusion tumors, metastatic tumors, humoral tumors, solid tumors, immunoneoplasms, hematological malignancies, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term “rapidly dividing cells” as used herein is defined as any cell that divides at a rate exceeding or faster than that expected or observed in adjacent or proximal cells within the same tissue. Hypoproliferative disorders include precancerous or precancerous conditions. Hypoproliferative disorders include cancer. Preferably, the methods provided herein are used to treat or alleviate the symptoms of cancer. The term "cancer" includes solid tumors, as well as hematological malignancies and / or malignant lesions. "Precancerous cells" are cells exhibiting a cytoproliferative disorder that is precancerous or a precancerous condition. "Cancer cells" are cells exhibiting a cytoproliferative disorder that is cancerous. Any reproducible measurement method can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified by the use of appropriate molecular markers.

[0169] Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritis conditions; sepsis; septic shock; endotoxin shock; Gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pneumonia; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic kidney disease; irritable bowel syndrome; fever (pyresis); restenosis; cerebral malaria; stroke and ischemic injury; neurological trauma; Alzheimer's disease; Huntington's disease; and This includes Kinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; hernia, rupture, or prolapsed disc syndrome; ossipitosis; thrombosis; restenosis; silicosis; pulmonary sarcosis; bone resorption disorders such as osteoporosis; graft-versus-host reaction; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as herpes zoster, herpes simplex virus type I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0170] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendiceal cancer, childhood cerebellar astrocytoma, childhood cranial astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, urinary tract bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brainstem glioma, cerebellar astrocytoma, cranial astrocytoma / malignant glioma, ependymal cell tumor, medulloblastoma, and supratentorial primitive neuroectoderm tumor. tumor), visual tract and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid, gastrointestinal cancer, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoneoplasm, mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, ocular cancer Intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational choriocarcinoma, glioma, head and neck cancer, hepatocellular carcinoma (liver) carcinoma, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, kidney cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-associated lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenström macroglobulinemia, medulloblastoma, melanoma, intraocular ( Eye) Melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic cervical squamous cell carcinoma, oral cancer, tongue cancer, multiple endocrine neoplasia, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial carcinoma, low-grade ovarian tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing sarcoma family tumors (ewing This includes family of sarcoma tumors, Kaposi's sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary tract, gestational trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, endometrial cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0171] "Hematological proliferative disorders" are proliferative disorders involving cells of the blood system. Hematological proliferative disorders may include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, spinal cord dysplasia, benign monoclonal globulinemia, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of unknown cause, and essential thrombocythemia. Hematological proliferative disorders may include hyperplasia, dysplasia, and metaplasia of cells of the blood system. Preferably, the compositions of the present invention can be used to treat hematological cancers or cancers selected from the group consisting of hematological proliferative disorders of the present invention. The blood cancers of the present invention may include multiple myeloma, lymphoma (including Hodgkin lymphoma, non-Hodgkin lymphoma, pediatric lymphoma, and lymphoma of lymphocyte and cutaneous origin), leukemia (including pediatric leukemia, pilocytic cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, and mast cell leukemia), myeloneoplasms, and mast cell neoplasms.

[0172] "Lung proliferative disorders" are proliferative disorders involving lung cells. Lung proliferative disorders may include all forms of proliferative disorders affecting lung cells. These may include lung cancer, precancerous or precancerous conditions of the lung, benign lung growths or lesions, and malignant lung growths or lesions, as well as metastatic lesions in tissues and organs of the body other than the lungs. Preferably, the compositions of the present invention can be used to treat lung cancer or lung proliferative disorders. Lung cancer may include all forms of cancer of the lung. Lung cancer may include malignant lung neoplasms, carcinoma in situ, typical carcinomatoids, and atypical carcinomatoids. Lung cancer may include small cell lung cancer ("SCLC"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adeno-squamous cell carcinoma, and mesothelioma. Lung cancer may include scar carcinoma, bronchoalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer may also include lung neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell type).

[0173] Lung cell proliferation disorders can include all forms of cell proliferation disorders affecting lung cells. Lung proliferative disorders may include lung cancer and precancerous conditions of the lung. Lung proliferative disorders may include lung hyperplasia, metaplasia, and dysplasia. Lung proliferative disorders may include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Lung proliferative disorders may include stratified squamous replacement of columnar epithelial cells and mucosal dysplasia. Individuals exposed to harmful inhaled environmental factors such as tobacco smoke and asbestos may be at high risk of developing lung proliferative disorders. Preceding lung diseases that may make individuals more susceptible to developing lung proliferative disorders may include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatoid-like diseases, sarcoidosis, interstitial parenchymal pulmonary inflammation, tuberculosis, recurrent pneumonia, idiopathic pulmonary fibrosis, granuloma, asbestosis, fibrotic alveolar septitis, and Hodgkin's disease.

[0174] "Colonial cell proliferation disorder" is a cell proliferation disorder involving the cells of the colon. Preferably, colonial cell proliferation disorder is colon cancer. Preferably, the compositions of the present invention can be used to treat colon cancer or colonial cell proliferation disorder. Colon cancer may include all forms of cancer of the colon. Colon cancer may include sporadic and hereditary colon cancer. Colon cancer may include malignant colon neoplasms, carcinoma in situ, typical carcinomatous tumors, and atypical carcinomatous tumors. Colon cancer may include adenocarcinoma, squamous cell carcinoma, and adeno-squamous cell carcinoma. Colon cancer may be associated with hereditary syndromes selected from the group consisting of hereditary polyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeggers syndrome, Turcott syndrome, and juvenile polyposis. Colon cancer may be caused by a genetic syndrome selected from the group consisting of hereditary polyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcott syndrome, and juvenile polyposis.

[0175] Colonic cytoproliferative disorders may include all forms of cytoproliferative disorders affecting colonic cells. These may include colon cancer, precancerous conditions of the colon, adenomatous polyps and pilosa metachronous lesions of the colon. Adenomas may also be included. Colonic cytoproliferative disorders may be characterized by colonic hyperplasia, metaplasia, and dysplasia. Preceding colonic diseases that may increase an individual's risk of developing colonic cytoproliferative disorders may include preceding colon cancer. Current diseases that may increase an individual's risk of developing colonic cytoproliferative disorders may include Crohn's disease and ulcerative colitis. Colonic cytoproliferative disorders may be associated with mutations in genes selected from the group consisting of p53, ras, FAP, and DCC. Individuals may have a high risk of developing colonic cytoproliferative disorders due to the presence of mutations in genes selected from the group consisting of p53, ras, FAP, and DCC.

[0176] "Pancreatic cell proliferation disorders" are cell proliferation disorders involving the cells of the pancreas. Pancreatic cell proliferation disorders may include all forms of cell proliferation disorders affecting pancreatic cells. These may include pancreatic cancer, precancerous or precancerous conditions of the pancreas, pancreatic hyperplasia and pancreatic dysplasia, benign proliferation or lesions of the pancreas and malignant proliferation or lesions of the pancreas, as well as metastatic lesions in tissues and organs of the body other than the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas. These may include tubular adenocarcinoma, adeno-squamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclastoid giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreaticblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma. Pancreatic cancer may also include pancreatic neoplasms that exhibit histological and ultrastructural heterogeneity (e.g., mixed cell type).

[0177] "Prostatic proliferative disorders" are cytoproliferative disorders involving the cells of the prostate gland. Prostatic proliferative disorders may include all forms of cytoproliferative disorders affecting prostate cells. These may include prostate cancer, precancerous or precancerous conditions of the prostate, benign proliferative or lesional conditions of the prostate, malignant proliferative or lesional conditions of the prostate, and metastatic lesions in tissues and organs of the body other than the prostate. Prostatic proliferative disorders may include prostatic hyperplasia, metaplasia, and dysplasia.

[0178] "Skin cell proliferation disorders" are cell proliferation disorders that involve skin cells. Skin cell proliferation disorders may include all forms of cell proliferation disorders affecting skin cells. Skin cell proliferation disorders may include precancerous or precancerous conditions of the skin, benign proliferations or lesions of the skin, melanoma, malignant melanoma and other malignant proliferations or lesions of the skin, as well as metastatic lesions in tissues and organs of the body other than the skin. Skin cell proliferation disorders may include skin hyperplasia, metaplasia, and dysplasia.

[0179] "Ovarian cytoproliferative disorders" are cytoproliferative disorders involving ovarian cells. Ovarian cytoproliferative disorders may include all forms of cytoproliferative disorders affecting ovarian cells. These may include ovarian precancerous or precancerous conditions, benign ovarian proliferation or lesions, ovarian cancer, malignant ovarian proliferation or lesions, and metastatic lesions in tissues and organs of the body other than the ovaries. Skin cytoproliferative disorders may include ovarian cell hyperplasia, metaplasia, and dysplasia.

[0180] "Mammary cell proliferation disorders" are cell proliferation disorders involving the cells of the breast. Mammary cell proliferation disorders may include all forms of cell proliferation disorders affecting mammary cells. Mammary cell proliferation disorders may include breast cancer, precancerous or precancerous conditions of the breast, benign growths or lesions of the breast, malignant growths or lesions of the breast, and metastatic lesions in tissues and organs of the body other than the breast. Mammary cell proliferation disorders may include breast hyperplasia, metaplasia, and dysplasia.

[0181] Cellular proliferative disorders of the breast can be precancerous conditions of the breast. The compositions of the present invention can be used to treat precancerous conditions of the breast. Precancerous conditions of the breast may include atypical hyperplasia of the breast, ductal carcinoma in situ (DCIS), ductal carcinoma, lobular carcinoma in situ (LCIS), lobular neoplasia, and stage 0 or grade 0 proliferation or lesions of the breast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ). Precancerous conditions of the breast may be staged according to the TNM classification scheme as accepted by the American Joint Committee on Cancer (AJCC), where the primary tumor (T) is assigned to stage T0 or Tis; the regional lymph nodes (N) are assigned to stage N0; and the distant metastases (M) are assigned to stage M0.

[0182] Cellular proliferative disorders of the breast can be breast cancer. Preferably, the compositions of the present invention can be used to treat breast cancer. Breast cancer includes all forms of cancer of the breast. Breast cancer may include primary epithelial breast cancer. Breast cancer may include cancer in which the breast is involved with other tumors such as lymphoma, sarcoma, or melanoma. Breast cancer may include carcinoma of the breast, tubular carcinoma of the breast, lobular carcinoma of the breast, undifferentiated carcinoma of the breast, phyllodes cystosarcoma of the breast, angiosarcoma of the breast, and primary lymphoma of the breast. Breast cancer may include breast cancer of stages I, II, IIIB, IIIC, and IV. Tubular carcinoma of the breast may include invasive carcinoma, invasive carcinoma in situ with a predominant tubular component, inflammatory breast cancer, and tubular carcinoma of the breast, and the histological type is selected from the group consisting of comedo, mucin (colloid), medullary, medullary with lymphocyte infiltration, papillary, rigid, and tubular. Lobular carcinoma of the breast may include invasive lobular carcinoma with a dominant in situ component, invasive lobular carcinoma, and invasive lobular carcinoma. Breast cancer may include Paget's disease, Paget's disease with ductal carcinoma, and Paget's disease with invasive ductal carcinoma. Breast cancer may also include mammary neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell type).

[0183] Preferably, the compounds of the present invention, or their pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, can be used to treat breast cancer. Breast cancer to be treated may include familial breast cancer. Breast cancer to be treated may include sporadic breast cancer. It may include: Breast cancer requiring treatment may occur in male subjects. Breast cancer requiring treatment may occur in female subjects. Breast cancer requiring treatment may occur in premenopausal or postmenopausal women. Breast cancer requiring treatment may occur in subjects aged 30 or older, or under 30 years of age. Breast cancer requiring treatment may occur in subjects aged 50 or older, or under 50 years of age. Breast cancer requiring treatment may occur in subjects aged 70 or older, or under 70 years of age.

[0184] Breast cancers to be treated may be classified to identify familial or incidental mutations in BRCA1, BRCA2, or p53. Breast cancers to be treated may be classified as having HER2 / neu gene amplification, overexpressing HER2 / neu, or having low, intermediate, or high levels of HER2 / neu expression. Breast cancers to be treated may be classified with respect to markers selected from the group consisting of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2, Ki-67, CA15-3, CA27-29, and c-Met. Breast cancers to be treated may be classified as having an unknown ER, being rich in ER, or being poor in ER. Breast cancers to be treated may be classified as ER-negative or ER-positive. ER classification of breast cancers may be performed by any reproducible means. ER classification of breast cancers may be performed as described in Onkologie 27: 175-179 (2004). Breast cancers that should be treated may be classified as having an unknown PR, being rich in PR, or having a poor PR. Breast cancers that should be treated may be classified as having a PR-negative or PR-positive status. Breast cancers that should be treated may be classified as having receptor-positive or receptor-negative status. Breast cancers that should be treated may be classified as being associated with elevated blood levels of CA15-3 or CA27-29, or both.

[0185] Breast cancers to be treated may include localized tumors of the breast. Breast cancers to be treated may include tumors of the breast associated with a negative sentinel lymph node (SLN) biopsy. Breast cancers to be treated may include tumors of the breast associated with a positive sentinel lymph node (SLN) biopsy. Breast cancers to be treated may include tumors of the breast associated with one or more positive axillary lymph nodes, where the axillary lymph nodes are staged by any applicable method. Breast cancers to be treated may include tumors of the breast classified as nodule-negative (e.g., nodule-negative) or nodule-positive (e.g., nodule-positive). Breast cancers to be treated may include tumors of the breast that have metastasized to other locations in the body. Breast cancers to be treated may be classified as having metastasized to a location selected from the group consisting of bone, lung, liver, or brain. Breast cancers that should be treated can be classified according to characteristics selected from the following groups: metastatic, localized, regional, local-regional, locally advanced, distant, multicentric, bilateral, ipsilateral, contralateral, newly diagnosed, recurrent, and inoperable.

[0186] The compounds or compositions of the present invention, or their pharmaceutically acceptable salts, esters, prodrugs, metabolites, polymorphs, or solvates, may be used to treat or prevent breast cell proliferation disorders or to treat or prevent breast cancer in subjects at high risk of developing breast cancer compared to the general population. Subjects at high risk of developing breast cancer compared to the general population include women with a family history or personal history of breast cancer. Subjects at high risk of developing breast cancer compared to the general population include women with germline or incidental mutations in BRCA1 or BRCA2, or both. Subjects at high risk of developing breast cancer compared to the general population include women with a family history of breast cancer and germline or incidental mutations in BRCA1 or BRCA2, or both. Subjects at high risk of developing breast cancer compared to the general population include women who are over 30, over 40, over 50, over 60, over 70, over 80, or over 90 years old. Individuals at higher risk of developing breast cancer compared to the general population include those with atypical breast hyperplasia, ductal carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS), and lobular neoplasia. The subjects are those with a mass or a stage 0 breast proliferation or lesion (e.g., stage 0 or grade 0 breast cancer or carcinoma in situ).

[0187] Breast cancers to be treated may be histologically graded according to the Scarff-Bloom-Richardson system, in which breast tumors are assigned a mitotic count score of 1, 2, or 3; a nuclear pleomorphism score of 1, 2, or 3; a tubulogenesis score of 1, 2, or 3; and a total Scarff-Bloom-Richardson score between 3 and 9. Breast cancers to be treated may be assigned a tumor grade according to the International Consensus Panel on the Treatment of Breast Cancer, selected from groups consisting of Grade 1, Grade 1–2, Grade 2, Grade 2–3, or Grade 3.

[0188] Cancers to be treated may be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where tumors (T) are assigned stages TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; regional lymph nodes (N) are assigned stages NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and distant metastases (M) may be assigned stages MX, M0, or M1. Cancers to be treated may be staged as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV according to the American Joint Committee on Cancer (AJCC) classification. Cancers to be treated may be graded according to the AJCC classification as Grade GX (e.g., no grade can be assigned), Grade 1, Grade 2, Grade 3, or Grade 4. Cancers to be treated may be staged according to the AJCC pathological classification (pN) as pNX, pN0, PN0(I-), PN0(I+), PN0(mol-), PN0(mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0189] Cancers to be treated may include tumors measured to be approximately 2 centimeters or less in diameter. Cancers to be treated may include tumors measured to be approximately 2 to 5 centimeters in diameter. Cancers to be treated may include tumors measured to be approximately 3 centimeters or more in diameter. Cancers to be treated may include tumors measured to be more than 5 centimeters in diameter. Cancers to be treated may be classified by microscopic appearance as well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated. Cancers to be treated may be classified by microscopic appearance in relation to mitotic count (e.g., the amount of cell division) or nuclear pleomorphism (e.g., cellular changes). Cancers to be treated may be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dead or degenerated cells). Cancers to be treated may be classified as having an abnormal karyotype, an abnormal number of chromosomes, or one or more chromosomes with abnormal appearance. Cancers to be treated may be classified as being aneuploid, triploid, or tetraploid, or having altered ploidy. Cancers that should be treated may be classified as having a chromosomal translocation, or a region of deletion or duplication of an entire chromosome, or a region of deletion, duplication, or amplification of a portion of a chromosome.

[0190] Cancers to be treated can be evaluated by DNA cytometry, flow cytometry, or imaging cytometry. Cancers to be treated may be classified as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthetic stage of cell division (e.g., S phase of cell division). Cancers to be treated may be classified as having a low or high percentage of S phase cells.

[0191] As used herein, “normal cells” are cells that cannot be classified as part of “proliferative disorders.” Normal cells lack uncontrolled or abnormal proliferation, or both, which can lead to the development of undesirable conditions or diseases. Preferably, normal cells have a normally functioning cell cycle checkpoint control mechanism.

[0192] As used herein, “bringing cells into contact” means that a compound or other material composition is in direct contact with cells or is close enough to cells to induce a desired biological effect.

[0193] As used herein, “Candidate Compound” or “Compound of the Invention” means a compound of formula (I), (II), (III), or (IV) or any pharmaceutically acceptable salt, ester, prodrug, metabolite, polymorph, or solvate thereof that has been or is to be tested in one or more in vitro or in vivo biological assays to determine whether the compound is likely to induce a desired biological or medical response sought by a researcher or physician in cells, tissues, systems, animals, or humans. A Candidate Compound is a compound of the Invention, or any pharmaceutically acceptable salt, ester, prodrug, metabolite, polymorph, or solvate thereof. This biological or medical response may be the treatment of cancer. The biological or medical response may be the treatment or prevention of a cell proliferation disorder. In vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0194] As used herein, “to treat” or “to treat” describes the management and medical care of a patient aimed at eliminating a disease, condition, or disorder, and includes the administration of the compounds of the present invention, or their pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate a disease, condition, or disorder.

[0195] The composition of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, can also be used for preventing a disease, condition or disorder. As used herein, "preventing" or "prevention" describes reducing or eliminating the onset of symptoms or complications of a disease, condition or disorder.

[0196] As used herein, the term "alleviating" is meant to describe a process by which the severity of the signs or symptoms of a disorder is reduced. Importantly, the signs or symptoms can be alleviated without being eliminated. In a preferred embodiment, administration of the pharmaceutical composition of the present invention results in elimination of the signs or symptoms, however, elimination is not required. An effective dosage is expected to reduce the severity of the signs or symptoms. For example, signs or symptoms of a disorder such as cancer that can occur in multiple locations are alleviated if the severity of the cancer is reduced in at least one of the multiple locations.

[0197] As used herein, the term "severity" is meant to describe the likelihood that cancer will transform from a pre-cancerous or benign state to a malignant state. Alternatively or in addition, severity is meant to describe the stage of the cancer (e.g., according to the TNM system (accepted by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)) or by other methods approved in the art). The stage of cancer refers to the degree or severity of cancer based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer to lymph nodes). Alternatively, or in addition, severity is meant to describe the tumor grade by methods approved in the art (see the National Cancer Institute, www.cancer.gov). Tumor grade is a system used to classify cancer cells in terms of how abnormal they appear microscopically and how quickly the tumor grows and metastasizes. When determining tumor grade, many factors are considered, including the cell structure and growth pattern. The specific factors used to determine tumor grade vary by cancer type. Severity also describes the histological grade, also called differentiation, which refers to how similar the tumor cells are to normal cells of the same tissue type (see the National Cancer Institute, www.cancer.gov). Additionally, severity describes the nuclear grade, which refers to the size and shape of the nuclei in the tumor cells and the percentage of tumor cells that are dividing (see the National Cancer Institute, www.cancer.gov).

[0198] In another aspect of the invention, severity describes the degree to which the tumor secretes growth factors, degrades the extracellular matrix, undergoes angiogenesis, loses adhesion to adjacent tissues, or metastasizes. Additionally, severity describes the number of locations to which the primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of various types and locations. For example, inoperable tumors, cancers with greater access to multiple body systems (hematological and immunological cancers), and cancers that are largely resistant to conventional treatments are considered the most severe. In these situations, an increase in the subject's mean life expectancy and / or a decrease in pain, a decrease in the percentage of cancer cells or a limitation of cells to one system, and an improvement in the cancer stage / tumor grade / histological grade / nuclear grade are considered to alleviate the signs or symptoms of cancer.

[0199] As used herein, the term “symptom” is defined as an indicator of disease, illness, injury, or something wrong within the body. A symptom is perceived and noticed by the individual experiencing it, but may not be readily noticed by others. Others are defined as non-healthcare professionals.

[0200] As used herein, the term “sign” is also defined as an indicator of something wrong in the body. However, a sign is defined as something that can be observed by a physician, nurse, or other healthcare professional.

[0201] Cancer is a group of diseases that can cause almost any sign or symptom. The signs and symptoms depend on where the cancer is located, its size, and the extent to which it affects neighboring organs or structures. If the cancer spreads (metastasizes), symptoms may appear in different parts of the body.

[0202] Disorders in which SRC-mediated protein methylation plays a role can be neurological disorders. Therefore, the compounds of the present invention can also be used to treat neurological disorders such as epilepsy, schizophrenia, bipolar disorder or other mental and / or psychiatric disorders, neuropathy, skeletal muscle atrophy, and neurodegenerative diseases, such as neurodegenerative diseases. Exemplary neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. Another group of neurodegenerative diseases includes diseases in which polyglutamine aggregation is at least partially the cause. This group of diseases includes Huntington's disease, spinal and bulbar muscular atrophy (SBMA or Kennedy disease), dentatorubral-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph disease m (MJD; SCA3), spinocerebellar ataxia type 6 (SCA6), spinocerebellar ataxia type 7 (SCAT), and spinocerebellar ataxia type 12 (SCA12).

[0203] In any other disease in which epigenetic methylation mediated by SRC plays a role, as specified herein The treatment or prevention may be possible using the compositions and methods described above.

[0204] Treating cancer can result in a reduction in tumor size. This reduction in tumor size is sometimes referred to as "tumor regression." Preferably, after treatment, the tumor size is reduced by 5% or more compared to its size before treatment; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. Tumor size can be measured by any reproducible measuring means. Tumor size can be measured as the diameter of the tumor.

[0205] Treating cancer can result in a reduction in tumor volume. Preferably, after treatment, the tumor volume is reduced by 5% or more compared to its size before treatment; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. The volume of the tumor can be measured by any reproducible measuring means.

[0206] Treating cancer results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more compared to its number before treatment; more preferably, the number of tumors is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. The number of tumors can be measured by any reproducible measuring means. The number of tumors can be measured with the naked eye or by counting visible tumors at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0207] Treating cancer can result in a reduction in the number of metastatic lesions in other tissues or organs distal to the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more compared to its number before treatment; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. The number of metastatic lesions can be measured by any reproducible measuring means. The number of metastatic lesions can be measured with the naked eye or by counting visible metastatic lesions at a specified magnification. Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

[0208] Treating cancer can result in an increase in the mean survival time of the treated population compared to the population that received only the carrier. Preferably, the mean survival time increases by more than 30 days; more preferably more than 60 days; more preferably more than 90 days; and most preferably more than 120 days. The increase in the mean survival time of the population can be measured by any reproducible means of measurement. The increase in the mean survival time of the population can be measured, for example, by calculating the length of mean survival after the start of treatment with the active compound for a given population. The increase in the mean survival time of the population can also be measured, for example, by calculating the length of mean survival after the completion of the first round of treatment with the active compound for a given population.

[0209] Treating cancer improves the average survival time of the treated group compared to the untreated group. This can result in an increase in mean survival time. Preferably, the mean survival time increases by more than 30 days; more preferably more than 60 days; more preferably more than 90 days; and most preferably more than 120 days. The increase in mean survival time of a population can be measured by any reproducible means of measurement. The increase in mean survival time of a population can be measured, for example, by calculating the length of mean survival after the start of treatment with the active compound for a given population. The increase in mean survival time of a population can also be measured, for example, by calculating the length of mean survival after the completion of the first round of treatment with the active compound for a given population.

[0210] Treating cancer may result in an increase in the mean survival time of the treated population compared to a population treated with monotherapy with a drug other than the compound of the present invention or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Preferably, the mean survival time increases by more than 30 days; more preferably more than 60 days; more preferably more than 90 days; and most preferably more than 120 days. The increase in mean survival time of the population can be measured by any reproducible means of measurement. The increase in mean survival time of the population can be measured, for example, by calculating the length of mean survival after the start of treatment with the active compound for a given population. The increase in mean survival time of the population can also be measured, for example, by calculating the length of mean survival after the completion of the first round of treatment with the active compound for a given population.

[0211] Treating cancer may result in a reduction in mortality in the treated population compared to a population that received only the carrier. Treating cancer may result in a reduction in mortality in the treated population compared to an untreated population. Treating cancer may result in a reduction in mortality in the treated population compared to a population that received monotherapy with a drug other than the compound of the present invention or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Preferably, the mortality reduction is greater than 2%; more preferably greater than 5%; more preferably greater than 10%; most preferably greater than 25%. The reduction in mortality in the treated population can be measured by any reproducible means of measurement. The reduction in population mortality can be measured, for example, by calculating the average number of disease-related deaths per unit time after the start of treatment with the active compound for a given population. The reduction in population mortality can also be measured, for example, by calculating the average number of disease-related deaths per unit time after the completion of the first round of treatment with the active compound for a given population.

[0212] Treating cancer can result in a reduction in tumor growth rate. Preferably, after treatment, the tumor growth rate decreases by at least 5% compared to the number before treatment; more preferably, it decreases by at least 10%; more preferably, at least 20%; more preferably, at least 30%; more preferably, at least 40%; more preferably, at least 50%; even more preferably, at least 50%; and most preferably, at least 75%. Tumor growth rate can be measured by any reproducible measuring means. Tumor growth rate can be measured by the change in tumor diameter per unit time.

[0213] Treating cancer can lead to a reduction in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%; more preferably less than 10%; more preferably less than 20%; more preferably less than 30%; more preferably less than 40%; more preferably less than 50%; even more preferably less than 50%; most preferably less than 75%. Tumor regrowth can be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring the increase in tumor diameter after a preceding tumor shrinkage following treatment. A reduction in tumor regrowth is indicated by the failure of the tumor to recur after treatment is stopped.

[0214] Treating or preventing cell proliferation disorders can lead to a decrease in the rate of cell proliferation. Preferably, after treatment, the rate of cell proliferation decreases by at least 5%; more preferably, at least 10%; more preferably, at least 20%; more preferably, at least 30%; more preferably, at least 40%; more preferably, at least 50%; even more preferably, at least 50%; and most preferably, at least 75%. The rate of cell proliferation can be measured by any reproducible measuring means. The rate of cell proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0215] Treating or preventing cell proliferation disorders can result in a decrease in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells decreases by at least 5%; more preferably at least 10%; more preferably at least 20%; more preferably at least 30%; more preferably at least 40%; more preferably at least 50%; even more preferably at least 50%; and most preferably at least 75%. The proportion of proliferating cells can be measured by any reproducible measuring means. Preferably, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of non-dividing cells in a tissue sample. The proportion of proliferating cells may be equivalent to the mitotic index.

[0216] Treating or preventing cell proliferation disorders can result in a reduction in the size of the cell proliferation area or region. Preferably, after treatment, the size of the cell proliferation area or region is reduced by at least 5% compared to its size before treatment; more preferably by at least 10%; more preferably by at least 20%; more preferably by at least 30%; more preferably by at least 40%; more preferably by at least 50%; even more preferably by at least 50%; and most preferably by at least 75%. The size of the cell proliferation area or region can be measured by any reproducible measuring means. The size of the cell proliferation area or region can be measured as the diameter or width of the cell proliferation area or region.

[0217] Treating or preventing cell proliferation disorders can result in a reduction in the number or percentage of cells with abnormal appearance or morphology. Preferably, after treatment, the number of cells with abnormal morphology is reduced by at least 5% compared to their size before treatment; more preferably by at least 10%; more preferably by at least 20%; more preferably by at least 30%; more preferably by at least 40%; more preferably by at least 50%; even more preferably by at least 50%; and most preferably by at least 75%. Abnormal cell appearance or morphology can be measured by any reproducible means. Abnormal cell morphology can be measured by microscopy, for example, using an inverted tissue culture microscope. Abnormal cell morphology can take the form of nuclear pleomorphism.

[0218] As used herein, the term “selectively” means that an event tends to occur more frequently in one population than in another. The population being compared may be a population of cells. Preferably, the compounds of the present invention, or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, act selectively on cancer cells or precancerous cells but not on normal cells. Preferably, the compounds of the present invention, or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, act selectively to modulate one molecular target (e.g., target protein methyltransferase) but not significantly modulate another molecular target (e.g., non-target protein methyltransferase). The present invention also provides methods for selectively inhibiting the activity of enzymes such as protein methyltransferases. Preferably, if an event occurs more than twice as frequently in population A compared to population B, then this event is selective in population A compared to population B. is occurring in. When an event occurs in group A at a frequency more than 5 times, this event is occurring selectively. When an event occurs in group A at a frequency more than 10 times compared to group B; more preferably, more than 50 times; even more preferably, more than 100 times; most preferably, more than 1000 times in group A, this event is occurring selectively. For example, when cell death occurs in cancer cells at a frequency more than 2 times compared to normal cells, it would be said that cell death occurs selectively in cancer cells.

[0219] In certain embodiments, the compositions of the present invention (e.g., compositions comprising a compound of any of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof), and one or more other therapeutic agents such as prednisone, can modulate the activity of a molecular target (e.g., the target protein methyltransferase). Modulating refers to stimulating or inhibiting the activity of the molecular target. Preferably, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, modulates the activity of a molecular target when it stimulates or inhibits the activity of the molecular target by at least 2-fold compared to the activity of the molecular target under the same conditions except for the absence of the presence of said compound. More preferably, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, modulates the activity of a molecular target when it stimulates or inhibits the activity of the molecular target by at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold compared to the activity of the molecular target under the same conditions except for the absence of the presence of said compound. The activity of the molecular target can be measured by any reproducible means. The activity of the molecular target can be measured in vitro or in vivo. For example, the activity of the molecular target can be measured in vitro by an enzyme activity assay or a DNA binding assay, or the activity of the molecular target can also be measured in vivo by assaying for the expression of a reporter gene.

[0220] The compositions of the present invention do not significantly modulate the activity of a molecular target if the addition of the compound does not stimulate or inhibit the activity of the molecular target by more than 10% compared to the activity of the molecular target under the same conditions except for the absence of the compound.

[0221] As used herein, the term “isozyme-selective” means preferential inhibition or stimulation of a first isoform of an enzyme compared to a second isoform of the enzyme (e.g., preferential inhibition or stimulation of protein methyltransferase isozyme alpha compared to protein methyltransferase isozyme beta). Preferably, the compounds of the present invention, or their pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, demonstrate a difference of at least four times, preferably ten times, and more preferably fifty times, in the dosage required to achieve a biological effect. Preferably, the compounds of the present invention, or their pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, demonstrate this difference across the entire range of inhibition, and the difference is IC for the molecular target of interest. 50 This is exemplified by 50% inhibition.

[0222] Administering the compositions of the present invention to cells or subjects requiring them may result in modulation (i.e., stimulation or inhibition) of the activity of the target protein methyltransferase.

[0223] Administration of a composition comprising a compound of the present invention, for example, any compound of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents such as prednisone, to cells or subjects requiring such treatment may result in modulation (i.e., stimulation or inhibition) of the activity of intracellular targets (e.g., substrates). Several intracellular targets, including protein methyltransferases, can be modulated with the compounds of the present invention.

[0224] Activation refers to placing a substance composition (e.g., a protein or nucleic acid) into a state suitable for performing a desired biological function. A substance composition that can be activated also has an inactive state. An activated substance composition may have inhibitory or stimulating biological functions, or both.

[0225] An increase refers to a desired increase in the biological activity of a substance composition (e.g., a protein or nucleic acid). This increase can occur due to an increase in the concentration of the substance composition.

[0226] As used herein, “cell cycle checkpoint pathway” refers to a biochemical pathway involved in the regulation of cell cycle checkpoints. A cell cycle checkpoint pathway may have a stimulating, inhibitory, or both effect on one or more functions, including cell cycle checkpoints. A cell cycle checkpoint pathway consists of at least two material compositions, preferably proteins, both of which contribute to the regulation of cell cycle checkpoints. A cell cycle checkpoint pathway can be activated by the activation of one or more members of the cell cycle checkpoint pathway. Preferably, a cell cycle checkpoint pathway is a biochemical signaling pathway.

[0227] As used herein, “cell cycle checkpoint regulator” refers to a composition of substance that can function, at least partially, in the regulation of cell cycle checkpoints. A cell cycle checkpoint regulator may have a stimulating effect, an inhibitory effect, or both, on one or more functions, including cell cycle checkpoints. A cell cycle checkpoint regulator may be a protein or not.

[0228] Treatment of cancer or cytoproliferative disorders may result in cell death, preferably a reduction of at least 10% in the number of cells in the population. More preferably, the cell death means a reduction of at least 20%; more preferably, at least 30%; more preferably, at least 40%; more preferably, at least 50%; most preferably, at least 75%. The number of cells in the population can be measured by any reproducible measurement method. Some cells in the population can be measured by fluorescence-activated cell sorting (FACS), immunofluorescence microscopy, and light microscopy. Methods for measuring cell death are shown in Li et al., Proc Natl Acad Sci US A. 100(5): 2674-8, 2003. In one embodiment, cell death occurs by apoptosis.

[0229] Preferably, an effective amount of the composition of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, is not significantly cytotoxic to normal cells. If administration of a therapeutically effective dose of the compound does not induce cell death in more than 10% of normal cells, then the therapeutically effective dose of the compound is not significantly cytotoxic to normal cells. If administration of a therapeutically effective dose of the compound does not induce cell death in more than 10% of normal cells, then the therapeutically effective dose of the compound does not significantly affect the viability of normal cells. In one embodiment, cell death occurs by apoptosis.

[0230] By contacting cells with the composition of the present invention, or its pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, selective cell death can be induced or activated in cancer cells. By administering the compound of the present invention, or its pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, to subjects requiring it, selective cell death can be induced or activated in cancer cells. By contacting cells with the composition of the present invention, or its pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, selective cell death can be induced in one or more cells suffering from cell proliferation disorders. Preferably, The composition of the present invention, or a pharmaceutically acceptable salt thereof, prodrug, metabolite, polymorph, or solvate thereof, is administered to a subject to selectively induce cell death in one or more cells suffering from cell proliferation disorders.

[0231] The following examples are provided to illustrate certain embodiments of the present invention. They are not intended to limit the invention in any way. Such modifications are intended to fall within the scope of the appended claims. [Examples]

[0232] Experiment and results: 1. Process for isolating and purifying the active ingredient from Vernonia cinerea: Preparation of plant raw materials and samples The entire plant of newly harvested Vernonia cinerea was chopped into pieces, thoroughly washed with water, and then ground in a mixer grinder to prepare an aqueous suspension. The suspension was filtered through a muslin cloth and then centrifuged at high speed (15,000 × g for 30 minutes) to remove all debris. The aqueous extract was treated with chloroform (1:1 v / v, 3 ×) to separate chlorophyll and other organic components. Trace amounts of chloroform were removed from the aqueous portion by rotary evaporation. The aqueous portion was then precipitated with ethanol by treatment with 100% ice-cold ethanol to precipitate proteins and nucleic acids. Trace amounts of ethanol were further removed by rotary evaporation, and then the aqueous portion was freeze-dried in a freeze-dryer. The crude powder was stored in an airtight container at room temperature. 50 g of crude Vernonia cinerea powder was added to 500 ml of Milli Q water and gently stirred overnight. The supernatant was decanted and dried in a freeze-dryer. The water-soluble dried powder was used in a biological assay to check its activity before proceeding to further downstream purification. The dried powder from the water extract was further resuspended in 500 ml of methanol and stirred continuously at ambient temperature for 2 hours. The methanol extract was further dried. The dried methanol extract was further analyzed for activity using a biological assay.

[0233] Process flowchart The purification process flow is shown below, along with the process parameters and the role of each step. [Table 1-1] [Table 1-2]

[0234] Description of the purification process Chromatography 1 (Capture Step) The dried methanol extract was purified using a multimode Capto adhere ImpRes resin (120 ml column volume) (GE Healthcare) according to the process parameters described above. The resin was equilibrated with 50 mM sodium acetate at pH 5.5, and the methanol extract was resuspended in the same equilibration buffer and loaded onto the column with a residence time of 4 minutes. The column was washed to further remove the unbound fraction, and then eluted using a linear gradient with 50 mM sodium acetate containing 300 mM sodium chloride at pH 5.5. The fractions were collected and analyzed by RP-HPLC and mass spectrometry. The fractions were also analyzed for activity using biological assay methods.

[0235] Chromatography 2 (Intermediate Step) The bioactive fraction was further collected and purified by RP-HPLC chromatography. A Chromachemie Puritas C18 (PP18-05-100-250C) Prep Column was used for two-step chromatographic purification. The column was equilibrated with 0.1% acetic acid, and the dried powder from the chromatography 1 eluent reservoir was resuspended in the same equilibration buffer and loaded onto the column with a residence time of 10 minutes. The column was washed to further remove the unbound fraction, and then eluted using a linear gradient with 0.1% acetic acid in 85% acetonitrile. The fractions were collected and analyzed by RP-HPLC, mass spectrometry, and biological assays.

[0236] Chromatography 3 (Polishing Step) The fraction containing the active substance was further collected and subjected to the polishing step for purification again using Capto adhere ImpRes (5 ml column volume) under the same buffer conditions and linear gradient (chromatography step 1) as described above. The eluted fraction was collected and stored, determined to be of the highest purity by analytical preparative HPLC, and then dried.

[0237] Chromatography 4 (Desalting step) The dried eluate reservoir from Column Chromatography 3 was resuspended and subjected to a desalting step using a Merck PharmPrep® P100 RP-18e (10 μm) column. The column was equilibrated with 0.1% acetic acid, and the dried powder of the Chromatography 3 eluate reservoir was resuspended in the same equilibration buffer and loaded onto the column with a residence time of approximately 8 minutes. The column was washed to further remove the salt fraction, and then eluted using a linear gradient with 0.1% acetic acid in 85% acetonitrile. The fractions were collected and analyzed by preparative HPLC, mass spectrometry, and biological assays.

[0238] Characterization of the active fraction: To clarify the structure, the active compound was subjected to elemental analysis. 1 H-NMR, 13 Analysis was performed using 13C-NMR, distortion-free sensitivity enhancement by polarization transfer (DEPT), infrared spectroscopy (IR), LC-MS, and X-ray crystallography.

[0239] Elemental analysis revealed only the elements C, H, and O (C: 57.62%, H: 4.72%, the remainder being O). The purified compound (E05) 1 Analysis was performed using 1H NMR. The analysis revealed the presence of a benzene ring structure with two OH groups, one COOH group, and one methylene group (Figure 5).

[0240] Purified compound (E05) 13 Analysis was performed using 13C NMR. The analysis confirmed the presence of nine different carbon atoms (Figure 6).

[0241] DEPT (Distortion-Free Sensitivity Enhancement by Polarization Transfer) demonstrated the presence of three carbon atoms with an odd number of hydrogen atoms and two carbon atoms with an even number of hydrogen atoms. (Figure 7)

[0242] The pure fraction (E05) was subjected to LC-MS analysis. MS analysis revealed the main peak at 182 Daltons (Figure 9).

[0243] X-ray crystallography: Single crystals suitable for single-crystal X-ray diffraction analysis were selected using a Leica microscope. A specimen of compound E-05 with approximate dimensions of 0.238 mm × 0.214 mm × 0.087 mm was used for X-ray crystallography. X-ray intensity data were measured using a Bruker D8 VENTURE Kappa Duo PHOTON II CPAD diffractometer equipped with an Incoatech multilayer mirror optical system. Intensity measurements were performed at 100(2) K using a Mo microfocus sealed tube diffraction source (Mo-Kα = 0.71073 Å). The X-ray generator was operated at 50 kV and 1.4 mA. A preliminary set of cell constants and direction matrices was calculated from three sets of 12 frames each. Data were collected with a 0.5° ω and φ scan width, using various settings for φ and ω, with a frame time of 20 seconds and a fixed distance of 4.00 cm between the sample and the detector. X-ray data acquisition was monitored using the APEX3 program (Bruker, 2016). The total exposure time was 5 hours. Frames were integrated using the narrow frame algorithm in the Bruker SAINT Software package. All data were corrected for Lorentzian polarization and absorption using the SAINT and SADABS programs. ShelX-97 was used for structural analysis at F2.2 and for refinement using the complete matrix least squares method. All hydrogen atoms were placed in geometrically ideal positions and constrained to rest on their parent atoms. The ORTEP III figure of the compound (Figure 10) is depicted on a 50% probability substitution ellipsoid, with H atoms shown as small spheres of arbitrary radius. Single crystal analysis revealed that the unknown compound was 3-(3,4-dihydroxyphenyl)propanoic acid. [Table 2]

[0244] 3. In vitro biological assay using water-soluble extract of Erigeron annuus, various different fractions during purification, pure and synthetic compounds, and 3-(3,4-dihydroxyphenyl)propanoic acid. F-36E cell line obtained from patients with erythroleukemia (Riken, BRC, RCB0776) F-36E cells exhibit complete growth dependence to EPO (erythropoietin). In this study, F-36E cells were used to measure in vitro activity in water-soluble plant extracts, various fractions collected by analytical techniques, purified samples (E05), and the synthetic compound [3-(3,4-dihydroxyphenyl)propanoic acid]. Cells were grown and maintained in RPMI-1640 complete medium supplemented with 1 IU / ml EPO. For the assay, F-36E cells were seeded at 10,000 cells / well in 96-well plates. Cells were cultured overnight in RPMI1640 containing 5% FBS and EPO. Cells were then treated with water-soluble extracts (200 ug / well), various fractions or purified compounds, or synthetic compounds for 24–48 hours. Cells treated with EPO (1 IU / ml) [EPO control] or without any growth factor (cell control) were used as controls. Cell viability was measured using Alamer Blue cell viability reagent. Readings were taken from a 96-well plate at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The resulting relative fluorescence units were directly proportional to the number of viable cells.

[0245] The antiproliferative activity of the synthetic compound [3-(3,4-dihydroxyphenyl)propanoic acid] and bosutinib was also tested using the F-36E bioassay. Values ​​obtained from various fractions were normalized against cellular control values.

[0246] The antiproliferative activity of *Erigeron annuus* extract was specific to leukemia cell lines F-36E and TF-1 (erythroleukemia cell line). EPO or GM-CSF treated cells were used as controls to normalize the values ​​of E05 treated cells. Chinese hamster ovary cells (CHO), epidermal carcinoma cells (A431), and rat medullary thyroid carcinoma cells (6-23) showed no effect on the extract treatment (Figure 11). Dose-dependent inhibition of proliferation in colon cancer cell line HCT116 and breast cancer cell line BT-474 was also observed with E05 treatment (Figures 12 and 13).

[0247] I C 50 The values ​​are comparable between the two molecules (Figure 14).

[0248] Kinase inhibitor screening assay The inhibitory activity of purified compounds against a broad panel of tyrosine kinases was checked using a kinase-selective profiling system from Promega. Following the manufacturer's protocol, kinase-selective assays were assembled in 384-well plates using 1 μl of purified compound (final concentration 1 μM), 2 μl of working stock for each kinase, and 2 μl of the corresponding ATP / substrate working stock. Kinase activity was quantified using the Promega ADP-Glo® kinase assay. Reactions assembled with kinase and corresponding ATP / substrate without purified compound were used as positive controls. From 16 tyrosine kinases, SRC kinase activity was found to be inhibited by purified compounds isolated from Erigeron annuus extract.

[0249] In vitro bioassay using a triple-negative breast cancer cell line MDA-MB-468 cells, isolated from pleural exudate in female patients with metastatic adenocarcinoma of the breast, are a triple-negative breast cancer (TNBC) cell line. The IC50 values ​​of E05, lapatinib (Sigma), or structural analogs of E05 were tested in this cell line.

[0250] In short, MDA-MB-468 cells (ATCC#HTB-32) were seeded at a density of 5,000 cells per well in a 96-well white plate (Costar Cat#3917) in DMEM medium (assay medium) supplemented with 10% FBS. The plate was incubated at 37°C and 5% CO2 for 24 hours. E05 and its analogues were diluted in assay medium and added to each well of the assay plate. The plate was further incubated at 37°C and 5% CO2 for 24 hours. After incubation... Cell viability was evaluated using CellTiter-Glo®, and luminescence was read from the plates using Cytation5 (Biotek). The obtained relative luminescence units (RLU) were plotted against concentration, and the EC50 value was estimated using Graphpad Prism5 software (Figure 15 and Table 2). [Table 3]

[0251] The antiproliferative activity of synthetic E05 was compared with that of lapatinib in the MDA-MB-468 trinegative breast cancer cell line. MDA-MB-468 cells (ATCC#HTB-32) were seeded at a density of 5,000 cells per well in a 96-well white plate (Costar Cat#3917) in DMEM medium (assay medium) supplemented with 10% FBS. The plate was incubated at 37°C and 5% CO2 for 24 hours. E05 and lapatinib were diluted in assay medium and added to each well of the assay plate. The plate was further incubated at 37°C and 5% CO2 for 8 hours. After incubation, cell viability was evaluated using CellTiter-Glo®. The luminescence of the plate was read using Cytation5 (Biotek). The obtained relative luminescence units (RLU) were plotted against concentration, and the EC50 value was estimated using Graphpad Prism5 software.

[0252] E05 showed stronger inhibition compared to lapatinib within 8 hours of incubation (Figure 16).

[0253] Xenograft study of E05 in SCID mice The efficacy studies of E05 and the positive control (5-fluorouracil) were conducted in a mouse xenograft model of triple-negative breast cancer (MDA-MB-468). Drug administration was carried out according to Table 3. [Table 4]

[0254] Female SCID (Severe Combined Immunodeficiency) mice were used for this study. Approximately 5 × 10 in a 0.2 mL LFBS-free medium containing 50% Matrigel 6 Cells were injected into the subcutaneous tissue of the right flank of each mouse. Treatment with E05 or a positive control was initiated when the mean tumor volume reached approximately 100 mm3. Tumor volume was measured periodically. A dose-dependent reduction in tumor volume was observed with the test compound. E05 demonstrated statistically significant efficacy in a mouse xenograft model of trinegative breast cancer (TNBC) (Figure 17).

[0255] Animal toxicological studies. A 7-day dose-range finding study (DRF) of repeated intravenous high-volume administration of E05 was conducted in Wistar rats. When administered daily via intravenous high-volume administration for 7 consecutive days, E05 did not cause any systemic toxicity up to a dose level of 500 mg / body weight. [Table 5]

[0256] A 7-day dose-range finding study (DRF) of E05 administered orally via forced oral administration was conducted in Wistar rats. No deaths, morbidities, or clinical signs were observed during the treatment period in this DRF study. No treatment-related changes were observed in food intake, organ weight, or relative organ weight in male and female rats from the treatment group. Based on these results, it can be concluded that E05, when administered orally via forced oral administration for 7 consecutive days in Wistar rats, did not cause any toxicity up to a dose level of 1000 mg / body weight. [Table 6]

[0257] A maximum tolerated dose (MTD) study was conducted using E05. In the MTD study, groups of three male and three female rats were administered 175 (group 1), 550 (group 2), 1750 (group 3), and 2000 (group 4) mg / kg body weight. In the MTD, no deaths, morbidities, or clinical signs were observed during the 72-hour observation period following a single dose of test item E05 at 175, 550, 1750, and 2000 mg / kg body weight. [Table 7]

[0258] Pharmacokinetic studies of E05 in male Sprague Dawley rats A study was conducted to determine the pharmacokinetics of E05 after a single oral administration (10 mg / kg) in male Sprague Dawley rats. The mean time to reach peak plasma concentration (Tmax) after a single forced oral administration of the E05 formulation (dose: 10 mg / kg) to male Sprague Dawley rats was found to be 0.25 hours, suggesting a rapid absorption rate. Exposures (Cmax and AUClast) were found to be 306 ng / mL and 151 ng.h / mL, respectively. The absolute oral bioavailability of the small molecule was 80% (Figure 18).

[0259] The patents and scientific documents referenced herein establish knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are incorporated by reference. All other published references, documents, manuscripts and scientific documents cited herein are incorporated by reference.

[0260] The present invention has been described in detail with reference to its preferred embodiments, and it will be understood by those skilled in the art that the form and details can be varied in various ways without departing from the scope of the invention as encompassed in the appended claims.

Claims

1. A method for regulating Src kinase, the following structure: 【Chemistry 1】 [In the formula, X is either O or S; R １ is a substituent or non-substituent group including hydrogen, or, without being limited thereto, lower alkyl, lower alkenyl, lower alkynyl, -(CH ２ ) ｍ R ７ , (CH ２ ) ｍ -OH, -(CH ２ ) ｍ -O-lower alkyl, -(CH ２ ) ｍ -O-lower alkenyl, -(CH ２ ) ｎ -O-(CH ２ ) ｍ -R ７ , -(CH ２ ) ｍ -SH, -(CH ２ ) ｍ -S-lower alkyl, -(CH ２ ) ｍ -S-lower alkenyl, -(CH ２ ) ｎ -S-(CH ２ ) ｍ -R ７ and is R ２ ~R ６ Each of these can independently be hydrogen, hydroxyl, halogen, lower alkyl, lower alkenyl, lower alkynyl, amino, nitro, azide, sulfate, sulfonate, sulfonamide, -(CH ２ ) ｍ R ７ , (CH ２ ) ｍ -OH, -(CH ２ ) ｍ -O- Lower alkyl, -(CH ２ ) ｍ -O- Lower alkenyl, -(CH ２ ) ｎ -O-(CH ２ ) ｍ -R ７ ,--(CH ２ ) ｍ -SH, -(CH ２ ) ｍ -S- Lower alkyl, -(CH ２ ) ｍ -S- Lower alkenyl, -(CH ２ ) ｎ -S-(CH ２ ) ｍ -R ７ And, R ７ , R ８ , and R ９ Each independently represents, in each occurrence, hydrogen, hydroxyl, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, benzyl, cycloalkyl, cycloalkenyl, or heterocycle; and Each occurrence of m and n is a separate and independent integer in the range of 1 to 9, and each occurrence of z is an independent integer in the range of 1 to 9. The method comprising administering a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereoisomer, racemic mixture, or stereoisomer mixture thereof.

2. R ３ and R ４ The method according to claim 1, wherein each of them is -OH.

3. R ２ and R ３ The method according to claim 1, wherein each of them is -OH.

4. z is 2 and R ８ and R ９ The method according to claim 1, wherein each of these is -H.

5. z is 2; R １ , R ２ , R ５ , R ６ , R ８ and R ９ Each of them is -H; and R ３ and R ４ The method according to claim 1, wherein each of them is -OH.

6. The method according to claim 1, wherein X is O.

7. R １ , R ２ , R ３ , R ６ , R ８ , and R ９ Each of these is -H; R ３ and R ４ Each of these is -OH; X is O; and The method according to claim 1, wherein Z is 2.

8. The compound of formula II has the following structure: 【Chemistry 2】 The method according to claim 1, further comprising a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereoisomer, racemate, or mixture of stereoisomers thereof.

9. The compound of formula II is a prodrug with the following structure: 【Transformation 3】 [In the formula, R １ The method according to claim 1, wherein the ester comprises ethyl esters, morpholinoethanol esters, acetate esters, dialkylaminoacetic acid esters, formic acid esters, phosphate esters, sulfate esters, and benzoic acid derivatives; carbamates comprising N,N-dimethylaminocarbonyl hydroxyl functional groups, and N-acyl derivatives.

10. The following prodrug: 【Chemistry 4】 [In the formula, R １ This includes esters containing ethyl esters, morpholinoethanol esters, acetate esters, dialkylaminoacetic acid esters, formic acid esters, phosphate esters, sulfate esters, and benzoic acid derivatives; carbamates containing the hydroxyl functional group N,N-dimethylaminocarbonyl, and N-acyl derivatives.

11. A method for treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), breast cancer, and colon cancer, comprising the following structure: 【Transformation 5】 [In the formula, X is either O or S; R １ is a substituent or unsubstituted substituent including hydrogen, or, without being limited thereto, lower alkyl, lower alkenyl, lower alkynyl, -(CH ２ ) ｍ R ７ , (CH ２ ) ｍ -OH, -(CH ２ ) ｍ -O-lower alkyl, -(CH ２ ) ｍ -O-lower alkenyl, -(CH ２ ) ｎ -O-(CH ２ ) ｍ -R ７ , -(CH ２ ) ｍ -SH, -(CH ２ ) ｍ -S-lower alkyl, -(CH ２ ) ｍ -S-lower alkenyl, -(CH ２ ) ｎ -S-(CH ２ ) ｍ -R ７ and R ２ ~R ６ Each of these can independently be hydrogen, hydroxyl, halogen, lower alkyl, lower alkenyl, lower alkynyl, amino, nitro, azide, sulfate, sulfonate, sulfonamide, -(CH ２ ) ｍ R ７ , (CH ２ ) ｍ -OH, -(CH ２ ) ｍ -O- Lower alkyl, -(CH ２ ) ｍ -O- Lower alkenyl, -(CH ２ ) ｎ -O-(CH ２ ) ｍ -R ７ ,--(CH ２ ) ｍ -SH, -(CH ２ ) ｍ -S- Lower alkyl, -(CH ２ ) ｍ -S- Lower alkenyl, -(CH ２ ) ｎ -S-(CH ２ ) ｍ -R ７ And, R ７ , R ８ , and R ９ Each independently represents, in each occurrence, hydrogen, hydroxyl, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, benzyl, cycloalkyl, cycloalkenyl, or heterocycle; and Each occurrence of m and n is a separate and independent integer in the range of 1 to 9, and each occurrence of z is an independent integer in the range of 1 to 9. The method comprising administering a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereoisomer, racemic mixture, or stereoisomer mixture thereof.

12. R ３ and R ４ The method according to claim 11, wherein each of them is -OH.

13. R ２ and R ３ The method according to claim 11, wherein each of them is -OH.

14. z is 2 and R ８ and R ９ The method according to claim 11, wherein each of these is -H.

15. z is 2; R １ , R ２ , R ５ , R ６ , R ８ and R ９ Each of them is -H; and R ３ and R ４ The method according to claim 11, wherein each of them is -OH.

16. The method according to claim 11, wherein X is O.

17. R １ , R ２ , R ３ , R ６ , R ８ , and R ９ Each of these is -H; R ４ and R ５ Each of these is -OH; X is O; and The method according to claim 11, wherein Z is 2.

18. The compound of formula II has the following structure: 【Transformation 6】 The method according to claim 11, further comprising a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereoisomer, racemate, or mixture of stereoisomers thereof.

19. The compound of formula II is a prodrug with the following structure: 【Transformation 7】 [In the formula, R1 is an ester comprising ethyl esters, morpholinoethanol esters, acetate esters, dialkylaminoacetic acid esters, formic acid esters, phosphate esters, sulfate esters, and benzoic acid derivatives; a carbamate comprising the hydroxyl functional group N,N-dimethylaminocarbonyl, and an N-acyl derivative.] The method according to claim 11.

20. The method according to claim 11, further comprising administering one or more additional therapeutic agents, including anticancer drugs or chemotherapy drugs.

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