7-Benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-A]pyrido[3,4-E]pyrimidine-5(1H)-one, its salt and method of use thereof

Abstract

To provide pharmaceutical compositions for use in treatment of a subject having or at risk of having cancer.SOLUTION: A pharmaceutical composition is provided which comprises a compound (2) represented by a chemical formula in the figure and a pharmaceutically acceptable carrier. The compound (2) is formulated into a dosage form for administration of a unit dose in a range from about 100 mg to about 200 mg each time.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application is a continuation in part of U.S. Patent Application No. 14 / 341,392 filed July 25, 2014, and International Patent Application PCT / US2014 / 048241 filed July 25, 2014, each of which is a continuation in part of U.S. Patent Application No. 14 / 208,657 filed March 13, 2014, and claims the interests of U.S. Provisional Patent Application No. 61 / 779,828 filed March 13, 2013, and U.S. Provisional Patent Application No. 61 / 904,718 filed November 15, 2013, all of which are incorporated herein by reference in whole. This application is also a continuation in part of U.S. Patent Application No. 14 / 208,657 filed March 13, 2014, and claims the interests of U.S. Provisional Patent Application No. 61 / 904,718 filed November 15, 2013. [Background technology]

[0002] TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that selectively induces apoptosis in cancer cells. TRAIL is a potent apoptosis inducer in a wide range of human cancer cell lines, mediated through pro-apoptotic cell death receptors 4 (DR4; TRAIL-R1) and 5 (DR5; TRAIL-R2) on the cell surface, via exogenous or endogenous apoptotic pathways. While TRAIL plays a direct role in tumor suppression during immune surveillance, this antitumor mechanism is lost during disease progression. Because TRAIL can selectively initiate apoptosis in cancer cells, clinical trials are currently underway using long-lived TRAIL-agonist antibodies targeting recombinant TRAIL or one of its two pro-apoptotic cell death receptors.

[0003] Despite its potency, recombinant TRAIL has characteristics that limit its effectiveness, such as a short serum half-life, stability, cost, and delivery. Delivery of recombinant TRAIL or TRAIL-agonist antibodies to the brain is limited because recombinant TRAIL and TRAIL-agonist antibodies cannot cross the blood-brain barrier. Therefore, there is a continuing need for anticancer compositions and methods. [Overview of the Initiative]

[0004] In one embodiment, the present invention relates to compound (1):

[0005] [ka]

[0006] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises compound (1) in the form of a pharmaceutically acceptable salt. In one embodiment, the pharmaceutical composition comprises compound (1) in the form of a pharmaceutically acceptable monosalt. In one embodiment, the pharmaceutical composition comprises compound (1) in the form of a pharmaceutically acceptable disalt. In one embodiment, the pharmaceutical composition comprises compound (1) in the form of a pharmaceutically acceptable salt selected from the group consisting of hydrochloride, hydrobromide, bisulfate, sulfate, phosphate, fumarate, succinate, oxalate and lactate, bisulfate, hydroxyl, tartrate, nitrate, citrate, bicarbonate, carbonate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, acetate, and carboxylate. In one embodiment, the pharmaceutical composition comprises a compound (1) in the form of a pharmaceutically acceptable salt selected from the group consisting of p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate, glucuronate, ascorbic acid, and maleate. In one embodiment, the pharmaceutical composition comprises a compound (1) in the form of a pharmaceutically acceptable salt selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, and lithium, and / or a compound (1) having other counterions such as methylamino, dimethylamino, diethylamino, and triethylamino counterions. In one embodiment, the pharmaceutical composition comprises a compound (1) in the form of a hydrochloride di-salt or hydrobromide di-salt.

[0007] In one embodiment, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier.

[0008] In some embodiments, the pharmaceutical composition according to the present invention comprises a second therapeutic substance. In one such embodiment, the second therapeutic substance is an anticancer agent. In one embodiment, the anticancer agent is a mitotic inhibitor. In one embodiment, the anticancer agent is selected from the group consisting of paclitaxel, docetaxel, and combinations thereof. In an alternative embodiment, the second therapeutic substance is an anti-angiogenic agent. In one embodiment, the anti-angiogenic agent is bevacizumab. In one embodiment, the second therapeutic substance is administered as part of a combination therapy to treat the patient. In one embodiment, details of the combination therapy are included in the prescribing information for compound (1).

[0009] In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0010] In another embodiment, the present invention provides a therapeutic method. In one embodiment, the therapeutic method comprises administering a pharmaceutical composition to a subject, wherein the pharmaceutical composition is a pharmaceutically effective amount of compound (1):

[0011] [ka]

[0012] or a pharmaceutically acceptable salt thereof.

[0013] In one embodiment, the treatment method includes administering a pharmaceutical composition containing a pharmaceutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof to a subject. In one embodiment, the treatment method includes administering a pharmaceutical composition containing a pharmaceutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject.

[0014] In some embodiments, the treatment method further includes administering an additional therapeutic substance. In one embodiment, the additional therapeutic substance includes an anticancer agent. In one embodiment, the additional anticancer agent includes an antimitotic agent. In one embodiment, the additional anticancer agent includes paclitaxel, docetaxel, bevacizumab, or any combination thereof.

[0015] In one embodiment, the treatment method further includes assaying tumor necrosis factor (TNF)-related apoptosis-inducing ligands in a sample obtained from a subject receiving treatment. In one embodiment, the TNF-related apoptosis-inducing ligands are assayed in a blood sample obtained from the subject.

[0016] In one embodiment of the treatment method according to the present invention, the subject receiving treatment has cancer or is at risk of developing cancer. In one embodiment, the cancer is selected from the group consisting of colon cancer, breast cancer, glioblastoma multiforme, mantle cell lymphoma, and colorectal cancer.

[0017] In one embodiment of the treatment method according to the present invention, the subject is at risk of having cancer. In one embodiment, the cancer is selected from the group consisting of actinic keratosis, Barrett's esophagus, atrophic gastritis, congenital keratosis, iron deficiency dysphagia, lichen planus, oral submucosal fibrosis, photoelastic fibrosis, cervical malformation, vitiligo, and erythroplakia.

[0018] In one embodiment of the therapeutic method according to the present invention, the pharmaceutical composition is administered via an oral route. In one embodiment, the pharmaceutical composition is administered via a route selected from the group consisting of the rectum, nose, lung, epidural, eye, ear, intra-arterial, intracardiac, intracerebral, intradermal, intravenous, intramuscular, intraperitoneal, intraosseous, intramedullary, intrabladder, subcutaneous, topical, transdermal, transmucosal, sublingual, buccal, and vaginal, as well as via an inhalation route.

[0019] In one embodiment, the present invention is a method for treating a subject who has brain cancer or is at risk of developing brain cancer, comprising a pharmaceutically effective amount of compound (1):

[0020] [ka]

[0021] The present invention provides a method comprising administering a pharmaceutical composition containing a pharmaceutically acceptable salt thereof to a subject. In one embodiment, a method for treating a subject having or at risk of having brain cancer comprises administering a pharmaceutical composition containing a pharmaceutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject.

[0022] In one embodiment, the present invention provides a therapeutic method comprising administering a pharmaceutical composition to a target, wherein the pharmaceutical composition is a pharmaceutically effective amount of compound (1):

[0023] [ka]

[0024] or comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0025] The above summary, as well as the following detailed description of embodiments of the therapeutic composition and method, will be better understood when read in conjunction with the attached claims. However, it should be understood that the present invention is not limited to the exact arrangement and means described herein.

[0026] In another aspect, the present invention relates to a therapeutic method comprising administering a combination of a first therapeutic substance and a second therapeutic substance, each containing the following compound (1), to a subject requiring such treatment, (i) Compound (1):

[0027] [ka]

[0028] Or administering the first therapeutic substance containing a pharmaceutically acceptable salt thereof, (ii) After administering the first therapeutic substance to the subject, wait until a predetermined waiting period has elapsed, (iii) administering a second therapeutic substance to the subject, The present invention provides a method for selecting a predetermined waiting time to achieve a delayed therapeutic effect of the first therapeutic substance without increasing or reducing the risk of possible combined toxic effects of the first therapeutic substance and the second therapeutic substance.

[0029] In another aspect, the present invention relates to a therapeutic method comprising administering a combination of a first therapeutic substance and a second therapeutic substance to a subject requiring such treatment, (i) Compound (1):

[0030] [ka]

[0031] Or administering the first therapeutic substance containing a pharmaceutically acceptable salt thereof, (ii) Monitoring the levels of compound (1) or its pharmaceutically acceptable salt or metabolite in the subject using a pharmacokinetic profile, (iii) Depending on the level of the first therapeutic agent in the subject, the second therapeutic agent is administered, This provides a method that includes this.

[0032] In another aspect, the present invention is a therapeutic method comprising administering a combination of a first therapeutic substance and a second therapeutic substance to a subject requiring such treatment, (i) Compound (1):

[0033] [ka]

[0034] Or administering the first therapeutic substance containing a pharmaceutically acceptable salt thereof, (iii) A treatment method is provided which includes administering a second therapeutic substance to the subject receiving treatment, depending on the expected half-life of exemplary compound (1), which is about 3 hours to about 8 hours. In some embodiments, the expected half-life of exemplary compound (1) is about 3 hours to about 24 hours in the subject receiving treatment.

[0035] In another aspect, the present invention is a therapeutic method comprising administering a combination of a first therapeutic substance and a second therapeutic substance to a subject requiring such treatment, (i) Compound (1):

[0036] [ka]

[0037] Or administering the first therapeutic substance containing a pharmaceutically acceptable salt thereof, (iii) A treatment method is provided which includes administering a second therapeutic substance depending on the adverse events of the first therapeutic substance that have resolved or are in the process of resolving. In some embodiments, the adverse events of the first therapeutic substance are related to the blood levels of the first therapeutic substance or its metabolites in the subject receiving treatment.

[0038] In another embodiment, the present invention provides a kit for monitoring compound (1) or a pharmaceutically acceptable salt or metabolite thereof in an individual treated with compound (1) or a pharmaceutically acceptable salt or metabolite thereof, using a pharmacokinetic profile, the kit comprising a plurality of point-of-care or point-of-use devices capable of quantifying the drug in a matrix suitable for storing at least two samples or at least two samples prior to laboratory quantification. In some embodiments, the kit according to the present invention further includes instructions for collecting and / or storing at least two samples.

[0039] The above summary, as well as the following detailed description of embodiments of the present invention, will be better understood when read in conjunction with the accompanying drawings of exemplary embodiments. However, it should be understood that the present invention is not limited to the exact arrangements and means shown. [Brief explanation of the drawing]

[0040] [Figure 1] The dose-response relationship is shown, illustrating the effect of various concentrations of compound (1), an exemplary compound of the present invention, on the survival rates of tumor cells and normal cells. [Figure 2] This shows a cell viability assay in human fetal lung fibroblast (MRC-5) cells after 72 hours of treatment with compound (1), an exemplary compound of the present invention. [Modes for carrying out the invention]

[0041] The scientific and technical terms used herein are intended to have meanings generally understood by those skilled in the art. Such terms are derived from: J. Sambrook and D. W. Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 3rd edition, 2001; F. M. Russell (ed.), Short Protocols in Molecular Biology, Current Protocols, 5th edition, 2002; B. Alberts et al., Molecular Biology of the Cell, 4th edition, Garland, 2002; DL. Nelson and M. M. Cox, Lehninger Principles of Biochemistry, 4th edition, WH. Freeman & Company, 2004; Engelke, D. R., RNA Interference (RNAi): Nuts and Bolts of RNAi Technology, DNA Press LLC, Eagleville, Pa., 2003; Herdewijn, P. (ed.), Oligonucleotide Synthesis: Methods and Applications, Methods of Molecular Biology, Humana Press, 2004; A. Nagy, M. Gertsenstein, K. Vintersten, R. Behringer, Mouse Embryo Manipulation: Laboratory Manual, 3rd Edition, Cold Spring Harbor Laboratory Press; December 15, 2002, ISBN-10:0879695919; Kursad Turksen (ed.), Embryonic Stem Cells: Methods and Protocols in Methods Mol Biol 2002; 185, Humana Press; Current Protocols in Stem Cell Biology, ISBN:9780470151808, and various standard references including U.S. Patent Application Publication No. 20120276088. The contents of each of the aforementioned references are incorporated herein by reference in their entirety.

[0042] The singular forms "one (a)," "one (an)," and "that" are not intended to be limiting and include multiple references unless explicitly stated or the context makes it particularly clear.

[0043] I. Composition In one embodiment, the present invention relates to compound (1):

[0044] [ka]

[0045] The present invention provides a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises compound (1) or a pharmaceutically acceptable mono salt thereof. In one embodiment, the pharmaceutical composition comprises compound (1) or a pharmaceutically acceptable di salt thereof. In one embodiment, the pharmaceutical composition comprises compound (1) or a pharmaceutically acceptable mono or polysalt thereof selected from the group consisting of hydrochloride, hydrobromide, bisulfate, sulfate, phosphate, fumarate, succinate, oxalate and lactate, bisulfate, hydroxyl, tartrate, nitrate, citrate, bicarbonate, carbonate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, and carboxylate salts (e.g., di or tri salt; throughout this disclosure, di salt is understood to encompass poly or tri salt). In one embodiment, the pharmaceutical composition comprises compound (1) or a pharmaceutically acceptable salt thereof selected from the group consisting of p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate and maleate. In one embodiment, the pharmaceutical composition comprises compound (1) or a pharmaceutically acceptable salt selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc and lithium, and / or having a counterion such as methylamino, dimethylamino, diethylamino and triethylamino counterions. In one embodiment, the pharmaceutical composition comprises compound (1), its hydrochloride disalt (e.g., dihydrochloride), or its hydrobromide disalt (e.g., dihydrobromide).

[0046] Compound (1) has the same chemical structure as that revealed by structural analysis (e.g., NMR, X-ray diffraction) of compound NSC350625, which is available from the National Cancer Institute's Developmental Therapy Program Repository.

[0047] In one embodiment, the pharmaceutical composition according to the present invention comprises a disalt (e.g., dihydrochloride) of compound (1).

[0048] A salt of compound (1) (e.g., a di-salt or tri-salt) is compound (1):

[0049] [ka]

[0050] It can be prepared from which it is commercially available or can be synthesized using standard chemical synthesis methods known to those skilled in the art.

[0051] In one embodiment, the pharmaceutical composition according to the present invention comprises at least one pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include, but are not limited to, those found in the Handbook of Pharmaceutical Excipients, 7th edition, edited by Raymond C. Rowe et al., American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and previous editions.

[0052] Exemplary pharmaceutically acceptable carriers, pharmaceutical compositions, and methods of manufacturing various dosage forms, as well as methods of administration, are, for example, in *Pharmaceutical Dosage Forms: Tablets*, edited by Larry L. Augsburger and Stephen W. Hoag, London: Informa Healthcare, 2008; and in *Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems*, 8th edition, by L.V. Allen, Jr. et al., Lippincott, Williams & Wilkins, 2004; in *The Science and Practice of Pharmacy*, Lippincott Williams & Wilkins, 21st edition, 2005, particularly Chapter 89, by ARGennaro, Remington; and in *The Pharmacological Basis of Therapeutics*, by J.Hardman et al., Goodman & Gilman, McGraw-Hill As detailed in Professional, 10th edition, 2001, this is publicly known to those skilled in the art.

[0053] In some embodiments, the pharmaceutical composition of the present invention is formulated for ocular administration. In some embodiments, the pharmaceutical composition of the present invention is formulated for topical ocular administration. In some embodiments, the pharmaceutical composition is formulated as an ointment, droplets, or liquid. In some embodiments, the pharmaceutical composition of the present invention may contain an aqueous, powdery, or oily base, or a conventional pharmaceutical carrier such as a thickener.

[0054] In some embodiments, the pharmaceutical composition of the present invention is formulated as an intravenous formulation. In one embodiment, the intravenous formulation comprises compound (1) or a pharmaceutically acceptable salt of compound (1) dissolved in a solvent. In one embodiment, the solvent is water. In such an embodiment, the intravenous formulation comprises compound (1) or a pharmaceutically acceptable salt of compound (1) dissolved in water at a concentration of 25 mg / ml. In some embodiments, the intravenous formulation comprises compound (1) or a pharmaceutically acceptable salt thereof at a higher or lower concentration. In one embodiment, the intravenous formulation comprises compound (1) or a pharmaceutically acceptable salt thereof at a concentration of about 5 mg / ml to about 100 mg / ml. In one embodiment, the intravenous formulation comprises compound (1) or a pharmaceutically acceptable salt thereof at a concentration of about 50 mg / ml. In one embodiment, the intravenous formulation comprises compound (1) or a pharmaceutically acceptable salt thereof at a concentration of about 5 mg / ml. In one embodiment, the intravenous formulation contains about 0.5% to about 10% of compound (1) or a pharmaceutically acceptable salt thereof. In another embodiment, the intravenous formulation contains about 5% or more of compound (1) or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the intravenous formulation has a pH of about 3. In one embodiment, the pH of the intravenous formulation is adjusted to pH 3 with phosphate buffer. In some embodiments, the intravenous formulation contains dextrose or sodium chloride. In one embodiment, an intravenous formulation containing compound (1) or a pharmaceutically acceptable salt thereof at a concentration of about 5 mg / ml and pH 3 forms a stable solution. In one embodiment, the intravenous formulation contains compound (1) or a pharmaceutically acceptable salt thereof at a concentration of about 5 mg / ml and pH less than 5 forms a stable solution. In one embodiment, the intravenous formulation contains compound (1) or a pharmaceutically acceptable salt thereof and one or more antioxidants. In one embodiment, the intravenous formulation contains a mixture of monohydrochloride and dihydrochloride of compound (1). In one embodiment, the intravenous formulation contains compound (1) or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg / ml as a 1% solution having compound (1) or a pharmaceutically acceptable salt thereof. In such an embodiment, the intravenous formulation is a solution having a pH of about 3.3. In one embodiment, the pH is less than 4.0.

[0056] In one embodiment, the pharmaceutical composition according to the present invention comprises about 0.1 to 99% of a salt of compound (1) or a pharmaceutically acceptable salt thereof. In such an embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In one embodiment, a suitable pharmaceutically acceptable carrier comprises oil. In one embodiment, a suitable pharmaceutically acceptable carrier comprises sterile water. In one embodiment, a suitable pharmaceutically acceptable carrier comprises an aqueous carrier.

[0057] In some embodiments, the intravenous formulation comprises dextrose and / or sodium.

[0058] In one embodiment, the intravenous formulation comprises compound (1) or the dihydrochloride of compound (1) dissolved in water at 25 mg / ml. In such an embodiment, the intravenous formulation is adjusted to pH 3 with a phosphate buffer. In such an embodiment, the intravenous formulation comprises dextrose or sodium chloride. In such an embodiment, the intravenous formulation comprises an increase or decrease in the concentration of the dihydrochloride of compound (1) that is higher or lower. In one embodiment, the intravenous formulation comprises compound (1) or the dihydrochloride of compound (1) at a concentration of about 5 mg / ml. In one embodiment, an intravenous formulation comprising compound (1) or the dihydrochloride of compound (1) at a concentration of about 5 mg / ml and pH 3 forms a stable solution. In one embodiment, the intravenous formulation comprises compound (1) or the dihydrochloride of compound (1) at a concentration of about 5 mg / ml and a pH less than 5 and forms a stable solution. In one embodiment, the intravenous formulation comprises compound (1) or the dihydrochloride of compound (1) and one or more antioxidants. In one embodiment, the intravenous formulation comprises a mixture of the monohydrochloride and dihydrochloride of compound (1). In one embodiment, the intravenous formulation comprises compound (1) or the dihydrochloride of compound (1) at a concentration of about 10 mg / ml as a 1% solution of compound (1) or the dihydrochloride of compound (1). In such an embodiment, the intravenous formulation is a solution having a pH of about 3.33. In one embodiment, the pH is less than 4.0.

[0059] In one embodiment, the intravenous formulation contains about 0.5% to about 10% (or about 5 mg / ml to about 100 mg / ml) of compound (1) or a disalt of compound (1). In one embodiment, the intravenous formulation contains about 5% (or about 50 mg / ml) or more of compound (1) or a disalt of compound (1). In one embodiment, the intravenous infusion rate may be slow to reduce the side effects of compound (1) or a disalt of compound (1).

[0060] In one embodiment, the pharmaceutical composition according to the present invention comprises about 0.1 to 99% of a salt of compound (1) and a pharmaceutically acceptable carrier, such as oil, sterile water, or other aqueous carrier. In one embodiment, the pharmaceutical composition according to the present invention comprises about 5% to about 50% of a monosalt or disalt of compound (1) for an oral dosage form.

[0061] In some embodiments, the pharmaceutical compositions of the present invention include antioxidants. Suitable antioxidants include ascorbic acid, ascorbic acid derivatives such as erythorbic acid and sodium ascorbate, thiol derivatives such as thioglycerol, cysteine, acetylcysteine, cysteine, dithioerythritol, dithiothreitol and glutathione, tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium sulfate, sodium bisulfite, sodium acetone bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, sodium thiosulfate, and nordihydroguaiaretic acid. Antioxidants used in aqueous formulations generally include sodium sulfite, sodium disulfite, sodium formaldehyde sulfoxylate and ascorbic acid and combinations thereof, while antioxidants used in oily solutions and organic solvents include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and propyl gallate and combinations thereof. In further embodiments, the antioxidant may be one or more of the following: flavanoids, isoflavones, monothioglycerol, L-cysteine, thioglycolic acid, α-tocopherol, ascorbic acid 6-palmitate, dihydrolipoic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, propyl gallate, β-carotene, and ascorbic acid. The antioxidant can generally be used at about 0.1% to 1.0% by weight, and more commonly at about 0.2% by weight.

[0062] In one embodiment, the pharmaceutical composition comprises compound (1) or a pharmaceutically acceptable salt thereof and at least one other therapeutic substance. In such one embodiment, at least one other therapeutic substance is a hormone analog and antihormone agent, aromatase inhibitor, LHRH agonist and antagonist, growth factor inhibitor, growth factor antibody, growth factor receptor antibody, tyrosine kinase inhibitor, antimetabolites, antitumor antibiotic, platinum derivative, alkylating agent, antimitotic agent, tubulin inhibitor, PARP inhibitor, topoisomerase inhibitor, serine / threonine kinase inhibitor, tyrosine kinase inhibitor, protein-protein interaction inhibitor, RAF inhibitor, MEK inhibitor, ERK inhibitor, IGF-1R inhibitor, ErbB receptor inhibitor, rapamycin analog, BTK inhibitor, CRM1 inhibitor (e.g., KPT185), P53 modulator (e.g., Nutrin), angiogenesis inhibitor (e.g., axitinib, aflibercept, sorafenib, and regorafenib), amifostine, anagre Lido, clodronate, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-alethine, 131-1-TM-601, 3CPA, 7-ethyl-10- Hydroxycamptothecin, 16-aza-epotilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, alovectin-7, altretamine, arbocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apadiquon, apomin, alanose, algravin, alzoxifen, atamestan, atrasentan, auristatin PE, AVLB, AZ 10992, ABX-EGF, AMG-479 (ganitumab), ARRY162, ARRY438162, ARRY-300, ARRY-142886 / AZD-6244 (selumetinib), ARRY-704 / AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-7362, ARQ 680,AS-703026 (Pimasertive), Avastin, AZD-2014, Azacitidine, Azaepotilone B, Azonafide, BAY-43-9006, BAY80-6946, BBR-3464, BBR-3576, Bevacizumab, BEZ-235, Bilicodal dicitrate, BCX-1777, BKM-120, Bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (Afatinib, Tomtoboc), BIBF 1120 (vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycin acid, bleomycin A, bleomycin B, brivanib, briostatin-1, bortezomib, brostaricin, busulfan, BYL-719, CA-4 prodrug, CA4, CapCell, calcitriol, canertinib, camphosphamide, capecitabine, carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, cefratonin, ceftriaxone, celecoxib B, cermoleukin, semadin, CH4987655 / RO-4987655, chlorotrianicene, silenditide, cyclosporine, CDA-II, CDC-394, CKD-602, CKI-27, clofarabine, colchicine, combretastatin A4, COT inhibitor, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, Decitabine, Doxorubicin, Deoxyrubicin, Deoxycoformycin, Depsipeptide, Desoxyepotilon B, Dexamethasone, Dexrazoxane, Diethylstilbestrol, Diflomotecan, Zidox, DMDC, Dorastatin 10, Dranidazole, DS-7423, E7010, E-6201, Edatrexate, Edtreotide, Efaproxial,Eflornithine, EGFR inhibitor, EKB-569, EKB-509, Enzastaurin, Enzalutamide, Erusamitrusin, Epotilon B, Epratuzumab, ER-86526, Erlotinib, ET-18-0CH3, Ethinylcytidine, Ethinylestradiol, Exatecan, Exatecan mesylate, Exemestane, Exislind, Fenretinide, Figitumumab, Furoxuridine, Folic acid, Forfox, Forfox 4, Forfiri, Formestan, Fotemustine, Galarubicin, Gallium maltolate, Gefitin Gemtuzumab, Gimatecan, Gluphosphamide, GCS-100, GDC-0623, GDC-0941 (Pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT Immunogen, GMK, GPX-100, gp100-Peptide Vaccine, GS-5126766, GSK-690693, GSK-1120212 (Trametinib), GSK-2118436 (Dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334 470, GSK-2110183, GSK-2141795, GW2016, Granisetron, Herceptin, Hexamethylmelamine, Histamine, Homohalingtonin, Hyaluronic acid, Hydroxyurea, Hydroxyprogesterone caproate, Ibandronate, Ibrutinib, Ibritumomab, Idatrexate, Idenestrol, IDN-5109, IGF-1R inhibitor, IMC-1C11, IMC-A12 (Sixtumumab), Imunol, Indislam, Interferon alpha-2a Interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, ilofluben, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepyrone, JRX-2, JSF-154, J-107088, conjugated estrogen, kahalido F, ketoconazole, KW-2170, KW-2450, lovaplatin, leflunomide, lenograstim, leuprolide, leuprorelin, lexidrona,LGD-1550, Linezolid, Lutetium Texaphylline, Lometrexol, Rosoxantrone, LU 223651, Rootecan, LY-S6AKT1, LY-2780301, Maphosphamide, Marimastate, Mechloroetamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, Midostaurin, Minodronate, Mitomycin, Mybobrin, MK-2206, MK-0646 (Darotuzumab), MLN518, Motexafingadolinium, MS-209, MS-275, MX6, Nelidronate, Neratinib, Nexavar, Neovastat, Nilotinib, Nimeslide, Nitroglycerin, Noratexed, Norelin, N-Acetylcysteine, O6-Benzylguanine, Oblimersen, Omeprazole, Oncophage, OncoVEXGM-CSF, Ormiplatin, Ortataxel, OX44 antibody, OSI-027, OSI-906 (Lincitinib), 4-IBB antibody, Oxatrazole, Estrogen, Panitumumab, Patupilone, Pegfilg Rastim, PCK-3145, Pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, peritinib, pemetrexed, pentrix, perifosine, periryl alcohol, pertuzumab, PI3K inhibitor, PI3K / mTOR inhibitor, P G-TXL, PG2, PLX-4032 / RO-5185426 (Vemurafenib), PLX-3603 / RO-5212054, PT-100, PWT-33597, PX-866, Picoplatin, Pivaloyloxymethylbutyrate, Pixantrone, Phenoxodiol O, PKI166, Previtrexed, Plicamycin, Polyprenic acid, Porphyromycin, Prednisone, Prednisolone, Quinamed, Quinupristin, R115777, RAF-265,Ramosetron, Lampirase, RDEA-119 / BAY 869766, RDEA436, Rebeccamycin analog, Receptor tyrosine kinase (RTK) inhibitor, Regorafenib, Levimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, Rizoxin, Rhu-MAb, Rinfabate, Risedronate, Rituximab, Lobatumumab, Rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881A, Rubidazone, Rubitecan, R-flurbiprofen, RX-0201, S-9788, Sabarbicin, SAHA, Salglamostim, Satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, Semustin, Theocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, Sorafenib, Spiroplatin, Squalamine, Suberanilohydroxamic acid, Stent, T 900607, T 138067, TAK-733, TAS-103, Tasejinarin, Talaporfin, Tarceva, Tariquitar, Tasisulam, Taxotere, Taxaoplexin, Tazarotene, Tegafur, Temozolam, Tesmirifen, Testosterone, Testosterone Propionate, Tesmirifen, Tetraplatin, Tetrodotoxin, Tezacitabine, Thalidomide Ido, Theralux, Teralubicin, Thimalfacin, Thimectacin, Thiazofrine, Tipifarnib, Tillapazamine, Tocladesine, Tomdex, Tremofin, Trabectedin, Trans-MID-107, Trans-retinic acid, Trastuzumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Trisirivine, Trimethrexate, TLK-286TXD 258, Tykerb / Tyberb, Urocidine, Barurubicin, Batalanib, Vincristine, Vinflunin, Birulizine, WX-UK1, WX-554, Vectibix, Xeloda, XELOX, XL-147, XL-228, XL-281, XL-518 / R-7420 / GDC-0973, XL-765, YM-511,The following are selected from the group consisting of YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, Zoledronate, Zoskidal, and combinations thereof.

[0063] In one embodiment, at least one other therapeutic agent comprises one or more hormonal analogs, and / or the antihormone agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide, and combinations thereof. In one embodiment, at least one other therapeutic agent comprises one or more LHRH agonists and / or antagonists selected from the group consisting of goserelin acetate, leuprolide acetate, triptrelyn pamoate, and combinations thereof, wherein the LHRH antagonist is selected from the group consisting of degarelix, cetrorelix, abarelix, ozarelix, degarelix, and combinations thereof. In one embodiment, at least one other therapeutic agent comprises one or more growth factor inhibitors selected from the group consisting of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER), and hepatocyte growth factor (HGF). In one embodiment, at least one other therapeutic agent comprises one or more inhibitors of human epidermal growth factors selected from the group consisting of HER2, HER3, and HER4. In one embodiment, at least one other therapeutic agent comprises one or more tyrosine kinase inhibitors selected from the group consisting of cetuximab, gefitinib, imatinib, lapatinib, and trastuzumab, and combinations thereof. In one embodiment, at least one other therapeutic agent comprises one or more aromatase inhibitors selected from the group consisting of anastrozole, letrozole, rialozol, volozol, exemestane, atamestane, and combinations thereof. In one embodiment, at least one other therapeutic substance comprises one or more antimetabolites, which are folate antimetabolites selected from the group consisting of methotrexate, larcitrexed, and pyrimidine analogs. In one embodiment, at least one other therapeutic substance comprises 5-fluorouracil,The present embodiment includes one or more antimetabolites, which are pyrimidine analogs selected from the group consisting of capecitabine and gemcitabine. In one embodiment, at least one other therapeutic agent includes one or more antimetabolites, which are purines and / or adenosine analogs selected from the group consisting of mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine and combinations thereof. In one embodiment, at least one other therapeutic agent includes one or more antitumor antibiotics selected from the group consisting of anthracyclines, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozosin and combinations thereof. In one embodiment, at least one other therapeutic agent includes one or more platinum derivatives selected from the group consisting of cisplatin, oxaliplatin, carboplatin and combinations thereof. In one embodiment, at least one other therapeutic agent comprises one or more alkylating agents selected from the group consisting of estramustine, mechloretamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosourea, and combinations thereof. In one embodiment, at least one other therapeutic agent comprises nitrosourea selected from the group consisting of carmustine, lomustine, thiotepa, and combinations thereof. In one embodiment, at least one other therapeutic agent comprises an antimitotic agent selected from the group consisting of vinca alkaloids and taxanes. In one embodiment, at least one other therapeutic agent comprises one or more taxanes selected from the group consisting of paclitaxel, docetaxel, and combinations thereof. In one embodiment, at least one other therapeutic agent comprises one or more vinca alkaloids selected from the group consisting of vinblastine, vindesine, vinorelbine, vincristine, and combinations thereof. In one embodiment, at least one other therapeutic agent comprises one or more topoisomerase inhibitors which are epipodophyllotoxins. In one embodiment, at least one other therapeutic agent comprises etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone,The present invention includes one or more epipodophyllotoxins selected from the group consisting of the above and combinations thereof. In one embodiment, at least one other therapeutic agent includes one or more serine / threonine kinase inhibitors selected from the group consisting of PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORCl inhibitors, PI3K inhibitors, mTOR / PI3K biinhibitors, STK 33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, aurora kinase inhibitors, and combinations thereof. In one embodiment, at least one other therapeutic agent includes one or more tyrosine kinase inhibitors that are PTK2 / FAK inhibitors. In one embodiment, at least one other therapeutic agent includes one or more protein-protein interaction inhibitors selected from the group consisting of IAP, Mcl-1, MDM2 / MDMX, and combinations thereof. In one embodiment, at least one other therapeutic agent includes one or more rapamycin analogs selected from the group consisting of everolimus, temsirolimus, ridafololimus, sirolimus, and combinations thereof. In one embodiment, at least one other therapeutic agent comprises one or more therapeutic agents selected from the group consisting of amifostine, anagrelide, clodronate, filgrastine, interferon, interferon alfa, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer, and combinations thereof. In one embodiment, at least one other therapeutic substance is 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-aretin, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epotilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, alovectin-7, altretamine, arbocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apadiquon, apomin, alanose, algravin, alzoxifen, atamestan, atrasentan, auristatin PE, AVLB, AZ 10992, ABX-EGF, AMG-479 (ganitsumab), ARRY 162, ARRY 438162, ARRY-300,ARRY-142886 / AZD-6244 (selumetinib), ARRY-704 / AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-7362, ARQ 680, AS-703026 (primasertib), Avastin, AZD-2014, Azacitidine, Azaepotilone B, Azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, Bevacizumab, BEZ-235, Bilicodal dicitrate, BCX-1777, BKM-120, Bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (Afatinib, Tomtoboc), BIBF 1120 (Vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, Bleomycin acid, Bleomycin A, Bleomycin B, Brivanib, Briostatin-1, Bortezomib, Brostarisin, Busulfan, BYL-719, CA4 prodrug, CA4, CapCell, Calcitriol, Canertinib, Camphosphamide, Capecitabine, Carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 Cefixime, Cefratonin, Ceftriaxone, Celecoxib , cermoloukin, semadotin, CH4987655 / RO-4987655, chlorotrianicene, silenditide, cyclosporine, CDA-II, CDC-394, CKD-602, CKI-27, clofarabine, colchicine, combretastatin A4, COT inhibitor, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine, doxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide,Deoxyepotilon B, Dexamethasone, Dexrazoxane, Diethylstilbestrol, Diflomotecan, Zidox, DMDC, Dorastatin 10, Dranidazole, DS-7423, E7010, E-6201, Edatrexate, Edtreotide, Efaproxial, Eflornithine, EGFR inhibitor, EKB-569, EKB-509, Enzastaurin, Enzalutamide, Elsamitolucin, Epotilon B, Epiratuzumab, ER-86526, Erlotinib, ET-18-0CH3, Ethinylcytidine, Ethinylestradiol, E Xatecan, Exatecan Mesylate, Exemestane, Exislind, Fenretinide, Figitumumab, Furoxuridine, Folic Acid, Forfox, Forfox 4, Forfiri, Formestan, Fotemustine, Galarubicin, Gallium Maltolate, Gefitinib, Gemtuzumab, Gimatecan, Gluphosphamide, GCS-100, GDC-0623, GDC-0941 (Pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT Epidemic, GMK, GPX-100, gp100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, Herceptin, hexamethylmelamine, histamine, homohalingotonin, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibul Tinib, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (sixtumumab), Imunol, Indislam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, ilofluben, isohomohalichondrin-B, isoflavones,Isotretinoin, Ixabepyrone, JRX-2, JSF-154, J-107088, Conjugated Estrogen, Kaharid F, Ketoconazole, KW-2170, KW-2450, Robaplatin, Leflunomide, Lenograstim, Leuprolid, Leuprorelin, Lexidronam, LGD-1550, Linezolid, Lutetium Texaphylline, Lometrexol, Ro, Soxantrone, LU223651, Rootthecan, LY-S6AKT1, LY-2780301, Maphosphamide, Marimast, Mechloroetamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, Midostaurin, Minodronate, Mitomycin, Mybobrin, MK-2206, MK-0646 (Darotuzumab), MLN518, Motexafingadolinium, MS-209, MS-275, MX6, Neridronate, Nerachi Nib, Nexavar, Neovastat, Nilotinib, Nimeslid, Nitroglycerin, Noratexed, Norelin, N-Acetylcysteine, O6-Benzylguanine, Oblimersen, Omeprazole, Oncophage, OncoVEXGM-CSF, Ormiplatin, Ortataxel, OX44 antibody, OSI-027, OSI-906 (Lincitinib), 4-IBB antibody, Oxatrazole, Estrogen, Panitumumab, Patupilone, Pegfilgrastim, PCK-3145, Pegfilgrastim PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, peritinib, pemetrexed, PenTrix, perifosine, periryl alcohol, pertuzumab, PI3K inhibitor, PI3K / mTOR inhibitor, PG-TXL, PG2, PLX-4032 / RO-5185426 (Vemura) Phenib, PLX-3603 / RO-5212054, PT-100, PWT-33597, PX-866, Picoplatin, Pivaloyloxymethylbutyrate, Pixantrone, Phenoxodiol O, PKI166, Previtrexed, Plicamycin, Polyprenic acid, Porphyromycin, Prednisone, Prednisolone, Quinamed, Quinupristin, R115777, RAF-265, Ramosetron, Lampirase, RDEA-119 / BAY869766, RDEA436, rebeccamycin analog, receptor tyrosine kinase (RTK) inhibitor, Levimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb, lymphabate, risedronate, rituximab, lobatumumab, rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, subbarbicin, SAHA, salglamostim, satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, Semustin, Theocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, Sorafenib, Spiroplatin, Squalamine, Suberanilohydroxamic acid, Stent, T 900607, T 138067, TAK-733, TAS-103, Tasejinarin, Talaporfin, Tarceva, Tariquitar, Tasisulam, Taxotere, Taxaoplexin, Tazarotene, Tegafur, Temozolam, Tesmirifen, Testosterone, Testosterone Propionate, Tesmirifen, Tetraplatin, Tetrodotoxin, Tezacitabine, Thalidomide Ido, Theralux, Teralubicin, Thimalfacin, Thimectacin, Thiazofrine, Tipifarnib, Tirapazamine, Tocladesine, Tomdex, Tremofin, Trabectedin, Trans-MID-107, Trans-retinic acid, Trastuzumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Trisirivine, Trimethrexate, TLK-286TXDThe formula includes one or more therapeutic substances selected from the group consisting of 258, Tykerb / Tyverb, Urocidin, Barrubicin, Batalanib, Vincristine, Vinflunin, Birulizine, WX-UK1, WX-554, Vectibix, Xeloda, Xelox, XL-147, XL-228, XL-281, XL-518 / R-7420 / GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, Zoledronate, Zoskidal, and combinations thereof.

[0064] In some embodiments, at least one other therapeutic agent includes a steroid. Examples of steroids include, but are not limited to, dexamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazole. In some embodiments, at least one other therapeutic agent includes an antiemetic. Examples of antiemetics include 5-HT3 receptor agonists (such as drasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine), dopamine agonists (such as domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, arizaprid, prochlorperazine, and metoclopramide), NK1 receptor antagonists (such as aprepitant and casopitant), and antihistamines. Examples of substances that can be used include, but are not limited to, cyclizine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine, etc.), cannabinoids (cannabis, dronabinol, nabilone, and Sativex, etc.), benzodiazepines (midazolam and lorazepam), anticholinergics (hyostine, etc.), trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol, and ajowan.

[0065] In some embodiments, at least one other therapeutic agent comprises an anticancer agent containing a mitotic inhibitor. In one embodiment, the mitotic inhibitor comprises a taxane. In one embodiment, the mitotic inhibitor comprises a taxane selected from the group consisting of paclitaxel and docetaxel.

[0066] In one embodiment, the pharmaceutical composition comprises compound (1) or a pharmaceutically acceptable salt thereof and at least one anticancer agent, the anticancer agent being, but not limited to, asibicin, acralubicin, acodazole, acronin, adzeresin, aldesleukin, alitretinoin, allopurinol, altretamine, ambamycin, ametantrone, amifostin, aminoglutethimide, amsacrin, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, Benzodepa, bevacizumab, bicalutamide, bisanthren, bisnafid dimesylate, bizeresin, bleomycin, braquinal, bropyrimin, busulfan, kactinomycin, carsterone, capecitabine, chalasemide, carvetimer, carboplatin, carmustine, carbicin, carzeresin, cedefingol, celecoxib, chlorambucil, ciloremycin, cisplatin, cladribine, cristatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, dexormapra Tin, desaguanine, desaguanine mesylate, diaziquan, docetaxel, doxorubicin, droroxifen, dromostanolone, duazomycin, edatrexate, eflomitin, erusamitolucin, enloplatin, empromate, epipropidine, epirubicin, erbrozole, esorubicin, estramustine, etanidazole, etoposide, etopurine, fadrozol, fazarabine, fenretinide, phloxuridine, fludarabine, fluorouracil, flurocitabine, fosquidone, fostoliesin, fulvestrant Gemcitabine, hydroxyurea, idarubicin, ifosfamide, irmofosin, interleukin II (including IL-2, recombinant interleukin II or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan, lanreotide, letrozole, leuprolide, rialozol, lometrexol, lomustine, losoxantrone, masopropyl,Maytansine, mechloretamine hydrochloride, megestrol, melengestrol acetate, melphalan, menogalyl, mercaptopurine, methotrexate, metoprine, metsuredepa, mitindomide, mitocalicin, mitocromine, mitoglyline, mitomarcine, mitomycin, mitospar, mitotane, mitoxantrone, mycophenolic acid, nelarabine, nocodazole, nogaramycin, omrunapatin Latin, Oxlan, Paclitaxel, Pegaspargaze, Periomycin, Pentamustine, Peplomycin, Perphosphamide, Pipobroman, Piposulfan, Piroxantrone Hydrochloride, Plicamycin, Promethane, Porfimer, Porphyromycin, Prednimustine, Procarbazine, Puromycin, Pyrazofrine, Ribopurine, Logretimide, Safingol, Semustine, Simtrazene, This product contains one or more of the following: sparfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, streptonigrin, streptozocin, throphenur, talyzomycin, tamoxifen, tecogalan, tegafur, tetoxantrone, temoporfin, teniposide, teroxylone, testactone, thiamiprine, thioguanine, thiotepa, thiazophrine, tirapazamine, topotecan, toremifene, trestron, trisirivine, trimethrexate, triptorelin, tubrozole, uracil mustard, uredepa, bapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine, vinepidine, vingricinate, vinoleulosine, vinorelbine, vinrosidine, vinzolidine, volozol, zeniplatin, dinostatin, zoledronate, zolubicin, and combinations thereof. ,

[0067] Examples of appropriate anticancer drugs include, but are not limited to, those listed in Goodman and Gilman's Pharmacological Basis of Therapeutic Substances, 12th edition, edited by Laurence Brunton, Bruce Chabner, and Bjorn Knollman, McGraw Hill Professional, 2010.

[0068] In some exemplary embodiments, the pharmaceutical composition comprises compound (1) and a salt (e.g., monosalt or disalt) of at least one other therapeutic agent, the at least one other therapeutic agent comprising an anti-angiogenic agent. In one such embodiment, the anti-angiogenic agent is bevacizumab. In one embodiment, the anti-angiogenic agent is aflibercept, axitinib, angiostatin, endostatin, 16kDa prolactin fragment, laminin peptide, fibronectin peptide, or tissue metalloproteinase inhibitor (TIMP). The following are selected from the group consisting of 1, 2, 3, 4), plasminogen activator inhibitors (PAI-1, PAI-2), tumor necrosis factor α (high dose, in vitro), TGF-β1, interferon (IFN-α, -β, -γ), ELR-CXC chemokines: IL-12; SDF-1; MIG; platelet factor 4 (PF-4); IP-10, thrombospondin (TSP), SPARC, 2-methoxyestradiol, proliferin-related proteins, suramin, sorafenib, regorafenib, thalidomide, cortisone, linomide, fumagiline (AGM-1470; TNP-470), tamoxifen, retinoids, CM101, dexamethasone, leukemia suppressor (LIF), hedgehog inhibitors, and combinations thereof.

[0069] The combination of agents according to the present invention may contain the first and second therapeutic substances in any desired proportion, provided that a synergistic or synergistic effect still occurs. The synergistic combination of agents according to the present invention preferably contains the first and second therapeutic substances in a ratio of about 1:9 to about 9:1. In one embodiment, the synergistic combination of agents contains the first and second therapeutic substances in a ratio of about 1:8 to about 8:1. In one embodiment, the synergistic combination of agents contains the first and second therapeutic substances in a ratio of about 1:7 to about 7:1. In one embodiment, the synergistic combination of agents contains the first and second therapeutic substances in a ratio of about 1:6 to about 6:1. In one embodiment, the synergistic combination of agents contains the first and second therapeutic substances in a ratio of about 1:5 to about 5:1. In one embodiment, the synergistic combination of agents contains the first and second therapeutic substances in a ratio of about 1:4 to about 4:1. In one embodiment, the synergistic combination of agents contains the first and second therapeutic substances in a ratio of about 1:3 to about 3:1. In one embodiment, the synergistic drug combination contains the first and second therapeutic substances in a ratio of approximately 1:2 to approximately 2:1.

[0070] In some preferred embodiments, the second therapeutic substance is allopurinol, arsenic trioxide, azacitidine, bortezomib, bevacizumab, capecitabine, carboplatin, celecoxib, chlorambucil, clofarabine, cytarabine, dacarbazine, daunorubicin HCl, docetaxel, doxorubicin HCl, phloxuridine, gemcitabine HCl, hydroxyurea, ifosfamide, imatinib mesylate, i The following are selected from the group consisting of xabepyrone, lenalidomide, megestrol acetate, methotrexate, mitotane, mitoxantrone HCl, oxaliplatin, paclitaxel, pralatrexate, romidepsin, sorafenib, streptozocin, tamoxifen citrate, topotecan HCl, tretinoin, vandetanib, bismodegib, vorinostat, and combinations thereof.

[0071] In some preferred embodiments, the second therapeutic agent comprises a small molecule multikinase inhibitor. In one embodiment, the small molecule multikinase inhibitor comprises sorafenib or regorafenib. In some preferred embodiments, the second therapeutic agent comprises a Hedgehog pathway inhibitor. In one preferred embodiment, the Hedgehog pathway inhibitor comprises bismodegib.

[0072] In some preferred embodiments, the second therapeutic substance includes members of the drug classes summarized in Tables 1A and 1B below.

[0073] [Table 1A]

[0074] [Table 1B]

[0075] In some embodiments, the second therapeutic substance comprises a drug that targets a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor. In one embodiment, the second therapeutic substance comprises recombinant TRAIL or an agonist antibody that activates one or more TRAIL receptors. In one embodiment, the second therapeutic substance comprises one or more antibodies or recombinant TRAIL that activate signaling via DR4 and / or DR5. In one embodiment, the second therapeutic substance comprises one or more of mapatumumab, lexatumumab, Apomab, AMG-655, LBY-135, and rhAPo2L / TRAIL. In one embodiment, the second therapeutic substance comprises an active agent selected from the group consisting of camptothecin, 5-FU, capecitabine, cisplatin, doxorubicin, irinotecan, paclitaxel, cisplatin, bortezomib, BH3I-2, rituximab, radiation, triterpenoid, sorafenib, gemcitabine, HDAC inhibitor, carboplatin, T-101 (gossypol derivative), ABT-263, ABT-737, and GX-15-070 (obatoclax), vorinostat, cetuximab, panitumumab, bevacizumab, ganitumab, interferon gamma, sorafenib, XIAP antagonist, Bcl-2 antagonist, and Smac mimetic.

[0076] II. Dosage In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof in a dose ranging from about 100 mg to about 2000 mg, the weight of which, in a particular embodiment, may be based on compound (1) in its free base form. In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof in a dose ranging from about 40 mg to about 2000 mg, the weight of which, in a particular embodiment, may be based on compound (1) in its free base form. In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof in a dose ranging from about 50 mg to about 2000 mg, the weight of which, in a particular embodiment, may be based on compound (1) in its free base form. In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof in a dose ranging from about 60 mg to about 2000 mg, the weight of which, in a particular embodiment, may be based on compound (1) in its free base form. In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dose level selected from the group consisting of approximately 50 mg to approximately 200 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 600 mg, approximately 50 mg to approximately 700 mg, approximately 50 mg to approximately 800 mg, approximately 50 mg to approximately 900 mg, approximately 50 mg to approximately 1000 mg, approximately 50 mg to approximately 1100 mg, approximately 50 mg to approximately 1200 mg, approximately 50 mg to approximately 1300 mg, approximately 50 mg to approximately 1400 mg, approximately 50 mg to approximately 1500 mg, approximately 50 mg to approximately 1600 mg, approximately 50 mg to approximately 1700 mg, approximately 50 mg to approximately 1800 mg, and approximately 50 mg to approximately 1900 mg, 40 mg to 2000 mg.In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dose level selected from the group consisting of approximately 40 mg to approximately 200 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 600 mg, approximately 40 mg to approximately 700 mg, approximately 40 mg to approximately 800 mg, approximately 40 mg to approximately 900 mg, approximately 40 mg to approximately 1000 mg, approximately 40 mg to approximately 1100 mg, approximately 40 mg to approximately 1200 mg, approximately 40 mg to approximately 1300 mg, approximately 40 mg to approximately 1400 mg, approximately 40 mg to approximately 1500 mg, approximately 40 mg to approximately 1600 mg, approximately 40 mg to approximately 1700 mg, approximately 40 mg to approximately 1800 mg, approximately 40 mg to approximately 1900 mg, and 40 mg to approximately 2000 mg. In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dose level selected from the group consisting of approximately 60 mg to approximately 200 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 600 mg, approximately 60 mg to approximately 700 mg, approximately 60 mg to approximately 800 mg, approximately 60 mg to approximately 900 mg, approximately 60 mg to approximately 1000 mg, approximately 60 mg to approximately 1100 mg, approximately 60 mg to approximately 1200 mg, approximately 60 mg to approximately 1300 mg, approximately 60 mg to approximately 1400 mg, approximately 60 mg to approximately 1500 mg, approximately 60 mg to approximately 1600 mg, approximately 60 mg to approximately 1700 mg, approximately 60 mg to approximately 1800 mg, and approximately 60 mg to approximately 1900 mg, and 60 mg to approximately 2000 mg. In one embodiment, the pharmaceutical composition according to the present invention is approximately 100 mg to approximately 200 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 600 mg, approximately 100 mg to approximately 700 mg, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 900 mg, approximately 100 mg to approximately 1000 mg, approximately 100 mg to approximately 1100 mg, approximately 100 mg to approximately 1200 mg The compound (1) or a pharmaceutically acceptable salt thereof is contained in dose levels selected from the group consisting of mg, approximately 100 mg to approximately 1300 mg, approximately 100 mg to approximately 1400 mg, approximately 100 mg to approximately 1500 mg, approximately 100 mg to approximately 1600 mg, approximately 100 mg to approximately 1700 mg, approximately 100 mg to approximately 1800 mg, and approximately 100 mg to approximately 1900 mg, 50 mg to 2000 mg, and 40 mg to 200 mg.In one embodiment, the pharmaceutical composition according to the present invention is available in doses of approximately 200 mg to approximately 300 mg, approximately 200 mg to approximately 400 mg, approximately 200 mg to approximately 500 mg, approximately 200 mg to approximately 600 mg, approximately 200 mg to approximately 700 mg, approximately 200 mg to approximately 800 mg, approximately 200 mg to approximately 900 mg, approximately 200 mg to approximately 1000 mg, and approximately 200 mg to approximately 1100 mg based on the compound (1) in its free base form. The compound (1) or a pharmaceutically acceptable salt thereof is contained at a dose level selected from the group consisting of mg, approximately 200 mg to approximately 1200 mg, approximately 200 mg to approximately 1300 mg, approximately 200 mg to approximately 1400 mg, approximately 200 mg to approximately 1500 mg, approximately 200 mg to approximately 1600 mg, approximately 200 mg to approximately 1700 mg, approximately 200 mg to approximately 1800 mg, and approximately 200 mg to approximately 1900 mg. In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dose level selected from the group consisting of about 400 mg to about 500 mg, about 400 mg to about 600 mg, about 400 mg to about 700 mg, about 400 mg to about 800 mg, about 400 mg to about 900 mg, about 400 mg to about 1000 mg, about 400 mg to about 1100 mg, about 400 mg to about 1200 mg, about 400 mg to about 1300 mg, about 400 mg to about 1400 mg, about 400 mg to about 1500 mg, about 400 mg to about 1600 mg, about 400 mg to about 1700 mg, about 400 mg to about 1800 mg, and about 400 mg to about 1900 mg, based on compound (1) in its free base form. In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dose level selected from the group consisting of about 50 mg to about 60 mg, about 50 mg to about 70 mg, about 50 mg to about 80 mg, about 50 mg to about 90 mg, about 50 to about 100 mg, about 60 mg to about 70 mg, about 60 mg to about 80 mg, about 60 mg to about 90 mg, about 60 mg to about 100 mg, about 70 mg to about 80 mg, about 70 mg to about 90 mg, about 70 to about 100 mg, about 80 mg to about 90 mg, about 80 mg to about 100 mg, and about 90 mg to about 100 mg.

[0077] In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof in doses ranging from about 1 mg / kg to about 40 mg / kg. In one embodiment, the pharmaceutical composition according to the present invention comprises about 1 mg / kg to about 40 mg / kg, about 2 mg / kg to about 40 mg / kg, about 3 mg / kg to about 40 mg / kg, about 4 mg / kg to about 40 mg / kg, about 5 mg / kg to about 40 mg / kg, about 6 mg / kg to about 40 mg / kg, about 7 mg / kg to about 40 mg / kg, about 8 mg / kg to about 40 mg / kg, about 9 mg / kg to about 40 mg / kg, about 10 mg / kg to about 40 mg / kg kg, about 11 mg / kg to about 40 mg / kg, about 12 mg / kg to about 40 mg / kg, about 13 mg / kg to about 40 mg / kg, about 14 mg / kg to about 40 mg / kg, about 15 mg / kg to about 40 mg / kg, about 16mg / kg~about 40mg / kg, about 17mg / kg~about 40mg / kg, about 18mg / kg~about 40mg / kg, about 19mg / kg~about 40mg / kg, about 20mg / kg~about 40mg / kg, about 21mg / kg kg~about 40mg / kg, about 22mg / kg~about 40mg / kg, about 23mg / kg~about 40mg / kg, about 24mg / kg~about 40mg / kg, about 25mg / kg~about 40mg / kg, about 26mg / kg~about 40mg / kg, about 27mg / kg to about 40mg / kg, about 28mg / kg to about 40mg / kg, about 29mg / kg to about 40mg / kg, about 30mg / kg to about 40mg / kg, about 31mg / kg to about 40mg / kg The compound (1) or a pharmaceutically acceptable salt thereof is contained at a dose level selected from the group consisting of approximately 32 mg / kg to approximately 40 mg / kg, approximately 33 mg / kg to approximately 40 mg / kg, approximately 34 mg / kg to approximately 40 mg / kg, approximately 35 mg / kg to approximately 40 mg / kg, approximately 36 mg / kg to approximately 40 mg / kg, approximately 37 mg / kg to approximately 40 mg / kg, approximately 38 mg / kg to approximately 40 mg / kg, and approximately 39 mg / kg to approximately 40 mg / kg.

[0078] In one embodiment, the pharmaceutical composition according to the present invention is approximately 1 mg / kg to approximately 30 mg / kg, approximately 2 mg / kg to approximately 30 mg / kg, approximately 3 mg / kg to approximately 30 mg / kg, approximately 4 mg / kg to approximately 30 mg / kg, approximately 5 mg / kg to approximately 30 mg / kg, approximately 6 mg / kg to approximately 30 mg / kg, approximately 7 mg / kg to approximately 30 mg / kg, approximately 8 mg / kg to approximately 30 mg / kg, approximately 9 mg / kg to approximately 30 mg / kg, approximately 10 mg / kg to approximately 30 mg / kg, approximately 11 mg / kg to approximately 30 mg / kg, approximately 12 mg / kg to approximately 30 mg / kg, approximately 13 mg / kg to approximately 30 mg / kg, approximately 14 mg / kg to approximately 30 mg / kg, approximately 15 mg / kg to approximately 30 mg / kg, approximately 16 mg / kg The compound (1) or a pharmaceutically acceptable salt thereof is contained at a dose level selected from the group consisting of approximately 30 mg / kg, approximately 17 mg / kg to approximately 30 mg / kg, approximately 18 mg / kg to approximately 30 mg / kg, approximately 19 mg / kg to approximately 30 mg / kg, approximately 20 mg / kg to approximately 30 mg / kg, approximately 21 mg / kg to approximately 30 mg / kg, approximately 22 mg / kg to approximately 30 mg / kg, approximately 23 mg / kg to approximately 30 mg / kg, approximately 24 mg / kg to approximately 30 mg / kg, approximately 25 mg / kg to approximately 30 mg / kg, approximately 26 mg / kg to approximately 30 mg / kg, approximately 27 mg / kg to approximately 30 mg / kg, approximately 28 mg / kg to approximately 30 mg / kg, and approximately 29 mg / kg to approximately 30 mg / kg.

[0079] In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dosage level selected from the group consisting of about 1 mg / kg to about 20 mg / kg, about 2 mg / kg to about 20 mg / kg, about 3 mg / kg to about 20 mg / kg, about 4 mg / kg to about 20 mg / kg, about 5 mg / kg to about 20 mg / kg, about 6 mg / kg to about 20 mg / kg, about 7 mg / kg to about 20 mg / kg, about 8 mg / kg to about 20 mg / kg, about 9 mg / kg to about 20 mg / kg, about 10 mg / kg to about 20 mg / kg, about 11 mg / kg to about 20 mg / kg, about 12 mg / kg to about 20 mg / kg, about 13 mg / kg to about 20 mg / kg, about 14 mg / kg to about 20 mg / kg, about 15 mg / kg to about 20 mg / kg, about 16 mg / kg to about 20 mg / kg, about 17 mg / kg to about 20 mg / kg, about 18 mg / kg to about 20 mg / kg, and about 19 mg / kg to about 20 mg / kg.

[0080] In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dosage level selected from the group consisting of about 1 mg / kg to about 10 mg / kg, about 2 mg / kg to about 10 mg / kg, about 3 mg / kg to about 10 mg / kg, about 4 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 6 mg / kg to about 10 mg / kg, about 7 mg / kg to about 10 mg / kg, about 8 mg / kg to about 10 mg / kg, and about 9 mg / kg to about 10 mg / kg.

[0081] In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dosage level in the range of about 37.5 mg / m 2 ~ about 1500 mg / m 2 In one embodiment, the pharmaceutical composition according to the present invention comprises compound (1) or a pharmaceutically acceptable salt thereof at a dosage level in the range of about 40 mg / m 2 ~ about 1500 mg / m 2 about 45 mg / m 2 ~ about 1500 mg / m 2 about 50 mg / m 2 ~ about 1500 mg / m 2 about 55 mg / m 2 ~ about 1500 mg / m 2 about 60 mg / m2 ~approximately 1500 mg / m 2 Approximately 65mg / m 2 ~approximately 1500 mg / m 2 Approximately 70 mg / m 2 ~approximately 1500 mg / m 2 Approximately 75 mg / m 2 ~approximately 1500 mg / m 2 Approximately 80 mg / m 2 ~approximately 1500 mg / m 2 Approximately 85 mg / m 2 ~approximately 1500 mg / m 2 Approximately 90 mg / m 2 ~approximately 1500 mg / m 2 Approximately 95mg / m 2 ~approximately 1500 mg / m 2 Approximately 100 mg / m 2 ~approximately 1500 mg / m 2 Approximately 105 mg / m 2 ~approximately 1500 mg / m 2 Approximately 110 mg / m 2 ~approximately 1500 mg / m 2 Approximately 115 mg / m 2 ~approximately 1500 mg / m 2 Approximately 120 mg / m 2 ~approximately 1500 mg / m 2 Approximately 125 mg / m 2 ~approximately 1500 mg / m 2 Approximately 130 mg / m 2 ~approximately 1500 mg / m 2 Approximately 135 mg / m 2 ~approximately 1500 mg / m 2 Approximately 140 mg / m 2 ~approximately 1500 mg / m 2 Approximately 145 mg / m 2 ~approximately 1500 mg / m 2 Approximately 150 mg / m 2 ~approximately 1500 mg / m 2 Approximately 155 mg / m 2 ~approximately 1500 mg / m 2 Approximately 160 mg / m 2 ~approximately 1500 mg / m 2 Approximately 165 mg / m 2 ~approximately 1500 mg / m 2 Approximately 170 mg / m 2~approximately 1500 mg / m 2 Approximately 175 mg / m 2 ~approximately 1500 mg / m 2 Approximately 180 mg / m 2 ~approximately 1500 mg / m 2 Approximately 185 mg / m 2 ~approximately 1500 mg / m 2 Approximately 190 mg / m 2 ~approximately 1500 mg / m 2 Approximately 195 mg / m 2 ~approximately 1500 mg / m 2 Approximately 200 mg / m 2 ~approximately 1500 mg / m 2 Approximately 205 mg / m 2 ~approximately 1500 mg / m 2 Approximately 210 mg / m 2 ~approximately 1500 mg / m 2 Approximately 215 mg / m 2 ~approximately 1500 mg / m 2 Approximately 220 mg / m 2 ~approximately 1500 mg / m 2 Approximately 225 mg / m 2 ~approximately 1500 mg / m 2 Approximately 230 mg / m 2 ~approximately 1500 mg / m 2 Approximately 235 mg / m 2 ~approximately 1500 mg / m 2 Approximately 240 mg / m 2 ~approximately 1500 mg / m 2 Approximately 245 mg / m 2 ~approximately 1500 mg / m 2 Approximately 250 mg / m 2 ~approximately 1500 mg / m 2 Approximately 255 mg / m 2 ~approximately 1500 mg / m 2 Approximately 260 mg / m 2 ~approximately 1500 mg / m 2 Approximately 265 mg / m 2 ~approximately 1500 mg / m 2 Approximately 270 mg / m 2 ~approximately 1500 mg / m 2 Approximately 275 mg / m 2 ~approximately 1500 mg / m 2 Approximately 280 mg / m 2 ~approximately 1500 mg / m2 Approximately 285 mg / m 2 ~approximately 1500 mg / m 2 Approximately 290 mg / m 2 ~approximately 1500 mg / m 2 Approximately 295 mg / m 2 ~approximately 1500 mg / m 2 Approximately 300 mg / m 2 ~approximately 1500 mg / m 2 Approximately 305 mg / m 2 ~approximately 1500 mg / m 2 Approximately 310 mg / m 2 ~approximately 1500 mg / m 2 Approximately 315 mg / m 2 ~approximately 1500 mg / m 2 Approximately 320 mg / m 2 ~approximately 1500 mg / m 2 Approximately 325 mg / m 2 ~approximately 1500 mg / m 2 Approximately 330 mg / m 2 ~approximately 1500 mg / m 2 Approximately 335 mg / m 2 ~approximately 1500 mg / m 2 Approximately 340 mg / m 2 ~approximately 1500 mg / m 2 Approximately 345 mg / m 2 ~approximately 1500 mg / m 2 Approximately 350 mg / m 2 ~approximately 1500 mg / m 2 Approximately 355 mg / m 2 ~approximately 1500 mg / m 2 Approximately 360 mg / m 2 ~approximately 1500 mg / m 2 Approximately 365 mg / m 2 ~approximately 1500 mg / m 2 Approximately 370 mg / m 2 ~approximately 1500 mg / m 2 Approximately 375 mg / m 2 ~approximately 1500 mg / m 2 Approximately 380 mg / m 2 ~approximately 1500 mg / m 2 Approximately 385 mg / m 2 ~approximately 1500 mg / m 2 Approximately 390 mg / m 2 ~approximately 1500 mg / m 2Approximately 395 mg / m 2 ~approximately 1500 mg / m 2 Approximately 400 mg / m 2 ~approximately 1500 mg / m 2 Approximately 405 mg / m 2 ~approximately 1500 mg / m 2 Approximately 410 mg / m 2 ~approximately 1500 mg / m 2 Approximately 415 mg / m 2 ~approximately 1500 mg / m 2 Approximately 420 mg / m 2 ~approximately 1500 mg / m 2 Approximately 425 mg / m 2 ~approximately 1500 mg / m 2 Approximately 430 mg / m 2 ~approximately 1500 mg / m 2 Approximately 435 mg / m 2 ~approximately 1500 mg / m 2 Approximately 440 mg / m 2 ~approximately 1500 mg / m 2 Approximately 445 mg / m 2 ~approximately 1500 mg / m 2 Approximately 450 mg / m 2 ~approximately 1500 mg / m 2 Approximately 455 mg / m 2 ~approximately 1500 mg / m 2 Approximately 460 mg / m 2 ~approximately 1500 mg / m 2 Approximately 465 mg / m 2 ~approximately 1500 mg / m 2 Approximately 470 mg / m 2 ~approximately 1500 mg / m 2 Approximately 475 mg / m 2 ~approximately 1500 mg / m 2 Approximately 480 mg / m 2 ~approximately 1500 mg / m 2 Approximately 485 mg / m 2 ~approximately 1500 mg / m 2 Approximately 490 mg / m 2 ~approximately 1500 mg / m 2 Approximately 495 mg / m 2 ~approximately 1500 mg / m 2 Approximately 500 mg / m 2 ~approximately 1500 mg / m 2 Approximately 505 mg / m2 ~approximately 1500 mg / m 2 Approximately 510 mg / m 2 ~approximately 1500 mg / m 2 Approximately 515 mg / m 2 ~approximately 1500 mg / m 2 Approximately 520 mg / m 2 ~approximately 1500 mg / m 2 Approximately 525 mg / m 2 ~approximately 1500 mg / m 2 Approximately 530 mg / m 2 ~approximately 1500 mg / m 2 Approximately 535 mg / m 2 ~approximately 1500 mg / m 2 Approximately 540 mg / m 2 ~approximately 1500 mg / m 2 Approximately 545 mg / m 2 ~approximately 1500 mg / m 2 Approximately 550 mg / m 2 ~approximately 1500 mg / m 2 Approximately 555 mg / m 2 ~approximately 1500 mg / m 2 Approximately 560 mg / m 2 ~approximately 1500 mg / m 2 Approximately 565 mg / m 2 ~approximately 1500 mg / m 2 Approximately 570 mg / m 2 ~approximately 1500 mg / m 2 Approximately 575 mg / m 2 ~approximately 1500 mg / m 2 Approximately 580 mg / m 2 ~approximately 1500 mg / m 2 Approximately 585 mg / m 2 ~approximately 1500 mg / m 2 Approximately 590 mg / m 2 ~approximately 1500 mg / m 2 Approximately 595 mg / m 2 ~approximately 1500 mg / m 2 Approximately 600 mg / m 2 ~approximately 1500 mg / m 2 Approximately 605 mg / m 2 ~approximately 1500 mg / m 2 Approximately 610 mg / m 2 ~approximately 1500 mg / m 2 Approximately 615 mg / m 2~approximately 1500 mg / m 2 Approximately 620 mg / m 2 ~approximately 1500 mg / m 2 Approximately 625 mg / m 2 ~approximately 1500 mg / m 2 Approximately 630 mg / m 2 ~approximately 1500 mg / m 2 Approximately 635 mg / m 2 ~approximately 1500 mg / m 2 Approximately 640 mg / m 2 ~approximately 1500 mg / m 2 Approximately 645 mg / m 2 ~approximately 1500 mg / m 2 Approximately 650 mg / m 2 ~approximately 1500 mg / m 2 Approximately 655 mg / m 2 ~approximately 1500 mg / m 2 Approximately 660 mg / m 2 ~approximately 1500 mg / m 2 Approximately 665 mg / m 2 ~approximately 1500 mg / m 2 Approximately 670 mg / m 2 ~approximately 1500 mg / m 2 Approximately 675 mg / m 2 ~approximately 1500 mg / m 2 Approximately 680 mg / m 2 ~approximately 1500 mg / m 2 Approximately 685 mg / m 2 ~approximately 1500 mg / m 2 Approximately 690 mg / m 2 ~approximately 1500 mg / m 2 Approximately 695 mg / m 2 ~approximately 1500 mg / m 2 Approximately 700 mg / m 2 ~approximately 1500 mg / m 2 Approximately 705 mg / m 2 ~approximately 1500 mg / m 2 Approximately 710 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 715 mg / m 2 ~approximately 1500 mg / m 2 Approximately 720 mg / m 2 ~approximately 1500 mg / m 2 Approximately 725 mg / m 2 ~approximately 1500 mg / m2 Approximately 730 mg / m 2 ~approximately 1500 mg / m 2 Approximately 735 mg / m 2 ~approximately 1500 mg / m 2 Approximately 740 mg / m 2 ~approximately 1500 mg / m 2 Approximately 745 mg / m 2 ~approximately 1500 mg / m 2 Approximately 750 mg / m 2 ~approximately 1500 mg / m 2 Approximately 755 mg / m 2 ~approximately 1500 mg / m 2 Approximately 760 mg / m 2 ~approximately 1500 mg / m 2 Approximately 765 mg / m 2 ~approximately 1500 mg / m 2 Approximately 770 mg / m 2 ~approximately 1500 mg / m 2 Approximately 775 mg / m 2 ~approximately 1500 mg / m 2 Approximately 780 mg / m 2 ~approximately 1500 mg / m 2 Approximately 785 mg / m 2 ~approximately 1500 mg / m 2 Approximately 790 mg / m 2 ~approximately 1500 mg / m 2 Approximately 795 mg / m 2 ~approximately 1500 mg / m 2 Approximately 800 mg / m 2 ~approximately 1500 mg / m 2 Approximately 805 mg / m 2 ~approximately 1500 mg / m 2 Approximately 810 mg / m 2 ~approximately 1500 mg / m 2 Approximately 815 mg / m 2 ~approximately 1500 mg / m 2 Approximately 820 mg / m 2 ~approximately 1500 mg / m 2 , Approximately 825 mg / m 2 ~approximately 1500 mg / m 2 Approximately 830 mg / m 2 ~approximately 1500 mg / m 2 Approximately 835 mg / m 2 ~approximately 1500 mg / m2 Approximately 840 mg / m 2 ~approximately 1500 mg / m 2 Approximately 845 mg / m 2 ~approximately 1500 mg / m 2 Approximately 850 mg / m 2 ~approximately 1500 mg / m 2 Approximately 855 mg / m 2 ~approximately 1500 mg / m 2 Approximately 860 mg / m 2 ~approximately 1500 mg / m 2 Approximately 865 mg / m 2 ~approximately 1500 mg / m 2 Approximately 870 mg / m 2 ~approximately 1500 mg / m 2 Approximately 875 mg / m 2 ~approximately 1500 mg / m 2 Approximately 880 mg / m 2 ~approximately 1500 mg / m 2 Approximately 885 mg / m 2 ~approximately 1500 mg / m 2 Approximately 890 mg / m 2 ~approximately 1500 mg / m 2 Approximately 895 mg / m 2 ~approximately 1500 mg / m 2 Approximately 900 mg / m 2 ~approximately 1500 mg / m 2 Approximately 905 mg / m 2 ~approximately 1500 mg / m 2 Approximately 910 mg / m 2 ~approximately 1500 mg / m 2 Approximately 915 mg / m 2 ~approximately 1500 mg / m 2 Approximately 920 mg / m 2 ~approximately 1500 mg / m 2 Approximately 925 mg / m 2 ~approximately 1500 mg / m 2 Approximately 930 mg / m 2 ~approximately 1500 mg / m 2 Approximately 935 mg / m 2 ~approximately 1500 mg / m 2 Approximately 940 mg / m 2 ~approximately 1500 mg / m 2 Approximately 945 mg / m 2 ~approximately 1500 mg / m 2Approximately 950 mg / m 2 ~approximately 1500 mg / m 2 Approximately 955 mg / m 2 ~approximately 1500 mg / m 2 Approximately 960 mg / m 2 ~approximately 1500 mg / m 2 Approximately 965 mg / m 2 ~approximately 1500 mg / m 2 Approximately 970 mg / m 2 ~approximately 1500 mg / m 2 Approximately 975 mg / m 2 ~approximately 1500 mg / m 2 Approximately 980 mg / m 2 ~approximately 1500 mg / m 2 Approximately 985 mg / m 2 ~approximately 1500 mg / m 2 Approximately 990 mg / m 2 ~approximately 1500 mg / m 2 Approximately 995 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1000 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1005 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1010 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1015 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1020 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1025 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1030 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1035 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1040 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1045 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1050 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1055 mg / m³ 2 ~approximately 1500 mg / m 2Approximately 1060 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1065 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1070 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1075 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1080 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1085 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1090 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1095 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1100 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1105 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1110 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1115 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1120 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1125 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1130 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1135 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1140 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1145 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1150 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1155 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1160 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1165 mg / m³ 2 ~approximately 1500 mg / m2 Approximately 1170 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1175 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1180 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1185 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1190 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1195 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1200 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1205 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1210 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1215 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1220 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1225 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1230 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1235 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1240 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1245 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1250 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1255 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1260 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1265 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1270 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1275 mg / m³ 2~approximately 1500 mg / m 2 Approximately 1280 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1285 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1290 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1295 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1300 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1305 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1310 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1315 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1320 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1325 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1330 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1335 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1340 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1345 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1350 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1355 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1360 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1365 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1370 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1375 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1380 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1385 mg / m³2 ~approximately 1500 mg / m 2 Approximately 1390 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1395 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1400 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1405 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1410 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1415 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1420 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1425 mg / m 2 ~approximately 1500 mg / m 2 Approximately 1430 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1435 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1440 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1445 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1450 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1455 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1460 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1465 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1470 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1475 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1480 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1485 mg / m³ 2 ~approximately 1500 mg / m 2 Approximately 1490 mg / m³ 2 ~approximately 1500 mg / m 2, and approximately 1495 mg / m² 2 ~about 1500mg / m 2 The compound (1) or a pharmaceutically acceptable salt thereof is included at a dose level selected from the group consisting of the following.

[0082] III. Dosage form A pharmaceutical composition suitable for use using the method of the present invention can be formulated into any dosage form that can be administered to a patient. In one embodiment, the pharmaceutical composition is in the form of an oral or parenteral administration unit. In one embodiment, the pharmaceutical composition is in the form of an oral administration unit. In some embodiments, the oral administration unit is divided into several smaller doses administered to the subject over a predetermined period of time in order to reduce the toxicity of the therapeutic substance being administered. In some embodiments, the oral administration unit is administered by a tablet or capsule containing a controlled-release formulation which may contain multiple particles, granules, pellets, mini-tablets or tablets. In one embodiment, the pharmaceutical composition is in the form of a parenteral administration unit. In one embodiment, the pharmaceutical composition is in the form of a parenteral administration unit, which is selected from the group consisting of intravenous (IV), subcutaneous (SC), intramuscular (M), rectal (PR), and transdermal administration units. In one embodiment, the pharmaceutical composition is a dosage form selected from the group consisting of sterile solutions, suspensions, suppositories, tablets and capsules. In one embodiment, the composition is an oral dosage form selected from the group consisting of tablets, caplets, capsules, lozenges, syrups, liquids, suspensions, and elixirs. In another embodiment, the composition is an oral dosage form selected from the group consisting of tablets, hard-shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids, and semi-solids.

[0083] In some embodiments, suitable forms of pharmaceutical compositions for use in the methods of the present invention include dermatological compositions adapted for topical administration to the skin. In some such embodiments, the dermatological composition includes a cosmetically acceptable or pharmaceutically acceptable medium. In some embodiments, the dermatological composition for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. In some embodiments, conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and skin enhancers, etc., may be required or desired and therefore used. Examples of suitable enhancers include, but are not limited to, ethers such as diethylene glycol monoethyl ether (commercially available as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, poloxamer (231, 182, 184), tween (20, 40, 60, 80), and lecithin (U.S. Patent No. 4,783,450); alcohols such as ethanol, propanol, octanol, and benzyl alcohol; polyethylene glycols and their esters such as polyethylene glycol monolaurate; amides; and other nitrogen compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes; alkanones; and organic acids, particularly citric acid and succinic acid. Azone® and sulfoxides such as DMSO and CiOMSO may be used, but this is not highly preferred.

[0084] In some embodiments, the pharmaceutical composition of the present invention is a dosage form selected from the group consisting of sustained-release, controlled-release, delayed-release, and response-release forms.

[0085] IV.How to use The compositions and methods of the present invention are useful in treating many diseases (conditions), including cancer (e.g., colorectal cancer, brain cancer, and glioblastoma). In one embodiment, the compositions and methods of the present invention are used to treat diseases such as ocular melanoma, fibrous round cell tumor, chondrosarcoma, leukoplakia disease, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal or rectal cancer, appendiceal cancer, astrocytoma, and atypical teratomatous / rhabdoid tumor. In one embodiment, the compositions and methods of the present invention are used to treat diseases such as basal cell carcinoma, basal cell nevus syndrome, Gaurin nevus syndrome, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma, and malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, and spinal cord tumor. In one embodiment, the compositions and methods of the present invention are used to treat diseases such as carcinoid tumors, unknown primary atypical teratoid / rhabdoid tumors of the central nervous system, leukoplasty, germ cell tumors of the central nervous system, lymphomas of the central nervous system, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, and cutaneous T-cell lymphomas (including, but not limited to, Sézary syndrome and mycosis fungoides (MF)). In one embodiment, the compositions and methods of the present invention are used to treat diseases such as germ cell tumors of the central nervous system, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma tumor family, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic cholangiocarcinoma, and ocular cancers. In one embodiment, the compositions and methods of the present invention are used to treat diseases such as gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, and gliomas. In one embodiment, the compositions and methods of the present invention are used to treat cancers selected from the group consisting of hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, histiocytosis, Hodgkin lymphoma, and hypopharyngeal cancer. In one embodiment, the compositions and methods of the present invention are used to treat diseases such as Kaposi's sarcoma and renal (renal cell) carcinoma. In one embodiment, the compositions and methods of the present invention are used to treat diseases such as Langerhans cell histiocytosis, laryngeal cancer, lip and oral cancer, liver cancer, lung cancer, non-Hodgkin lymphoma, and primary central nervous system lymphoma.In one embodiment, the compositions and methods of the present invention are used to treat diseases such as Waldenström macroglobulinemia (lymphoplasic lymphoma), malignant fibrous histiocytoma and osteosarcoma of bone, medulloblastoma, medullary epithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of unknown primary origin, multiple endocrine neoplasia syndrome, oral cancer, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, and myeloproliferative disorders. In one embodiment, the compositions and methods of the present invention are used to treat cancer. In one embodiment, the compositions and methods of the present invention are used to treat diseases such as nasal cavity cancer and paranasal sinus cancer, nasopharyngeal cancer, and neuroblastoma. In one embodiment, the compositions and methods of the present invention are used to treat diseases such as oral cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian germ cell tumors, ovarian epithelial carcinoma, and low-grade ovarian tumors. In one embodiment, the compositions and methods of the present invention are used to treat diseases such as pancreatic cancer, papillomatosis, paranasal sinus cancer and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, intermediate-differentiated pineal parenchymal tumors and pineoblastoma, supratentorial primitive neuroectoderm tumors, pituitary tumors, pleuropneumonocytes, cancers during pregnancy and breast cancer, primary central nervous system lymphoma, and prostate cancer. In one embodiment, the compositions and methods of the present invention are used to treat cancers selected from the group consisting of rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter, airway cancers involving the NUT gene on chromosome 15, retinoblastoma, and rhabdomyosarcoma. In one embodiment, the composition and method of the present invention are used to treat high-grade prostate cancer. In one embodiment, the composition and method of the present invention are used to treat moderate-grade prostate cancer. In one embodiment, the composition and method of the present invention are used to treat low-grade prostate cancer. In one embodiment, the composition and method of the present invention are used to treat castration-resistant prostate cancer.

[0086] In one embodiment, the compositions and methods of the present invention are used to treat a proliferative skin disease. In one embodiment, the compositions and methods of the present invention are used to treat a proliferative skin disease, which is psoriasis. In one embodiment, the compositions and methods of the present invention are used to treat cancers selected from the group consisting of salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, eye cancer, skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell carcinoma of unknown primary origin for the neck, and supratentorial primitive neuroectodermal tumor. In one embodiment, the compositions and methods of the present invention are used to treat cancers selected from the group consisting of T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, and gestational trophoblastic neoplasm. In one embodiment, the compositions and methods of the present invention are used to treat cancers selected from the group consisting of cell tumors of unknown primary site, cancers of unknown primary site, rare childhood cancers, transitional cell carcinomas of the renal pelvis and ureters, urethral cancers, and uterine sarcomas. In one embodiment, the compositions and methods of the present invention are used to treat cancers selected from the group consisting of vaginal cancers and vulvar cancers. In one embodiment, the compositions and methods of the present invention are used to treat cancers selected from the group consisting of Wilms' tumors and female cancers.

[0087] In some embodiments, the compositions and methods of the present invention are used as first-line therapy (sometimes called primary therapy). In some embodiments, the compositions and methods of the present invention are used as second-line therapy. In some embodiments, the compositions and methods of the present invention are used as third-line therapy. In some embodiments, the compositions and methods of the present invention are used as salvage therapy. As used herein, “salvage therapy” means a therapeutic substance that can be used in any treatment plan after the initial treatment plan for the subject has failed or after the subject’s condition has not responded to the initial treatment. In some embodiments, the compositions and methods of the present invention are used as rescue therapy. In one embodiment of rescue therapy, the compositions of the present invention are used as rescue drugs to counteract the effects of the initial treatment. In one embodiment of rescue therapy, the compositions of the present invention are used as rescue drugs administered to a subject who has become resistant to standard or initial treatment. In some embodiments, the compositions and methods of the present invention are used as neoadjuvant therapy. In one embodiment, neoadjuvant therapy involves administering one or more of the therapeutic substances of the present invention to a subject before main or first-line therapy. In one embodiment, neoadjuvant therapy reduces the size or extent of a cancer being treated before the subject receives primary or first-line therapy. In some embodiments, the compositions and methods of the present invention are used as adjuvant therapy. In one embodiment, adjuvant therapy comprises administering one or more therapeutic substances of the present invention to a subject, the one or more therapeutic substances altering the effects of other therapeutic substances already administered to the subject, administered concurrently to the subject, or administered subsequently to the subject.

[0088] In some embodiments, the compositions and methods of the present invention reduce the possibility of drug interactions. In some embodiments, the compositions and methods of the present invention, compound (1) and / or pharmaceutically acceptable salts thereof are removed from the patient's body before they may interact with another pharmaceutically active agent.

[0089] In some embodiments, the compositions and methods of the present invention, compound (1) and / or pharmaceutically acceptable salts thereof exhibit osmotic pressure levels that facilitate combination with other drugs.

[0090] The usefulness of the methods and compositions of the present invention is not limited to any particular animal species. In one embodiment, the subject treated according to the methods and compositions of the present invention may be a mammal or a non-mammal. In one embodiment, the mammalian subject may include, but is not limited to, humans; non-human primates; rodents such as mice, rats, or guinea pigs; domesticated pets such as cats or dogs; and any mammal including, but not limited to, horses, cattle, pigs, sheep, goats, or rabbits. In one embodiment, the non-mammalian subject may include, but is not limited to, birds such as ducks, geese, chickens, or turkeys. In one embodiment, the subject may be of either sex and of any age. The compositions and methods can also be used to prevent cancer. The compositions and methods can also be used to stimulate the immune system.

[0091] The usefulness of the methods and compositions of the present invention is not limited to any particular age of the subject. In one embodiment, a subject treated according to the method of the present invention and using the composition of the present invention may be over 50 years old, over 55 years old, over 60 years old, or over 65 years old. In one embodiment, a subject treated according to the method of the present invention and using the composition of the present invention may be under 50 years old, under 55 years old, under 60 years old, or under 65 years old.

[0092] In one embodiment, the subject receives pre-administration of at least one therapeutic substance. In another embodiment, the subject receives pre-administration of at least two, at least three, or at least four therapeutic substances. In one embodiment, the pre-administered therapeutic substances are ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, cytarabine, cisplatin, rituximab, 5-fluorouracil, oxaliplatin, leucovorin, or lenalidomide.

[0093] In one embodiment, the subject is treated with radiation. In another embodiment, the subject is treated with surgery.

[0094] In some embodiments of methods for treating cancer, the cancer no longer responds to treatment with ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, cytarabine, cisplatin, rituximab, 5-fluorouracil, oxaliplatin, leucovorin, lenalidomide, radiation, surgery, or a combination thereof.

[0095] In some embodiments, the compositions and methods of the present invention have dose-response relationships in cancer cells that differ from those of the same compositions and methods in normal cells. Figure 1 shows, for example, the dose-response relationships showing the effects of a representative compound (1) on proliferation and cell death in normal cells and tumor cells. Figure 1 shows the cell viability after treatment with the representative compound (1) at the indicated concentrations for 72 hours. The tumors tested included human colon cancer cell lines (HCT116), breast tumor cell lines (MDA-MB-231), and human primary glioblastoma cell lines (U87). The normal cells tested included human precipitous fibroblasts (HFF), human fetal lung fibroblasts (MRC-5) cells, and human lung fibroblast cell lines (WI-38). Doxorubicin was used as a positive control at 1 μg / mL in normal fibroblasts. As shown in Figure 1, the cell viability of tested normal cells was at least 75% at concentrations of approximately 1-5 mg / mL of representative compound (1), while the viability of tumor cells was significantly lower (e.g., less than 50%) at the same concentration of representative compound (1). Furthermore, when the concentration of representative compound (1) increased beyond approximately 5 mg / mL, the viability of normal cells remained at approximately 75%, while the viability of tumor cells decreased to less than 25%.

[0096] Figure 2 shows a cell viability assay in human fetal lung fibroblasts (MRC-5) after 72 hours of treatment with representative compound (1) (5 μM) or DMSO, and the indicated recovery period in drug-free complete medium after this treatment. Time points are given as the time after removal of representative compound (1) following 72 hours of treatment. As shown in Figure 2, cell recovery was observed with representative compound (1) but not with DMSO.

[0097] In some embodiments, the compositions and methods of the present invention are useful for treating cancer in a subject. In one embodiment, the compositions and methods of the present invention are useful for treating cancer in a human subject. In one embodiment, the treatment method comprises administering to a subject requiring such treatment (i) a first therapeutic substance comprising a compound comprising compound (1) or a pharmaceutically acceptable salt thereof, in combination with (ii) a second therapeutic substance, wherein the first and second therapeutic substances are administered simultaneously or sequentially. The second therapeutic substance may be any suitable therapeutic substance comprising any of the pharmaceutically active agents disclosed herein. In one embodiment, a pharmaceutically acceptable salt of compound (1) is compound (2):

[0098] [ka]

[0099] Contains a dihydrochloride salt having the structure of [this structure].

[0100] It is understood that compound (2), or any alternative disalt thereof evident from the teachings of this disclosure, may be substituted for compound (1) in any of the compositions or dosage regimens described herein.

[0101] In some embodiments, the treatment method includes administering a pharmaceutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a subject requiring such treatment.

[0102] In some embodiments, the therapeutic method of the present invention comprises administering a synergistic combination of agents simultaneously or sequentially to a subject requiring such treatment, the synergistic combination of agents comprising (i) a first therapeutic substance comprising compound (1) or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic substance. In one embodiment, the therapeutic method comprises administering to a subject requiring such treatment a therapeutically synergistic effective amount of the first therapeutic substance comprising compound (1) or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic substance, simultaneously or sequentially. In one embodiment, the therapeutic method comprises administering to a subject requiring such treatment an effective amount of the first therapeutic substance comprising compound (1) or a pharmaceutically acceptable salt thereof, in combination with an effective amount of the second therapeutic substance, the combination resulting in a synergistic effect in in vivo treatment of cancers sensitive to this combination, and the first and second therapeutic substances are administered simultaneously or sequentially. In one embodiment, the treatment method comprises administering to a subject requiring such treatment an effective amount of a first therapeutic substance comprising compound (1) or a pharmaceutically acceptable salt thereof in combination with an effective amount of a second therapeutic substance, the combination of which produces a synergistic effect in in vivo treatment of minimal residual disease sensitive to the combination, and the first and second therapeutic substances are administered simultaneously or sequentially.

[0103] In some embodiments, the second drug may be given before or prior to compound (1).

[0104] In one embodiment, the therapeutic method of the present invention targets cancer, and the cancer is selected from the group consisting of solid tumors, humoral tumors, lymphomas, leukemias, or myelomas.

[0105] In one embodiment, the therapeutic method of the present invention targets solid tumors, which include cervical cancer, endometrial cancer, extracranial germ cell tumors, extragonadal germ cell tumors, germ cell tumors, gestational choriocarcinoma, ovarian cancer, ovarian germ cell tumors, epithelial ovarian cancer, and low-grade ovarian tumors, penile cancer, prostate cancer, cancer during pregnancy, and breast cancer, high-grade prostate cancer, intermediate-grade prostate cancer, low-grade prostate cancer, castration-resistant prostate cancer, breast cancer, bile duct cancer, extrahepatic bile duct cancer, cancerous gallbladder, hepatocellular (liver) cancer, and kidney (renal cell) cancer. Cellular carcinoma, liver cancer, renal cell carcinoma (kidney), renal pelvis and ureter, basal cell carcinoma, basal cell nevus syndrome, Gauring nevus syndrome, malignant melanoma, Merkel cell carcinoma, papillomatosis, multiple endocrine neoplastic syndrome, pancreatic cancer, parathyroid cancer, ocular melanoma, eye cancer, retinoblastoma, malignant fibrous histiocytoma, Ewing sarcoma tumor family, fibrinogenic round cell tumor, chondrosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, spinal cord tumor, leptomeningeal disease, central nervous system germ cell tumor, chordoma, central nervous system germ cell tumor Blastoma, ependymoblastoma, ependymoma, neuroblastoma, intermediate differentiated pineal parenchymal tumor, pineoblastoma, adrenal cortical carcinoma, bone cancer, osteosarcoma, malignant fibrous histiocytoma and osteosarcoma of bone, osteosarcoma and malignant fibrous histiocytoma of bone, carcinoid tumor, cell tumor of unknown primary origin, bronchial tumor, lung cancer, carcinoma of the pleuropneumonium, airway cancer involving the NUT gene on chromosome 15, astrocytoma, atypical teratomatoid / rhabdoid tumor, atypical teratomatoid / rhabdoid tumor of the central nervous system, craniopharynx The group is selected from the following: tumors, gliomas, brain cancers, medulloblastomas, medullary epitheliomas, supratentorial primitive neuroectodermal tumors, pituitary tumors, gastric cancers, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GISTs), bladder cancers, anal and rectal cancers, appendiceal cancers, esophageal cancers, hypopharyngeal cancers, laryngeal cancers, lip and oral cancers, metastatic squamous cell carcinoma of unknown primary origin, oral cancers, nasal and paranasal sinus cancers, pharyngeal cancers, oral cancers, lip and oral cancers, oropharyngeal cancers, paranasal and nasal sinus cancers, pharyngeal cancers, head and neck cancers, and mesotheliomas.

[0106] In one embodiment, the therapeutic method of the present invention targets lymphoma, and the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Sézary syndrome, mycosis fungoides (MF), histiocytosis, Burkitt lymphoma, and central nervous system lymphoma, non-Hodgkin lymphoma, and primary central nervous system lymphoma, Hodgkin lymphoma, Waldenström macroglobulinemia, mycosis fungoides, primary central nervous system lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma.

[0107] In one embodiment, the therapeutic method of the present invention targets non-Hodgkin lymphoma (NHL), and non-Hodgkin lymphoma is selected from the group consisting of mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, lymphoplasmacytic NHL, Waldenström macroglobulinemia, and cutaneous lymphoma.

[0108] In one embodiment, the therapeutic method of the present invention targets leukemia, and the leukemia is selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloproliferative disorders, hairy cell leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and Langerhans cell histiocytosis.

[0109] In one embodiment, the therapeutic method of the present invention targets acute leukemia, and the acute leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic disorders, or myeloproliferative disorders.

[0110] In one embodiment, the therapeutic method of the present invention targets myeloma, and the myeloma is selected from the group consisting of IgA myeloma, IgG myeloma, IgM myeloma, IgD myeloma, IgE myeloma, light chain myeloma, nonsecretory myeloma, multiple myeloma / plasmacytic neoplasm, multiple myeloma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, and myeloproliferative disorder.

[0111] In one embodiment, the therapeutic method of the present invention targets cancer, which is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal or rectal cancer, appendiceal cancer, astrocytoma, and atypical teratomatoid / rhabdoid tumor.

[0112] In one embodiment, the therapeutic method of the present invention targets cancer, and the cancer is selected from the group consisting of basal cell carcinoma, basal cell nevus syndrome, Gorling nevus syndrome, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, and spinal cord tumor.

[0113] In one embodiment, the therapeutic method of the present invention targets cancer, which is selected from the group consisting of carcinoid tumors, cell tumors of unknown primary origin, atypical teratomas / rhabdoid tumors of the central nervous system, germ cells of the central nervous system, lymphomas of the central nervous system, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, colorectal cancer, colorectal cancer, craniopharyngioma, and cutaneous T-cell lymphomas (including, but not limited to, Sézary syndrome and mycosis fungoides).

[0114] In one embodiment, the therapeutic method of the present invention targets cancer, which is selected from the group consisting of central nervous system germ cell tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma tumor family, fibrous round cell tumor, chondrosarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, and ocular cancers including intraocular melanoma and retinoblastoma.

[0115] In one embodiment, the therapeutic method of the present invention targets cancer, and the cancer is selected from the group consisting of gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GISTs), germ cell tumors, gestational trophoblastic tumors, and gliomas.

[0116] In one embodiment, the therapeutic method of the present invention targets cancer, and the cancer is selected from the group consisting of hairy cell leukemia, head and neck cancer, hepatocellular carcinoma (liver carcinoma), histiocytic proliferative disease, Hodgkin lymphoma, and hypopharyngeal carcinoma.

[0117] In one embodiment, the therapeutic method of the present invention targets cancer, and the cancer is selected from the group consisting of Kaposi's sarcoma and renal (renal cell) carcinoma.

[0118] A method for treating cancer according to claim 1, wherein the cancer is selected from the group consisting of Langerhans cell histiocytosis, laryngeal cancer, lip cancer and oral cancer, liver cancer, lung cancer including non-small cell lung cancer and small cell lung cancer, non-Hodgkin lymphoma, and primary central nervous system lymphoma.

[0119] In one embodiment, the therapeutic method of the present invention targets cancer, and the cancer is selected from the group consisting of Waldenström macroglobulinemia (lymphoplasmocyte lymphoma), malignant fibrous histiocytoma and osteosarcoma of bone, medulloblastoma, medullary epithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of unknown primary origin, multiple endocrine neoplasia syndrome, oral cancer, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, and myeloproliferative disorders.

[0120] In one embodiment, the therapeutic method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, and neuroblastoma.

[0121] In one embodiment, the therapeutic method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of oral cancer, lip and oral cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian germ cell tumor, epithelial ovarian cancer, and low-grade ovarian tumor.

[0122] In one embodiment, the therapeutic method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of pancreatic cancer, papilloma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, intermediate-differentiated pineal parenchymal tumors, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumors, pleuropneumonocytes, cancers during pregnancy and breast cancer, primary central nervous system lymphoma, and prostate cancer.

[0123] In one embodiment, the therapeutic method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of rectal cancer, renal cell (kidney) carcinoma, renal pelvis and ureter, airway cancer involving the NUT gene on chromosome 15, retinoblastoma, and rhabdomyosarcoma.

[0124] In one embodiment, the therapeutic method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell carcinoma of unknown primary origin for the neck, and supratentorial primitive neuroectodermal tumor.

[0125] In one embodiment, the therapeutic method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, and gestational trophoblastic tumor.

[0126] In one embodiment, the therapeutic method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of cell carcinoma of unknown primary site, cancer of unknown primary site, rare childhood cancers, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, and uterine sarcoma.

[0127] In one embodiment, the treatment method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of vaginal cancer and vulvar cancer.

[0128] In one embodiment, the therapeutic method of the present invention is useful for treating cancer, and the cancer is selected from the group consisting of Wilms' tumor and female cancers.

[0129] In some embodiments, cancer treatment includes prevention of tumor growth in a cancer subject. In some embodiments, cancer treatment includes prevention of cancer metastasis formation in a cancer subject. In some embodiments, cancer treatment includes targeted therapy for minimal residual disease in a cancer subject known to have minimal residual disease or a subject at risk of having minimal residual disease.

[0130] This may be observed after surgical treatment of the primary tumor and / or after chemotherapy (e.g., radiotherapy) has been initiated or deemed effective. Disseminated tumor cells may be in a quiescent state and often cannot be attacked by chemotherapy (radiotherapy). Patients treated in this way appear to be cured, a state sometimes described as "minimal residual disease." Nevertheless, quiescent tumor cells can still form metastases if stimulated to proliferate, even after a longer period of quiescence.

[0131] As used herein, “minimal residual disease” means a small number of cancer cells that remain in a subject during treatment or after treatment when the subject is in remission (showing no symptoms or signs of the disease). The methods described herein are preferably applicable to all forms of the diseases listed herein, including adult and pediatric forms of these diseases.

[0132] In one embodiment, the therapeutic method of the present invention is useful for treating autoimmune diseases. Autoimmune diseases include, but are not limited to, alopecia areata, antiphospholipids, autoimmune hepatitis, celiac disease, type 1 diabetes, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, inflammatory muscle disease, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, and vitiligo.

[0133] In one embodiment, the therapeutic method of the present invention is useful for treating autoimmune and inflammatory diseases of the peripheral nervous system, such as amyotrophic lateral sclerosis (Lou Gehrig's disease), based on various factors including metabolic disorders including diabetes, vitamin B12 and folic acid deficiency, chemotherapy drugs used to treat HIV, toxins that cause peripheral nerve damage, cancers that cause peripheral neuropathy and paraneoplastic syndromes, alcoholism, chronic kidney disease, injuries that cause nerve compression and other lesions, infections such as Lyme disease, certain inflammatory diseases such as Guillain-Barré syndrome, connective tissue disease, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, and sarcoidosis, genetic diseases such as celiac disease and Charcot-Marie dental syndrome, ataxia of Friedreich, and / or idiopathic diseases of unknown cause but caused by inflammatory and / or autoimmune mechanisms.

[0134] In one embodiment, the therapeutic method of the present invention is useful for treating autoimmune and inflammatory diseases that present with ocular symptoms. Such ocular symptoms include, but are not limited to, ocular pemphigoid, Mohren's corneal ulcer, various forms of uveitis, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, relapsing polychondritis, Wegener's granuloma, scleroderma, Behçet's disease, Reiter's disease, inflammatory bowel disease (ulcerative colitis and Crohn's disease), as well as ankylosing spondylitis, retinitis pigmentosa, macular degeneration, keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, peripheral corneal ulcers, as well as less common entities such as choroiditis, retinal vasculitis, episcleral nodules, retinal detachment, and / or macular edema.

[0135] In one embodiment, the therapeutic method of the present invention is useful for treating acute allograft rejection in transplant patients. In one embodiment, the therapeutic method of the present invention is useful for treating ischemic stroke. In one embodiment, the therapeutic method of the present invention is useful for treating inflammatory diseases. Inflammatory diseases include, but are not limited to, arthritis, psoriasis, asthma, and colitis.

[0136] In one embodiment, the first therapeutic substance includes a pharmaceutically acceptable mono salt of compound (1). In one embodiment, the first therapeutic substance includes a pharmaceutically acceptable di salt of compound (1). As described herein, some of the inventors' analogues may be tri salts. In one embodiment, the first therapeutic substance includes compound (1) in the form of a pharmaceutically acceptable mono salt or di salt selected from the group consisting of hydrochloride, hydrobromide, bisulfate and bisulfate. In one embodiment, the first therapeutic substance includes a compound (1) in the form of a pharmaceutically acceptable monosalt or disalt selected from p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate and maleate. In one embodiment, the first therapeutic substance includes a compound (1) in the form of a pharmaceutically acceptable monosalt or disalt having a counterion selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc and lithium, and / or a counterion such as methylamino, dimethylamino, diethylamino, triethylamino, and combinations thereof. In one embodiment, the first therapeutic substance includes a compound (1) in the form of a hydrochloride disalt (i.e., dihydrochloride) or a hydrobromic acid disalt.

[0137] In some embodiments of the treatment method, the second therapeutic substance includes an anticancer agent. In some embodiments of the treatment method, the second therapeutic substance is, but is not limited to, asibicin, acralubicin, acodazole, acronin, adzeresin, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, ametantrone, amifostine, aminoglutethimide, amsacrin, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bevacizumab, bicalutamide, bisantren, and visna. Phydodimesylate, bizeresin, bleomycin, bracinal, bropyrimin, busulfan, kactinomycin, carsterone, capecitabine, chalasemide, carvetimer, carboplatin, carmustine, carbicin, carzeresin, cedefingol, celecoxib, chlorambucil, ciloremycin, cisplatin, cladribine, cristatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, di Aziquan, docetaxel, doxorubicin, doroxifen, dromostanolone, duazomycin, edatrexate, eflomitin, erusamitolucin, enloplatin, empromate, epipropidine, epirubicin, erbrozole, esorubicin, estramustine, etanidazole, etoposide, etopurine, fadrozol, fazarabine, fenretinide, phloxuridine, fludarabine, fluorouracil, flurocitabine, fosquidone, fostoriesin, fulvestrant, gemcitabine, hydroxyu Rhea, Idarubicin, Ifosfamide, Irmofosin, Interleukin II (IL-2, Recombinant Interleukin II or rIL2), Interferon Alpha-2a, Interferon Alpha-2b, Interferon Alpha-n1, Interferon Alpha-n3, Interferon Beta-Ia, Interferon Gamma-Ib, Iproplatin, Irinotecan, Lanreotide, Letrozole, Leuprolide, Rialozol, Lometrexol, Lomustine, Loxoxantrone, Masopropyl, Maytansine,Mechloretamine hydrochloride, megestrol, melengestrol acetate, melphalan, menogalyl, mercaptopurine, methotrexate, metoprine, metsuredepa, mitindomide, mitocalicin, mitocromine, mitogillin, mitomarcine, mitomycin, mitospar, mitotane, mitoxantrone, mycophenolic acid, nelarabine, nocodazole, nogaramycin, ormnaplatin, oxlan, paclitaxel, pegaspargaze, periomycin, pentamustine, peplomycin, perphosphamide, pipobromane, piposulfan, piroxantrone hydrochloride, plicamycin, promethan, porfimer, porphyromycin, prednimustine, procarbazine, puromycin, pyrazofulin, ribopurine, logretimide, safingol, semustine, simtraze Selected from: sparfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, streptonigrin, streptozocin, throphenur, talyzomycin, tamoxifen, tecogalan, tegafur, tetoxantrone, temoporfin, teniposide, teroxylone, testactone, thiamiprine, thioguanine, thiotepa, thiazophrine, tirapazamine, topotecan, toremifene, trestron, trisirivine, trimethrexate, triptorelin, tubrozole, uracil mustard, uredepa, bapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine, vinepidine, vinglisinate, vinoleulosine, vinorelbine, vinrosidine, vinzolidine, volozol, zeniplatin, dinostatin, zoledronate, zolubicin, and combinations thereof. ,

[0138] In some embodiments of the treatment method, the second therapeutic substance is, but is not limited to, hormone analogs and antihormone agents, aromatase inhibitors, LHRH agonists and antagonists, growth factor inhibitors, growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors, antimetabolites, antitumor antibiotics, platinum derivatives, alkylating agents, antimitotic agents, tubulin inhibitors, PARP inhibitors, topoisomerase inhibitors, serine / threonine kinase inhibitors, tyrosine kinase inhibitors, protein-protein interaction inhibitors, MEK inhibitors, ERK inhibitors, IGF-1 R inhibitors, ErbB receptor inhibitors, rapamycin analogs, amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alfa, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-aretin, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epotylon B, A 105972, A 204197, abiraterone, aldesleukin, alitretinoin, alovectin-7, altretamine, arbocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apadiquan, apomin, alanose, algravin, alzoxifen, atamestan, atrasentan, auristatin PE, AVLB, AZ 10992, ABX-EGF, AMG-479 (ganitsumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886 / AZD-6244 (selumetinib), ARRY-704 / AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (Primasertib), Avastin, AZD-2014, Azacitidine, Azaepotilone B, Azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, Bevacizumab, BEZ-235, Bilicodal dicitrate, BCX-1777, BKM-120,Bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (Afatinib, Tomtobok), BIBF 1120 (vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, Bleomycin acid, Bleomycin A, Bleomycin B, Brivanib, Briostatin-1, Bortezomib, Brostarisin, Busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, Calcitriol, Canertinib, Camphosphamide, Capecitabine, Carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 Cefixime, Cefratonin, Ceftriaxone, Celecoxib B, cermoleukin, semadin, CH4987655 / RO-4987655, chlorotrianicene, silenditide, cyclosporine, CDA-II, CDC-394, CKD-602, CKI-27, clofarabine, colchicine, combretastatin A4, COT inhibitor, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, Decitabine, Doxorubicin, Deoxyrubicin, Deoxycoformycin, Depsipeptide, Desoxyepotilon B, Dexamethasone, Dexrazoxane, Diethylstilbestrol, Diflomotecan, Zidox, DMDC, Dorastatin 10, Dranidazole, DS-7423, E7010, E-6201, Edatrexate, Edtreotide, Efaproxial, Eflornithine, EGFR inhibitor, EKB-569, EKB-509, Enzastaurin, Enzalutamide, Erusamitrusin, Epotilon B, Epratuzumab, ER-86526, Erlotinib, ET-18-0CH3, Ethinylcytidine, Ethinylestradiol, Exatecan, Exatecan Mesylate, Exemestane, Exislind,Fenretinide, Figitumumab, Furoxuridine, Folic Acid, Forfox, Forfox 4, Forfiri, Formestan, Fotemustine, Galarubicin, Gallium Maltolate, Gefitinib, Gemtuzumab, Gimatecan, Gluphosphamide, GCS-100, GDC-0623, GDC-0941 (Pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT Immunogen, G MK, GPX-100, gp100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, Herceptin, hexamethylmelamine, histamine, homohalingotonin, hyaluronic acid, hydroxyurea, caproic acid Hydroxyprogesterone, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (sixtumumab), Imunol, Indislam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117, INK-128, INSM-18, Ionaf Alnib, Ipilimumab, Iproplatin, Ilofluben, Isohomohalichondrin-B, Isoflavone, Isotretinoin, Ixabepyrone, JRX-2, JSF-154, J-107088, Conjugated Estrogen, Kahalid F, Ketoconazole, KW-2170, KW-2450, Lovaplatin, Leflunomide, Renograstim, Leuprolid, Leuprorelin, Lexidonam, LGD-1550, Linezolid, Lutetium Texaphylline, Lometrexol, Rosoxantrone, LU 223651, Rootthecan, LY-S6AKT1, LY-2780301, Maphosfamide, Marimast, Mechloroetamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573,MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, Midostaurin, Minodronate, Mitomycin, Mybobrin, MK-2206, MK-0646 (Darotuzumab), MLN518, Motexafingadolinium, MS-209, MS-275, MX6, Neridronate, Neratinib, Nexavar, Neovastat, Nilotinib, Nimeslide, Nitroglycerin, Nolatrexed, Norelin, N-Acetylcysteine, 06-Benzylguanine Oblimersen, Omeprazole, Oncophage, OncoVEXGM-CSF, Olmiplatin, Ortataxel, OX44 antibody, OSI-027, OSI-906 (Lincitinib), 4-IBB antibody, Oxatrazole, Estrogen, Panitumumab, Patupilone, Pegfilgrastim, PCK-3145, Pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-P Clitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, peritinib, pemetrexed, pentrix, perifosine, periryl alcohol, pertuzumab, PI3K inhibitor, PDK / mTOR inhibitor, PG-TXL, PG2, PLX-4032 / RO-5185426 (vemurafenib), PLX-3603 / RO-5212054, PT-100, PWT-33597, PX-866, Picoplatin, Pivaloyloxymethylbutyrate, Pixantrone, Phenoxodiol O, PKI166, Previtrexed, Plicamycin, Polyprenic acid, Porphyromycin, Prednisone, Prednisolone, Quinamed, Quinupristin, R115777, RAF-265, Ramosetron, Lampirase, RDEA-119 / BAY 869766, RDEA436, Rebeccamycin analog, Receptor tyrosine kinase (RTK) inhibitor, Levimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, Rhizoxin, Rhu-MAb, Rinfabate, Risedronate,Rituximab, lobatumumab, rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881 A, rubidazon, lubitecan, R-flurbiprofen, RX-0201, S-9788, subbarbicin, SAHA, salglamostim, satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, Semustin, Theocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, Sorafenib, Spiroplatin, Squalamine, Suberanilohydroxamic acid stent, T 900607, T 138067, TAK-733, TAS-103, Tasejinarin, Talaporfin, Tarceva, Tariquitar, Tasisulam, Taxotere, Taxaoplexin, Tazarotene, Tegafur, Temozolam, Tesmirifen, Testosterone, Testosterone Propionate, Tesmirifen, Tetraplatin, Tetrodotoxin, Tezacitabine, Thalidomide Ido, Theralux, Teralubicin, Thimalfacin, Thimectacin, Thiazofrine, Tipifarnib, Tirapazamine, Tocladesine, Tomdex, Tremofin, Trabectedin, Trans-MID-107, Trans-retinic acid, Trastuzumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Trisirivine, Trimethrexate, TLK-286TXD Selected from 258, Tykerb / Tyverb, Urocidin, Barrubicin, Batalanib, Vincristine, Vinflunin, Birulizine, WX-UK1, WX-554, Vectibix, Xeloda, XELOX, XL-147, XL-228, XL-281, XL-518 / R-7420 / GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, Zoledronate, Zoskidal, and combinations thereof.

[0139] In some embodiments of the treatment method, the second therapeutic substance is selected from the group consisting of tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance is selected from the group consisting of LHRH agonists and LHRH antagonists, but is not limited. In some embodiments of the treatment method, the second therapeutic substance includes an LHRH agonist selected from the group consisting of goserelin acetate, leuprolide acetate, triptoreline pamoate, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes an LHRH antagonist, which is selected from the group consisting of degarelix, cetrorelix, abarelix, ozarelix, degarelix, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes a growth factor inhibitor. In some embodiments of the treatment method of the second therapeutic substance, the growth factor inhibitor is selected from the group consisting of, but are not limited to, inhibitors of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER), hepatocyte growth factor (HGF), and combinations thereof.

[0140] In some embodiments of the treatment method, the second therapeutic substance includes a growth factor inhibitor. In some embodiments of the treatment method, the second therapeutic substance includes a human epidermal growth factor (HER) inhibitor. In some embodiments of the treatment method, the second therapeutic substance includes a growth factor inhibitor selected from the group consisting of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER), and hepatocyte growth factor (HGF). In some embodiments of the treatment method, the second therapeutic substance includes a human epidermal growth factor (HER) inhibitor. In some embodiments of the treatment method, the second therapeutic substance includes a human epidermal growth factor (HER) inhibitor selected from the group consisting of HER2, HER3, and HER4. In some embodiments of the treatment method, the second therapeutic substance includes a tyrosine kinase inhibitor. In some embodiments of the treatment method, the second therapeutic agent includes, but is not limited to, a tyrosine kinase inhibitor selected from the group consisting of cetuximab, gefitinib, imatinib, lapatinib, and trastuzumab, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes an aromatase inhibitor. In some embodiments of the treatment method, the second therapeutic agent includes an aromatase inhibitor selected from the group consisting of anastrozole, letrozole, rialozol, borozol, exemestane, atamestane, and combinations thereof.

[0141] In some embodiments of the treatment method, the second therapeutic substance includes an antimetabolite. In some embodiments of the treatment method, the second therapeutic substance includes an antimetabolite, including an antifolic acid agent. In some embodiments of the treatment method, the second therapeutic substance includes an antifolic acid agent selected from the group consisting of methotrexate, larcitrexed, pyrimidine analogs, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes an antimetabolite that is a pyrimidine analog. In some embodiments of the treatment method, the second therapeutic substance includes a pyrimidine analog selected from the group consisting of 5-fluorouracil, capecitabine, gemcitabine, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes an antimetabolite that is a purine analog or an adenosine analog. In some embodiments of the treatment method, the second therapeutic substance includes a purine analog or adenosine analog selected from the group consisting of mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes an antitumor antibiotic. In some embodiments of the treatment method, the antitumor antibiotic is selected from the group consisting of anthracyclines, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin, streptozosin, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes a platinum derivative. In some embodiments of the treatment method, the platinum derivative is selected from the group consisting of cisplatin, oxaliplatin, carboplatin, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes an alkylating agent. In some embodiments of the treatment method, the second therapeutic agent includes an alkylating agent selected from the group consisting of estramustine, mechloretamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosourea, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes nitrosourea. In some embodiments of the treatment method,The second therapeutic agent includes nitrosourea selected from the group consisting of carmustine, lomustine, thiotepa, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes an antimitotic agent. In some embodiments of the treatment method, the second therapeutic agent includes an antimitotic agent selected from the group consisting of vinca alkaloids and taxanes. In some embodiments of the treatment method, the second therapeutic agent includes a taxane selected from the group consisting of paclitaxel, docetaxel, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes vinca alkaloids selected from the group consisting of vinblastine, vindesine, vinorelbine, vincristine, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes a topoisomerase inhibitor. In some embodiments of the treatment method, the second therapeutic agent includes a topoisomerase inhibitor that is epipodophyllotoxin. In some embodiments of the treatment method, the second therapeutic substance includes a topoisomerase inhibitor, which is an epipodophyllotoxin selected from the group consisting of etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes a serine / threonine kinase inhibitor. In some embodiments of the treatment method, the second therapeutic substance includes a serine / threonine kinase inhibitor selected from the group consisting of PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORCl inhibitors, PI3K inhibitors, mTOR / PI3K bi-inhibitors, STK 33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, aurora kinase inhibitors, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance includes a tyrosine kinase inhibitor. In some embodiments of the treatment method, the second therapeutic substance includes a PTK2 / FAK inhibitor. In some embodiments of the treatment method, the second therapeutic substance includes a protein-protein interaction inhibitor. In some embodiments of the treatment method, the second therapeutic substance includes IAP, Mcl-1,The treatment method includes protein-protein interaction inhibitors selected from the group consisting of MDM2 / MDMX and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes rapamycin analogs. In some embodiments of the treatment method, the second therapeutic agent includes rapamycin analogs selected from the group consisting of everolimus, temsirolimus, ridafololimus, sirolimus, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent is selected from the group consisting of amifostine, anagrelide, clodronate, filgrastine, interferon, interferon alfa, leucovorin, rituximab, procarbazine, levamizole, mesna, mitotane, pamidronate, and porfimer, and combinations thereof. In some embodiments of the treatment method, the second therapeutic substance is 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-aretin, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epotilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, alovectin-7, altretamine, arbocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apadiquon, apomin, alanose, algravin, alzoxifen, atamestan, atrasentan, auristatin PE, AVLB, AZ 10992, ABX-EGF, AMG-479 (ganitsumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886 / AZD-6244 (selumetinib), ARRY-704 / AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (Primasertib), Avastin, AZD-2014, Azacitidine, Azaepotilone B, Azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, bilicodal dicitrate, BCX-1777, BKM-120, bleocinBLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (Afatinib, Tomtoboku), BIBF 1120 (vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, Bleomycin acid, Bleomycin A, Bleomycin B, Brivanib, Briostatin-1, Bortezomib, Brostarisin, Busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, Calcitriol, Canertinib, Camphosphamide, Capecitabine, Carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 Cefixime, Cefratonin, Ceftriaxone, Celecoxib B, cermoleukin, semadin, CH4987655 / RO-4987655, chlorotrianicene, silenditide, cyclosporine, CDA-II, CDC-394, CKD-602, CKI-27, clofarabine, colchicine, combretastatin A4, COT inhibitor, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, Decitabine, Doxorubicin, Deoxyrubicin, Deoxycoformycin, Depsipeptide, Desoxyepotilon B, Dexamethasone, Dexrazoxane, Diethylstilbestrol, Diflomotecan, Zidox, DMDC, Dorastatin 10, Doranidazole, DS-7423, E7010, E-6201, Edatrexate, E Dotreotide, Efaproxial, Eflornithine, EGFR inhibitors, EKB-569, EKB-509, Enzastaurin, Enzalutamide, Elsamitrusin, Epotilon B, Epratuzumab, ER-86526, Erlotinib, ET-18-0CH3, Ethinylcytidine, Ethinylestradiol, Exatecan, Exatecan mesylate, Exemestane, Exislind,Fenretinide, Figitumumab, Furoxuridine, Folic Acid, Forfox, Forfox 4, Forfiri, Formestan, Fotemustine, Galarubicin, Gallium Maltolate, Gefitib, Gemtuzumab, Gimatecan, Gluphosphamide, GCS-100, GDC-0623, GDC-0941 (Pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT Immunogen, G MK, GPX-100, gp100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, Herceptin, hexamethylmelamine, histamine, homohalintonin, hyaluronic acid, hydroxyurea, caproate Droxyprogesterone, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (sixtumumab), Imunol, Indislam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafa Lunib, Ipilimumab, Iproplatin, Ilofluben, Isohomohalichondrin-B, Isoflavone, Isotretinoin, Ixabepyrone, JRX-2, JSF-154, J-107088, Conjugated Estrogen, Kahalid F, Ketoconazole, KW-2170, KW-2450, Lovaplatin, Leflunomide, Renograstim, Leuprolid, Leuprorelin, Lexidronam, LGD-1550, Linezolid, Lutetium Texaphylline, Lometrexol, Rosoxantrone, LU 223651, Rootthecan, LY-S6AKT1, LY-2780301, Maphosfamide, Marimast, Mechloroetamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573, MEN-10755,MDX-H210, MDX-447, MDX-1379, MGV, Midostaurin, Minodronate, Mitomycin, Mibobrine, MK-2206, MK-0646 (Dalotuzumab), MLN518, Motexafingadolinium, MS-209, MS-275, MX6, Neridronate, Neratinib, Nexavar, Neovastat, Nilotinib, Nimesri, Nitroglycerin, Noratexed, Norelin, N-acetylcysteine, 06-benzylguanine, Oblimersen, Omeprazole, Oncophage, OncoVEXGM-CSF, Ormiplatin, Ortataxel, OX44 antibody, OSI-027, OSI-906 (Lincitinib), 4-IBB antibody, Oxatrazole, Estrogen, Panitumumab, Patupilone, Pegfilgrastim, PCK-3145, Pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, Albumin-stabilized paclitaxel, PEP-00 5, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, Peritinib, Pemetrexed, Pentrix, Perifosine, Periryl Alcohol, Pertuzumab, PI3K Inhibitor, PI3K / mTOR Inhibitor, PG-TXL, PG2, PLX-4032 / RO-5185426 (Vemurafenib), PLX-3603 / RO-5212054, PT-100, PWT-33597, PX-866, Picoplatin, Pivaloyloxymethylbutyrate, Pixantrone, Phenoxodiol O, PKI166, Previtrexed, Plicamycin, Polyprenic acid, Porphyromycin, Prednisone, Prednisolone, Quinamed, Quinupristin, R115777, RAF-265, Ramosetron, Lampirase, RDEA-119 / BAY 869766, RDEA436, Rebeccamycin analog, Receptor tyrosine kinase (RTK) inhibitor, Levimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, Rizoxin, rhu-MAb, Rinfabate, Risedronate, Rituximab, Lobatumumab, Rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881 A, Rubidazon, Lubitecan, R-Flurbiprofen, RX-0201, S-9788, Sabarbicin, SAHA, Salglamostim, Satraplatin, SB408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, Semustin, Theocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, Sorafenib, Spiroplatin, Squalamine, Suberanilohydroxamic acid, Stent, T 900607, T 138067, TAK-733, TAS-103, Tasejinarin, Talaporfin, Tarceva, Tariquitar, Tasisulam, Taxotere, Taxaoplexin, Tazarotene, Tegafur, Temozolam, Tesmirifen, Testosterone, Testosterone Propionate, Tesmirifen, Tetraplatin, Tetrodotoxin, Tezacitabine, Thalidomide Ido, Theralux, Teralubicin, Thimalfacin, Thimectacin, Thiazofrine, Tipifarnib, Tirapazamine, Tocladesine, Tomdex, Tremofin, Trabectedin, Trans-MID-107, Trans-retinic acid, Trastuzumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Trisirivine, Trimethrexate, TLK-286TXD The group consists of 258, Tykerb / Tyverb, Urocidin, Barrubicin, Batalanib, Vincristine, Vinflunin, Birulizine, WX-UK1, WX-554, Vectibix, Xeloda, XELOX, XL-147, XL-228, XL-281, XL-518 / R-7420 / GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, Zoledronate, Zoskidal, and combinations thereof.

[0142] In some embodiments, at least one other therapeutic agent is a steroid. Steroids include, but are not limited to, dexamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazole. In some embodiments, at least one other therapeutic agent is an antiemetic. Antiemetics include 5-HT3 receptor agonists (such as drasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine), dopamine agonists (such as domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, arizaprid, prochlorperazine, and metoclopramide), NK1 receptor antagonists (such as aprepitant and casopitant), and antihistamines (such as cytoplasm). This includes, but is not limited to, lysine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine, etc., cannabinoids (cannabis, dronabinol, nabilone, and Sativex, etc.), benzodiazepines (midazolam and lorazepam, etc.), anticholinergics (hyostine, etc.), trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol, and ajowan.

[0143] The pharmaceutical composition of the present invention may be administered to a subject via any suitable route of administration. In one embodiment, the pharmaceutical composition is administered to the subject orally, parenterally, transdermally, or transmucosally. In one embodiment, the pharmaceutical composition is administered to the subject in parenteral dosage form. In one embodiment, the pharmaceutical composition is administered to the subject as parenteral administration. In one embodiment, the pharmaceutical composition is administered to the subject via a parenteral route of administration selected from the group consisting of intravenous (IV), subcutaneous (SC), and intramuscular (IM). In one embodiment, the pharmaceutical composition is administered to the subject via a route of administration selected from rectal (PR) and transdermally. In one embodiment, the pharmaceutical composition is administered to the subject in dosage form selected from the group consisting of sterile solutions, suspensions, suppositories, tablets, and capsules. In one embodiment, the pharmaceutical composition is administered to the subject in oral dosage form selected from the group consisting of tablets, caplets, capsules, lozenges, syrups, liquids, suspensions, and elixirs. In one embodiment, the pharmaceutical composition is administered to the subject in an oral dosage form selected from the group consisting of tablets, hard-shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids, and semi-solids.

[0144] In some embodiments, the pharmaceutical composition is administered to the subject as a dosage form selected from the group consisting of sustained-release, controlled-release, delayed-release, and response-release forms.

[0145] In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject once a day. In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject by a low-frequency dosing treatment plan (e.g., once a week or less). In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject by a high-frequency dosing treatment plan (e.g., more than once a week). In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject once a week. In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject once every four weeks. In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject twice a week. In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject once every two weeks. In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject once every three weeks. In some embodiments, the pharmaceutical composition according to the present invention is administered to the subject in a repeating cycle of weekly, every two weeks, every three weeks, every four weeks, or a combination thereof.

[0146] In one embodiment, the treatment method comprises administering to a subject requiring such treatment (i) a first therapeutic substance comprising a compound (1) or a pharmaceutically acceptable salt thereof in combination with (ii) a second therapeutic substance, wherein the first and second therapeutic substances are administered simultaneously or sequentially, and further comprising assaying the expression of endoplasmic reticulum (ER) stress response genes in a biological sample. In some embodiments, the ER stress response genes are selected from a group including, but not limited to, C / EBP homologous protein (CHOP), activating transcription factor 3 (ATF3), and both CHOP and ATF3. The biological sample may be a tumor, peripheral blood mononuclear cells, or a skin biopsy. The biological sample may be obtained before, during, or after drug administration. In some embodiments, the treatment method further comprises adjusting the dose of compound (1) to achieve induction of approximately 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, or more than 600% of one or more ER stress genes. In some embodiments, the treatment method further includes adjusting the dose of the compound to achieve induction of approximately 50% to approximately 100%, approximately 100% to approximately 150%, approximately 150% to approximately 200%, approximately 200% to approximately 250%, approximately 250% to approximately 300%, approximately 300% to approximately 350%, approximately 350% to approximately 400%, approximately 400% to approximately 450%, approximately 450% to approximately 500%, approximately 500% to approximately 550%, approximately 550% to approximately 600%, or more than 600% of the ER stress gene. In some embodiments, the therapeutic method further comprises adjusting the dose of compound (1) to achieve induction of approximately 50% to approximately 100%, approximately 100% to approximately 200%, approximately 200% to approximately 300%, approximately 300% to approximately 400%, approximately 400% to approximately 500%, approximately 500% to approximately 600%, or more than 600% of the ER stress gene.

[0147] In one embodiment, the treatment method comprises administering to a subject requiring such treatment (i) a first therapeutic substance comprising a compound (1) or a pharmaceutically acceptable salt thereof in combination with (ii) a second therapeutic substance, wherein the first and second therapeutic substances are administered simultaneously or sequentially, and further comprising assaying the expression of proteasome activity in a biological sample. In some embodiments, the proteasome activity may be chymotrypsin-like, trypsin-like, and / or caspase-like activity. In some embodiments, the biological sample may be a tumor, peripheral blood mononuclear cells, or skin cells. The biological sample may be obtained before, during, or after drug administration. In some embodiments, the therapeutic method further includes adjusting the dose to achieve inhibition of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of proteasome activity. In some embodiments, the therapeutic method further includes adjusting the dose to achieve inhibition of at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of proteasome activity. In some embodiments, the therapeutic method further includes adjusting the dose to achieve inhibition of approximately 20% to approximately 30%, approximately 30% to approximately 40%, approximately 40% to approximately 50%, approximately 50% to approximately 60%, approximately 60% to approximately 70%, approximately 70% to approximately 80%, approximately 80% to approximately 90%, or more than 90% of proteasome activity.

[0148] In one embodiment, the present invention is a therapeutic method comprising administering a combination of a first therapeutic substance and a second therapeutic substance, each containing the following compound (1), to a subject requiring such treatment, (i) Compound (1):

[0149] [ka]

[0150] Or administering a first therapeutic substance containing a pharmaceutically acceptable salt thereof (e.g., di salt or tri salt), (ii) Waiting until a predetermined waiting period has elapsed after the administration of the first therapeutic substance to the subject, and / or until the adverse event has been resolved or has been resolved, (iii) administering a second therapeutic substance to the subject, A method is provided for selecting a predetermined waiting time to achieve a delayed therapeutic effect of a first therapeutic agent without increasing the risk of possible combined toxic effects of the first and second therapeutic agents. In some embodiments of the therapeutic method, the predetermined waiting time is determined based on the clearance rate of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments of the therapeutic method, the predetermined waiting time is determined by quantitative assessment of renal function and renal parameters. In some embodiments of the therapeutic method, the predetermined waiting time is determined by an assay for determining renal function, which is selected from the group consisting of serum levels of compound (1) or a pharmaceutically acceptable salt thereof, the clearance rate of compound (1) or a pharmaceutically acceptable salt thereof, or 24-hour urinary clearance of compound (1) or a pharmaceutically acceptable salt thereof or its metabolites.

[0151] In one embodiment of the treatment method, the predetermined waiting time is substantially equal to the time required for systemic clearance of compound (1) or its pharmaceutically acceptable salt from the subject's body. In one embodiment of the treatment method, the predetermined waiting time is substantially equal to the time required for renal clearance of compound (1) or its pharmaceutically acceptable salt from the subject's body. In one embodiment of the treatment method, the predetermined waiting time is substantially equal to the time required for hepatic clearance of compound (1) or its pharmaceutically acceptable salt from the subject's body. In one embodiment of the treatment method, the predetermined waiting time is substantially equal to the time required for total clearance of compound (1) or its pharmaceutically acceptable salt from the subject's body. In one embodiment of the treatment method, the predetermined waiting time is approximately 4 hours. In other embodiments, the waiting time is 1 day. In some embodiments, the waiting time is until the Cmax of compound (1) has elapsed. In other embodiments, the waiting time is after or during the resolution of most adverse events. In one embodiment of the treatment method, the predetermined waiting time is approximately 2 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 3 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 4 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 5 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 6 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 7 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 1 to 7 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 1 to 6 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 1 to 5 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 1 to 4 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 1 to 3 days. In one embodiment of the treatment method, the predetermined waiting time is approximately 1 to 2 days. In some embodiments, the waiting time is up to 3 weeks. The above are considered the "treatment period".

[0152] If the order of administration is reversed, the timing of the administration of compound (1) may be after the Cmax of the first administered drug has elapsed. In some embodiments, the administration of compound (1) may be after most or substantially all of the first administered drug has been eliminated from the body, or when the toxic effects of the first administered drug have been resolved or are being resolved.

[0153] In some embodiments, the treatment method further includes monitoring the levels of compound(1), its pharmaceutically acceptable salt, or its metabolites in a subject using a pharmacokinetic profile. In some such embodiments, monitoring the levels of compound(1), its pharmaceutically acceptable salt, or its metabolites in a subject using a pharmacokinetic profile includes constructing a pharmacokinetic profile of compound(1), its pharmaceutically acceptable salt, or its metabolites for a subject using the concentrations of compound(1), its pharmaceutically acceptable salt, or its metabolites in at least two samples taken from the subject at a time suitable for constructing a pharmacokinetic profile. In some embodiments of the method, which includes monitoring the levels of compound(1), its pharmaceutically acceptable salt, or its metabolites in a subject using a pharmacokinetic profile, at least two samples are collected from the subject at a point of care or point of use, either on a point-of-care or point-of-use device, or on a matrix suitable for sample storage, or by self-collection, prior to quantification in the laboratory. In some embodiments of the treatment method, each of the point-of-care or point-of-use devices can quantify compound (1), its pharmaceutically acceptable salt, or its metabolites. In some embodiments of the method, which include monitoring the levels of compound (1), its pharmaceutically acceptable salt, or its metabolites in the subject, one or more samples are collected from the subject at the point of care or point of use by a biopsy device for analysis or storage at the point-of-care or point-of-use device before laboratory analysis. In some embodiments of the method, a biopsy is taken 3 to 8 hours after administration of compound (1), its pharmaceutically acceptable salt, or its metabolites to the subject. In some embodiments of the method, a biopsy is taken 3 to 24 hours after administration of compound (1), its pharmaceutically acceptable salt, or its metabolites to the subject. In some embodiments of the method, a biopsy is taken 8 to 24 hours after administration of compound (1), a pharmaceutically acceptable salt thereof, or a metabolite thereof to a subject.In some embodiments of the method, a biopsy is taken two days after administration of compound (1), its pharmaceutically acceptable salt, or its metabolite to the subject. In some embodiments of the method, a biopsy is taken three days after administration of compound (1), its pharmaceutically acceptable salt, or its metabolite to the subject. In some embodiments of the method, a biopsy is taken four days after administration of compound (1), its pharmaceutically acceptable salt, or its metabolite to the subject. In some embodiments of the method, a biopsy is taken one to seven days after administration of compound (1), its pharmaceutically acceptable salt, or its metabolite to the subject.

[0154] In some embodiments of the treatment method, the pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding the administration of compound (1) or a pharmaceutically acceptable salt thereof for the subject being treated. In some embodiments of the treatment method, after administration thereof to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is in the range of approximately 1000 ng / dl to 1500 ng / dl during the treatment period. In some embodiments, Cmax is less than 1500 ng / dl and greater than 85 ng / dl during the treatment period. In some embodiments of the treatment method, after administration thereof to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is in the range of approximately 1000 ng / ml to 1500 ng / ml during the treatment period. In some embodiments, Cmax is less than 1500 ng / ml and greater than 85 ng / ml during the treatment period.

[0155] In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is approximately 1000 ng / dl to 1500 ng / dl, approximately 1010 ng / dl to 1500 ng / dl, approximately 1020 ng / dl to 1500 ng / dl, approximately 1030 ng / dl to 1500 ng / dl, approximately 1040 ng / dl to 1500 ng / dl, approximately 1050 ng / dl to 1500 ng / dl, approximately 1060 ng / dl to 1500 ng / dl, approximately 1070 ng / dl to 1500 ng / dl, and approximately 1080 ng / dl. g / dl~about 1500ng / dl, about 1090ng / dl~about 1500ng / dl, about 1100ng / dl~about 1500ng / dl, about 1110ng / dl~about 1500ng / dl, about 1120ng / dl~about 1500ng / dl, about 1130ng / dl~about 1500ng / dl dl, about 1140ng / dl~about 1500ng / dl, about 1150ng / dl~about 1500ng / dl, about 1160ng / dl~about 1500ng / dl, about 1170ng / dl~about 1500ng / dl, about 1180ng / dl~about 1500ng / dl, about 1190ng / dl~ About 1500ng / dl, about 1200ng / dl~about 1500ng / dl, about 1210ng / dl~about 1500ng / dl, about 1220ng / dl~about 1500ng / dl, about 1230ng / dl~about 1500ng / dl, about 1240ng / dl~about 1500ng / dl, about 1 250ng / dl~about 1500ng / dl, about 1260ng / dl~about 1500ng / dl, about 1270ng / dl~about 1500ng / dl, about 1280ng / dl~about 1500ng / dl, about 1290ng / dl~about 1500ng / dl, about 1300ng / dl~about 1500 ng / dl, about 1310ng / dl to about 1500ng / dl, about 1320ng / dl to about 1500ng / dl, about 1330ng / dl to about 1500ng / dl, about 1340ng / dl to about 1500ng / dl, about 1350ng / dl to about 1500ng / dl, about 1360ng / dl~about 1500ng / dl, about 1370ng / dl~about 1500ng / dl, about 1380ng / dl~about 1500ng / dl, about 1390ng / dl~about 1500ng / dl, about 1400ng / dl~about 1500ng / dl, about 1410ng / dl~about 1500ng / dl,The Cmax ranges are approximately 1420 ng / dl to 1500 ng / dl, 1430 ng / dl to 1500 ng / dl, 1440 ng / dl to 1500 ng / dl, 1450 ng / dl to 1500 ng / dl, 1460 ng / dl to 1500 ng / dl, 1470 ng / dl to 1500 ng / dl, 1480 ng / dl to 1500 ng / dl, or 1490 ng / dl to 1500 ng / dl.

[0156] In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is approximately 1000 ng / ml to 1500 ng / ml, approximately 1010 ng / ml to 1500 ng / ml, approximately 1020 ng / ml to 1500 ng / ml, approximately 1030 ng / ml to 1500 ng / ml, approximately 1040 ng / ml to 1500 ng / ml, approximately 1050 ng / ml to 1500 ng / ml, approximately 1060 ng / ml to 1500 ng / ml, approximately 1070 ng / ml to 1500 ng / ml, and approximately 1080 ng / ml~about 1500ng / ml, about 1090ng / ml~about 1500ng / ml, about 1100ng / ml~about 1500ng / ml, about 1110ng / ml~about 1500ng / ml, about 1120ng / ml~about 1500ng / ml, about 1130ng / ml~about 1500ng / m l, about 1140ng / ml to about 1500ng / ml, about 1150ng / ml to about 1500ng / ml, about 1160ng / ml to about 1500ng / ml, about 1170ng / ml to about 1500ng / ml, about 1180ng / ml to about 1500ng / ml, about 1190ng / ml to about 1500ng / ml, about 1200ng / ml to about 1500ng / ml, about 1210ng / ml to about 1500ng / ml, about 1220ng / ml to about 1500ng / ml, about 1230ng / ml to about 1500ng / ml, about 1240ng / ml to about 1500ng / ml, about 12 50ng / ml~about 1500ng / ml, about 1260ng / ml~about 1500ng / ml, about 1270ng / ml~about 1500ng / ml, about 1280ng / ml~about 1500ng / ml, about 1290ng / ml~about 1500ng / ml, about 1300ng / ml~about 1500n g / ml, about 1310ng / ml to about 1500ng / ml, about 1320ng / ml to about 1500ng / ml, about 1330ng / ml to about 1500ng / ml, about 1340ng / ml to about 1500ng / ml, about 1350ng / ml to about 1500ng / ml, about 1360ng / ml ml~about 1500ng / ml, about 1370ng / ml~about 1500ng / ml, about 1380ng / ml~about 1500ng / ml, about 1390ng / ml~about 1500ng / ml, about 1400ng / ml~about 1500ng / ml, about 1410ng / ml~about 1500ng / ml,The Cmax ranges are approximately 1420 ng / ml to 1500 ng / ml, 1430 ng / ml to 1500 ng / ml, 1440 ng / ml to 1500 ng / ml, 1450 ng / ml to 1500 ng / ml, 1460 ng / ml to 1500 ng / ml, 1470 ng / ml to 1500 ng / ml, 1480 ng / ml to 1500 ng / ml, or 1490 ng / ml to 1500 ng / ml.

[0157] In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is approximately 1000 ng / dl, approximately 1010 ng / dl, approximately 1020 ng / dl, approximately 1030 ng / dl, approximately 1040 ng / dl, approximately 1050 ng / dl, approximately 1060 ng / dl, approximately 1070 ng / dl, and approximately 108 ng / dl. 0ng / dl, approx. 1090ng / dl, approx. 1100ng / dl, approx. 1110ng / dl, approx. 1120ng / dl, approx. 1130ng / dl, approx. 1140ng / dl, approx. 115 0ng / dl, approx. 1160ng / dl, approx. 1170ng / dl, approx. 1180ng / dl, approx. 1190ng / dl, approx. 1200ng / dl, approx. 1210ng / dl, approx. 1220 ng / dl, approx. 1230ng / dl, approx. 1240ng / dl, approx. 1250ng / dl, approx. 1260ng / dl, approx. 1270ng / dl, approx. 1280ng / dl, approx. 1290 ng / dl, approx. 1300ng / dl, approx. 1310ng / dl, approx. 1320ng / dl, approx. 1330ng / dl, approx. 1340ng / dl, approx. 1350ng / dl, approx. 1360n The values ​​are selected from g / dl, approximately 1370 ng / dl, approximately 1380 ng / dl, approximately 1390 ng / dl, approximately 1400 ng / dl, approximately 1410 ng / dl, 1420 ng / dl, approximately 1430 ng / dl, approximately 1440 ng / dl, approximately 1450 ng / dl, approximately 1460 ng / dl, approximately 1470 ng / dl, approximately 1480 ng / dl, and approximately 1490 ng / dl.

[0158] In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is approximately 1000 ng / ml, approximately 1010 ng / ml, approximately 1020 ng / ml, approximately 1030 ng / ml, approximately 1040 ng / ml, approximately 1050 ng / ml, approximately 1060 ng / ml, approximately 1070 ng / ml, approximately 1080 ng / ml, approximately 1090 ng / ml, approximately 1100 ng / ml, approximately 1110 ng / ml, approximately 1120 ng / ml, approximately 1130 ng / ml, approximately 1140 ng / ml, approximately 1150 ng / ml, approximately 1160 ng / ml, approximately 1170 ng / ml, approximately 1180 ng / ml, approximately 1190 ng / ml, approximately 1200 ng / ml, approximately 1210 ng / ml, and approximately 1220 ng / ml. ng / ml, approximately 1230ng / ml, approximately 1240ng / ml, approximately 1250ng / ml, approximately 1260ng / ml, approximately 1270ng / ml, approximately 1280ng / ml, approximately 1290 ng / ml, approximately 1300ng / ml, approximately 1310ng / ml, approximately 1320ng / ml, approximately 1330ng / ml, approximately 1340ng / ml, approximately 1350ng / ml, approximately 1360n The dosage is selected from g / ml, approximately 1370 ng / ml, approximately 1380 ng / ml, approximately 1390 ng / ml, approximately 1400 ng / ml, approximately 1410 ng / ml, 1420 ng / ml, approximately 1430 ng / ml, approximately 1440 ng / ml, approximately 1450 ng / ml, approximately 1460 ng / ml, approximately 1470 ng / ml, approximately 1480 ng / ml, and approximately 1490 ng / ml.

[0159] In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is approximately 85 ng / dl, 95 ng / dl, 105 ng / dl, 115 ng / dl, 125 ng / dl, 135 ng / dl, 145 ng / dl, 155 ng / dl, 165 ng / dl, 175 ng / dl, 185 ng / dl, 195 ng / dl, 205 ng / dl, 215 ng / dl, 225 ng / dl, 235 ng / dl, 245 ng / dl, 255 ng / dl, and 265 ng / dl. / dl, about 275ng / dl, about 285ng / dl, about 295ng / dl, about 305ng / dl, about 315ng / dl, about 325ng / dl, about 335ng / dl, about 345ng / dl, about 355ng / dl, about 365ng / dl, about 375ng / dl, about 385ng / dl, Approximately 395ng / dl, approximately 405ng / dl, approximately 415ng / dl, approximately 425ng / dl, approximately 435ng / dl, approximately 445ng / dl, approximately 455ng / dl, approximately 465ng / dl, approximately 475ng / dl, approximately 485ng / dl, approximately 495ng / dl, approximately 505ng / dl, approximately 515 ng / dl, approximately 525ng / dl, approximately 535ng / dl, approximately 545ng / dl, approximately 555ng / dl, approximately 565ng / dl, approximately 575ng / dl, approximately 585ng / dl, approximately 595ng / dl, approximately 605ng / dl, approximately 615ng / dl, approximately 625ng / dl, approximately 635ng / d l, about 645ng / dl, about 655ng / dl, about 665ng / dl, about 675ng / dl, about 685ng / dl, about 695ng / dl, about 705ng / dl, about 715ng / dl, about 725ng / dl, about 735ng / dl, about 745ng / dl, about 755ng / dl, about 7 65ng / dl, approximately 775ng / dl, approximately 785ng / dl, approximately 795ng / dl, approximately 805ng / dl, approximately 815ng / dl, approximately 825ng / dl, approximately 835ng / dl, approximately 845ng / dl, approximately 855ng / dl, approximately 865ng / dl, approximately 875ng / dl, approximately 885ng / dl, about 895ng / dl, about 905ng / dl, about 915ng / dl, about 925ng / dl, about 935ng / dl, about 945ng / dl, about 955ng / dl, about 965ng / dl, about 975ng / dl, about 985ng / dl, about 995ng / dl, about 1005ng / dl,Approx. 1015ng / dl, approx. 1025ng / dl, approx. 1035ng / dl, approx. 1045ng / dl, approx. 1055 / dl, approx. 1065ng / dl, approx. 1075 ng / dl, approx. 1085ng / dl, approx. 1095ng / dl, approx. 1105ng / dl, approx. 1115ng / dl, approx. 1125ng / dl, approx. 1135ng / dl, approx. 1145ng / dl, approx. 1155ng / dl, approx. 1165ng / dl, approx. 1175ng / dl, approx. 1185ng / dl, approx. 1195ng / dl, Approx. 1205ng / dl, approx. 1215ng / dl, approx. 1225ng / dl, approx. 1235ng / dl, approx. 1245ng / dl, approx. 1255ng / dl, approx. 12 65ng / dl, approx. 1275ng / dl, approx. 1285ng / dl, approx. 1295ng / dl, approx. 1305ng / dl, approx. 1315ng / dl, approx. 1325n g / dl, approx. 1335ng / dl, approx. 1345ng / dl, approx. 1355, approx. 1365ng / dl, approx. 1375ng / dl, approx. 1385ng / dl, approx. 13 The following values ​​are selected: 95 ng / dl, approximately 1405 ng / dl, approximately 1415 ng / dl, approximately 1425 ng / dl, approximately 1435 ng / dl, approximately 1445 ng / dl, approximately 1455 ng / dl, approximately 1465 ng / dl, approximately 1475 ng / dl, approximately 1485 ng / dl, approximately 1495 ng / dl, and approximately 1500 ng / dl.

[0160] In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is approximately 85 ng / ml, 95 ng / ml, 105 ng / ml, 115 ng / ml, 125 ng / ml, 135 ng / ml, 145 ng / ml, 155 ng / ml, 165 ng / ml, 175 ng / ml, 185 ng / ml, 195 ng / ml, 205 ng / ml, 215 ng / ml, 225 ng / ml, 235 ng / ml, 245 ng / ml, 255 ng / ml, and 265 ng / ml. / ml, about 275ng / ml, about 285ng / ml, about 295ng / ml, about 305ng / ml, about 315ng / ml, about 325ng / ml, about 335ng / ml, about 345ng / ml, about 355ng / ml, about 365ng / ml, about 375ng / ml, about 385ng / ml, Approximately 395ng / ml, approximately 405ng / ml, approximately 415ng / ml, approximately 425ng / ml, approximately 435ng / ml, approximately 445ng / ml, approximately 455ng / ml, approximately 465ng / ml, approximately 475ng / ml, approximately 485ng / ml, approximately 495ng / ml, approximately 505ng / ml, approximately 515 ng / ml, approximately 525ng / ml, approximately 535ng / ml, approximately 545ng / ml, approximately 555ng / ml, approximately 565ng / ml, approximately 575ng / ml, approximately 585ng / ml, approximately 595ng / ml, approximately 605ng / ml, approximately 615ng / ml, approximately 625ng / ml, approximately 635ng / m l, about 645ng / ml, about 655ng / ml, about 665ng / ml, about 675ng / ml, about 685ng / ml, about 695ng / ml, about 705ng / ml, about 715ng / ml, about 725ng / ml, about 735ng / ml, about 745ng / ml, about 755ng / ml, about 7 65ng / ml, approximately 775ng / ml, approximately 785ng / ml, approximately 795ng / ml, approximately 805ng / ml, approximately 815ng / ml, approximately 825ng / ml, approximately 835ng / ml, approximately 845ng / ml, approximately 855ng / ml, approximately 865ng / ml, approximately 875ng / ml, approximately 885ng / ml, about 895ng / ml, about 905ng / ml, about 915ng / ml, about 925ng / ml, about 935ng / ml, about 945ng / ml, about 955ng / ml, about 965ng / ml, about 975ng / ml, about 985ng / ml, about 995ng / ml, about 1005ng / ml,Approximately 1015ng / ml, approximately 1025ng / ml, approximately 1035ng / ml, approximately 1045ng / ml, approximately 1055 / ml, approximately 1065ng / ml, approximately 1075ng / ml, approximately 1085ng / ml, approximately 1095ng / ml, approximately 1105ng / ml, approximately 1115ng / ml, approximately 1125ng / ml, approximately 1135ng / ml, about 1145ng / ml, about 1155ng / ml, about 1165ng / ml, about 1175ng / ml, about 1185ng / ml, about 1195ng / ml, about 1205ng / ml, about 1215ng / ml, about 1225ng / ml, about 1235ng / ml, about 1245ng / ml, about 1255ng / ml, about 12 The following concentrations are selected: 65 ng / ml, approximately 1275 ng / ml, approximately 1285 ng / ml, approximately 1295 ng / ml, approximately 1305 ng / ml, approximately 1315 ng / ml, approximately 1325 ng / ml, approximately 1335 ng / ml, approximately 1345 ng / ml, approximately 1355 ng / ml, approximately 1365 ng / ml, approximately 1375 ng / ml, approximately 1385 ng / ml, approximately 1395 ng / ml, approximately 1405 ng / ml, approximately 1415 ng / ml, approximately 1425 ng / ml, approximately 1435 ng / ml, approximately 1445 ng / ml, approximately 1455 ng / ml, approximately 1465 ng / ml, approximately 1475 ng / ml, approximately 1485 ng / ml, approximately 1495 ng / ml, and approximately 1500 ng / ml.

[0161] In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is in the range of approximately 85 ng / dl to 1500 ng / dl. In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is in the range of approximately 85 ng / dl to approximately 1500 ng / dl, approximately 95 ng / dl to approximately 1500 ng / dl, approximately 105 ng / dl to approximately 1500 ng / dl, approximately 115 ng / dl to approximately 1500 ng / dl, approximately 125 ng / dl to approximately 1500 ng / dl, approximately 135 ng / dl to approximately 1500 ng / dl, approximately 145 ng / dl to approximately 1500 ng / dl, approximately 155 ng / dl to approximately 1500 ng / dl. g / dl, about 165ng / dl to about 1500ng / dl, about 175ng / dl to about 1500ng / dl, about 185ng / dl to about 1500ng / dl, about 195ng / dl to about 1500ng / dl, about 205ng / dl to about 1500ng / dl, about 21 5ng / dl~about 1500ng / dl, about 225ng / dl~about 1500ng / dl, about 235ng / dl~about 1500ng / dl, about 245ng / dl~about 1500ng / dl, about 255ng / dl~about 1500ng / dl, about 265ng / dl~about 1500ng / dl, about 275ng / dl to about 1500ng / dl, about 285ng / dl to about 1500ng / dl, about 295ng / dl to about 1500ng / dl, about 305ng / dl to about 1500ng / dl, about 315ng / dl to about 1500ng / dl dl, about 325ng / dl to about 1500ng / dl, about 335ng / dl to about 1500ng / dl, about 345ng / dl to about 1500ng / dl, about 355ng / dl to about 1500ng / dl, about 365ng / dl to about 1500ng / dl, about 375n g / dl~about 1500ng / dl, about 385ng / dl~about 1500ng / dl, about 395ng / dl~about 1500ng / dl, about 405ng / dl~about 1500ng / dl, about 415ng / dl~about 1500ng / dl, about 425ng / dl~about 15 00ng / dl, about 435ng / dl to about 1500ng / dl, about 445ng / dl to about 1500ng / dl, about 455ng / dl to about 1500ng / dl, about 465ng / dl to about 1500ng / dl, about 475ng / dl to about 1500ng / dl,Approximately 485 ng / dl to approximately 1500 ng / dl, approximately 495 ng / dl to approximately 1500 ng / dl, approximately 505 ng / dl to approximately 1500 ng / dl, approximately 515 ng / dl to approximately 1500 ng / dl, approximately 525 ng / dl to approximately 1500 ng / dl, approximately 535 ng / dl to approximately 1500 ng / dl, approximately 545 ng / dl to approximately 1500 ng / dl, approximately 555 ng / dl to approximately 1500 ng / dl, approximately 565 ng / dl to approximately 1500 ng / dl, approximately 575 ng / dl to approximately 1500 ng / dl, approximately 585 ng / dl to approximately 1500 ng / dl, approximately 595 ng / dl to approximately 1500 ng / dl ng / dl, approximately 605ng / dl to approximately 1500ng / dl, approximately 615ng / dl to approximately 1500ng / dl, approximately 625ng / dl to approximately 1500ng / dl, approximately 635ng / dl to approximately 1500ng / dl, approximately 645ng / dl to approximately 1500ng / dl, approximately 655ng / dl to approximately 1500ng / dl, approximately 665ng / dl to approximately 1500ng / dl, approximately 675ng / dl to approximately 1500ng / dl, approximately 685ng / dl to approximately 1500ng / dl, approximately 695ng / dl to approximately 1500ng / dl, approximately 705ng / dl to approximately 1500ng / dl, approximately 715ng / dl Approximately 1500 ng / dl, approximately 725 ng / dl ~ approximately 1500 ng / dl, approximately 735 ng / dl ~ approximately 1500 ng / dl, approximately 745 ng / dl ~ approximately 1500 ng / dl, approximately 755 ng / dl ~ approximately 1500 ng / dl, approximately 765 ng / dl ~ approximately 1500 ng / dl, approximately 785 ng / dl ~ approximately 1500 ng / dl, approximately 795 ng / dl ~ approximately 1500 ng / dl, approximately 805 ng / dl ~ approximately 1500 ng / dl, approximately 815 ng / dl ~ approximately 1500 ng / dl, approximately 825 ng / dl ~ approximately 1500 ng / dl, approximately 835 ng / dl ~ approximately 1500 ng / dl, approximately 845 ng / dl g / dl ~ approx. 1500 ng / dl, approx. 855 ng / dl ~ approx. 1500 ng / dl, approx. 865 ng / dl ~ approx. 1500 ng / dl, approx. 875 ng / dl ~ approx. 1500 ng / dl, approx. 885 ng / dl ~ approx. 1500 ng / dl, approx. 895 ng / dl ~ approx. 1500 ng / dl, approx. 905 ng / dl ~ approx. 1500 ng / dl, approx. 915 ng / dl ~ approx. 1500 ng / dl, approx. 925 ng / dl ~ approx. 1500 ng / dl, approx. 935 ng / dl ~ approx. 1500 ng / dl, approx. 945 ng / dl ~ approx. 1500 ng / dl, approx. 955 ng / dl ~ approx. 1500 ng / dlApproximately 965 ng / dl to approximately 1500 ng / dl, approximately 975 ng / dl to approximately 1500 ng / dl, approximately 985 ng / dl to approximately 1500 ng / dl, approximately 995 ng / dl to approximately 1500 ng / dl, approximately 1005 ng / dl to approximately 1500 ng / dl, approximately 1015 ng / dl to approximately 1500 ng / dl, approximately 1025 ng / dl to approximately 1500 ng / dl, approximately 1035 ng / dl to approximately 1500 ng / dl, approximately 1045 ng / dl to approximately 1500 ng / dl, approximately 1055 ng / dl to approximately 1500 ng / dl, approximately 1065 ng / dl to approximately 1500 ng / dl, approximately 1075 ng / dl dl ~ approx. 1500 ng / dl, approx. 1085 ng / dl ~ approx. 1500 ng / dl, approx. 1095 ng / dl ~ approx. 1500 ng / dl, approx. 1105 ng / dl ~ approx. 1500 ng / dl, approx. 1115 ng / dl ~ approx. 1500 ng / dl, approx. 1125 ng / dl ~ approx. 1500 ng / dl, approx. 1135 ng / dl ~ approx. 1500 ng / dl, approx. 1145 ng / dl ~ approx. 1500 ng / dl, approx. 1155 ng / dl ~ approx. 1500 ng / dl, approx. 1165 ng / dl ~ approx. 1500 ng / dl, approx. 1175 ng / dl ~ approx. 1500 ng / dl, approx. 1185 ng / dl ~ approx. 1 500 ng / dl, approximately 1195 ng / dl to approximately 1500 ng / dl, approximately 1205 ng / dl to approximately 1500 ng / dl, approximately 1215 ng / dl to approximately 1500 ng / dl, approximately 1225 ng / dl to approximately 1500 ng / dl, approximately 1235 ng / dl to approximately 1500 ng / dl, approximately 1245 ng / dl to approximately 1500 ng / dl, approximately 1255 ng / dl to approximately 1500 ng / dl, approximately 1265 ng / dl to approximately 1500 ng / dl, approximately 1275 ng / dl to approximately 1500 ng / dl, approximately 1285 ng / dl to approximately 1500 ng / dl, approximately 1295 ng / dl to approximately 1500 ng / dl g / dl, approximately 1305 ng / dl to approximately 1500 ng / dl, approximately 1315 ng / dl to approximately 1500 ng / dl, approximately 1325 ng / dl to approximately 1500 ng / dl, approximately 1335 ng / dl to approximately 1500 ng / dl, approximately 1345 ng / dl to approximately 1500 ng / dl, approximately 1355 ng / dl to approximately 1500 ng / dl, approximately 1365 ng / dl to approximately 1500 ng / dl, approximately 1375 ng / dl to approximately 1500 ng / dl, approximately 1385 ng / dl to approximately 1500 ng / dl, approximately 1395 ng / dl to approximately 1500 ng / dl, approximately 1405 ng / dl to approximately 1500 ng / dlThe following ranges are selected: approximately 1415 ng / dl to approximately 1500 ng / dl, approximately 1425 ng / dl to approximately 1500 ng / dl, approximately 1435 ng / dl to approximately 1500 ng / dl, approximately 1445 ng / dl to approximately 1500 ng / dl, approximately 1455 ng / dl to approximately 1500 ng / dl, approximately 1465 ng / dl to approximately 1500 ng / dl, approximately 1475 ng / dl to approximately 1500 ng / dl, approximately 1485 ng / dl to approximately 1500 ng / dl, approximately 1495 ng / dl to approximately 1500 ng / dl, and approximately 1500 ng / dl to approximately 1500 ng / dl.

[0162] In some embodiments, after administration to the subject, the maximum concentration ("Cmax") of the first therapeutic substance in the subject's blood (whole blood, plasma, or serum) is in the range of approximately 85 ng / ml to 1500 ng / ml. g / ml, about 165ng / ml to about 1500ng / ml, about 175ng / ml to about 1500ng / ml, about 185ng / ml to about 1500ng / ml, about 195ng / ml to about 1500ng / ml, about 205ng / ml to about 1500ng / ml, about 21 5ng / ml~about 1500ng / ml, about 225ng / ml~about 1500ng / ml, about 235ng / ml~about 1500ng / ml, about 245ng / ml~about 1500ng / ml, about 255ng / ml~about 1500ng / ml, about 265ng / ml~about 1500ng / ml, about 275ng / ml to about 1500ng / ml, about 285ng / ml to about 1500ng / ml, about 295ng / ml to about 1500ng / ml, about 305ng / ml to about 1500ng / ml, about 315ng / ml to about 1500ng / ml ml, about 325ng / ml to about 1500ng / ml, about 335ng / ml to about 1500ng / ml, about 345ng / ml to about 1500ng / ml, about 355ng / ml to about 1500ng / ml, about 365ng / ml to about 1500ng / ml, about 375n g / ml~about 1500ng / ml, about 385ng / ml~about 1500ng / ml, about 395ng / ml~about 1500ng / ml, about 405ng / ml~about 1500ng / ml, about 415ng / ml~about 1500ng / ml, about 425ng / ml~about 15 00ng / ml, about 435ng / ml to about 1500ng / ml, about 445ng / ml to about 1500ng / ml, about 455ng / ml to about 1500ng / ml, about 465ng / ml to about 1500ng / ml, about 475ng / ml to about 1500ng / ml,Approximately 485 ng / ml to approximately 1500 ng / ml, approximately 495 ng / ml to approximately 1500 ng / ml, approximately 505 ng / ml to approximately 1500 ng / ml, approximately 515 ng / ml to approximately 1500 ng / ml, approximately 525 ng / ml to approximately 1500 ng / ml, approximately 535 ng / ml to approximately 1500 ng / ml, approximately 545 ng / ml to approximately 1500 ng / ml, approximately 555 ng / ml to approximately 1500 ng / ml, approximately 565 ng / ml to approximately 1500 ng / ml, approximately 575 ng / ml to approximately 1500 ng / ml, approximately 585 ng / ml to approximately 1500 ng / ml, approximately 595 ng / ml to approximately 1500 ng / ml ng / ml, approximately 605ng / ml to approximately 1500ng / ml, approximately 615ng / ml to approximately 1500ng / ml, approximately 625ng / ml to approximately 1500ng / ml, approximately 635ng / ml to approximately 1500ng / ml, approximately 645ng / ml to approximately 1500ng / ml, approximately 655ng / ml to approximately 1500ng / ml, approximately 665ng / ml to approximately 1500ng / ml, approximately 675ng / ml to approximately 1500ng / ml, approximately 685ng / ml to approximately 1500ng / ml, approximately 695ng / ml to approximately 1500ng / ml, approximately 705ng / ml to approximately 1500ng / ml, approximately 715ng / ml Approximately 1500 ng / ml, approximately 725 ng / ml to approximately 1500 ng / ml, approximately 735 ng / ml to approximately 1500 ng / ml, approximately 745 ng / ml to approximately 1500 ng / ml, approximately 755 ng / ml to approximately 1500 ng / ml, approximately 765 ng / ml to approximately 1500 ng / ml, approximately 785 ng / ml to approximately 1500 ng / ml, approximately 795 ng / ml to approximately 1500 ng / ml, approximately 805 ng / ml to approximately 1500 ng / ml, approximately 815 ng / ml to approximately 1500 ng / ml, approximately 825 ng / ml to approximately 1500 ng / ml, approximately 835 ng / ml to approximately 1500 ng / ml, approximately 845 ng / ml g / ml ~ approx. 1500 ng / ml, approx. 855 ng / ml ~ approx. 1500 ng / ml, approx. 865 ng / ml ~ approx. 1500 ng / ml, approx. 875 ng / ml ~ approx. 1500 ng / ml, approx. 885 ng / ml ~ approx. 1500 ng / ml, approx. 895 ng / ml ~ approx. 1500 ng / ml, approx. 905 ng / ml ~ approx. 1500 ng / ml, approx. 915 ng / ml ~ approx. 1500 ng / ml, approx. 925 ng / ml ~ approx. 1500 ng / ml, approx. 935 ng / ml ~ approx. 1500 ng / ml, approx. 945 ng / ml ~ approx. 1500 ng / ml, approx. 955 ng / ml ~ approx. 1500 ng / mlApproximately 965 ng / ml to approximately 1500 ng / ml, approximately 975 ng / ml to approximately 1500 ng / ml, approximately 985 ng / ml to approximately 1500 ng / ml, approximately 995 ng / ml to approximately 1500 ng / ml, approximately 1005 ng / ml to approximately 1500 ng / ml, approximately 1015 ng / ml to approximately 1500 ng / ml, approximately 1025 ng / ml to approximately 1500 ng / ml, approximately 1035 ng / ml to approximately 1500 ng / ml, approximately 1045 ng / ml to approximately 1500 ng / ml, approximately 1055 ng / ml to approximately 1500 ng / ml, approximately 1065 ng / ml to approximately 1500 ng / ml, approximately 1075 ng / ml Approximately 1500 ng / ml, approximately 1085 ng / ml, approximately 1095 ng / ml, approximately 1105 ng / ml, approximately 1115 ng / ml, approximately 1125 ng / ml, approximately 1135 ng / ml, approximately 1145 ng / ml, approximately 1155 ng / ml, approximately 1165 ng / ml, approximately 1175 ng / ml, approximately 1185 ng / ml, approximately 1500 ng / ml. 500 ng / ml, approximately 1195 ng / ml to approximately 1500 ng / ml, approximately 1205 ng / ml to approximately 1500 ng / ml, approximately 1215 ng / ml to approximately 1500 ng / ml, approximately 1225 ng / ml to approximately 1500 ng / ml, approximately 1235 ng / ml to approximately 1500 ng / ml, approximately 1245 ng / ml to approximately 1500 ng / ml, approximately 1255 ng / ml to approximately 1500 ng / ml, approximately 1265 ng / ml to approximately 1500 ng / ml, approximately 1275 ng / ml to approximately 1500 ng / ml, approximately 1285 ng / ml to approximately 1500 ng / ml, approximately 1295 ng / ml to approximately 1500 ng / ml g / ml, approximately 1305 ng / ml to approximately 1500 ng / ml, approximately 1315 ng / ml to approximately 1500 ng / ml, approximately 1325 ng / ml to approximately 1500 ng / ml, approximately 1335 ng / ml to approximately 1500 ng / ml, approximately 1345 ng / ml to approximately 1500 ng / ml, approximately 1355 ng / ml to approximately 1500 ng / ml, approximately 1365 ng / ml to approximately 1500 ng / ml, approximately 1375 ng / ml to approximately 1500 ng / ml, approximately 1385 ng / ml to approximately 1500 ng / ml, approximately 1395 ng / ml to approximately 1500 ng / ml, approximately 1405 ng / ml to approximately 1500 ng / mlThe following ranges are selected: approximately 1415 ng / ml to approximately 1500 ng / ml, approximately 1425 ng / ml to approximately 1500 ng / ml, approximately 1435 ng / ml to approximately 1500 ng / ml, approximately 1445 ng / ml to approximately 1500 ng / ml, approximately 1455 ng / ml to approximately 1500 ng / ml, approximately 1465 ng / ml to approximately 1500 ng / ml, approximately 1475 ng / ml to approximately 1500 ng / ml, approximately 1485 ng / ml to approximately 1500 ng / ml, approximately 1495 ng / ml to approximately 1500 ng / ml, and approximately 1500 ng / ml to approximately 1500 ng / ml.

[0163] In some embodiments of the method, the total drug exposure over time, measured as the area under the curve ("AUC") of a plot of the drug concentration in the subject's blood (whole blood, plasma, or serum) after drug administration against time after drug administration, is in the range of approximately 150 ng hr / ml to approximately 8000 ng hr / ml. In some embodiments, the AUC is less than 8000 ng hr / ml and greater than or equal to 150 ng hr / ml.

[0164] In some embodiments of the method, total drug exposure over time, measured as the area under the curve ("AUC") of a plot of drug concentration in the subject's blood (whole blood, plasma, or serum) after drug administration against time after drug administration, is approximately 100 ng hr / ml to 8000 ng hr / ml, approximately 150 ng hr / ml to 8000 ng hr / ml, approximately 200 ng hr / ml to 8000 ng hr / ml, approximately 400 ng hr / ml to 8000 ng hr / ml, approximately 600 ng hr / ml to 8000 ng hr / ml, approximately 800 ng hr / ml to 8000 ng hr / ml, approximately 1000 ng hr / ml to 8000 ng hr / ml, approximately 1200 ng hr / ml to 8000 ng hr / ml, and approximately 1400 ng hr / ml to 8000 ng hr / ml, about 1600ng hr / ml~about 8000ng hr / ml, about 1800ng hr / ml~about 8000ng hr / ml, about 2000ng hr / ml~about 8000ng hr / ml, about 2200ng hr / ml~about 8000ng hr / ml, about 2400ng hr / ml~about 8000ng hr / ml, about 2600ng hr / ml~about 8000ng hr / ml, about 2800ng hr / ml~about 8000ng hr / ml, about 3000ng hr / ml~about 8000ng hr / ml, about 3200ng hr / ml~about 8000ng hr / ml, about 3400ng hr / ml~about 8000ng hr / ml, approx. 3600ng hr / ml ~ approx. 8000ng hr / ml, about 3800ng hr / ml to about 8000ng hr / ml, about 4000ng hr / ml to about 8000ng hr / ml, about 4200ng hr / ml to about 8000ng hr / ml, about 4400ng hr / ml to about 8000ng hr / ml, about 4600ng hr / ml to about 8000ng hr / ml, about 4800ng hr / ml~about 8000ng hr / ml, about 5000ng hr / ml~about 8000ng hr / ml, about 5200ng hr / ml~about 8000ng hr / ml, about 5400ng hr / ml~about 8000ng hr / ml, about 5600ng hr / ml~about 8000ng hr / ml, approx. 5800ng hr / ml ~ approx. 8000ng hr / ml, approx. 6000ng hr / ml ~ approx. 8000ng hr / ml, approx. 6200ngThe AUCs are as follows: hr / ml to approximately 8000ng hr / ml, approximately 6400ng hr / ml to approximately 8000ng hr / ml, approximately 6600ng hr / ml to approximately 8000ng hr / ml, approximately 6800ng hr / ml to approximately 8000ng hr / ml, approximately 7000ng hr / ml to approximately 8000ng hr / ml, approximately 7200ng hr / ml to approximately 8000ng hr / ml, approximately 7400ng hr / ml to approximately 8000ng hr / ml, approximately 7600ng hr / ml to approximately 8000ng hr / ml, and approximately 7800ng hr / ml to approximately 8000ng hr / ml.

[0165] In some embodiments of the method, total drug exposure over time, measured as the area under the curve ("AUC") of a plot of drug concentration in the subject's blood (whole blood, plasma, or serum) after drug administration against time, is approximately 100 ng hr / ml to approximately 8000 ng hr / ml, approximately 150 ng hr / ml to approximately 7800 ng hr / ml, approximately 150 ng hr / ml to approximately 7600 ng hr / ml, approximately 150 ng hr / ml to approximately 7400 ng hr / ml, approximately 150 ng hr / ml to approximately 7200 ng hr / ml, approximately 150 ng hr / ml to approximately 7000 ng hr / ml, approximately 150 ng hr / ml to approximately 6800 ng hr / ml, approximately 150 ng hr / ml to approximately 6600 ng hr / ml, approximately 150 ng hr / ml to approximately 6400 ng hr / ml, and approximately 150 ng hr / ml~about 6200ng hr / ml, about 150ng hr / ml~about 6000ng hr / ml, about 150ng hr / ml~about 5800ng hr / ml, about 150ng hr / ml~about 5600ng hr / ml, about 150ng hr / ml~about 5400ng hr / ml, about 150ng hr / ml~about 5200ng hr / ml, about 150ng hr / ml to about 5000ng hr / ml, about 150ng hr / ml to about 4800ng hr / ml, about 150ng hr / ml to about 4600ng hr / ml, about 150ng hr / ml to about 4400ng hr / ml, about 150ng hr / ml to about 4200ng hr / ml, about 150ng hr / ml ~ approx. 4000ng hr / ml, about 150ng hr / ml to about 3800ng hr / ml, about 150ng hr / ml to about 3600ng hr / ml, about 150ng hr / ml to about 3400ng hr / ml, about 150ng hr / ml to about 3200ng hr / ml, about 150ng hr / ml to about 3000ng hr / ml, about 150ng hr / ml ~ approx. 2800ng hr / ml, approx. 150ng hr / ml ~ approx. 2600ng hr / ml, approx. 150ng hr / ml ~ approx. 2400ng hr / ml, approx. 150ng hr / ml ~ approx. 2200ng hr / ml, approx. 150ng hr / ml ~ approx. 2000ng hr / ml, approx. 150ng hr / ml ~ approx. 1800ng hr / ml, approximately 150ng hr / ml ~ approx. 1600ng hr / ml, approx. 150ng hr / ml ~ approx. 1400ngThe AUC is approximately hr / ml, 150ng hr / ml to 1200ng hr / ml, 150ng hr / ml to 1000ng hr / ml, 150ng hr / ml to 800ng hr / ml, 150ng hr / ml to 600ng hr / ml, 150ng hr / ml to 400ng hr / ml, 150ng hr / ml to 200ng hr / ml, or 100ng hr / ml to 200ng hr / ml.

[0166] In some embodiments of the method, total drug exposure over time, measured as the area under the curve ("AUC") of a plot of drug concentration in the subject's blood (whole blood, plasma, or serum) after drug administration against time, is approximately 100 ng hr / ml, 150 ng hr / ml, 200 ng hr / ml, 400 ng hr / ml, 600 ng hr / ml, 800 ng hr / ml, 1000 ng hr / ml, 1200 ng hr / ml, 1400 ng hr / ml, 1600 ng hr / ml, 1800 ng hr / ml, 2000 ng hr / ml, 2200 ng hr / ml, 2400 ng hr / ml, 2600 ng hr / ml, 2800 ng hr / ml, 3000 ng hr / ml, 3200 ng hr / ml, and 3400 ng hr / ml. hr / ml, approximately 3600ng hr / ml, approximately 3800ng hr / ml approximately 4000ng hr / ml, approximately 4200ng hr / ml, approximately 4400ng hr / ml, approximately 4600ng hr / ml, approximately 4800ng hr / ml, approximately 5000ng hr / ml, approximately 5200ng hr / ml, approximately 5400ng hr / ml, approximately 5600ng hr / ml, approximately 5800ng hr / ml, approximately 6000ng hr / ml, approximately 6200ng hr / ml, approximately 6400ng hr / ml, approximately 6600ng hr / ml, approximately 6800ng hr / ml, approximately 7000ng hr / ml, approximately 7200ng hr / ml, approximately 7400ng hr / ml, approx. 7600ng hr / ml, approx. 7800ng The values ​​are hr / ml and selected from approximately 8000 ng hr / ml.

[0167] In another embodiment, the present invention relates to a method of treatment, or a method of using a composition for treating a disease (condition), comprising administering a combination of a first therapeutic substance and a second therapeutic substance to a subject requiring such treatment. (i) Compound (1):

[0168] [ka]

[0169] Or administering the first therapeutic substance containing a pharmaceutically acceptable salt thereof, (ii) Monitoring the levels of compound (1) or its pharmaceutically acceptable salt or metabolite in the subject using a pharmacokinetic profile, (iii) Depending on the level of the first therapeutic agent in the subject, the second therapeutic agent is administered, The present invention provides a method comprising the following steps: In some embodiments of the method, the monitoring step includes constructing a pharmacokinetic profile of compound (1) or its pharmaceutically acceptable salt or its metabolite for a subject using the concentrations of compound (1) or its pharmaceutically acceptable salt or its metabolite in at least two samples taken from the subject at a time suitable for constructing a pharmacokinetic profile. In some embodiments of the method, at least two samples are collected at a point of care or point of use, either on a point-of-care or point-of-use device, or by collection or self-collection on a matrix suitable for sample storage of at least two samples, prior to the quantification of compound (1) or its pharmaceutically acceptable salt or its metabolite in the laboratory. In some embodiments of the method, each of the point-of-care or point-of-use devices can quantify compound (1) or its pharmaceutically acceptable salt or its metabolite. In some embodiments of the method, the pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding the administration of compound (1) or its pharmaceutically acceptable salt for the subject. In some embodiments of the method, the sample comprises at least two types of samples, comprising 2 to 12 types of samples. In some embodiments of the method, the sample comprises at least two types of samples, collected over periods of up to 8 hours, 24 hours, 48 ​​hours, or 72 hours. In some embodiments of the method, the pharmacokinetic parameters comprise at least one parameter selected from the group consisting of AUC, AUCinf, Tmax, Cmax, time above threshold, steady-state concentration, absorption rate, clearance rate, distribution rate, half-life T-1 / 2, or parameters derived from compartment PK analysis, including non-compartmental pharmacokinetic (PK) analysis or physiological model-based compartment PK analysis. In some embodiments of the method, the treatment method further comprises generating a report containing the pharmacokinetic profile of the subject. In some embodiments of the method, the report includes recommendations for medication based on the pharmacokinetic profile of the subject.In some embodiments of the method, dose reduction of compound (1) or a pharmaceutically acceptable salt thereof is indicated to reduce toxicity risk based on one or more pharmacokinetic parameters. In some embodiments of the method, dose reduction of compound (1) or a pharmaceutically acceptable salt thereof is indicated based on the time above a threshold, where the threshold is the drug concentration beyond which toxicity occurs, or one or more of AUC, AUCinf, mean residence time (MRT), an index defining the pharmacokinetic profile, steady-state volume of distribution (Vss), terminal phase volume of distribution (Vz), or a combination of groups of pharmacokinetic variables that adequately describe the pharmacokinetic profile. In some embodiments of the method, dose adjustment of compound (1) or a pharmaceutically acceptable salt thereof is indicated to increase efficacy based on one or more pharmacokinetic parameters. In some embodiments of the method, the increase in the dose of compound (1) or a pharmaceutically acceptable salt thereof is indicated based on one or more of the following: AUC, AUCinf, MRT, an index defining the pharmacokinetic profile, volume of distribution at steady state (Vss), volume of distribution at terminal phase (Vz), or a combination of groups of pharmacokinetic variables to adequately describe the pharmacokinetic profile. In some embodiments of the method, the dose of compound (1) or a pharmaceutically acceptable salt thereof is adjusted to within 5% to 25% of a desired target value. In some embodiments of the method, each of at least two samples is applied to a point-of-care or point-of-use device for determining the concentration of compound (1) or a pharmaceutically acceptable salt thereof or its metabolite, the point-of-care or point-of-use device includes a lateral flow strip having a structure and composition such that application to one or more of the at least two samples combines the drug fraction in the sample with the components of the lateral flow strip, producing a detectable signal proportional to the drug concentration in the sample being applied. In some embodiments of the method, at least two samples are applied to a matrix suitable for storing at least two samples before quantification in the laboratory. In some embodiments of the method, at least two samples are stored as dried blood spots.In some embodiments of the method, the drug concentration is measured by ELISA, LC-MS, LC-UV, or LC-MS. In some embodiments of the method, the pharmacokinetic parameters include at least one of steady-state concentration, absorption, and half-life Tl / 2. In some embodiments of the method, at least one of at least two samples is whole blood.

[0170] V.TNF-related apoptosis-inducing ligand ("TRAIL") The TRAIL protein can be assayed in test samples obtained from subjects to detect TRAIL expression induced by compound (1) or a pharmaceutically acceptable salt thereof. Immunoassays are used to assay TRAIL in samples and include, but are not limited to, enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunofiltration assay (ELIFA), flow cytometry, immunoblotting, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescence immunoassay (LIA), fluorescence immunoassay (FIA), and radioimmunoassay. Qualitative and / or quantitative results may be obtained using the assay methods. Specific details of assay methods suitable for both qualitative and quantitative analysis of samples are described in standard references, including representative works such as E. Harlow and D. Lane, Antibodies: Laboratory Manual, Cold Spring Harbor Laboratory Press, 1988; F. Breitling and S. Diibel, Recombinant Antibodies, John Wiley & Sons, New York, 1999; H. Zola, Monoclonal Antibodies: Preparation and Use of Monoclonal Antibodies and Engineered Antibody Derivatives, From Background to Bench, BIOS Scientific Publishers, 2000; BKCLo, Antibody Engineering: Methods and Protocols, Methods in Molecular Biology, Humana Press, 2003; FMAusubel et al. (eds.), Short Protocols in Molecular Biology Biology), Current Protocol, Wiley, 2002; S. Klussman (ed.), The Aptamer Handbook: Functional Oligonucleotides and Their Applications, Wiley, 2006; Ormerod, MGThis includes *Flow Cytometry: A Practical Approach*, Oxford University Press, 2000; *Givan, AL*, *Flow Cytometry: First Principles*, Wiley, New York, 2001; *Gorczyca, W.*, *Flow Cytometry in Neoplastic Hematology: Morphological-Immunophenotypic Correlation*, Taylor & Francis, 2006; *Crowther, JR*, *The ELISA Guidebook: Methods of Molecular Biology*, Humana Press, 2000; *Wild, D.*, *The Immunoassay Handbook*, 3rd edition, Elsevier Science, 2005; and *J. Sambrook and DWRussell*, *Molecular Cloning: A Laboratory Manual*, Cold Spring Harbor Laboratory Press, 3rd edition, 2001.

[0171] An example of a protocol for assaying and analyzing a sample with respect to TRAIL for detecting the effects of the pharmaceutical composition of the present invention is described in U.S. Patent Application No. 012 / 0276088 by Wafik S. El-deiry et al., which is incorporated herein by reference in its entirety.

[0172] In some embodiments of the present invention, assays for TRAIL are used to monitor subjects. For example, test samples are taken from subjects at one or more time points before, during, and / or after treatment using the pharmaceutical composition of the present invention to evaluate the efficacy of the treatment. In further examples, test samples are taken from subjects at various time points to evaluate the course or progression of the disease or healing. In one embodiment, cell death receptors from circulating tumor cells can also be analyzed to determine whether administration of compound (1) or a pharmaceutically acceptable salt thereof increases the amount or type of cell death receptors.

[0173] Cancers treated with the methods and compositions described herein are characterized by abnormal cell proliferation, including but not limited to pre-neoplastic hyperplasia, carcinoma in situ, tumors, and metastases. The methods and compositions of the present invention can be used for the prevention of cancer and for the improvement of its signs and / or symptoms. The terms “treating” and “treatment” used to refer to the treatment of cancer in the subject include preventing, inhibiting, or improving cancer in the subject, such as delaying the progression of cancer and / or reducing or improving the signs or symptoms of cancer. Examples of cancers treated with the methods and compositions of the present invention include, but are not limited to, breast cancer, CNS cancer, colon cancer, ovarian cancer, prostate cancer, leukemia, lung cancer, and lymphoma.

[0174] VI. Multimodal Treatment Methods In one embodiment, the present invention relates to a multimodal therapeutic method in which the administration of compound (1) or a pharmaceutically acceptable salt thereof to a subject requiring such treatment is supplemented by the administration of other modes of treatment. In one embodiment, the multimodal therapeutic method of the present invention includes administering a pharmaceutical composition containing compound (1) or a pharmaceutically acceptable salt thereof to a subject in combination with radiotherapy, or after it has been determined that radiotherapy has not been effective. In one embodiment, the multimodal therapeutic method of the present invention includes administering a pharmaceutical composition containing compound (1) or a pharmaceutically acceptable salt thereof to a subject in combination with radiotherapy, wherein the pharmaceutical composition containing compound (1) or a pharmaceutically acceptable salt thereof and radiotherapy are administered simultaneously or sequentially in any order. In one embodiment, the multimodal therapeutic method includes administering a pharmaceutical composition containing compound (1) or a pharmaceutically acceptable salt thereof to a subject in combination with radiotherapy in a sequential setting. In one embodiment, the multimodal therapeutic method includes administering a pharmaceutical composition containing compound (1) or a pharmaceutically acceptable salt thereof to a subject requiring such treatment simultaneously with radiotherapy. In one embodiment, the multimodal therapeutic method of the present invention is used for the treatment of cancer. In one embodiment, the multimodal therapeutic method comprises administering a pharmaceutical composition containing compound (1) or a pharmaceutically acceptable salt thereof to a cancer subject requiring such treatment, and irradiating cancer cells with a radiation beam. In one embodiment, the multimodal therapeutic method uses isoangle radiotherapy (CRT) techniques to deliver a dose-volume histogram (DVH) prescribed to the cancer subject. In one embodiment, the multimodal therapeutic method uses intensity-modulated radiation therapy (IMRT) techniques to deliver radiation to cancer cells. In one embodiment, the multimodal therapeutic method uses techniques to compensate for tumor movement in the subject during treatment (for example, if the dose of radiation must be administered to a thoracic tumor that moves as the patient breathes). In one embodiment, the multimodal therapeutic method adjusts the delivered radiation field using four-dimensional computed tomography (4D CT) scanning techniques to compensate for tumor movement over the respiratory cycle.

[0175] Any suitable type of radiation, including gamma radiation which is a predetermined fraction of IMRT (intensity-modulated radiation therapy), gamma knife, proton therapy, and close-range radiotherapy, can be used in the multimodal therapeutic method of the present invention. Brain tumors, such as those that have metastasized to the brain from glioblastoma or lung cancer, can be treated with radiotherapy and compound (1) or a pharmaceutically acceptable salt thereof. Lung cancer, pancreatic cancer, rectal cancer, breast cancer, sarcoma, prostate cancer, gynecological malignancies, and lymphomas can be treated using the multimodal therapeutic method of the present invention. Gamma knife is frequently used to treat brain metastases. In one embodiment, the multimodal therapeutic method of the present invention includes the use of proton therapy for treating cancer, including brain tumors, prostate cancer, and any tumors located close to vital organs where minimizing toxicity to nearby normal tissue is extremely important.

[0176] In one embodiment, the multimodal therapeutic method of the present invention eliminates minimal residual disease without adding to the toxicity arising from the therapeutic compound (1) or a pharmaceutically acceptable salt thereof. In one embodiment, the multimodal therapeutic method of the present invention improves the prognosis and / or reduces adverse side effects related to the disease (condition) or the condition in the treated subject.

[0177] VII. Synthesis of salts and related analogues of compound (1) The compound represented by compound (1) above can be prepared by the synthesis method shown in Scheme 1 below.

[0178] [ka]

[0179] In one embodiment, the process for producing the dihydrochloride of compound (1) begins with an intermediate compound (3), also known as N-benzyl-3-carbomethoxy-4-piperidone hydrochloride, which is commercially available. In one embodiment, the synthesis process includes neutralizing the intermediate compound (3) with a base (step 1) to produce the compound of the free base (4). In one embodiment, the synthesis process includes neutralizing the intermediate compound (3) with an inorganic base to produce the compound of (4). In one embodiment, the synthesis process includes neutralizing the intermediate compound (3) with an organic base to produce the compound of (4). In one embodiment, the intermediate compound (3) is neutralized in the presence of an alcohol. In such an embodiment, the intermediate compound (3) is neutralized in the presence of n-butanol. In one embodiment, the intermediate compound (3) is neutralized in the presence of at least one organic solvent. In such an embodiment, the intermediate compound (3) is neutralized in the presence of n-butanol and / or ethyl acetate. In one embodiment, the intermediate compound (3) is neutralized in the presence of a base and at least one organic solvent. In one such embodiment, the intermediate compound of (3) is neutralized in the presence of NaHCO3 and n-butanol. In another embodiment, the intermediate compound of (3) is neutralized in the presence of n-butanol and triethylamine (Et3N).

[0180] In one embodiment, the synthesis method comprises reacting compound (4) with compound (5) (step 2) to produce intermediate compound (1). In one embodiment, the reaction in step 2 comprises heating compound (4) together with compound (5). In one embodiment, the reaction in step 2 comprises heating compound (4) and compound (5) under reflux in the presence of a solvent. In one embodiment, the reaction in step 2 comprises using a Dean-stark trap to remove water and / or methanol (MeOH) formed during the reaction.

[0181] In one embodiment, the synthesis method includes forming a dihydrochloride salt of compound (1) (step 3). In one embodiment, the reaction in step 3 includes treating compound (1) with HCl in dioxane. In one embodiment, the reaction in step 3 includes treating compound (3) with 4N HCl in dioxane.

[0182] In one embodiment, the synthesis process optionally includes recrystallization of the disalt of compound (1).

[0183] In a preferred embodiment, the synthesis method for preparing the dihydrochloride of compound (1) is as shown in Scheme 2 below.

[0184] [ka]

[0185] VIII. Compound (1) and related compounds, derivatives, analogues, and salts In one embodiment, the present invention provides analogues and related salts of compound (1), as well as methods for producing the same. Those skilled in the art will understand that the same general principles and concepts described above in combination with compound (1) and its salts, including principles and concepts relating to methods and pharmaceutical compositions, apply equally to derivatives and analogues of compound (1), as well as salts of compound (1) and their salts.

[0186] In one embodiment, the compound related to compound (1) is compound (10):

[0187] [ka]

[0188] The above formula has the structure of H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 benzyl-piperazine, and C 1-4 Selected from the group consisting of alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketones, and C 1-4 Benzyl piperazine is C 1-4 They are optionally substituted with alkyl, hydroxyl, or halo. In yet another embodiment, the compound related to compound (1) has the structure of compound (10), where R1 and R2 are independently H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO- ( 4 - F-Ph ) Selected from the group consisting of (hereinafter, "(CH2)3CO-(4-F-Ph)" may be written as "(CH2)3CO-4F-Ph"). In some embodiments, if R1 represents CH2Ph, R2 does not represent CH2-((2-CH3)-Ph).

[0189] As shown in schemes 3 and 4, compound (10) can be synthesized by starting with 1-R1-4-oxo-3-piperidinecarboxylate or by reacting compound (6) with compound (12).

[0190] [ka]

[0191] Scheme 3 shows the synthesis of compound (10) starting from compound (6). In one embodiment, as shown in Scheme 3, compound (6) was converted to 4-amino-3-pyridinecarboxylic acid methyl ester (7) (or methyl 4-amino-1-R1-1,2,5,6-tetrahydro-3-pyridinecarboxylate) by reaction with ammonia. In one embodiment, compound (7) (or 4-amino-3-pyridinecarboxylic acid methyl ester (7)) was treated with 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole (8) to produce compound (9), which was alkylated with R2X (where R2 is as defined above and X is a halogen or an equivalent leaving group) to produce compound (10) having different values ​​depending on the R2 substituent.

[0192] [ka]

[0193] Scheme 4 shows the synthesis of compound (10) starting from compound (6) and compound (12). In one embodiment, compound (12) is prepared from compound (8) as shown in Scheme 4. In one embodiment, compound (12) is treated with compound (6) to produce compound (10) having different values ​​at the R2 substituent.

[0194] [ka]

[0195] Scheme 5 shows the synthesis of compound (10) starting from compound (11). In one embodiment, as shown in Scheme 5, compound (11), which has a nitrogen protecting group (P) on the N atom at position 7 of the ring, is first deprotected and then alkylated with R1X (wherein R1 is as defined above, and X is a halogen or an equivalent leaving group) to produce compound (10) with different values ​​depending on the R1 substituent. In some embodiments, compound (10) can be prepared as a salt, for example, a 2TFA salt or a 2HCl salt. In some embodiments, compound (10) can be prepared as a 2HCl salt by the following scheme, which is similar to Scheme 2 described above.

[0196] [Table 2]

[0197] In one embodiment, the analog is compound (25):

[0198] [ka]

[0199] The compound has the structure shown above. In the above formula, Y represents NR4 or O, and R1, R2, R3, and R4 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclic groups. In some embodiments, R1, R2, R3, and R4 are optionally substituted. In some embodiments, some or all of the hydrogens in R1, R2, R3, and R4 may be substituted with deuterium. In other embodiments, the analog has the structure of compound (25), where R1, R2, R3, and R4 independently represent H, C 1-4 Alkyl, C1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 benzylpiperazine, and C 1-4 Selected from the group consisting of alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 They are optionally substituted with alkyl, hydroxyl, or halo. In further embodiments, the analog has the structure of compound (25), where R1, R2, R3, and R4 are independently selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-PH), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.

[0200] In one embodiment, the analog is compound (26):

[0201] [ka]

[0202] The above formula has the structure of: In the above formula, R1 and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclic groups. In some embodiments, R1 and R2 are optionally substituted. In some embodiments, some or all of the hydrogens in R1 and R2 may be substituted with deuterium. In other embodiments, the analog has the structure of compound (26), where R1 and R2 independently represent H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 benzylpiperazine, and C 1-4 Selected from the group consisting of alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketones, and C 1-4 Benzylpiperazine is C 1-4It is optionally substituted with alkyl, hydroxyl, or halo. In further embodiments, the analog has the structure of compound (26), where R1 and R2 are independently selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-(2,3,4-triF-Ph), CH2-(2,3,4,5-quadraF-Ph), CH2-(pentaF-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph. In yet another embodiment, the analog has the structure of compound (26), and R1 and R2 are independently selected from the group consisting of C6H4(CH3), C6H3(CH3)2, C6H2(CH3)3, C6H(CH3)4, C6(CH3)5, CH2-C6H4(CH3), CH2-C6H3(CH3)2, CH2-C6H2(CH3)3, CH2-C6H(CH3)4, and CH2-C6(CH3)5. In yet another embodiment, the analog has the structure of compound (26), and R1 and R2 are independently selected from the group consisting of C6H4(OH), C6H3(OH)2, C6H2(OH)3, C6H(OH)4, C6(OH)5, CH2-C6H4(OH), CH2-C6H3(OH)2, CH2-C6H2(OH)3, CH2-C6H(OH)4, and CH2-C6(OH)5.

[0203] In one embodiment, the analog is compound (27):

[0204] [ka]

[0205] The above formula has the structure of: In the above formula, R1 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclic groups. In some embodiments, R1 is optionally substituted. In some embodiments, some or all of the hydrogens in R1 may be substituted with deuterium. In other embodiments, the analog has the structure of compound (27), where R1 is H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 benzylpiperazine, and C 1-4 Selected from the group consisting of alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 It is optionally substituted with alkyl, hydroxyl, or halo. In further embodiments, the analog has the structure of compound (27), where R1 is selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.

[0206] In one embodiment, the analog is compound (28):

[0207] [ka]

[0208] The above formula has the structure of: In the above formula, R1 and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclic groups. In some embodiments, R1 and R2 are optionally substituted. In some embodiments, some or all of the hydrogens in R1 and R2 may be substituted with deuterium. In other embodiments, the analog has the structure of compound (28), where R1 and R2 independently represent H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 benzylpiperazine, and C 1-4 Selected from the group consisting of alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 They are optionally substituted with alkyl, hydroxyl, or halo. In further embodiments, the analog has the structure of compound (28), where R1 and R2 are independently selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.

[0209] In one embodiment, the analog is compound (29):

[0210] [ka]

[0211] The above formula has the structure of: In the above formula, R1 and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclic groups. In some embodiments, R1 and R2 are optionally substituted. In some embodiments, some or all of the hydrogens in R1 and R2 may be substituted with deuterium. In other embodiments, the analog has the structure of compound (29), where R1 and R2 independently represent H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 benzylpiperazine, and C 1-4 Selected from the group consisting of alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 They are optionally substituted with alkyl, hydroxyl, or halo. In further embodiments, the analog has the structure of compound (29), where R1 and R2 are independently selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.

[0212] In one embodiment, the analog is compound (30):

[0213] [ka]

[0214] The above formula has the structure of: In the above formula, R1 and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclic groups. In some embodiments, R1 and R2 are optionally substituted. In some embodiments, some or all of the hydrogens in R1 and R2 may be substituted with deuterium. In other embodiments, the analog has the structure of compound (30), where R1 and R2 independently represent H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 benzylpiperazine, and C 1-4 Selected from the group consisting of alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 Benzylpiperazine is C 1-4 It is optionally substituted with alkyl, hydroxyl, or halo. In further embodiments, the analog has the structure of compound (30), where R1 and R2 are independently selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.

[0215] In one embodiment, the analog is compound (31):

[0216] [ka]

[0217] The above formula has the structure of: In the above formula, R1 and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclic groups. In some embodiments, R1 and R2 are optionally substituted. In some embodiments, some or all of the hydrogens in R1 and R2 may be substituted with deuterium. In other embodiments, the analog has the structure of compound (31), where R1 and R2 independently represent H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketone, C 1-4 benzylpiperazine, and C 1-4 Selected from the group consisting of alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkylphenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 The compounds are optionally substituted with alkyl, hydroxyl, or halo. In further embodiments, the analog has the structure of compound (31), where R1 and R2 are independently selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.

[0218] IX. Examples It should be understood that the descriptions and specific examples provided below are for illustrative purposes only and are not intended to limit the scope of this disclosure. Examples 1 and 2 illustrate the synthesis of the dihydrochloride of compound (1), starting with compound (1). In these examples and throughout this application, the dihydrochloride of compound (1) is referred to as compound (2). The following examples are for illustrative purposes only and should not be construed as limiting to the embodiments disclosed. Additional compounds not described below can be prepared using the continuation of the reaction scheme described above or appropriate variations or modifications thereof.

[0219] Example 1. Synthesis of 2-chlorobenzylamino-2-imidazoline hydroiodide 2-chlorobenzylamine (141 mg, 1.0 mmol) was added to a stirred solution of 2-methylthio-2-imidazoline hydroiodide (244 mg, 1.00 mmol) in dried dioxane (2.0 mL). The reaction mixture was stirred at 70°C for 90 minutes under an argon atmosphere. The solution was cooled to room temperature, filtered through a sintering funnel, washed with cold dioxane (2 mL), and dried under vacuum. Compound 4·HI (R2=2-chlorobenzyl) (242 mg, 72%) was obtained as a white solid and used without further purification.

[0220] Example 2. Synthesis of 2-chlorobenzylaminoimidazoline A stirred solution of 2-chlorobenzylamino-2-imidazoline hydroiodide (242 mg, 0.72 mmol) in water (3 mL) was mixed with 1.0 N sodium hydroxide (2 mL) at 7 °C. The reaction mixture was stirred under argon at 7 °C for 30 minutes. Then, methylene chloride (5 mL) was added and the mixture was stirred for a further 5 minutes. The reaction mixture was extracted with methylene chloride (2 × 2.5 mL), the organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated. The resulting free base (150 mg, 100%) was obtained as a viscous liquid and used in the next reaction without further purification. MS(ESI)210(M+H).

[0221] Example 3. Synthesis of methyl-1-benzyl-4-oxo-3-piperidinecarboxylate (compound (6)) To methyl-1-benzyl-4-oxo-3-piperidine carboxylate hydrochloride (5.7 g, 20 mmol) in ethyl acetate (50 mL), triethylamine (6 mL) was added at 7°C. The reaction mixture was stirred under an argon atmosphere at 7°C for 30 minutes. This reaction mixture was extracted with ethyl acetate (2 × 50 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated. The free base residue (5, R1=benzyl) obtained as a viscous oily substance was used in the next reaction without further purification. MS(ESI)248(M+H).

[0222] Example 4. Synthesis of ONC902 (Compound (14)) To a solution of 2-chlorobenzylamino-2-imidazoline (150 mg, 0.72 mmol) and methyl-1-benzyl-4-oxo-3-piperidine carboxylate (5, R1=benzyl) (195 mg, 0.79 mmol) in 1-butanol (2 mL), PPTS (10 mg) was added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then refluxed at 125°C to 130°C for 2 hours. The solvent was removed under vacuum, the mixture was extracted with ethyl acetate (10 mL), and washed with saturated sodium bicarbonate solution (2 × 10 mL) and water (10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated. The crude free base was purified by RP HPLC (10% to 40% acetonitrile / water) to obtain ONC902 TFA salt as a white solid (228 mg, 50% yield). MS(ESI)407(M+H).

[0223] Using the same process starting with different benzylamines, various analogues, such as ONC903, 904, 905, and 906, were prepared.

[0224] Example 5. Synthesis of ONC907 (Compound (19)) To a suspension of 60% sodium hydride (3.5 g, 88 mmol) in dry toluene (50 mL), dimethyl carbonate (4.32 g, 48.0 mmol) was added dropwise over 0.5 hours at room temperature under a nitrogen atmosphere. After adding a few drops of methanol, a solution of 1-tert-butoxycarbonyl-4-piperidone (4.8 g, 24 mmol) dissolved in dry toluene (20 mL) was added dropwise to the reaction mixture over 1 hour at 80°C with stirring. The reaction mixture was stirred at the same temperature for 3 hours, then cooled to 0°C (ice bath), and the pH was adjusted to 6-6.5 with acetic acid. The resulting cold mixture was diluted with water (10 mL) and the pH was adjusted to 8 with a 5% sodium hydroxide solution. The toluene layer was separated, and the aqueous layer was extracted with toluene (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This compound was dried in a vacuum to obtain methyl-1-tert butoxycarbonyl-4-oxo-3-piperidine carboxylate (5.0 g, 80%). The obtained compound was used in the next reaction without further purification.

[0225] 10.0 mg of PPTS was added to 1-butanol (2 mL), 2-methylbenzylamino-2-imidazoline (190 mg, 1 mmol), and methyl-1-tert butoxycarbonyl-4-oxo-3-piperidine carboxylate (315 mg, 1.1 mmol), and the mixture was stirred at room temperature for 48 hours. After this, the reaction mixture was refluxed at 125°C to 130°C for 2 hours. The solvent was removed under vacuum, extracted with ethyl acetate (10 mL), and washed with saturated sodium bicarbonate solution (2 × 10 mL) and water (10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated. The crude free base was cleaved with 10% trifluoroacetic acid in dichloromethane and purified by RP HPLC (10% to 40% acetonitrile / water) to obtain ONC907 (262 mg, 50%) TFA salt as a white solid. MS(ESI)297(M+H).

[0226] Example 6. Synthesis of ONC909 (Compound 21) A mixture of ONC907 (100 mg, 0.2 mmol), phenylethyl bromide (55.0 mg, 0.28 mmol), and potassium carbonate (150 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL) was heated to 70°C for 12 hours. The solvent was removed under vacuum, the mixture was extracted with ethyl acetate (10 mL), and washed with water (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated. The crude free base was purified by RP HPLC (10%-40% acetonitrile / water) to obtain ONC909 (62 mg, 50%) TFA salt as a white solid. MS(ESI)401(M+H).

[0227] Example 7. Synthesis of ONC908 (Compound 20) PPTS (10.0 mg) was added to a solution of 2-methylbenzylamino-2-imidazoline (190.0 mg, 1.0 mmol) and methyl-1-methyl-4-oxo-3-piperidine carboxylate (185.0 mg, 1.0 mmol) in 1-butanol (2.0 mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then refluxed at 125°C to 130°C for 2 hours. The solvent was removed under vacuum, the mixture was extracted with ethyl acetate (10 mL), and washed with saturated sodium bicarbonate solution (2 × 10 mL) and water (10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated. The crude free base was purified by HPLC using 10% to 40% acetonitrile and water to obtain ONC908 (270.0 mg, 50%) TFA salt as a white solid. MS(ESI)311(M+H).

[0228] Example 8. Synthesis of ONC201 (Compound 1) Compound (3) (239.7 g, 0.845 mol, 1.6 equivalents) was added in small increments to 800 mL of stirred saturated NaHCO3 in a 2 L round-bottom flask. 500 mL of n-butanol was added to the resulting mixture, which was stirred for 30 minutes and then transferred to a separatory funnel. The organic phase containing compound (4) was separated and transferred to a 2 L three-necked round-bottom flask equipped with mechanical stirring, an N2 inlet, a thermocouple, a condenser, and a Dean-Stark trap. Compound (5) (100 g, 0.528 mol, 1 equivalent) and pyridinium p-toluenesulfonate (PPTS) (6.63 g, 0.026 mol, 5 mol%) were added to the contents of this flask. The resulting mixture was heated under reflux for 6 hours. Water in the reaction mixture was separated into a Dean-Stark trap as needed. The reflux temperature was increased from 93°C to 118°C. The reaction was monitored by HPLC. The reaction was stopped when the peak area of ​​compound (1) on the HPLC remained constant with respect to the reaction time.

[0229] Example 9. Synthesis of the disalt of ONC201 (compound (2)) Without isolating compound (1), the reaction mixture from Example 8 was washed with 500 mL of water and diluted with methyl tert-butyl ether (MTBE) (800 mL). The organic phase was washed twice with 500 mL of water and transferred to a 3 L three-necked round-bottom flask equipped with mechanical stirring, an N2 inlet, a thermocouple, a condenser, and a Dean-Stark trap. While stirring the reaction mixture, 1N HCl from the dioxane-MTBE solution was added dropwise until no solid precipitate formed from the reaction mixture upon addition of HCl (4N HCl in dioxane: 300 mL, 1.2 mol, 2.27 equivalents; MTBE: 1200 mL). The reaction mixture was heated under reflux at 60-65°C for 2 hours. If necessary, water was separated into a Dean-Stark trap. After cooling to room temperature, the solid precipitate was filtered through a sintered glass funnel and washed with n-butanol-MTBE (1:2, 600 mL) and MTBE (600 mL), respectively. The solid was dried overnight in a vacuum oven at 65°C (16 hours) to obtain 200 g of yellow solid.

[0230] 200 g of the above solid was added to a 2 L three-necked round-bottom flask equipped with mechanical stirring, an N2 inlet, a thermocouple, and a condenser, followed by the addition of ethanol (1000 mL). The mixture was heated under reflux at 78 °C for 2 hours. After cooling to room temperature, the solid was filtered through a sintered glass funnel and washed with ethanol (200 mL, 3 times). The wet solid was dried in a vacuum oven at 85 °C for 3 days until the residual solvent met the specifications. 120 g of compound (2) was obtained as a white solid with a yield of 49% and an HPLC purity of 99.7%.

[0231] Those skilled in the art will understand that the illustrated exemplary embodiments described above can be modified without departing from the broad concept of the invention. Therefore, it should be understood that the present invention is not limited to the illustrated and described exemplary embodiments, but is intended to encompass modifications that are in line with the spirit and scope of the invention as defined by the claims. For example, certain features of the exemplary embodiments may be part of or not part of the claimed invention, and features of the disclosed embodiments may be combined. Unless specifically stated herein, the terms “a,” “an,” and “it” should not be limited to a single element, but rather should be read as meaning “at least one.”

[0232] At least portions of the drawings and description of this invention have been simplified to focus on elements relevant to a clear understanding of the invention, and for clarity, other elements that will be recognized by those skilled in the art may also be part of the invention, although they have been omitted. However, since such elements are well known in the art and do not necessarily facilitate a better understanding of the invention, a description of such elements is not provided herein.

[0233] Furthermore, the particular order of the steps described herein should not be construed as limiting the claims to the extent that the method does not depend on the particular order of the steps. It will be readily apparent to those skilled in the art that the claims for the method of the present invention should not be limited to performing those steps in the order written, and that even if the steps are modified, the invention will still remain in spirit and scope.

[0234] All references, including publications, patent applications, and patents, are incorporated herein by reference to the same extent as if they were included in this specification, each reference being incorporated individually and specifically by reference.

Claims

1. The following chemical formula A method for producing compound (2) represented by, Step (a): Neutralize N-benzyl-3-carbomethoxy-4-piperidone hydrochloride to obtain the following chemical formula A step of producing a compound represented by, the step being carried out in the presence of n-butanol or ethyl acetate and NaHCO3 or triethylamine, Step (b): The compound produced in step (a) is given the following chemical formula When reacted with a compound represented by the following chemical formula, the following chemical formula is obtained. A step of forming a compound (1) represented by, Step (c): A step of forming a dihydrochloride salt of compound (1) by treating compound (1) with dioxane containing HCl, Step (d): A step of recrystallizing the dihydrochloride salt formed in one or more types of recrystallization solvents, A method that includes this.

2. The method according to claim 1, In the step (a), NaHCO ３ and a method carried out in the presence of n-butanol.

3. The method according to claim 1, A method comprising heating the compound produced in step (a) under reflux in the presence of a solvent.

4. The method according to claim 2, A method in which the solvent is n-butanol.

5. The method according to claim 1, The method wherein the HCl is 4N HCl.

6. The method according to claim 1, The method wherein the one or more recrystallization solvents are selected from water, ethanol, methanol, ethyl acetate, hexane, diethyl ether, toluene, and acetone.

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