7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo [1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, analogs and salts thereof and their use method in therapy

Abstract

To provide anticancer compositions and uses thereof.SOLUTION: Provided are treatment methods using compound (1) or analogs thereof, and pharmaceutically acceptable salts thereof. Also provided are compound (10) and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the same. Also provided are treatment methods, for example for cancer, comprising administering the compound and salts thereof to a subject in need of such treatment.SELECTED DRAWING: None

Description

[Background technology]

[0001] TNF-related apoptosis-inducing ligand (TRAIL, Apo2L) is an endogenous protein that selectively induces apoptosis in cancer cells. TRAIL is a potent inducer of apoptosis in a wide range of human cancer cell lines by engaging either the extrinsic or intrinsic apoptotic pathways via the cell surface proapoptotic death receptor 4 (DR4, TRAIL-R1) and death receptor 5 (DR5, TRAIL-R2). TRAIL plays a direct role in tumor suppression during immune surveillance, but this antitumor mechanism is lost during disease progression. Because TRAIL can selectively initiate apoptosis in cancer cells, clinical trials are currently underway involving the administration of recombinant TRAIL and long-lived TRAIL-agonist antibodies targeting either of its two proapoptotic death receptors.

[0002] Despite its efficacy, recombinant TRAIL has properties that limit its effectiveness, such as short serum half-life, stability, cost, and delivery. Delivery of recombinant TRAIL or TRAIL-agonist antibodies to the brain is limited by the inability of recombinant TRAIL and TRAIL-agonist antibodies to cross the blood-brain barrier. Therefore, there is a continuing need for anti-cancer compositions and methods. Summary of the Invention [Means for solving the problem]

[0003] In one aspect, the present disclosure provides a compound of formula (10):

[0004] [ka]

[0005] wherein R1 and R2 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, and acyl groups, and when R1 is CH2Ph, R2 is not CH2-((2-CH3)-Ph). In some embodiments, R1 and R2 are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, and acyl groups; 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, C 1-4 Alkylthienyl, C 1-4 Alkylpyridinyl, C 1-4 Alkylisoxazolidinyl, C 1-4 Alkylmorpholinyl, C 1-4 Alkylthiazolyl, and C 1-4 alkylpyrazinyl, independently selected from the group consisting of C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, C 1-4 Alkylthienyl, C 1-4 Alkylpyridinyl, C 1-4 Alkylisoxazolidinyl, C 1-4 Alkylmorpholinyl, C 1-4 Alkylthiazolyl, and C 1-4 Alkylpyrazinyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, R and / or R are substituted or unsubstituted aryl alkyl or heteroaryl alkyl. In some embodiments, heteroaryl alkyl is C 1-4 Alkylpyrrolyl, C 1-4 Alkylfuryl, C 1-4 Alkylpyridyl, C 1-4 Alkyl-1,2,4-thiadiazolyl, C1-4 Alkylpyrimidyl, C 1-4 Alkylthienyl, C 1-4 Alkylisothiazolyl, C 1-4 Alkyl imidazolyl, C 1-4 Alkyltetrazolyl, C 1-4 Alkylpyrazinyl, C 1-4 Alkylpyrimidyl, C 1-4 Alkylquinolyl, C 1-4 Alkylisoquinolyl, C 1-4 Alkylthiophenyl, C 1-4 Alkylbenzothienyl, C 1-4 Alkylisobenzofuryl, C 1-4 Alkylpyrazolyl, C 1-4 Alkyl indolyl, C 1-4 Alkylpurinyl, C 1-4 Alkylcarbazolyl, C 1-4 Alkylbenzimidazolyl, and C 1-4 In some embodiments, R and / or R are selected from the group consisting of substituted or unsubstituted benzyl or phenylethyl. In some embodiments, R and / or R are selected from the group consisting of one or more of the following substituents on the benzyl ring: X, —CH, —NO, —OCH, —CN, —CXH, —CXH, C-C alkyl, —CX, —CH(CX), —CH(CX), —C(CX), —C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m is benzyl optionally substituted with R m and R n are independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20; X is a halogen.

[0006] In one embodiment, compound (10) has the structure of compound (90):

[0007] [ka]

[0008] During the ceremony, R2 is as defined above, R b1 , R b2 , R b3 , R b4 , and R b5 is hydrogen, X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m are each independently selected from the group consisting of: R m and R n are independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20; X is a halogen.

[0009] In one embodiment, compound (10) has the structure of compound (40):

[0010] [ka]

[0011] During the ceremony, R1 is as defined above, R a1 , R a2 , R a3 , R a4 , and R a5 is hydrogen, X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m are each independently selected from the group consisting of: R m and R n are independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20; X is a halogen.

[0012] In one embodiment, compound (10) has the structure of compound (50):

[0013] [ka]

[0014] During the ceremony, R1 is as defined above, R bis X, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m is selected from the group consisting of R a1 , R a2 , R a4 , and R a5 is hydrogen, X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m are each independently selected from the group consisting of: R m and R n are independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20; X is a halogen.

[0015] In one embodiment, compound (10) has the structure of compound (80):

[0016] [ka]

[0017] During the ceremony, R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , and R b5 is hydrogen, X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m are each independently selected from the group consisting of: R m and R n are independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20; X is a halogen.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (10) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (10). In one embodiment, the salt is a pharmaceutically acceptable mono-salt of a compound of Formula (10). In one embodiment, the salt is a pharmaceutically acceptable di-salt of a compound of Formula (10). In one embodiment, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, bisulfate, sulfate, phosphate, fumarate, succinate, oxalate, lactate, bisulfate, hydroxyl, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, acetate, and carboxylate. In one embodiment, the pharmaceutically acceptable salt is selected from the group consisting of p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate, glucuronate, ascorbate, and maleate. In one embodiment, the pharmaceutically acceptable salt is selected from ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and / or with other counterions such as methylamino, dimethylamino, diethylamino, and triethylamino counterions. In one embodiment, the pharmaceutical composition comprises the hydrochloride di-salt or hydrobromide di-salt of the compound of Formula (10). In some embodiments, the pharmaceutical compositions of the invention comprise a pharmaceutically acceptable carrier.

[0019] In some embodiments, the pharmaceutical composition of the invention comprises a second therapeutic agent. In one embodiment, the second therapeutic agent is an anti-cancer agent. In one embodiment, the anti-cancer agent is a mitotic inhibitor. In one embodiment, the anti-cancer agent is selected from the group consisting of paclitaxel, docetaxel, and combinations thereof. In an alternative embodiment, the second therapeutic agent is an anti-angiogenic agent. In one embodiment, the anti-angiogenic agent is bevacizumab. In one embodiment, the second therapeutic agent is administered as part of a combination therapy to treat the patient. In one embodiment, details of the combination therapy are included in the package insert for the compound of Formula (10).

[0020] In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0021] In another aspect, the present invention provides a method of treatment. In one embodiment, the method of treatment comprises administering to a subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (10) or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment, the method of treatment comprises administering to a subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (10) or a pharmaceutically acceptable salt thereof. In one embodiment, the method of treatment comprises administering to a subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (10) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0023] In some embodiments, the method of treatment further comprises administering an additional therapeutic agent. In one embodiment, the additional therapeutic agent comprises an anti-cancer agent. In one embodiment, the additional anti-cancer agent comprises an anti-mitotic agent. In one embodiment, the additional anti-cancer agent comprises paclitaxel, docetaxel, bevacizumab, or any combination thereof.

[0024] In one embodiment, the method of treatment further comprises assaying tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in a sample obtained from the subject undergoing treatment. In one embodiment, the sample is a blood sample.

[0025] In one embodiment of the method of treatment, the subject being treated has or is at risk of having 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. In one embodiment, the cancer is selected from the group consisting of actinic keratosis, Barrett's esophagus, atrophic gastritis, dyskeratosis congenita, iron deficiency dysphagia, lichen planus, oral submucous fibrosis, solar elastosis, cervical dysplasia, leukoplakia, and erythroplakia.

[0026] In one embodiment of the method of treatment, the pharmaceutical composition is administered via an oral route of administration, hi one embodiment, the pharmaceutical composition is administered via a route of administration selected from the group consisting of intravenous, rectal, nasal, pulmonary, epidural, ophthalmic, aural, intra-arterial, topical, intracardiac, intraventricular, intradermal, intramuscular, intraperitoneal, intraosseous, intrathecal, intravesical, subcutaneous, transdermal, transmucosal, sublingual, buccal, vaginal, and by inhalation.

[0027] In one embodiment, the present invention provides a method of treating a subject having or at risk of having brain cancer, the method comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (10) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.

[0028] In one embodiment, the present invention provides a method of treatment comprising administering to a subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (10) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0029] In another aspect, the present invention provides a method of treating a subject in need of such treatment, the method comprising: (i) administering to a subject a first therapeutic agent comprising a compound of formula (10) or a pharmaceutically acceptable salt thereof; (ii) waiting until a predetermined waiting time has elapsed after administering the first therapeutic agent to the subject; and (iii) administering to the subject a second therapeutic agent, wherein the predetermined waiting time is selected to achieve a delayed therapeutic effect of the first therapeutic agent without increasing or reducing the risk of possible combined toxic effects of the first and second therapeutic agents.

[0030] In another aspect, the present invention provides a method of treating a subject in need of such treatment, the method comprising: (i) administering to a subject a first therapeutic agent comprising a compound of formula (10) or a pharmaceutically acceptable salt thereof; (ii) monitoring the level of a compound of formula (10) or a salt thereof, or a metabolite thereof, in a subject using pharmacokinetic profiling; and (iii) administering a second therapeutic agent in response to the level of the first therapeutic agent in the subject.

[0031] In another aspect, the present invention provides a method of treating a subject in need of such treatment, the method comprising: (i) administering to a subject a first therapeutic agent comprising a compound of formula (10) or a pharmaceutically acceptable salt thereof; (ii) administering a second therapeutic agent according to the predicted half-life of the compound of Formula (10) in the subject being treated.

[0032] In another aspect, the present disclosure provides a compound of formula (10) below or an analog of a compound of formula (1), and pharmaceutically acceptable salts thereof, and processes for their preparation:

[0033] [ka]

[0034] [ka]

[0035] In one aspect, the present disclosure provides a method of treatment. In one embodiment, the method of treatment comprises administering to a subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (10) or Formula (1), or an analog thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In one embodiment, the subject being treated has or is at risk of having cancer. In one embodiment, the subject is human.

[0036] In another aspect, the present invention provides a method of treating a subject in need of such treatment, the method comprising: (i) administering to the subject a first therapeutic agent comprising an analog of Compound (1) (e.g., a compound of Formula (10)) or a pharmaceutically acceptable salt thereof; and (ii) administering a second therapeutic agent in response to a resolved or resolving adverse event from the first therapeutic agent, in some embodiments, the adverse event from the first therapeutic agent is related to the blood levels of the drug or a metabolite thereof in the subject receiving the treatment.

[0037] In another aspect, the present invention provides kits for monitoring Compound (1) analogs (e.g., compounds of Formula (10)) or pharmaceutically acceptable salts thereof, or metabolites thereof, in individuals treated with the analogs using pharmacokinetic profiling, the kits comprising multiple point-of-care or point-of-use devices capable of quantifying drug in at least two samples or matrices suitable for storing the samples prior to laboratory quantification. In some embodiments, the kits further comprise instructions for collecting and / or storing the at least two samples.

[0038] In some embodiments, the method of treatment includes (i) administering to a subject a pharmaceutical composition containing a pharmaceutically effective amount of a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring the level of the compound or a pharmaceutically acceptable salt thereof, or a metabolite thereof, in the subject using pharmacokinetic profiling, wherein the dosage of the compound or its salt is selected to maintain a concentration of the compound or its metabolite of at least about 400 ng / mL in the subject's whole blood, plasma, serum, or cerebrospinal fluid over a treatment period within 4 hours of treatment. In some embodiments, the subject being treated has or is at risk of having cancer. In some embodiments, the method of treatment further includes waiting a predetermined waiting time (e.g., the waiting time is the same length as the first time interval) between one or more repetitions of step (i). In some embodiments, the subject is human.

[0039] In some embodiments, the method of treatment comprises: (i) administering to a subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring the level of the compound or a metabolite thereof in the subject using pharmacokinetic profiling, wherein a dosage of the compound or a salt thereof is selected to achieve an AUC of the compound or a metabolite thereof of at least about 3,500 hr-ng / mL in the subject's whole blood, plasma, serum, or cerebrospinal fluid over 2, 6, 12, 24, 48, 72 hours, or more than 72 hours or extrapolated to infinity after treatment.

[0040] In some embodiments, the method of treatment comprises: (i) administering to a subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring the level of Compound (1), a pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein the dosing of the compound or its salt is selected to achieve an undetectable concentration of the compound or its metabolite in the subject's whole blood, plasma, serum, or cerebrospinal fluid on days 3, 4, 5, 6, or 7 after treatment.

[0041] In some embodiments, the method of treatment includes (i) administering multiple doses of a therapeutic agent comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof over a first time interval (e.g., 7 days), wherein the multiple doses are administered over a second time interval within the first time interval (e.g., 2-5 consecutive days during the first time interval of 1 week); and (ii) repeating step (i) one or more additional times. In some embodiments, the subject being treated has or is at risk of having cancer. In some embodiments, the method of treatment further includes waiting a predetermined waiting time (e.g., the waiting time is the same length as the first time interval) between one or more repetitions of step (i). In some embodiments, the subject is human.

[0042] In some embodiments, the pharmaceutical composition is administered to the subject once daily. In some embodiments, the pharmaceutical composition is administered to the subject using an infrequent dosing schedule (e.g., once per week or less frequently). In some embodiments, the pharmaceutical composition is administered to the subject using a frequent dosing schedule (e.g., administered twice per week or more frequently). In some embodiments, the pharmaceutical composition is administered to the subject once per week. In some embodiments, the pharmaceutical composition is administered to the subject once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject twice per week. In some embodiments, the pharmaceutical composition is administered to the subject three times per week. In some embodiments, the pharmaceutical composition is administered to the subject four times per week. In some embodiments, the pharmaceutical composition is administered to the subject once every two weeks. In some embodiments, the pharmaceutical composition is administered to the subject once every three weeks. In some embodiments, the pharmaceutical composition is administered to the subject in a repeating cycle of weekly, once every two weeks, once every three weeks, once every four weeks, or a combination thereof.

[0043] In one aspect, the present disclosure provides a method for determining whether a subject with a disease state is likely to respond to a treatment regimen. In some embodiments, the method includes: (i) obtaining a biological sample from a subject; (ii) measuring in the sample RNA modification levels and / or expression or activity levels of one or more proteins in Tables 1 and 3 and / or one or more mutations in at least one gene encoding one or more proteins in Tables 1 and 3; (iii) comparing the measured levels and / or found mutations in the sample with predetermined standard data; and (iv) determining whether the subject is likely to respond to a treatment regimen based on the measured levels and / or found mutations in the sample relative to predetermined standard data. In one aspect, the present disclosure provides a method for providing a prognosis for a subject with a disease state. In some embodiments, the method includes: (i) obtaining a biological sample from a subject; (ii) measuring, in the sample, RNA modification levels and / or expression or activity levels of one or more proteins of Tables 1 and 3 and / or one or more mutations in at least one gene encoding one or more proteins of Tables 1 and 3; (iii) comparing the measured levels and / or found mutations in the sample with predetermined reference data; and (iv) determining a prognosis for the subject based on the measured levels and / or found mutations in the sample relative to the predetermined reference data.

[0044] In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the treatment regimen comprises administering an effective amount of Compound (1) or an analog thereof. In one embodiment, the RNA is mRNA. In one embodiment, the RNA is miRNA. In one embodiment, the RNA modification is methylation. In one embodiment, the RNA modification is N 6 -methyladenosine (m 6 A). In one embodiment, the modification of the RNA is m 6A is mRNA methylation. In one embodiment, the subject is a human. In one embodiment, the subject is a domesticated pet, for example, a cat or a dog. In one embodiment, the protein is an RNA reader, for example, YTHDF3. In one embodiment, the protein is an RNA writer. In one embodiment, the protein is an RNA eraser.

[0045] In one aspect, the present disclosure provides a method for identifying and treating a subject having a medical condition who is likely to respond to a treatment regimen of the present disclosure. In some embodiments, the method includes (i) determining whether a subject having the medical condition is likely to respond to a treatment regimen of the present disclosure; and (ii) treating the subject determined to be likely to respond to the treatment regimen with the treatment regimen. In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the treatment regimen includes administering an effective amount of Compound (1) or an analog thereof.

[0046] In one aspect, the present disclosure provides a method for assessing the effectiveness of or monitoring a subject having a medical condition and being treated with a therapeutic regimen of the present disclosure. In some embodiments, the method includes: (i) obtaining a biological sample from the subject; (ii) measuring, in the sample, RNA modification levels and / or expression or activity levels of one or more proteins of Tables 1 and 3 and / or one or more mutations in at least one gene encoding one or more proteins of Tables 1 and 3; (iii) comparing the measured levels and / or found mutations in the sample with predetermined reference data; and (iv) determining whether the subject will respond to the therapeutic regimen based on the measured levels and / or found mutations in the sample relative to the predetermined reference data.

[0047] In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the treatment regimen comprises administering an effective amount of Compound (1) or an analog thereof. In one embodiment, the RNA is mRNA. In one embodiment, the RNA is miRNA. In one embodiment, the RNA modification is methylation. In one embodiment, the RNA modification is N 6 -methyladenosine (m 6 A). In one embodiment, the modification of the RNA is m 6 A is mRNA methylation. In one embodiment, the subject is a human. In one embodiment, the subject is a domesticated pet, for example, a cat or a dog. In one embodiment, the protein is an RNA reader, for example, YTHDF3. In one embodiment, the protein is an RNA writer. In one embodiment, the protein is an RNA eraser.

[0048] In one aspect, the present disclosure provides a method for screening potential therapeutic agents for a disease state. In some embodiments, the method includes: (i) contacting a protein of Tables 1 and 3 with a test compound suspected of having a therapeutic effect against the disease state; (ii) measuring the binding affinity or interaction of the test compound with the protein; and (iii) comparing the binding affinity or interaction of the test compound with a predetermined threshold, wherein an affinity or interaction of the test compound equal to or greater than the threshold is indicative of a therapeutic agent for the disease state. In some embodiments, the disease state is cancer. In some embodiments, the predetermined threshold is the affinity or interaction of Compound (1) or an analog thereof with the protein. In some embodiments, the predetermined threshold is the affinity or interaction of Compound (1) with the protein. In some embodiments, the protein is an RNA reader, e.g., YTHDF3. In some embodiments, the protein is an RNA writer. In some embodiments, the protein is an RNA eraser.

[0049] In one aspect, the present disclosure provides a method for screening potential therapeutic agents for a disease state. In some embodiments, the method includes: (i) contacting a protein of Tables 1 and 3 with a reference compound under conditions in which the reference compound binds to or interacts with the protein; (ii) contacting the protein of Tables 1 and 3 with a test compound believed to be a therapeutic agent for the disease state; (iii) measuring the binding affinity or interaction of the reference and test compounds with the protein; and (iv) comparing the binding affinity or interaction of the reference and test compounds, wherein a comparable or stronger affinity or interaction of the test compound relative to the reference compound is indicative of a therapeutic agent for the disease state. In one embodiment, the reference compound is Compound (1) or an analog thereof. In one embodiment, the reference compound is Compound (1). In one embodiment, the disease state is cancer. In one embodiment, the protein is an RNA reader, e.g., YTHDF3. In one embodiment, the protein is an RNA writer. In one embodiment, the protein is an RNA eraser.

[0050] In one aspect, the present disclosure provides a method for screening potential therapeutic agents for a disease state. In some embodiments, the method includes: (i) using a processor to model the binding or interaction, if any, of a three-dimensional structure of a test compound that is a potential therapeutic agent for the condition with the three-dimensional structure of a protein in Tables 1 and 3; (ii) using a processor to determine the binding affinity or interaction of the test compound's structure with the protein structure; and (iii) using a processor to compare the binding affinity or interaction of the test compound with a predetermined threshold, wherein an affinity or interaction of the test compound that is equal to or greater than the threshold is indicative of a therapeutic agent for the disease state. In one embodiment, the predetermined threshold is the affinity or interaction of Compound (1) or an analog thereof with the protein. In one embodiment, the predetermined threshold is the affinity or interaction of Compound (1) with the protein. In some embodiments, the disease state is cancer. In one embodiment, the protein is an RNA reader, e.g., YTHDF3. In one embodiment, the protein is an RNA writer. In one embodiment, the protein is an RNA eraser.

[0051] In one aspect, the present disclosure provides a method for screening potential therapeutic agents for a disease state. In some embodiments, the method includes, using a processor, (i) using a computational docking method to model the binding or interaction of one or more three-dimensional structures (conformations) of a test molecule (test compound) for the disease state, which is a potential therapeutic agent for the disease state, with a three-dimensional structure or model of a protein in Tables 1 and 3; (ii) using the computational method to predict the binding or interaction, if any, of the three-dimensional structure of the test molecule with the structure or model of the protein; (iii) using the computational method to compare the binding affinity or interaction of a reference and a test compound with the protein; and (iv) using a processor to compare the binding affinity or interaction of the reference and test compound structures, wherein a binding affinity or interaction of the test compound that is equal to or greater than the reference compound is indicative of a therapeutic agent for the disease state. In one embodiment, the reference compound structure is the structure of Compound (1) or an analog thereof. In some embodiments, the reference compound structure is the structure of Compound (1). In some embodiments, the disease state is cancer. In some embodiments, the protein is an RNA reader, e.g., YTHDF3. In some embodiments, the protein is an RNA writer. In some embodiments, the protein is an RNA eraser.

[0052] In one aspect, the present disclosure provides a method for treating a subject with a condition, such as cancer, by administering a drug that modulates the transcription, translation, or biological activity of YTHDF3 or other proteins in Tables 1 and 3, or nucleic acids encoding these proteins. Drugs include, but are not limited to, siRNAs, antisense nucleic acids, ribozymes, triple-helix-forming agents, antibodies, and polypeptides, as well as small molecule compounds. Preferably, the siRNAs, antisense nucleic acids, ribozymes, and triple-helix-forming agents inhibit the translation or transcription of one or more genes in Tables 1 and 3. To achieve this, oligonucleotides are designed based on appropriate sequences unique to the target gene. Various gene therapy approaches can be used in accordance with the present invention to modulate the expression of genes in Tables 1 and 3. For example, antisense DNA molecules can be designed and used to inhibit the translation of YTHDF3 mRNA in vivo. Alternatively, ribozyme molecules can be designed to cleave and destroy YTHDF3 mRNA in vivo. Alternatively, oligonucleotides designed to hybridize to the 5' site of the YTHDF3 gene (including the region upstream of the coding sequence) and form a triple helix structure inhibit or reduce transcription of the YTHDF3 gene. In yet another alternative, a nucleic acid encoding a full-length wild-type YTHDF3 message can be introduced in vivo into cells that otherwise cannot produce the wild-type YTHDF3 gene product in sufficient quantities or at all.

[0053] In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the subject has or is at risk of being infected with a virus. In some embodiments, the subject is human. In some embodiments, the dosage of Compound (1) or a pharmaceutically acceptable salt thereof ranges from about 125 mg to about 625 mg. In some embodiments, a sample obtained from the subject is assayed for cleaved and / or intact cytokeratin 18, and a determination is made as to whether to continue the treatment regimen based on the results of the cleaved and / or intact cytokeratin 18 assay. In some embodiments, the treatment regimen of the present disclosure further comprises administering a second therapeutic agent, wherein Compound (1), a pharmaceutically acceptable salt thereof, or an analog thereof is administered before, simultaneously with, or after the administration of the second therapeutic agent.

[0054] In one aspect, the present disclosure provides a method for determining whether a subject with a disease state is likely to respond to a treatment regimen of the present disclosure. In some embodiments, the method includes: (i) obtaining a biological sample from the subject; (ii) measuring the expression, post-translational modification, or activity level or mutation of eIF2-alpha, ATF4, CHOP, or DR5 in the sample; (iii) comparing the measured level and / or found mutation in the sample with predetermined reference data; and (iv) determining whether the subject is likely to respond to the treatment regimen based on the measured level and / or found mutation in the sample relative to predetermined reference data. In another aspect, the present disclosure provides a method for evaluating or monitoring the effectiveness of a treatment regimen of the present disclosure or providing a prognosis for a subject with a disease state. In some embodiments, the method includes (i) obtaining a biological sample from a subject; (ii) measuring the expression, post-translational modification, or activity level or mutation of eIF2-alpha, ATF4, CHOP, or DR5 in the sample; (iii) comparing the measured level and / or detected mutation in the sample with predetermined reference data; and (iv) determining a prognosis or whether the subject will respond to a treatment regimen based on the measured level and / or detected mutation in the sample relative to the predetermined reference data. In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the subject is infected with or at risk of being infected with a virus. In some embodiments, the treatment regimen includes administering an effective amount of Compound (1), a pharmaceutically acceptable salt thereof, or an analog thereof.

[0055] In one aspect, the present disclosure provides a method for determining whether a subject with a disease state is likely to respond to the treatment regimen of the present disclosure.In some embodiments, the method includes: (i) obtaining a biological sample from a subject; (ii) measuring the expression, post-translational modification, or activity level or mutation of at least one dopamine receptor in the sample; (iii) comparing the measured level and / or found mutation in the sample with predetermined standard data; and (iv) determining whether the subject is likely to respond to the treatment regimen based on the measured level and / or found mutation in the sample relative to predetermined standard data.In another aspect, the present disclosure provides a method for evaluating or monitoring the effectiveness of the treatment regimen of the present disclosure or providing a prognosis for a subject with a disease state. In some embodiments, the method includes: (i) obtaining a biological sample from a subject; (ii) measuring the expression, post-translational modification, or activity level or mutation of at least one dopamine receptor in the sample; (iii) comparing the measured level and / or detected mutation in the sample with predetermined reference data; and (iv) determining a prognosis or determining whether the subject will respond to a treatment plan based on the measured level and / or detected mutation in the sample relative to the predetermined reference data. In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the treatment plan includes administering an effective amount of Compound (1), a pharmaceutically acceptable salt thereof, or an analog thereof. In some embodiments, the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3. In some embodiments, the dopamine receptor is from the D2-like family of dopamine receptors.

[0056] In one aspect, the present disclosure provides a method for screening potential therapeutic agents for a disease state. In some embodiments, the method includes: (i) contacting at least one G protein-coupled receptor (GPCR) with a test molecule that is a potential therapeutic agent for the disease state; (ii) measuring the binding affinity or interaction or GPCR signaling of the test compound with the GPCR; and (iii) comparing the binding affinity or interaction of the test molecule with a predetermined threshold, wherein a GPCR antagonism or GPCR signaling antagonism of the test molecule that is equal to or greater than the threshold is indicative of a therapeutic agent for the disease state. In one embodiment, the disease state is cancer. In one embodiment, the predetermined threshold is the GPCR antagonism or GPCR signaling antagonism of compound (1), or a pharmaceutically acceptable salt thereof, or an analog thereof.

[0057] In one aspect, the present disclosure provides a method for screening potential therapeutic agents for a disease state. In some embodiments, the method includes: (i) contacting at least one dopamine receptor with a test molecule believed to be a therapeutic agent for the disease state; (ii) measuring the binding affinity or interaction of the test molecule with the at least one dopamine receptor; and (iii) comparing the binding affinity or interaction of the test molecule to a predetermined threshold, wherein inhibition of the at least one dopamine receptor by the test molecule that is equal to or greater than the threshold is indicative of a therapeutic agent for the disease state. In some embodiments, the disease state is cancer. In some embodiments, the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3. In some embodiments, inhibition of the D2-like dopamine receptor family is indicative of a therapeutic agent for the disease state. In some embodiments, inhibition of both DRD2 and DRD3 is indicative of a therapeutic agent for the disease state. In some embodiments, the predetermined threshold is inhibition of at least one dopamine receptor by compound (1), or a pharmaceutically acceptable salt thereof, or an analog thereof.

[0058] In one aspect, the present disclosure provides a method for screening potential therapeutic agents for a disease state. In some embodiments, the method includes, using a processor, (i) using a computer docking method to model the binding or interaction, if any, of one or more three-dimensional structures (conformations) of a test molecule for the disease state, which is a potential therapeutic agent for the disease state, with a three-dimensional structure or model of at least one dopamine receptor; (ii) using the computational method to estimate the binding affinity or interaction of the test molecule with the structure or model of at least one dopamine receptor; and (iii) using the computational method to compare the binding affinity or interaction of the reference and test molecules with a predetermined threshold, wherein inhibition of at least one dopamine receptor by the test molecule that is equal to or greater than the threshold is indicative of a therapeutic agent for the disease state. In one embodiment, the disease state is cancer. In some embodiments, the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3. In one embodiment, inhibition of the D2-like dopamine receptor family is indicative of a therapeutic agent for the disease state. In one embodiment, inhibition of both DRD2 and DRD3 is indicative of a therapeutic agent for the condition. In one embodiment, the predetermined threshold is inhibition of at least one dopamine receptor by compound (1) or a pharmaceutically acceptable salt or analog thereof. In one embodiment, different dopamine antagonist compounds can be compared in three dimensions using pharmacophore modeling techniques, as described in Hogberg & Norinder, Chapter 3. Theoretical and Experimental Methods in Drug Design applied to Antipsychotic Dopamine Antagonists, in "A Textbook of Drug Design and Development," 1991, pp. 54-91, Krogsgaard-Larsen & Bundgaard, Eds., Harwood Academic Publishers GmbH, Chur, Switzerland.

[0059] In one aspect, the present disclosure provides methods of treating a subject having a medical condition and methods of assessing the effectiveness of the treatment. In some embodiments, the methods include (i) treating the subject with a treatment method of the present disclosure and (ii) assessing the effectiveness of the treatment as disclosed herein. In some embodiments, the subject has or is at risk of having cancer. In one embodiment, the treatment regimen includes administering an effective amount of Compound (1), a pharmaceutically acceptable salt thereof, or an analog thereof.

[0060] The foregoing summary, as well as the following detailed description of embodiments of therapeutic compositions and methods, will be better understood when read in conjunction with the appended claims. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities described herein. [Brief explanation of the drawings]

[0061] The foregoing summary, as well as the following detailed description of embodiments of the invention, will be better understood when read in conjunction with the accompanying drawings of illustrative embodiments, it being understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.

[0062] [Figure 1] 1 shows a dose-response relationship showing the effect of various concentrations of compound (1) on tumor and normal cell viability. [Figure 2] 1 shows a cell viability assay of human fetal lung fibroblast (MRC-5) cells after 72 hours of treatment with compound (1). [Figure 3] 1 shows the antagonism of dopamine receptors (DRD1, DRD2S, DRD2L, DRD3, DRD4, and DRD5) by ONC201. [Figure 4] Soluble prolactin detected by ELISA assay in peripheral blood of patients with advanced solid tumors at baseline and after a single dose of ONC201 (125-625 mg PO). Post-treatment sampling time points include 6 hours, 1, 2, 7, and 21 days after treatment. [Figure 5] Figure 1 shows the mean ONC201 plasma concentration versus time after the first dose of ONC201. Concentrations are shown as (A) the mean for each dosing cohort, or (B) for individuals treated with 625 mg. Error bars indicate standard deviation. [Figure 6] Individual measurements of ONC201 (A) AUC and (B) Cmax versus dose are shown. *Predicted linear dose proportionality based on men in the 625 mg dose group. [Figure 7] (A) shows the M30 assay ratio versus time after first dose, and (B) shows the M30 assay ratio for each patient. [Figure 8] In vitro susceptibility compared to patient susceptibility in this study is shown. DETAILED DESCRIPTION OF THE INVENTION

[0063] Scientific and technical terms used herein are intended to have meanings that are commonly understood by those of ordinary skill in the art. Such terms are found to be defined and used in the context of various reference sources. Examples of these sources include:J. Sambrook and DWRussell,Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Laboratory Press;3rd Ed.,2001;FMAusubel,Ed.,Short Protocols in Molecular Biology,Current Protocols;5th Ed.,2002;B.Alberts et al.,Molecular Biology of the Cell,4th Ed.,Garland,2002;DLNelson and MMCox,Lehninger Principles of Biochemistry,4th Ed.,WHFreeman & Company,2004;Engelke,DR,RNA Interference(RNAi):Nuts and Bolts of RNAi Technology,DNA Press LLC,Eagleville,Pa.,2003;Herdewijn,P.(Ed.),Oligonucleotide Synthesis:Methods and Applications,Methods in Molecular Biology,Humana Press, 2004; A. Nagy, M. Gertsenstein, K. Wintersten, R. Behringer, Manipulating the Mouse Embryo: A 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 U.S. Patent No. 8,673,923. The contents of each of the foregoing documents are incorporated herein by reference in their entirety.

[0064] The singular forms "a," "an," and "the" are not intended to be limiting and include plural referents unless expressly indicated or clearly indicated otherwise by context.

[0065] As used herein, the term "substituted" means replacing any one or more hydrogens on the specified atom with a group selected from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom and results in a stable compound. When the substituent is keto (i.e., =0), two hydrogens on the atom are replaced. Keto substituents do not occur on aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0066] In any substituent or formula of a compound, any variable (e.g., R 4 ) occurs more than one time, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, a group may contain 0 to 3 R 4 When a group is indicated to be substituted with a moiety, the group may optionally be substituted with up to three R 4 well substituted with part, and also with each occurrence of R 4 is R 4 Similarly, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0067] When an atom or chemical moiety is followed by a subscripted numerical range (e.g., C 1-6 ), it will be understood to include each value within a range as well as all intermediate ranges. For example, "C 1-6 "Alkyl" is meant to include alkyl groups having 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.

[0068] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C 1-6 Alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, s-pentyl, neopentyl, and n-hexyl. In certain embodiments, straight chain or branched chain alkyls have 6 or fewer carbon atoms in their backbone (e.g., C1-C6 for straight chain, C3-C6 for branched chain), while in other embodiments, straight chain or branched chain alkyls have 4 or fewer carbon atoms. Similarly, cycloalkyls have from 3 to 8 carbon atoms in their ring structure, while in other embodiments, cycloalkyls have 5 or 6 carbons in the ring structure. Most preferred are (C1-C6) alkyls, particularly ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0069] As used herein, the term "substituted alkyl" refers to alkyl as defined above substituted with one, two, or three substituents selected from the group consisting of halogen, -OH, alkoxy, -NH, -N(CH), -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C-C)alkyl, -C(=O)NH, -SONH, -C(=NH)NH, and -NO, preferably containing one or two substituents selected from halogen, -OH, alkoxy, -NH, trifluoromethyl, -N(CH), and -C(=O)OH, more preferably selected from halogen, alkoxy, and -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0070] Unless the number of carbon atoms is otherwise specified, "lower alkyl" includes alkyl groups, as defined above, having from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of from 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms.

[0071] "Alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl- or alkenyl-substituted cycloalkenyl groups, and cycloalkyl- or cycloalkenyl-substituted alkenyl groups. In certain embodiments, straight-chain or branched-chain alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight chains, C3-C6 for branched chains). Likewise, cycloalkenyl groups have from 3-8 carbon atoms in their ring structure, and in some embodiments, cycloalkenyl groups have 5 or 6 carbons in the ring structure. The term "C2-C6" includes alkenyl groups containing 2-6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3-6 carbon atoms.

[0072] "Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyl groups described above, but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonyl, decynyl), branched-chain alkynyl groups, and cycloalkyl- or cycloalkenyl-substituted alkynyl groups. In certain embodiments, a straight-chain or branched-chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms.

[0073] As used herein, "cycloalkyl" means a monocyclic or polycyclic aromatic group in which each atom forming the ring (i.e., skeletal atom) is a carbon atom. In one embodiment, the cycloalkyl group is saturated or partially unsaturated. In another embodiment, the cycloalkyl group is fused with an aromatic ring. Cycloalkyl groups include groups having 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

[0074] [ka]

[0075] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl groups include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyl groups include adamantane and norbornane. The term cycloalkyl includes "unsaturated non-aromatic carbocyclyl" or "non-aromatic unsaturated carbocyclyl" groups, both of which mean non-aromatic carbocyclic ring compounds, as defined herein, containing at least one carbon-carbon double bond or one carbon-carbon triple bond.

[0076] As used herein, "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group. Examples of cycloalkylalkyl groups include cyclopropylalkyl, cyclohexylalkyl, and the like.

[0077] As used herein, "heterocycloalkyl" refers to a non-aromatic heterocyclic compound in which one or more ring-forming atoms can be a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., 2, 3, or 4 fused rings) ring systems as well as spirocycles. Examples of heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. The definition of heterocycloalkyl can also include moieties having one or more aromatic rings fused to (i.e., sharing a common bond with) a non-aromatic heterocycle, such as quinolyl, isoquinolyl, and benzo derivatives of heterocyclic compounds. Heterocycloalkyl groups having one or more fused aromatic rings can be bonded through either the aromatic or non-aromatic portion. The definition of heterocycloalkyl can also include moieties in which one or more ring-forming atoms can be substituted with one or two oxo or sulfido groups. In some embodiments, heterocycloalkyl groups have 1 to about 20 carbon atoms, and in further embodiments, about 3 to about 20 carbon atoms. In some embodiments, heterocycloalkyl groups contain 3 to about 20, 3 to about 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups contain 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

[0078] As used herein, "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl group. Examples of heterocycloalkylalkyl groups include morpholinoalkyl and piperazinylalkyl, and the like.

[0079] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., 2, 3, or 4 fused rings) aromatic hydrocarbon, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, etc. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.

[0080] As used herein, "arylalkyl" refers to an alkyl group substituted with an aryl group. Examples of arylalkyl groups include benzyl and phenylethyl.

[0081] As used herein, a "heteroaryl" group refers to an aromatic heterocyclic compound having at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., 2, 3, or 4 fused ring) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety. Examples of heteroaryl groups include, but are not limited to, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, heteroaryl groups have 1 to about 20 carbon atoms, and in further embodiments, from about 3 to about 20 carbon atoms. In some embodiments, heteroaryl groups contain 3 to about 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups contain 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0082] As used herein, a "heteroarylalkyl" group refers to an alkyl group substituted with a heteroaryl group. An example of a heteroarylalkyl group is pyridylmethyl.

[0083] As used herein, "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine. The term "perhalogenated" means a moiety where all hydrogens have been replaced with halogen atoms.

[0084] The term "haloalkyl" means an alkyl moiety having halogen atoms replacing hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. A C1-C6 haloalkyl is intended to include a straight- or branched-chain alkyl having up to 6 carbon atoms in its backbone and halogen atoms replacing hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone.

[0085] The terms "alkoxy" and "alkoxyl" include substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. C1-C6 alkoxy refers to a moiety having six or fewer carbon atoms in the hydrocarbon backbone. Examples of alkoxy groups (or alkoxyl radicals) include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Preferred are (C1-C3) alkoxy, particularly ethoxy and methoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups.

[0086] The term "hydroxy" or "hydroxyl" refers to -OH or -O - The group includes a group having the formula:

[0087] The present invention also includes pharmaceutically acceptable salts of the disclosed compounds. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound has been modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention are synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are usually preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, Journal of Pharmaceutical Science, 66:2 (1977), and P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised edition, Weinheim / Zurich: Wiley-VCH / VHCA (2011), each of which is incorporated herein by reference in its entirety.

[0088] Examples of suitable inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid, while examples of suitable organic acids can include carboxylic acids, sulfonic acids, or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, maleic acid, salicylic acid, trifluoroacetic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, gluconic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, or naphthalene-2-sulfonic acid. Examples of suitable inorganic bases may include sodium hydroxide, potassium hydroxide and ammonia, while examples of suitable organic bases are amines, for example, tertiary amines such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline, isoquinoline, α-picoline, β-picoline, γ-picoline, quinaldine or pyrimidine.

[0089] I. Compound (1), its salts and synthesis thereof

[0090] The inventors have discovered in in vitro models, animal models, and human clinical trials that ONC201 (compound (1)) has broad anticancer activity, low toxicity with few, if any, adverse effects, low genotoxicity, and high bioavailability, including oral bioavailability. These characteristics make ONC201 and various analogs particularly suitable for a variety of uses.

[0091] In one aspect, the present invention provides a compound (1) represented by the following chemical formula, its analogs, and pharmaceutically acceptable salts thereof, as well as processes for their preparation:

[0092] [ka]

[0093] Compound (1) can be prepared by the synthetic process shown in Scheme 1 below. [ka]

[0094] In one embodiment, the synthesis of the dihydrochloride salt of compound (1) begins with the commercially available intermediate N-benzyl-3-carbomethoxy-4-piperidone hydrochloride, compound (3). In one embodiment, the synthesis process involves neutralizing intermediate compound (3) with a base (Step 1) to produce the free base of compound (4). In one embodiment, the synthesis process involves neutralizing intermediate compound (3) with an inorganic base to produce compound (4). In one embodiment, the synthesis process involves neutralizing intermediate compound (3) with an organic base to produce compound (4). In one embodiment, intermediate compound (3) is neutralized in the presence of an alcohol. For example, intermediate compound (3) is neutralized in the presence of n-butanol. In one embodiment, intermediate compound (3) is neutralized in the presence of at least one organic solvent. For example, intermediate compound (3) is neutralized in the presence of n-butanol and / or ethyl acetate. In one embodiment, intermediate compound (3) is neutralized in the presence of a base and at least one organic solvent. For example, intermediate compound (3) is neutralized in the presence of NaHCO and n-butanol. In one embodiment, intermediate compound (3) is neutralized in the presence of n-butanol and triethylamine (EtN).

[0095] In one embodiment, the synthesis process includes reacting compound (4) with compound (5) (Step 2) to produce intermediate compound (1). In one embodiment, the reaction in Step 2 includes heating compound (4) with compound (5). In one embodiment, the reaction in Step 2 includes heating compound (4) and compound (5) to reflux in the presence of a solvent. In one embodiment, the reaction in Step 2 includes using a Dean-Stark trap to remove water and / or methanol (MeOH) formed during the reaction.

[0096] In one embodiment, the synthetic process 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. In one embodiment, the synthetic process optionally includes recrystallization of the di-salt of compound (1).

[0097] In one preferred embodiment, the synthetic process for the preparation of the dihydrochloride salt of compound (1) is as shown in Scheme 2 below.

[0098] [ka]

[0099] II. TNF-Related Apoptosis-Inducing Ligand ("TRAIL")

[0100] TRAIL protein can be assayed in a test sample obtained from a subject to detect TRAIL expression induced by the compounds of the present disclosure and their salts. TRAIL can be assayed in a sample using immunoassay methods, including but not limited to enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunofiltration assay (ELIFA), flow cytometry, immunoblot, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescence immunoassay (LIA), fluorescence immunoassay (FIA), and radioimmunoassay. Qualitative and / or quantitative results can be obtained using assay methods. Specific details of suitable assay methods for both qualitative and quantitative assay of samples are described in standard literature, including the following examples: E. Harlow & D. Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1988; F. Breitling & S. Diibel, Recombinant Antibodies, John Wiley & Sons, New York, 1999; H. Zola, Monoclonal Antibodies: Preparation and Use of Monoclonal Antibodies and Engineered Antibody Derivatives, Basics: 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,Current Protocols,Wiley,2002;S.Klussman,Ed.,The Aptamer Handbook:Functional Oligonucleotides and Their Applications,Wiley,2006;Ormerod,MG,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:morphologic-immunophenotypic correlation,Taylor & Francis,2006;Crowther,JR,The ELISA Guidebook(Methods in 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 ed., 2001.

[0101] An example of a protocol for assaying and analyzing samples for TRAIL to detect the effects of a pharmaceutical composition is described in U.S. Patent No. 8,673,923 to Wafik S. El-deiry et al., which is incorporated herein by reference in its entirety.

[0102] In one embodiment, a subject is monitored using a TRAIL assay. Thus, for example, test samples are obtained from a subject before treatment with a pharmaceutical composition, and one or more times during and / or after treatment to evaluate the effectiveness of the treatment. In a further example, test samples are obtained from a subject at various time points to evaluate the course or progression of a disease or cure. In one embodiment, death receptors from circulating tumor cells can also be analyzed to determine whether administration of compound (1) or a salt thereof of the present disclosure increases the amount or type of death receptors.

[0103] Cancers that can be treated using the methods and compositions of the present disclosure are characterized by abnormal cell proliferation, including, but not limited to, preneoplastic hyperproliferation, intraepithelial carcinoma, tumors, and metastases. The methods and compositions of the present disclosure can be used to prevent cancer and ameliorate signs and / or symptoms. The terms "treating" and "treatment," when used to refer to the treatment of a subject's cancer, include preventing, inhibiting, or ameliorating the subject's cancer, such as slowing the progression of cancer and / or reducing or ameliorating the signs or symptoms of cancer. Examples of cancers that can be treated using the methods and compositions of the present disclosure include, but are not limited to, breast cancer, CNS cancer, colon cancer, ovarian cancer, prostate cancer, leukemia, lung cancer, and lymphoma.

[0104] III. Compound (10) and its salts

[0105] In one aspect, the present disclosure provides compounds of formula (10) and related salts, and methods for their preparation. Those skilled in the art will understand that the general principles and concepts of the present disclosure relating to compound (1) and its salts, including principles and concepts related to methods and pharmaceutical compositions, apply equally to compounds of formula (10) and their salts.

[0106] In some embodiments, the present disclosure provides a compound represented by the following chemical formula (10):

[0107] [ka]

[0108] wherein R1 and R2 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, and acyl groups, and when R1 is CH2Ph, then R2 is not CH2-((2-CH3)-Ph).

[0109] In some embodiments, R and R are H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, C 1-4 Alkylthienyl, C 1-4 Alkylpyridinyl, C 1-4 Alkylisoxazolidinyl, C 1-4 Alkylmorpholinyl, C 1-4 Alkylthiazolyl, and C 1-4 alkylpyrazinyl, independently selected from the group consisting of C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, C 1-4 Alkylthienyl, C 1-4 Alkylpyridinyl, C 1-4 Alkylisoxazolidinyl, C 1-4 Alkylmorpholinyl, C 1-4 Alkylthiazolyl, and C 1-4 Alkylpyrazinyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, R and / or R are substituted or unsubstituted aryl alkyl or heteroaryl alkyl. In some embodiments, heteroaryl alkyl is C 1-4 Alkylpyrrolyl, C 1-4 Alkylfuryl, C 1-4 Alkylpyridyl, C 1-4 Alkyl-1,2,4-thiadiazolyl, C 1-4 Alkylpyrimidyl, C 1-4 Alkylthienyl, C 1-4 Alkylisothiazolyl, C 1-4 Alkyl imidazolyl, C 1-4 Alkyltetrazolyl, C 1-4 Alkylpyrazinyl, C 1-4 Alkylpyrimidyl, C1-4 Alkylquinolyl, C 1-4 Alkylisoquinolyl, C 1-4 Alkylthiophenyl, C 1-4 Alkylbenzothienyl, C 1-4 Alkylisobenzofuryl, C 1-4 Alkylpyrazolyl, C 1-4 Alkyl indolyl, C 1-4 Alkylpurinyl, C 1-4 Alkylcarbazolyl, C 1-4 Alkylbenzimidazolyl, and C 1-4 alkylisoxazolyl.

[0110] In some embodiments, R1 and / or R2 are selected from one or more of the following substituents on the benzyl ring: X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m benzyl optionally substituted with R m and R n are independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20, and X is a halogen including a fluorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine.

[0111] In some embodiments, R1 is H, CH3, CH2Ph, CH2-(4-CF3-Ph), CH2-(4-F-Ph), CH2-(4-Cl-Ph), CH2-(OCH3-Ph), CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2-(3-thienyl), CH2-2-pyridinyl, CH2-4-methyl-2-thiazolyl, CH2-2-pyridinyl, CH2CH2Ph, CH2CH2 (4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-(3,4-diCl-Ph), CH2-(3,4-diF-Ph), CH2-(3,5-diF-Ph), CH2-((2-CH3)-Ph), CH2CH(OH)Ph, (4-F-Ph)-4-oxobutyl, CH2CH2NHCOOC(CH3)3, CH2CH2CH2NH2, and CD2C6D5. In some embodiments, R2 is H, CH3, CH2Ph, CH2-(4-CF3-Ph), CH2-((2-Cl)-Ph), CH2-((2-F)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzylpiperazine), CH2-(2,4-diF-Ph), CH2-(2,4-diF-Ph), CH2-(2,4-diCl-Ph), CH2-(3,4-diCl-Ph), CH2-(3,4-diF-Ph), CH2-(3,5-diF-Ph), CH2 -((2-CH3)-Ph), CH2(2-CH3,4-F-Ph), CH2-((4-OCH3)-Ph), CH2-(3-pyridinyl), CH2-(3-isoxazolidinyl), CH2CH2-(4-morpholinyl), CH2-(2-F,4-CF3-Ph), CH2CH(OH)Ph, (CH2)3CO-4F-Ph, (4-F-Ph)-4-oxobutyl, CH2CH2NHCOOC(CH3)3, CH2CH2CH2NH2, and CD2C6D5.

[0112] In some embodiments, R is hydrogen. In some embodiments, R is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C1-4 It is substituted with alkyl or halo.

[0113] In one embodiment, R2 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In one embodiment, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In one embodiment, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R2 is a substituted or unsubstituted heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In one embodiment, R2 is a substituted or unsubstituted heteroarylalkyl, such as an isoxazolidinylmethyl or pyridylmethyl group. In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, —CH 3 , —CF 3 , and —OCH 3 .

[0114] In one embodiment, compound (10) has the structure of compound (80):

[0115] [ka]

[0116] In the formula, R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , and R b5is X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m R m and R n is independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20, and X is a halogen.

[0117] In one embodiment, compound (10) has the structure of compound (90):

[0118] [ka]

[0119] where R2 is as defined above and R b1 , R b2 , R b3 , R b4 , and R b5 is X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R.m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m R m and R n is independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20, and X is a halogen.

[0120] In one embodiment, compound (10) has the structure of compound (40):

[0121] [ka]

[0122] where R1 is as defined above and R a1 , R a2 , R a3 , R a4 , and R a5 is hydrogen, X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m R m and R nare independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20, and X is halogen. In one embodiment, R1 is hydrogen. In one embodiment, R1 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In one embodiment, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 It is substituted with alkyl or halo. In one embodiment, the benzyl is substituted with one or more halogens. In one embodiment, the benzyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, the benzyl is substituted with one halogen substituent, for example, a fluorine substituent at the ortho or para position. In one embodiment, the benzyl is substituted with two halogen substituents, for example, a fluorine substituent at both meta positions.

[0123] In one embodiment, compound 40 has the structure of compound 45:

[0124] [ka]

[0125] In the formula, R a1 , R a2 , R a3 , R a4 , and R a5 is as defined above. In one embodiment, benzyl is substituted with one or more halogens. In some embodiments, benzyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R a1 or R a5 is a halogen, for example, fluorine. In one embodiment, R a2 or R a3 is a halogen, e.g., fluorine, substituent.

[0126] In one embodiment, compound (10) has the structure of compound (50):

[0127] [ka]

[0128] where R1 is as defined above and R b is X, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2R m , C(O)R m , and C(O)OR m selected from the group consisting of: R m and R n are independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20, X is a halogen, and R a1 , R a2 , R a4 , and R a5 is hydrogen, X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, -OC p H 2p+1 , -OC p X 2p+1 , OR m , S.R. m , N.R. m R n , N.R. m C(O)R n , SOR m , SO2Rm , C(O)R m , and C(O)OR m R m and R n are independently selected from hydrogen or C1-C4 alkyl; p is an integer from 2 to 20, and X is halogen. In one embodiment, R1 is hydrogen. In one embodiment, R1 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In one embodiment, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In one embodiment, R b is selected from the group consisting of halo, -CH, -CF, and -OCH. a1 , R a2 , R a4 , and R a5 In one embodiment, one or more of R a1 , R a2 , R a4 , and R a5 is hydrogen and R b is selected from the group consisting of halo, —CH, —CF, and —OCH. In one embodiment, R b is a halogen, e.g., fluorine, and R a1 is methyl. In one embodiment, R b is fluorine or chlorine, and R a2 is fluorine or chlorine. In one embodiment, R b is CF. In one embodiment, R b is —OCH3. In one embodiment, R b is chlorine and R a1 is chlorine.

[0129] In one embodiment, compound (50) has the structure of compound (55):

[0130] [ka]

[0131] In the formula, R a1 , R a2 , R a4 , R a5 , and R b is as defined above. In one embodiment, R b is selected from the group consisting of halo, -CH, -CF, and -OCH. a1 , R a2 , R a4 , and R a5 In one embodiment, one or more of R a1 , R a2 , R a4 , and R a5 is hydrogen and R b is selected from the group consisting of halo, —CH, —CF, and —OCH. In one embodiment, R b is a halogen, e.g., fluorine, and R a1 is methyl. In one embodiment, R b is fluorine or chlorine, and R a2 is fluorine or chlorine. In one embodiment, R b is CF. In one embodiment, R b is OCH. In one embodiment, R b is chlorine and R a1 is chlorine.

[0132] In one embodiment, compound (10) has the structure of compound (60):

[0133] [ka]

[0134] In some embodiments, R is hydrogen. In some embodiments, R is substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, R is substituted or unsubstituted heterocycloalkylalkyl, or substituted or unsubstituted heteroarylalkyl, such as CH-(2-thienyl), CH-(3-thienyl), CH-2-pyridinyl, CH-3-pyridinyl, CH-4-methyl-2-thiazolyl, CH-2-pyrazinyl, CHCH(4-N-benzylpiperazine), CH-(3-isoxazolidinyl), and CHCH-(4-morpholinyl). In one embodiment, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 It is substituted with alkyl or halo. In one embodiment, benzyl is substituted with one or more halogens. In some embodiments, benzyl is substituted with one or more substituents selected from the group consisting of halo (e.g., fluorine), -CH3, -CF3, and -OCH3. In one embodiment, benzyl is substituted at the para position with a substituent selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R1 is fluorophenyloxobutyl or hydroxyphenylethyl.

[0135] Scheme 3 illustrates the synthesis of a compound of formula (10):

[0136] [ka]

[0137] Compounds of formula (10) above are synthesized starting from substituted piperidones, which are converted by reaction with substituted aminoimidazolines to give the core compounds (10). Two routes are available, one in which the R1 substituent is present in the piperidone (e.g., 68). In this route, 68 is acylated with dimethyl carbonate in toluene using sodium hydride at 80 °C to form the piperidone ester (69). Commercially available methylthioimidazoline HI salt (63) is reacted with an amine in dioxane at 70 °C to give the R2-substituted aminoimidazoline (64) as its HI salt. Direct reaction of 64 with the piperidone ester (69) in 1-butanol at reflux with water removal using a Dean-Stark trap for 3–6 h affords the tricyclic compounds (10). In a variation of this scheme, N-BOC-protected piperidone 61 is converted to the BOC-protected compound 65 in the same manner, and the BOC group is removed by treatment with HCl in dioxane, followed by conversion to the free base 66 using 1N NaOH and extraction with methylene chloride. Subsequent treatment of 66 with halide 67 or epoxide 70 affords the desired compound 10.

[0138] The crude product can be purified by column chromatography eluting with methylene chloride:methanol or by HPLC using acetonitrile:TFA:HO to yield the final product as the free base or TFA salt. Treatment of the free base with HCl in dioxane or lyophilization of the TFA salt yields product (10) as the HCl or TFA salt. Alternatively, the free base may be treated with another inorganic or organic acid to form other salts, typically selected from those known to be pharmaceutically acceptable salts. Salts of compound (10) are typically solids, and in some instances have been crystallized from ethanol or other solvents to yield high-quality crystals. The tricyclic chemical formula structure has been conclusively confirmed in the case of compound (1) by X-ray crystallography and NMR.

[0139] The compounds of the present disclosure, with or without an aminoalkyl linker (e.g., compound 33), can be used to identify molecules (e.g., proteins) that interact with them in specific cellular contexts. Expression of these binding targets can be used to predict response to compound 1 (ONC201) or its analogs (i.e., serve as biomarkers). Additionally, these compounds can be used to screen structurally unrelated anti-cancer compounds using competition assays known in the art to identify drugs that can outcompete target interactions with higher affinity. Furthermore, these molecules may possess drug properties that provide therapeutic improvements or enable additional therapeutic uses by altering drug properties, including, but not limited to, pharmacokinetics, efficacy, safety, biodistribution, or metabolism.

[0140] [Table 12-1]

[0141] [Table 12-2]

[0142] As described in Example 12 below, compound 1 was used with an aminoalkyl linker (i.e., compound 33) to identify proteins that interact with compound 1. Compound 1 binds to N6-methyladenosine (m 6 A) It was found to interact with proteins involved in mRNA methylation. 6 Proteins involved in mRNA epigenetic modification include those in Table 1. These proteins include those that methylate mRNA (RNA writers), such as METTL3, METTL14, WTAP, and KIAA1429; 6 A mRNA demethylators (RNA erasers); and m 6A. It includes something that specifically recognizes RNA (RNA leader).

[0143] [Table 1]

[0144] IV. Evaluating the sensitivity and efficacy of the treatment regimen Measuring the expression, post-translational modification, or activity levels of eIF2-alpha, ATF4, CHOP, DR5, or truncated or intact cytokeratin 18, or mutations thereof, can be used to predict response or susceptibility to the therapeutic methods of the present disclosure and to identify subjects likely to respond to the therapeutic methods of the present disclosure, such as treatment with compound (1), its pharmaceutically acceptable salts, or analogs thereof. Furthermore, measuring the expression, post-translational modification, or activity levels of eIF2-alpha, ATF4, CHOP, DR5, or truncated or intact cytokeratin 18, or mutations thereof, can be used to evaluate or monitor the efficacy of the therapeutic methods of the present disclosure. Furthermore, measuring the expression, post-translational modification, or activity levels of eIF2-alpha, ATF4, CHOP, DR5, or truncated or intact cytokeratin 18, or mutations thereof, can enable in vivo, in vitro, or in silico screening of structurally unrelated anticancer compounds. For example, competition and other assays known in the art can be used to identify drugs that can outcompete target interactions with higher affinity and compare changes in those levels to the respective changes caused by compound (1) or an analog thereof. Assays can also be performed on living mammalian cells, which more closely approximates the effect of a drug on specific serum levels in the body or on microsomal extracts prepared from cultured cell lines.

[0145] In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the treatment regimen comprises administering an effective amount of Compound (1) or Compound (10), or an analog thereof. In some embodiments, the treatment regimen comprises administering an effective amount of Compound (1). In some embodiments, the treatment regimen comprises administering an effective amount of a compound of Formula (10). In some embodiments, the compound of Formula (10) is a compound of Formula (40), e.g., a compound of Formula (45). In some embodiments, the compound of Formula (10) is a compound of Formula (50), e.g., a compound of Formula (55). In some embodiments, the compound of Formula (10) is a compound of Formula (80). In some embodiments, the compound of Formula (10) is a compound of Formula (90). In some embodiments, the compound of Formula (10) is a compound of Formula (60). In some embodiments, the analog of compound (1) has a structure selected from the structures of compound (25), compound (26), compound (27), compound (28), compound (29), compound (30), or compound (31).

[0146] The predetermined reference level can be, for example, the mean or median value measured in samples from the subject. The predetermined reference level can be measured under the same or substantially similar experimental conditions as those for measuring samples from the subject. The predetermined reference level can be obtained from subjects who respond to treatment with Compound (1) or Compound (10) or an analog thereof. In one embodiment, the predetermined reference level is obtained from subjects who respond to treatment with the compound, and if the level in the sample from the subject is similar to the reference value, the subject can be classified as likely to respond to the treatment. The predetermined reference level can be obtained from subjects who respond to treatment with the compound. In one embodiment, the predetermined reference level is obtained from subjects who do not respond to treatment with the compound, and if the level in the sample from the subject is different from the predetermined reference value (e.g., up- or down-regulated), the subject can be classified as likely to respond to the treatment. The predetermined reference level can be obtained from healthy subjects.

[0147] Immunoassays can be used to assay protein or methylation levels in a sample, including, but not limited to, enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunofiltration assay (ELIFA), flow cytometry, immunoblot, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescence immunoassay (LIA), fluorescence immunoassay (FIA), and radioimmunoassay. 6 A mRNA methylation level can be obtained by methylated RNA immunoprecipitation (Me-RIP) or other quantitative biochemical assays known in the art.

[0148] Nucleic acid mutations can be determined by any of a number of known procedures. For example, a biological sample from an individual can first be obtained. Such biological samples include, but are not limited to, bodily fluids (e.g., urine, saliva, plasma, or serum) or tissue samples (e.g., oral tissue samples or oral cells). The biological sample can then be sequenced or scanned using known methods. For example, DNA arrays can be used to analyze at least a portion of a subject's genome sequence. Additionally, full or partial genome sequence information can be used. Such sequences can be determined using standard sequencing methods, including chain termination (Sanger dideoxynucleotide), dye-terminator sequencing, and SOLID™ sequencing (Applied Biosystems). The entire genome sequence can be digested with restriction enzymes or (mechanically) cut into shorter fragments for sequencing. DNA sequences can also be amplified using known methods, such as PCR and vector-based cloning methods (e.g., E. coli). In one embodiment, at least a portion of a subject's genetic material (e.g., DNA, RNA, mRNA, cDNA, other nucleotide bases, or derivatives thereof) is scanned or sequenced to identify the presence or absence of mutations or changes in copy number, for example, using conventional DNA sequencers or chip-based technology.

[0149] In one aspect, the present disclosure provides a method for identifying and treating a subject having a medical condition who is likely to respond to a treatment regimen of the present disclosure. In one embodiment, the method includes (i) determining whether a subject having the medical condition is likely to respond to a treatment regimen of the present disclosure; and (ii) treating the subject determined to be likely to respond to the treatment regimen with the treatment regimen. In one embodiment, the subject has or is at risk of having cancer. In one embodiment, the treatment regimen includes administering an effective amount of Compound (1) or Compound (10), or an analog thereof. In some embodiments, the treatment regimen includes administering an effective amount of Compound (1). In some embodiments, the treatment regimen includes administering an effective amount of a compound of Formula (10). In some embodiments, the compound of Formula (10) is a compound of Formula (40), e.g., a compound of Formula (45). In some embodiments, the compound of Formula (10) is a compound of Formula (50), e.g., a compound of Formula (55). In some embodiments, the compound of Formula (10) is a compound of Formula (80). In some embodiments, the compound of Formula (10) is a compound of Formula (90). In some embodiments, the compound of Formula (10) is a compound of Formula (60). In some embodiments, the analog of Compound (1) has a structure selected from the structures of Compound (25), Compound (26), Compound (27), Compound (28), Compound (29), Compound (30), or Compound (31).

[0150] The predetermined reference level can be, for example, the mean or median value measured in samples from the subject. The predetermined reference level can be measured under the same or substantially similar experimental conditions as those for measuring samples from the subject. The predetermined reference level can be obtained from subjects who respond to treatment with Compound (1) or Compound (10) or an analog thereof. In one embodiment, the predetermined reference level is obtained from subjects who respond to treatment with the compound, and if the level in the sample from the subject is similar to the reference value, the subject can be classified as likely to respond to the treatment. The predetermined reference level can be obtained from subjects who respond to treatment with the compound. In one embodiment, the predetermined reference level is obtained from subjects who do not respond to treatment with the compound, and if the level in the sample from the subject is different from the predetermined reference value (e.g., up- or down-regulated), the subject can be classified as likely to respond to the treatment. The predetermined reference level can also be obtained from healthy subjects. The level of a protein in a sample can be assayed using an immunoassay.

[0151] In one aspect, the present disclosure provides methods of treating a subject having a medical condition and methods of assessing the effectiveness of the treatment. In some embodiments, the methods include (i) treating the subject with a treatment method of the present disclosure and (ii) assessing the effectiveness of the treatment as disclosed herein. In some embodiments, the subject has or is at risk of having cancer. In some embodiments, the treatment regimen includes administering an effective amount of Compound (1) or Compound (10), or an analog thereof. In some embodiments, the treatment regimen includes administering an effective amount of Compound (1). In some embodiments, the treatment regimen includes administering an effective amount of a compound of Formula (10). In some embodiments, the compound of Formula (10) is a compound of Formula (40), e.g., a compound of Formula (45). In some embodiments, the compound of Formula (10) is a compound of Formula (50), e.g., a compound of Formula (55). In some embodiments, the compound of Formula (10) is a compound of Formula (80). In some embodiments, the compound of Formula (10) is a compound of Formula (90). In some embodiments, the compound of Formula (10) is a compound of Formula (60). In some embodiments, the analog of Compound (1) has a structure selected from the structures of Compound (25), Compound (26), Compound (27), Compound (28), Compound (29), Compound (30), or Compound (31).

[0152] Other conditions that may be suitable for the methods described herein include, but are not limited to, attention deficit disorder; addiction; epilepsy; viral infections; inflammation; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, etc.; cardiovascular diseases such as coronary artery disease, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, arrhythmias, inflammatory heart disease, endocarditis, inflammatory cardiac hypertrophy, myocarditis, valvular heart disease, cerebrovascular disease, peripheral arterial disease, congenital heart disease, rheumatic heart disease, and light chain amyloidosis.

[0153] V. Composition

[0154] In one aspect, there is provided a pharmaceutical composition comprising a compound of the following formula (10) or a compound of the following formula (1), and pharmaceutically acceptable salts thereof.

[0155] [ka]

[0156] [ka]

[0157] In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound. In one embodiment, the salt is a pharmaceutically acceptable mono-salt of the compound. In one embodiment, the salt is a pharmaceutically acceptable di-salt of the compound. In one embodiment, the salt is a pharmaceutically acceptable mono- or multi-salt (e.g., di-salt, tri-salt) selected from the group consisting of hydrochloride, hydrobromide, bisulfate, sulfate, phosphate, fumarate, succinate, oxalate, lactate, bisulfate, hydroxyl, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, acetate, and carboxylate. In one embodiment, the salt is a pharmaceutically acceptable salt selected from the group consisting of p-toluenesulfonate, benzenesulfonate, citrate, methanesulfonate, oxalate, succinate, tartrate, fumarate, and maleate. In one embodiment, the salt is a pharmaceutically acceptable salt having a counterion selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and / or a counterion such as methylamino, dimethylamino, diethylamino, and triethylamino, hi one embodiment, the salt is a dihydrochloride or dihydrobromide salt of the compound.

[0158] Compound (1) has the same chemical structure as revealed by structural analysis (eg, NMR, X-ray diffraction) of compound NSC350625, available from the National Cancer Institute's Drug Discovery Program Repository.

[0159] In one embodiment, the pharmaceutical composition comprises a di-salt (e.g., a di-hydrochloride salt) of Compound (1) or an analog thereof (e.g., a compound of Formula (10)). Salts (e.g., di- or tri-salts) of analogs of Compound (1) can be prepared from analogs of Compound (1), which can be synthesized as disclosed herein or using standard chemical synthesis methods known to those of skill in the art.

[0160] In one embodiment, pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier.Suitable pharmaceutically acceptable carrier includes but is not limited to those found in 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. Representative pharmaceutically acceptable carriers, pharmaceutical compositions, and methods of manufacturing various dosage forms, as well as methods of administration, are known in the art, as detailed, for example, in Pharmaceutical Dosage Forms: Tablets, edited by Larry L. Augsburger & Stephen W. Hoag, London: Informa Healthcare, 2008; L.V. Allen, Jr. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Ed., Philadelphia, Pa.: Lippincott, Williams & Wilkins, 2004; A.R. Gennaro, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st Ed., 2005, particularly chapter 89; and J.G. Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill Professional, 10th Ed., 2001.

[0161] In one embodiment, the pharmaceutical composition is formulated for ocular administration. In one embodiment, the pharmaceutical composition is formulated for topical ocular administration. In one embodiment, the pharmaceutical composition is formulated as drops, an ointment, or a solution. In one embodiment, the pharmaceutical composition comprises a conventional pharmaceutical carrier, such as an aqueous, powder, or oily base, a thickener, or the like.

[0162] In some embodiments, the pharmaceutical composition is a formulation for intravenous administration. In one embodiment, the intravenous formulation comprises a compound of Formula (10), or a pharmaceutically acceptable salt thereof, dissolved in a solvent. In one embodiment, the solvent comprises water. In one embodiment, the intravenous formulation comprises the compound or a salt thereof at a concentration of about 0.05, about 0.25, about 0.5, about 2.5, about 5, about 25, or about 50 mg / mL. In one embodiment, the intravenous formulation comprises the compound or a salt thereof at a concentration of about 0.05, 0.5, or 5 mg / mL to about 1, 10, or 100 mg / mL. In one embodiment, the intravenous formulation comprises about 0.005%, 0.05%, or 0.5% to about 0.1%, 1%, or 10% of the compound or a salt thereof. In one embodiment, the intravenous formulation comprises about 0.05%, 0.5%, or 5% of the compound or a salt thereof. In some embodiments, the intravenous formulation contains a higher or lower concentration of the compound or salt thereof.

[0163] In some embodiments, the intravenous formulation has a pH of about 3. In one embodiment, the intravenous formulation is adjusted to pH 3 with a phosphate buffer. In one embodiment, the intravenous formulation comprises dextrose or sodium chloride. In one embodiment, an intravenous formulation containing the compound or its salt at a concentration of about 5 mg / ml and at pH 3 forms a stable solution. In one embodiment, an intravenous formulation containing the compound or its salt at a concentration of about 5 mg / ml, has a pH of less than 5, and forms a stable solution. In one embodiment, the intravenous formulation comprises the compound or its salt and one or more antioxidants. In one embodiment, the intravenous formulation comprises a mixture of the monohydrochloride and dihydrochloride salts of the compound. In one embodiment, the intravenous formulation comprises the compound or its salt as a 1% solution at a concentration of about 10 mg / mL. For example, the intravenous formulation is a solution having a pH of about 3.3. In one embodiment, the pH is less than 4.0.

[0164] In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In one embodiment, a suitable pharmaceutically acceptable carrier comprises an oil. In one embodiment, the pharmaceutically acceptable carrier comprises sterile water. In one embodiment, a suitable pharmaceutically acceptable carrier comprises an aqueous carrier. In some embodiments, the intravenous formulation comprises dextrose and / or sodium.

[0165] In one embodiment, the intravenous formulation comprises Compound (1) or an analog thereof or its dihydrochloride salt dissolved in water at 25 mg / ml. In one embodiment, the intravenous formulation is adjusted to pH 3 with a phosphate buffer. In one embodiment, the intravenous formulation comprises dextrose or sodium chloride. In one embodiment, the intravenous formulation comprises a higher or lower concentration of Compound (1) or an analog thereof or its dihydrochloride salt. In one embodiment, the intravenous formulation comprises Compound (1) or an analog thereof or its dihydrochloride salt at a concentration of about 5 mg / ml. In one embodiment, the intravenous formulation comprises Compound (1) or an analog thereof or its dihydrochloride salt at a concentration of about 5 mg / ml and forms a stable solution at pH 3. In one embodiment, the intravenous formulation comprises Compound (1) or an analog thereof or its dihydrochloride salt at a concentration of about 5 mg / ml and forms a stable solution at a pH below 5. In one embodiment, the intravenous formulation comprises Compound (1) or an analog thereof or its dihydrochloride salt and one or more antioxidants. In one embodiment, the intravenous formulation comprises a mixture of the monohydrochloride and dihydrochloride salts of Compound (1) or an analog thereof. In one embodiment, the intravenous formulation comprises Compound (1) or an analog thereof or their dihydrochloride salts as a 1% solution at a concentration of about 10 mg / ml. For example, the intravenous formulation is a solution having a pH of about 3.3. In one embodiment, the pH is less than 4.0.

[0166] 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 an analogue thereof or a di-salt thereof. In one embodiment, the intravenous formulation contains about 5% (or about 50 mg / ml) of Compound (1) or Compound (1) or an analogue thereof or a di-salt thereof. In one embodiment, the intravenous infusion rate may be slowed to reduce side effects of Compound (1) or an analogue thereof or a di-salt thereof.

[0167] In one embodiment, the pharmaceutical composition comprises about 0.1-99% of a salt of Compound (1) or an analog thereof and a pharmaceutically acceptable carrier, such as oil or sterile water or other aqueous carrier. In one embodiment, the pharmaceutical composition comprises a mono- or di-salt of Compound (1) or an analog thereof in the range of about 5% to about 50% for oral dosage forms.

[0168] In some embodiments, the pharmaceutical composition contains an antioxidant. Suitable antioxidants include ascorbic acid, erythorbic acid, ascorbic acid derivatives such as sodium ascorbate, thioglycerol, cysteine, acetylcysteine, cysteine, dithioerythritol, dithiothreitol, glutathione, and other thiol derivatives, tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sulfites such as sodium sulfate, sodium bisulfite, sodium acetone bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate, and nordihydroguaiaretic acid. It should be noted that 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 still other embodiments, the antioxidant can be one or more of 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, beta-carotene, and ascorbic acid. Antioxidants can typically be used at about 0.1% to 1.0% by weight, more typically at about 0.2%.

[0169] In one embodiment, the pharmaceutical composition comprises Compound (1) or Compound (10), or an analog thereof, or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent. For example, the other therapeutic agent may be hormone analogs and antihormones, 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, RAF inhibitors, MEK inhibitors, ERK inhibitors, IGF-1 inhibitors, or the like. R inhibitors, ErbB receptor inhibitors, rapamycin analogues, BTK inhibitors, CRM1 inhibitors (e.g., KPT185), P53 modulators (e.g., Nutlin), angiogenesis inhibitors (e.g., axitinib, aflibercept, sorafenib, and regorafenib), amifostine, anagrelide, 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-epothilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, a Ranose, Arglabin, Arzoxifene, Atamestane, Atrasentan, Auristatin PE, AVLB, AZ10992, 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-736, ARQ680,AS-703026 (primasertib), Avastin, AZD-2014, Azacitidine, Azaepothilone B, Azonafide, BAY-43-9006, BAY80-6946, BBR-3464, BBR-3576, Bevacizumab, BEZ-235, Bilicodextrin 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, bryostatin-1, bortezomib, brostallicin, busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1, cefixime, cefratonin, ceftriaxone, celecoxib B, cermoleukin, cemadotin, CH4987655 / RO-4987655, chlorotrianisene, cilengitide, 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, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexate, edotreotide, efaproxiral,Eflornithine, EGFR inhibitor, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3, ethinylcytidine, ethinyl estradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, Forfox, Forfox 4, forfili, formestane, fotemustine, galarubicin, gallium maltolate, gefitinib , gemtuzumab, gimatecan, glufosfamide, 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, GSK-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, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (cixutumumab), Immunol, indisulam, interferon alfa-2a , interferon alfa-2b, pegylated interferon alfa-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, Kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuprorelin, lexidronam,LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, lutetecan, LY-S6AKT1, LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitor, MEK-162, methyltestosterone, methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaphyrin gadolinium, MS-209, MS-275, MX6, Neridronate, neratinib, Nexavar, Neovastat, Nilotinib, Nimesulide, Nitroglycerin, Nolatrexed, Norelin, N-acetylcysteine, 6-benzylguanine, Oblimersen, Omeprazole, Oncophage, OncoVEX, GM-CSF, Ormiplatin, Ortataxel, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-IBB antibody, Oxatrazol, Estrogen, Panitumumab, Patupilone, Pegfil 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, pelitinib, pemetrexed, pentrix, perifosine, perillyl 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, polybutene, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, R115777, RAF-265,Ramosetron, ranpirnase, RDEA-119 / BAY 869766, RDEA436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, regorafenib, Revimid, 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 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabalubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, 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, tacedinaline, talaporfin, tarceva, tariquitar, tasisulam, taxotere, taxoplexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide Id, Theralux, terarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, tremofine, trabectedin, trans MID-107, trans retinoic acid, trastuzumab, tremelimumab, tretinoin, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, Tykerb / Tyverb, Urocidine, valrubicin, vatalanib, vincristine, vinflunine, virudin, WX-UK1, WX-554, Vectibix, Xeloda, XELOX, XL-147, XL-228, XL-281, XL-518 / R-7420 / GDC-0973, XL-765, YM-511,Selected from the group consisting of YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronate, zosuquidar, and combinations thereof.

[0170] In one embodiment, the other therapeutic agent comprises a hormone analog, an antihormonal agent, or both 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, the other therapeutic agent comprises one or more LHRH agonists and / or antagonists selected from the group consisting of goserelin acetate, leuprolide acetate, triptorelin 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, the other therapeutic agent comprises one or more growth factor inhibitors selected from the group consisting of 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), and hepatocyte growth factor (HGF). In one embodiment, the other therapeutic agent comprises one or more inhibitors of human epidermal growth factor selected from the group consisting of HER2, HER3, and HER4. In one embodiment, the 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, the other therapeutic agent comprises one or more aromatase inhibitors selected from the group consisting of anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more antimetabolites that are antifolates selected from the group consisting of methotrexate, raltitrexed, and pyrimidine analogs. In one embodiment, the other therapeutic agent comprises one or more antimetabolites that are pyrimidine analogs selected from the group consisting of 5-fluorouracil, capecitabine, and gemcitabine. In one embodiment, the other therapeutic agent comprises one or more antimetabolites that are pyrimidine analogs selected from the group consisting of mercaptopurine, thioguanine,The other therapeutic agents include one or more antimetabolites that are purine and / or adenosine analogs selected from the group consisting of cladribine and pentostatin, cytarabine, fludarabine, and combinations thereof. In one embodiment, the other therapeutic agents include one or more antitumor antibiotics selected from the group consisting of anthracyclines, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin, and combinations thereof. In one embodiment, the other therapeutic agents include one or more platinum derivatives selected from the group consisting of cisplatin, oxaliplatin, carboplatin, and combinations thereof. In one embodiment, the other therapeutic agents include one or more alkylating agents selected from the group consisting of estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, and combinations thereof. In one embodiment, the other therapeutic agent comprises a nitrosourea selected from the group consisting of carmustine, lomustine, thiotepa, and combinations thereof. In one embodiment, the other therapeutic agent comprises an antimitotic agent selected from the group consisting of vinca alkaloids and taxanes. In one embodiment, the other therapeutic agent comprises one or more taxanes selected from the group consisting of paclitaxel, docetaxel, and combinations thereof. In one embodiment, the 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, the other therapeutic agent comprises one or more topoisomerase inhibitors that are epipodophyllotoxins. In one embodiment, the other therapeutic agent comprises one or more epipodophyllotoxins selected from the group consisting of etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, and combinations thereof. In one embodiment, the other therapeutic agent is a PDK 1 inhibitor, a B-Raf inhibitor, an mTOR inhibitor, an mTORCl inhibitor, a PI3K inhibitor, a dual mTOR / PI3K inhibitor, an STK 33 inhibitor, an AKT inhibitor, a PLK1 inhibitor,The other therapeutic agent comprises one or more serine / threonine kinase inhibitors selected from the group consisting of CDK inhibitors, Aurora kinase inhibitors, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more tyrosine kinase inhibitors that are PTK2 / FAK inhibitors. In one embodiment, the other therapeutic agent comprises one or more protein-protein interaction inhibitors selected from the group consisting of IAP, Mcl-1, MDM2 / MDMX, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more rapamycin analogs selected from the group consisting of everolimus, temsirolimus, ridaforolimus, sirolimus, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more therapeutic agents selected from the group consisting of amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer, and combinations thereof. In one embodiment, the other therapeutic agent is 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-arretin, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, aza-epothilone B, 16-a ... Pomin, Alanose, Arglabin, Arzoxifene, Atamestane, Atrasentan, Auristatin PE, AVLB, AZ10992, 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-736, ARQ 680, AS-703026 (pimasertib), Avastin, AZD-2014, azacitidine, azaepothilone B, azonafide,BAY-43-9006, BAY80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, biricodaril 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, bryostatin-1, bortezomib, brostallicin, busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1, cefixime, cefratonin, ceftriaxone, celecoxib B, cermoleukin, cemadotin, CH4987655 / RO-4987655, chlorotrianisene, cilengitide, 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, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexate, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratuzumab,ER-86526, erlotinib, ET-18-0CH3, ethinylcytidine, ethinylestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, Forfox, Forfox 4, forfili, formestane, fotemustine, galarubicin, gallium maltolate, gefitinib, gemtuzumab, gimatecan, glufosfamide, GCS-100, GDC-0623, GDC-0941 (pictrelisib sib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, 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, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (cixutumumab), Immunol, indisulam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-111 7, INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, Kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuprorelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, lutecan, LY-S6AKT1,LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitor, MEK-162, methyltestosterone, methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, Midstau, Phosphorus, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexafine gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, Oncophage, OncoVEXGM- CSF, ormiplatin, ortataxel, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-IBB antibody, oxatrazol, 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, pelitinib, pemetrexed, pentrix, perifosine, perillyl alcohol, pertuzumab, PI3K inhibitors, PI3K / mTOR inhibitors, 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, polybutene, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY 869766, RDEA436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, Revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG7440, rhizoxin, rhu-MAb, rinfabate, risedronate, rituximab, lobatumumab, rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabalubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, 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, tacedinaline, talaporfin, tarceva, tariquitar, tasisulam, taxotere, taxoplexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide Id, Theralux, Terarubicin, Thymalfasin, Timectacin, Tiazofurin, Tipifarnib, Tirapazamine, Tocladesine, Tomudex, Tremofin, Trabectedin, Trans MID-107, Trans Retinoic Acid, Trastuzumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Triciribine, Trimetrexate, TLK-286TXD258, Tykerb / Tyverb, Urocidin, Valrubicin, Vatalanib, Vincristine, Vinflunine, Virulizine, 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, Zosuquidar, and combinations thereof.

[0171] In one embodiment, the other therapeutic agent comprises a steroid. Steroids include, but are not limited to, dexamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazol. In one embodiment, the other therapeutic agent comprises an antiemetic. Antiemetics include 5-HT3 receptor agonists (e.g., dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine), dopamine agonists (e.g., domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine, and metoclopramide), NK1 receptor antagonists (e.g., aprepitant and casopitant), antihistamines (e.g., cyclosporine ... These include, but are not limited to, lysine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine, etc.), cannabinoids (e.g., cannabis, dronabinol, nabilone, and Sativex), benzodiazepines (e.g., midazolam and lorazepam), anticholinergics (e.g., hyoscine), trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol, and ajwain.

[0172] In some embodiments, the other therapeutic agent comprises an anti-cancer agent, including an antimitotic agent. In one embodiment, the antimitotic agent comprises a taxane. In one embodiment, the antimitotic agent comprises a taxane selected from the group consisting of paclitaxel and docetaxel.

[0173] In one embodiment, the pharmaceutical composition comprises Compound (1) or Compound (10) or an analog thereof or a pharmaceutically acceptable salt thereof, and at least one anticancer agent, including, but not limited to, acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, amethanthrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacytidine, azamis ... Zetepa, azotomycin, batimastat, benzodepa, bevacizumab, bicalutamide, bisantrene, visnafide dimesylate, bizelesin, bleomycin, brequinar, bropirimine, busulfan, cactinomycin, calsterone, capecitabine, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefingol, celecoxib, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, Dow Norubicin, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, droloxifene, dromostanolone, duazomycin, edatrexate, eflomitine, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin, elbrozole, esorubicin, estramustine, etanidazole, etoposide, etopurine, fadrozole, fazarabine, fenretinide, floxuridine, fludarabine, fluorouracil, flurocitabine, foskidone , fostriecin, fulvestrant, gemcitabine, hydroxyurea, idarubicin, ifosfamide, ilmofosine, 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, liarozole, lometrexol, lomustine,losoxantrone, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, metoprine, meturedepa, mitindomide, mitocalicin, mitochromine, mitogillin, mitomarcine, mitomycin, mitospar, mitotane, mitoxantrone, mycophenolate, nelarabine, nocodazole, nogalamycin, omulna Platin (omrnaplatin), oxlan, paclitaxel, pegaspargase, periomycin, pentamustine, peplomycin, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer, porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, ribopurin, rogletimide, safingol, semustine, ciprofloxacin Mutrazene, sparfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talizomycin, tamoxifen, tecogalan, tegafur, tetoxantrone, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, topotecan, toremifene, trestro and combinations thereof.

[0174] Examples of suitable anti-cancer agents include, but are not limited to, those described in The Pharmacological Basis of Therapeutics, 12th Edition, by Goodman and Gilman, edited by Laurence Brunton, Bruce Chabner, and Bjorn Knollman, McGraw Hill Professional, 2010.

[0175] In some exemplary embodiments, the pharmaceutical composition comprises a salt (e.g., a mono- or di-salt) of Compound (1) or Compound (10) or an analog thereof and at least one other therapeutic agent, wherein the other therapeutic agent comprises an anti-angiogenic agent. For example, the anti-angiogenic agent is bevacizumab. In one embodiment, the anti-angiogenic agent is aflibercept, axitinib, angiostatin, endostatin, 16 kDa prolactin fragment, laminin peptide, fibronectin peptide, tissue inhibitor of metalloproteinase (TIMP) 1, 2, 3, 4), plasminogen activator inhibitors (PAI-1, PAI-2), tumor necrosis factor alpha (high dose, in vitro), TGF-β1, interferons (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 protein, suramin, sorafenib, regorafenib, thalidomide, cortisone, linomide, fumagillin (AGM-1470, TNP-470), tamoxifen, retinoids, CM101, dexamethasone, leukemia inhibitory factor (LIF), hedgehog inhibitors, and combinations thereof.

[0176] The pharmaceutical combination can include the first and second therapeutic agents in any desired ratio, provided that a synergistic or synergistic effect still results. Synergistic pharmaceutical combinations preferably contain the first and second therapeutic agents in a ratio of about 1:9 to about 9:1. In one embodiment, the synergistic pharmaceutical combination contains the first and second therapeutic agents in a ratio of about 1:8 to about 8:1, about 1:7 to about 7:1, about 1:6 to about 6:1, about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, or about 1:2 to about 2:1. In one embodiment, the synergistic pharmaceutical combination contains the first and second therapeutic agents in a ratio of about 1:1.

[0177] In one embodiment, the second therapeutic agent is allopurinol, arsenic trioxide, azacitidine, bortezomib, bevacizumab, capecitabine, carboplatin, celecoxib, chlorambucil, clofarabine, cytarabine, dacarbazine, daunorubicin HCl, docetaxel, doxorubicin HCl, floxuridine, gemcitabine HCl, hydroxyurea, ifosfamide, imatinib mesylate, ixabepirin The agent is selected from the group consisting of lenalidomide, megestrol acetate, methotrexate, mitotane, mitoxantrone HCl, oxaliplatin, paclitaxel, pralatrexate, romidepsin, sorafenib, streptozocin, tamoxifen citrate, topotecan HCl, tretinoin, vandetanib, vismodegib, vorinostat, and combinations thereof.

[0178] In one embodiment, the second therapeutic agent comprises a small molecule multikinase inhibitor, such as sorafenib or regorafenib. In one embodiment, the second therapeutic agent comprises a hedgehog pathway inhibitor, such as vismodegib. In one embodiment, the second therapeutic agent is a drug selected from Table 2 below.

[0179] [Table 2-1]

[0180] [Table 2-2]

[0181] In some embodiments, the second therapeutic agent comprises a drug that targets the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor. In one embodiment, the second therapeutic agent comprises recombinant TRAIL or an agonist antibody that activates one or more TRAIL receptors. In one embodiment, the second therapeutic agent comprises one or more antibodies or recombinant TRAIL that activate signaling through DR4, DR5, or both. In one embodiment, the second therapeutic agent comprises one or more of AMG-655, LBY-135, mapatumumab, lexatumumab, apomab, and rhAPo2L / TRAIL. In one embodiment, the second therapeutic agent comprises an active agent selected from the group consisting of camptothecin, 5-FU, capecitabine, cisplatin, doxorubicin, irinotecan, paclitaxel, cisplatin, bortezomib, BH3I-2, rituximab, radiation, triterpenoids, sorafenib, gemcitabine, HDAC inhibitors, carboplatin, T-101 (a gossypol derivative), ABT-263, ABT-737, and GX-15-070 (obatoclax), vorinostat, cetuximab, panitumumab, bevacizumab, ganitumab, interferon gamma, sorafenib, XIAP antagonists, Bcl-2 antagonists, and Smac mimetics.

[0182] VI. Dosage

[0183] In one embodiment, the pharmaceutical composition comprises Compound (1) or Compound (10), or an analog thereof, or a pharmaceutically acceptable salt thereof, in a dose ranging from about 40, 50, 60, or 100 mg to about 2000 mg; from about 4, 5, 6, or 10 mg to about 200 mg; or from about 0.4, 0.5, 0.6, or 1 mg to about 20 mg, wherein the weights can be based on the compound in its free base form. In one embodiment, the pharmaceutical composition comprises from about 50 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; from about 5 mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; or about 0.5 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 mg of Compound (1) or Compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises: about 40 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; about 4 mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; or 200 mg; or about 0.4 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of Compound (1) or Compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, the pharmaceutical composition comprises from about 60 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; from about 6 mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; or 200 mg; or about 0.6 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of Compound (1) or Compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises from about 100 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 mg, or 2000 mg; from about 10 mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 , 130, 140, 150, 160, 170, 180, 190, or 200 mg; or at dosage levels ranging from about 1 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of Compound (1) or Compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises from about 200 mg to about 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; from about 20 mg to about 30, 40, 50, 60, 70, 80, 90, 100, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg, based on the compound in its free base form. or 20 mg; or at dosage levels ranging from about 2 mg to about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of Compound (1) or Compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, the pharmaceutical composition comprises Compound (1) or Compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof, at a dosage level ranging from about 400 mg to about 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; from about 40 mg to about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg, based on the compound in its free base form. In one embodiment, the pharmaceutical composition comprises from about 50 mg to about 60, 70, 80, 90, or 100 mg; from about 60 mg to about 70, 80, 90, or 100 mg; from about 70 mg to about 80, 90, or 100 mg; from about 80 mg to about 90 or 100 mg; from about 90 to about 100 mg; from about 5 mg to about 6, 7, 8, 9, or 10 mg; from about 6 mg to about 7, 8, 9, or 10 mg; from about 7 mg to about 8, 9, or 10 mg; from about 8 mg to about 9 or about 10 mg; about 9 mg to about 10 mg; about 0.5 mg to 0.6, 0.7, 0.8, 0.9, or 1 mg; about 0.6 mg to 0.7, 0.8, 0.9, or 1 mg; about 0.7 mg to 0.8, 0.9, or 1 mg; about 0.8 mg to 0.9, or 1 mg; or about 0.9 mg to 1 mg of Compound (1) or Compound (10), or an analog thereof, or a pharmaceutically acceptable salt thereof.

[0184] In one embodiment, the pharmaceutical composition comprises Compound (1) or Compound (10), or an analog thereof, or a pharmaceutically acceptable salt thereof, at a dose ranging from about 1 mg / kg to about 40 mg / kg; from about 0.1 mg / kg to about 4 mg / kg; or from about 0.01 mg / kg to about 0.40 mg / kg. In one embodiment, the pharmaceutical composition provides a dose of from about 1, 2, 3, 4, 5, 6, 7, 8, or 9 mg / kg to about 10, 20, 30, or 40 mg / kg; from about 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 mg / kg to about 20, 30, or 40 mg / kg; from about 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 mg / kg to about 30 or 40 mg / kg; or from about 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39 mg / kg. g to about 40 mg / kg; about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 mg / kg to about 1, 2, 3, or 4 mg / kg; about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 mg / kg to about 2, 3, or 4 mg / kg; about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, or 2.9 mg / kg to about 3 or 4 mg / kg; or about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, or 3.9 mg / kg to about 4 mg / kg; about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 mg / kg to about 0.10, 0.20, 0.30, or 0.40 mg / kg; about 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, or 0.19 mg / kg to about 0.20, 0.30, or 0.40 mg / kg or about 0.30 or 0.40 mg / kg; or about 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, or 0.39 mg / kg to about 0.40 mg / kg of Compound (1) or Compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof.

[0185] In one embodiment, the pharmaceutical composition contains about 37.5 mg / m 2 ~about 1500mg / m 2 ; approx. 3.75mg / m 2 ~about 150mg / m 2 ; approx. 0.4mg / m 2 ~about 15mg / m 2at dosage levels ranging from 0.1 to 1.0, and including Compound (1) or Compound (10) or their analogs, or pharmaceutically acceptable salts thereof. In one embodiment, the pharmaceutical composition comprises about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550 5, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 91 0, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, 1000, 1005, 1010, 1015, 1020, 1025, 1030, 1035, 1040, 1045, 1050, 1055, 1060, 1065, 1070, 1075, 1080, 1085, 1090, 1095, 1100, 1105, 1110, 1115, 1120, 1125, 1130, 1135, 1140, 1145, 1150, 1155, 1160,1165, 1170, 1175, 1180, 1185, 1190, 1195, 1200, 1205, 1210, 1215, 1220, 1225, 1230, 1235, 1240, 1245, 1250, 1255, 1260, 1265, 1270, 1275, 1280, 1285, 1290, 1295, 1300, 1305, 1310, 1315, 1320, 1325, 1330 , 1335, 1340, 1345, 1350, 1355, 1360, 1365, 1370, 1375, 1380, 1385, 1390, 1395, 1400, 1405, 1410, 1415 , 1420, 1425, 1430, 1435, 1440, 1445, 1450, 1455, 1460, 1465, 1470, 1475, 1480, 1485, 1490, 1495mg / m, 2 ~about 1500mg / m 2 ; approx. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 , 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 mg / m 2 ~about 150mg / m 2or about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 111, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 mg / m 2 ~about 15mg / m 2 at dosage levels ranging from 0.1 to 1.0, and including Compound (1) or Compound (10) or their analogs, or pharmaceutically acceptable salts thereof.

[0186] VII. Dosage Form

[0187] Pharmaceutical compositions suitable for use with the disclosed methods can be formulated into a dosage form that can be administered to a patient. In one embodiment, the pharmaceutical composition is in the form of an oral dosage unit or a parenteral dosage unit. In one embodiment, the pharmaceutical composition is in the form of an oral dosage unit. In some embodiments, the oral dosage unit is divided into several smaller doses administered to a subject over a predetermined period of time to reduce toxicity of the administered therapeutic agent. In some embodiments, the oral dosage unit is administered via a tablet or capsule containing a controlled-release formulation that can include multiple particles, granules, pellets, mini-tablets, or tablets. In one embodiment, the pharmaceutical composition is in the form of a parenteral dosage unit. In one embodiment, the pharmaceutical composition is in the form of a parenteral dosage unit selected from the group consisting of intravenous (IV), subcutaneous (SC), intramuscular (M), rectal (PR), and transdermal dosage units. In one embodiment, the pharmaceutical composition is in 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 a tablet, a caplet, a capsule, a lozenge, a syrup, a liquid, a suspension, and an elixir. In one embodiment, the composition is an oral dosage form selected from the group consisting of a tablet, a hard shell capsule, a soft gelatin capsule, a bead, a granule, an agglomerate, a powder, a gel, a solid, and a semi-solid.

[0188] In some embodiments, suitable forms of pharmaceutical compositions for use in the disclosed methods include dermatological compositions adapted for topical administration to the skin. For example, dermatological compositions include a cosmetically or pharmaceutically acceptable vehicle. Dermatological compositions 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, skin enhancers, and the like may be required or desired, and therefore can be 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, poloxamers (231, 182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Pat. 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 ureas, other nitrogen compounds such as 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 also be used, but are less preferred.

[0189] In some embodiments, the pharmaceutical composition is in a dosage form selected from the group consisting of sustained release form, controlled release form, delayed release form, and responsive release form.

[0190] VIII.How to use The compositions and methods of the present disclosure are useful for treating many conditions, including cancer (e.g., colon cancer, brain cancer, and glioblastoma). In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as ocular melanoma, desmoplastic round cell tumor, chondrosarcoma, leptomeningeal disease, diffuse large B-cell lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal or rectal cancer, appendix cancer, astrocytoma, and atypical teratoid / rhabdoid tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as basal cell carcinoma, basal cell nevus syndrome, Gorlin-nevus syndrome, bile duct cancer, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, and spinal tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as carcinoid tumors, central nervous system atypical teratoid / rhabdoid tumor of unknown primary, leptomeningeal disease, central nervous system embryonal tumors, central nervous system lymphomas, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, and cutaneous T-cell lymphoma (including, but not limited to, Sézary syndrome and mycosis fungoides (MF)). In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as central nervous system embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma tumor family, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, and eye cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, and glioma. In one embodiment, the compositions and methods of the present disclosure are used to treat cancer selected from the group consisting of hairy cell leukemia, head and neck cancer, hepatocellular (liver) carcinoma, histiocytosis, Hodgkin's lymphoma, and hypopharyngeal carcinoma. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as Kaposi's sarcoma and kidney (renal cell) carcinoma.In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lung cancer, non-Hodgkin's lymphoma, and primary central nervous system lymphoma. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), malignant fibrous histiocytoma and osteosarcoma of bone, medulloblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell neck cancer of unknown primary, multiple endocrine neoplasia syndrome, oral cancer, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, and myeloproliferative disorders. In one embodiment, the compositions and methods of the present disclosure are used to treat cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as nasal and paranasal sinus cancer, nasopharyngeal cancer, and neuroblastoma. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer, and ovarian low malignant potential tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as pancreatic cancer, papillomatosis, paranasal and nasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, intermediately differentiated pineal parenchymal tumor and pineoblastoma, supratentorial primitive neuroectodermal tumor, pituitary tumor, pleuropulmonary blastoma, cancer of pregnancy and breast cancer, primary central nervous system lymphoma, and prostate cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat cancers selected from the group consisting of rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter, airway cancer involving the NUT gene on chromosome 15, retinoblastoma, and rhabdomyosarcoma. In one embodiment, the compositions and methods of the present disclosure are used to treat high-grade prostate cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat intermediate-grade prostate cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat low-grade prostate cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat castration-resistant prostate cancer.

[0191] The inventors have discovered in in vitro models, animal models, and human clinical trials that ONC201 (compound (1)) has broad anticancer activity, low toxicity with few, if any, adverse effects, low genotoxicity, and high bioavailability, including oral bioavailability. These characteristics make ONC201 and various analogs particularly suitable for pediatric patients. These characteristics also make ONC201 and various analogs particularly suitable for long-term treatment, for high-risk patients, and for ensuring sustained response or stable disease or preventing disease recurrence.

[0192] In one embodiment, the compositions and methods of the present disclosure are used to treat pediatric cancer (e.g., pediatric solid tumors, pediatric sarcoma, pediatric Ewing's sarcoma, pediatric glioma, pediatric central nervous system cancer, pediatric leukemia, and pediatric lymphoma).

[0193] In one embodiment, the compositions and methods of the present disclosure are used to treat proliferative skin disorders such as psoriasis. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer 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 cervical carcinoma of unknown primary site, and supratentorial primitive neuroectodermal tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer 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. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer selected from the group consisting of carcinoma of unknown primary site, carcinoma of unknown primary site, rare cancers of childhood, transitional cell carcinoma of the renal pelvis and ureter, urethral carcinoma, and uterine sarcoma. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer selected from the group consisting of vaginal cancer and vulvar cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer selected from the group consisting of Wilms' tumor and female cancer.

[0194] In some embodiments, the compositions and methods of the present disclosure are used as first-line therapy (sometimes referred to as primary therapy). In some embodiments, the compositions and methods of the present disclosure are used as second-line therapy. In some embodiments, the compositions and methods of the present disclosure are used as third-line therapy. In some embodiments, the compositions and methods of the present disclosure are used as salvage therapy. As used herein, the term "salvage therapy" refers to a therapeutic agent that can be employed in any treatment regimen after a subject's initial treatment regimen 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 disclosure are used as rescue therapy. In one embodiment of rescue therapy, the composition is used as a rescue drug to counteract the effects of the initial treatment. In one embodiment of rescue therapy, the composition is used as a rescue drug administered to a subject who has developed resistance to standard or initial therapy. In some embodiments, the compositions and methods of the present disclosure are used as neoadjuvant therapy. In one embodiment, neoadjuvant therapy involves administering one or more therapeutic agents of the present disclosure to a subject prior to primary or first-line therapy. In one embodiment, neoadjuvant therapy reduces the size or extent of the cancer being treated before the main or first-line treatment is administered to the subject being treated. In some embodiments, the compositions and methods of the present disclosure are used as adjuvant therapy. In one embodiment, adjuvant therapy involves administering to the subject one or more therapeutic agents of the present disclosure, which alter the effect of other therapeutic agents that have already been administered to the subject, or that are administered simultaneously or subsequently to the subject.

[0195] In some embodiments, the compositions and methods of the present disclosure reduce the potential for drug-drug interactions. In some embodiments, Compound (1) or Compound (10), or an analog thereof, is eliminated from the patient's body before it can interact with another pharmaceutically active agent.

[0196] In some embodiments, the compositions and methods of the present disclosure exhibit a level of toxicity that facilitates combination with other agents.

[0197] The methods and compositions of the present disclosure are not limited to any particular animal species. In one embodiment, the subject treated according to the methods and compositions of the present disclosure can be a mammal or a non-mammal. In one embodiment, the mammal of the mammal subject includes, but is not limited to, a human; a non-human primate; a rodent such as a mouse, rat, or guinea pig; a domestic pet such as a cat or dog; a horse, a cow, a pig, a sheep, a goat, or a rabbit. In one embodiment, the non-mammal subject includes, but is not limited to, a bird such as a duck, a goose, a chicken, or a turkey. In some embodiments, the subject is a human. In one embodiment, the subject can be of either gender 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.

[0198] The method and composition of the present disclosure are not limited to the subject of a specific age.In one embodiment, the subject that is treated according to the method of the present disclosure and with the composition of the present disclosure can be over 50 years old, over 55 years old, over 60 years old, or over 65 years old.In one embodiment, the subject that is treated according to the method of the present disclosure and with the composition of the present disclosure can be under 50 years old, under 55 years old, under 60 years old, or under 65 years old.

[0199] In one embodiment, the subject treated with the composition of the present disclosure according to the method of the present disclosure can be a pediatric patient. In one embodiment, the pediatric patient is younger than 18 years old, younger than 17 years old, younger than 16 years old, younger than 15 years old, younger than 14 years old, younger than 13 years old, younger than 12 years old, younger than 11 years old, younger than 10 years old, younger than 9 years old, younger than 8 years old, younger than 7 years old, younger than 6 years old, younger than 5 years old, younger than 4 years old, younger than 3 years old, younger than 2 years old, younger than 1 year old. In one embodiment, the pediatric patient is younger than 12 months old, younger than 11 months old, younger than 10 months old, younger than 9 months old, younger than 8 months old, younger than 7 months old, younger than 6 months old, younger than 5 months old, younger than 4 months old, younger than 3 months old, younger than 2 months old, younger than 1 month old. In one embodiment, the pediatric patient is younger than 4 weeks old, younger than 3 weeks old, younger than 2 weeks old, younger than 1 week old. In one embodiment, the pediatric patient is younger than 7 days, younger than 6 days, younger than 5 days, younger than 4 days, younger than 3 days, younger than 2 days, or younger than 1 day old. In one embodiment, the pediatric patient is a newborn. In one embodiment, the pediatric patient is born prematurely. In one embodiment, the pediatric patient is a newborn.

[0200] In one embodiment, the patient weighs less than 45 kg, less than 40 kg, less than 35 kg, less than 30 kg, less than 25 kg, less than 20 kg, less than 15 kg, less than 14 kg, less than 10 kg, less than 5 kg, less than 4 kg, less than 3 kg, less than 2 kg, or less than 1 kg.

[0201] In one embodiment, the subject has received at least one prior therapeutic agent. In one embodiment, the subject has received at least two, at least three, or at least four prior therapeutic agents. In one embodiment, the prior therapeutic agent is ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, cytarabine, cisplatin, rituximab, 5-fluorouracil, oxaliplatin, leucovorin, or lenalidomide.

[0202] In one embodiment, the subject is being treated with radiation, in one embodiment, the subject is being treated with surgery, in one embodiment, the subject is being treated with adoptive T cell therapy.

[0203] In some embodiments, 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.

[0204] In some embodiments, the compositions and methods of the present disclosure have a dose-response relationship in cancer cells that differs from the dose-response relationship of the same compositions and methods in normal cells. Figure 1, for example, shows the dose-response relationship of compound (1) on proliferation and cell death in normal and tumor cells. Figure 1 shows cell viability after 72 hours of treatment with compound (1) at the indicated concentrations. Tested tumors included a human colon cancer cell line (HCT116), a breast tumor cell line (MDA-MB-231), and a human primary glioblastoma cell line (U87). Tested normal cells also included human foreskin fibroblasts (HFF), human fetal lung fibroblasts (MRC-5), and a human lung fibroblast cell line (WI-38). Doxorubicin at 1 μg / mL was used as a positive control in normal fibroblasts. As shown in Figure 1, cell viability of the tested normal cells was at least about 75% at compound (1) concentrations of about 1-5 mg / mL, while tumor cell viability was significantly lower (e.g., 50% or less) at the same concentrations of compound (1). Furthermore, as the concentration of compound (1) increased beyond about 5 mg / mL, normal cell viability remained at about 75%, while tumor cell viability decreased to less than 25%.

[0205] Figure 2 shows a cell viability assay in human fetal lung fibroblasts (MRC-5) following 72-hour treatment with compound 1 (5 μM) or DMSO, and the indicated recovery periods in drug-free complete medium following treatment. Time points are given as the time after compound 1 was removed after 72 hours of treatment. As shown in Figure 2, cell recovery was observed with compound 1 but not with DMSO.

[0206] In some embodiments, the disclosed compositions and methods are useful for treating cancer in a subject. In one embodiment, the disclosed compositions and methods are useful for treating cancer in a human subject. In some embodiments, the method of treatment comprises administering a pharmaceutically effective amount of Compound (1) or Compound (10), or an analog thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier to a subject in need of such treatment.

[0207] In one embodiment, a method of treatment comprises administering (i) a first therapeutic agent comprising Compound (1) or Compound (10), or an analog thereof, or a pharmaceutically acceptable salt thereof, in combination with (ii) a second therapeutic agent to a subject in need of such treatment, wherein the first and second therapeutic agents are administered simultaneously or sequentially. The second therapeutic agent can be any suitable therapeutic agent, including any of the pharmaceutically active agents of the present disclosure. Pharmaceutically acceptable salts of Compound (1) include the dihydrochloride salt shown below.

[0208] [ka]

[0209] It is understood that the dihydrochloride salt of Compound (1) or an analog thereof (including, but not limited to, the compound of Formula (10)), or a di-salt thereof of an alternative obvious from the teachings of this disclosure, can be substituted for Compound (1) or an analog thereof in the compositions or dosing regimens of this disclosure.

[0210] In some embodiments, methods of treatment comprise administering, simultaneously or sequentially, a synergistic pharmaceutical combination to a subject in need of such treatment, the synergistic pharmaceutical combination comprising (i) a first therapeutic agent comprising Compound (1) or Compound (10), or an analog thereof, or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic agent. In one embodiment, the method of treatment comprises administering, simultaneously or sequentially, a therapeutically synergistic amount of the first therapeutic agent in combination with the second therapeutic agent to a subject in need of such treatment. In one embodiment, the method of treatment comprises administering, to a subject in need of such treatment, an effective amount of the first therapeutic agent in combination with an effective amount of the second therapeutic agent, the combination providing a synergistic effect in the in vivo treatment of a cancer susceptible to the combination, wherein the first and second therapeutic agents are administered simultaneously or sequentially. In one embodiment, a method of treatment comprises administering to a subject in need of such treatment an effective amount of a first therapeutic agent in combination with an effective amount of a second therapeutic agent, the combination providing a synergistic effect in the in vivo treatment of minimal residual disease susceptible to the combination, wherein the first and second therapeutic agents are administered simultaneously or sequentially.

[0211] In some embodiments, the second therapeutic agent can be administered before or prior to the first therapeutic agent.

[0212] In one embodiment, the therapeutic method targets a cancer selected from the group consisting of a solid tumor, a liquid tumor, a lymphoma, a leukemia, or a myeloma.

[0213] In one embodiment, the therapeutic method targets solid tumors, and solid tumors include cervical cancer, endometrial cancer, extracranial germ cell tumor, extragonadal germ cell tumor, germ cell tumor, gestational trophoblastic tumor, ovarian cancer, ovarian germ cell tumor, epithelial ovarian cancer, and ovarian low-grade malignant tumor, 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, cholangiocarcinoma, extrahepatic bile duct cancer, cancer of the gallbladder, hepatocellular (liver) cancer, kidney (renal cell) cancer, liver cancer, renal cell (kidney) cancer, renal pelvis and ureter, basal cell carcinoma, basal cell nevus syndrome, Gorlin-nevus syndrome, malignant melanoma, Merkel cell carcinoma, papillomatosis, multiple endocrine neoplasia syndrome, pancreatic cancer, parathyroid cancer, ocular melanoma, eye cancer, retinoblastoma, malignant fibrous histiocytoma, Ewing's sarcoma tumor. Family, desmoplastic round cell tumor, chondrosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, spinal cord tumors, leptomeningeal disease, central nervous system embryonal tumor, chordoma, embryonal tumor of the central nervous system, ependymoblastoma, ependymoma, neuroblastoma, intermediately differentiated pineal parenchymal tumor, pineoblastoma, adrenocortical carcinoma, bone cancer, osteosarcoma, malignant fibrous histiocytoma and osteosarcoma of bone, carcinoma Id tumors, unknown primary tumors, bronchial tumors, lung cancer, pleuropulmonary carcinoma blastoma, respiratory tract cancer involving the NUT gene on chromosome 15, astrocytoma, atypical teratoid / rhabdoid tumors, central nervous system atypical teratoid / rhabdoid tumors, craniopharyngioma, glioma, brain cancer, medulloblastoma, medulloepithelioma, supratentorial primitive neuroectodermal tumor, pituitary tumor, gastric cancer Cancer), gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), bladder cancer, anal and rectal cancer, appendix cancer, esophageal cancer, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, metastatic squamous cell neck cancer of unknown primary, mouth cancer, nasal and paranasal cavity cancer, pharyngeal cancer, oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, paranasal and nasal cavity cancer, pharyngeal cancer, head and neck cancer, and mesothelioma.

[0214] In one embodiment, the treatment method targets a lymphoma selected from the group consisting of diffuse large B-cell lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Sezary syndrome, mycosis fungoides (MF), histiocytosis, Burkitt lymphoma, and central nervous system lymphoma, non-Hodgkin's lymphoma, and primary central nervous system lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, mycosis fungoides, primary central nervous system lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma.

[0215] In one embodiment, the treatment method targets a non-Hodgkin's lymphoma (NHL) selected from the group consisting of mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, lymphoplasmacytic NHL, Waldenstrom's macroglobulinemia, and cutaneous lymphoma.

[0216] In one embodiment, the therapeutic method targets a leukemia selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloproliferative disease, hairy cell leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and Langerhans cell histiocytosis.

[0217] In one embodiment, the treatment method targets an acute leukemia selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, myelodysplastic disorders, and myeloproliferative disorders.

[0218] In one embodiment, the therapeutic method targets a myeloma selected from the group consisting of IgA myeloma, IgG myeloma, IgM myeloma, IgD myeloma, IgE myeloma, light chain myeloma, non-secretory myeloma, multiple myeloma / plasma cell neoplasm, multiple myeloma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, and myeloproliferative disorder.

[0219] In one embodiment, the treatment method targets a cancer selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal or rectal cancer, appendix cancer, astrocytoma, and atypical teratoid / rhabdoid tumor.

[0220] In one embodiment, the method of treatment targets a cancer selected from the group consisting of basal cell carcinoma, basal cell nevus syndrome, Gorlin-nevus syndrome, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, and spinal tumor.

[0221] In one embodiment, the therapeutic method targets a cancer selected from the group consisting of carcinoid tumor, carcinoma of unknown primary origin, central nervous system atypical teratoid / rhabdoid tumor, central nervous system embryonal tumor, central nervous system lymphoma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, and cutaneous T-cell lymphoma (including, but not limited to, Sézary syndrome and mycosis fungoides).

[0222] In one embodiment, the therapeutic method targets a cancer selected from the group consisting of embryonal tumors of the central nervous system, endometrial carcinoma, ependymoblastoma, ependymoma, esophageal carcinoma, Ewing's sarcoma tumor family, desmoplastic round cell tumor, chondrosarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct carcinoma, and eye cancers, including intraocular melanoma and retinoblastoma.

[0223] In one embodiment, the therapeutic method targets a cancer selected from the group consisting of gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, and glioma.

[0224] In one embodiment, the compositions and methods target a cancer selected from the group consisting of hairy cell leukemia, head and neck cancer, hepatocellular (liver) carcinoma, histiocytosis, Hodgkin's lymphoma, and hypopharyngeal carcinoma.

[0225] In one embodiment, the method of treatment targets a cancer selected from the group consisting of Kaposi's sarcoma and kidney (renal cell) carcinoma.

[0226] In one embodiment, the method of treatment targets a cancer selected from the group consisting of Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer; lung cancer, including non-small cell lung cancer and small cell lung cancer; non-Hodgkin's lymphoma, and primary central nervous system lymphoma.

[0227] In one embodiment, the therapeutic method targets a cancer selected from the group consisting of Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), malignant fibrous histiocytoma and osteosarcoma of bone, medulloblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell neck cancer of occult primary, multiple endocrine neoplasia syndrome, oral cancer, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, and myeloproliferative disorders.

[0228] In one embodiment, the method of treatment is useful for treating a cancer selected from the group consisting of nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, and neuroblastoma.

[0229] In one embodiment, the method of treatment is useful for treating a cancer selected from the group consisting of oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian germ cell tumor, epithelial ovarian cancer, and ovarian low malignant potential tumor.

[0230] In one embodiment, the method of treatment is useful for treating a cancer selected from the group consisting of pancreatic cancer, papillomatosis, sinonasal and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, intermediately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, pleuropulmonary blastoma, cancer of pregnancy and breast cancer, primary central nervous system lymphoma, and prostate cancer.

[0231] In one embodiment, the method of treatment is useful for treating a cancer selected from the group consisting of rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter, respiratory tract cancer involving the NUT gene on chromosome 15, retinoblastoma, and rhabdomyosarcoma.

[0232] In one embodiment, the method of treatment is useful for treating a cancer selected from the group consisting of salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, eye cancer, skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell cervical carcinoma of occult primary, and supratentorial primitive neuroectodermal tumor.

[0233] In one embodiment, the method of treatment is useful for treating a cancer 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.

[0234] In one embodiment, the method of treatment is useful for treating a cancer selected from the group consisting of carcinoma of unknown primary site, carcinoma of unknown primary site, rare cancers of childhood, transitional cell carcinoma of the renal pelvis and ureter, carcinoma of the urethra, and sarcoma of the uterus.

[0235] In one embodiment, the method of treatment is useful for treating a cancer selected from the group consisting of vaginal cancer and vulvar cancer.

[0236] In one embodiment, the method of treatment is useful for treating a cancer selected from the group consisting of Wilms' tumor and women's cancer.

[0237] In some embodiments, treating cancer comprises preventing tumor growth in a subject with cancer. In some embodiments, treating cancer comprises preventing the formation of cancer metastases in a subject with cancer. In some embodiments, treating cancer comprises targeted treatment of minimal residual disease in a subject with cancer known to have minimal residual disease in the cancer or at risk of having minimal residual disease.

[0238] This may be indicated after treatment of the primary tumor with surgery and / or after chemotherapy (radiotherapy) has been initiated or deemed effective. Disseminated tumor cells may be dormant and are often invulnerable to chemotherapy (radiotherapy). Patients treated in this manner appear cured, a state also known as "minimal residual disease." Nevertheless, dormant tumor cells have the potential to form metastases even after longer periods of dormancy if proliferative stimuli cause them to become metastatic cells.

[0239] As used herein, "minimal residual disease" refers to a small number of cancer cells that persist in a subject during treatment or after treatment when the subject is in remission (exhibiting no symptoms or signs of the disease). The methods of the present disclosure are preferably applied to the forms of the diseases listed herein, including adult and pediatric forms of these diseases.

[0240] In one embodiment, the method of treatment is useful for treating autoimmune diseases.Autoimmune diseases include but are not limited to alopecia areata, antiphospholipid, autoimmune hepatitis, celiac disease, type 1 diabetes, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, inflammatory myopathy, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus and vitiligo.

[0241] In one embodiment, the method of treatment is useful for treating autoimmune and inflammatory diseases of the peripheral nervous system, such as amyotrophic lateral sclerosis (Lou Gehrig's disease), which are based on a variety of factors, including diabetes, metabolic disorders including B12 and folate vitamin deficiencies, 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, Guillain-Barré syndrome, connective tissue diseases, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, certain inflammatory conditions such as sarcoidosis, genetic diseases such as celiac disease, Charcot-Marie dental syndrome, Friedreich's ataxia, and / or idiopathic diseases in which the specific cause is unknown but in which inflammatory and / or autoimmune mechanisms are responsible for the development.

[0242] In one embodiment, the method of treatment is useful for treating autoimmune and inflammatory diseases that manifest ocular symptoms. Such ocular symptoms include, but are not limited to, ocular cicatricial pemphigoid, Mooren's corneal ulcer, various forms of uveitis, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, relapsing polychondritis, Wegener's granulomatosis, scleroderma, Behçet's disease, Reiter's disease, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and ankylosing spondylitis, retinitis pigmentosa, macular degeneration, keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, peripheral corneal ulcer, and less common entities such as choroiditis, retinal vasculitis, episcleral nodules, retinal detachment, and / or macular edema.

[0243] In one embodiment, the method of treatment is useful for treating acute allograft rejection in transplant patients. In one embodiment, the method of treatment is useful for treating ischemic stroke. In one embodiment, the method of treatment is useful for treating inflammatory diseases, including, but not limited to, arthritis, psoriasis, asthma, and colitis.

[0244] In one embodiment, the therapeutic agent comprises a pharmaceutically acceptable mono-salt of Compound (1) or an analog thereof (e.g., a compound of Formula (10)). In one embodiment, the therapeutic agent comprises a pharmaceutically acceptable di-salt of Compound (1) or an analog thereof (e.g., a compound of Formula (10)). As disclosed herein, some analogs may be tri-salts. In one embodiment, the therapeutic agent comprises Compound (1) or an analog thereof (e.g., a compound of Formula (10)) in the form of a pharmaceutically acceptable mono- or di-salt selected from the group consisting of hydrochloride, hydrobromide, bisulfate, sulfate, phosphate, fumarate, succinate, oxalate, and lactate, bisulfate, hydroxyl, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, acetate, and carboxylate. In one embodiment, the therapeutic agent includes compound (1) or an analog thereof in the form of a pharmaceutically acceptable mono- or di-salt selected from p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate, and maleate salts. In one embodiment, the therapeutic agent includes compound (1) or an analog thereof in the form of a pharmaceutically acceptable mono- or di-salt with a counterion selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and / or a counterion such as methylamino, dimethylamino, diethylamino, triethylamino, and combinations thereof. In one embodiment, the therapeutic agent includes a compound of the present disclosure in the form of a halide di-salt, such as a dihydrochloride or dihydrobromide salt.

[0245] In some embodiments of the method of treatment, the second therapeutic agent comprises an anti-cancer agent. In some embodiments of the method of treatment, the second therapeutic agent includes, but is not limited to, acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, amethanthrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bevacizumab, bicalutamide, bisantrene, visnaf dimesylate, bizelesin, bleomycin, brequinar, bropirimine, busulfan, cactinomycin, calsterone, capecitabine, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefingol, celecoxib, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diazolimus Diquone, docetaxel, doxorubicin, droloxifene, dromostanolone, duazomycin, edatrexate, eflomitin, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin, elbrozole, esorubicin, estramustine, etanidazole, etoposide, etopurine, fadrozole, fazarabine, fenretinide, floxuridine, fludarabine, fluorouracil, flurocitabine, foskidone, fostriecin, fulvestrant, gemcitabine, hydroxyurea a, idarubicin, ifosfamide, ilmofosine, 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, liarozole, lometrexol, lomustine, losoxantrone, masoprocol, maytansine,Mechlorethamine hydrochloride, megestrol, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, metoprine, meturedepa, mitindomide, mitocalicin, mitochromine, mitogillin, mitomarcine, mitomycin, mitospar, mitotane, mitoxantrone, mycophenolate, nelarabine, nocodazole, nogalamycin, omrnaplatin, oxlan, paclitaxel, pegaspargase, periomycin, pentamustine, peplomycin, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer, porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, ribopurine, rogletimide, safingol, semustine, simtrazene, spa Rufosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talizomycin, tamoxifen, tecogalan, tegafur, tetoxantrone, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, topotecan, toremifene, trestron, triciribine, trimetrexate, triptorelin, tubrozole, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine, vinepidine, vinglisinate, vinleurosine, vinorelbine, vinrocidine, vinzolidine, vorozole, zeniplatin, zinostatin, zoledronate, zorubicin and combinations thereof.

[0246] In some embodiments of the method of treatment, the second therapeutic agent is selected from the group consisting of, but not limited to, hormone analogs and antihormones, aromatase inhibitors, LHRH agonists and antagonists, inhibitors of growth factors, 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-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs, amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyisothiazolinone, 2-methylpropional ... Tradiol, 2C4, 3-alethine, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, alanose, arglabin, arzoxyle Phen, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, 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-736, ARQ 680, AS-703026 (pimasertib), Avastin, AZD-2014, azacitidine, azaepothilone B, azonafide, BAY-43-9006, BAY80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, bilirubin 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, bryostatin-1, bortezomib, brostallicin, busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1, cefixime, cefratonin, ceftriaxone, celecoxib B, cermoleukin, cemadotin, CH4987655 / RO-4987655, chlorotrianisene, cilengitide, 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, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexate, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3, ethinylcytidine, ethinyl estradiol, exatecan, exatecan mesylate, exemestane, exisulind,Fenretinide, figitumumab, floxuridine, folic acid, Forfox, Forfox 4, Forfili, formestane, fotemustine, galarubicin, gallium maltolate, gefitinib, gemtuzumab, gimatecan, glufosfamide, 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, homoharringtonine, hyaluronic acid, hydroxyurea, caproic acid Hydroxyprogesterone, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (cixutumumab), Immunol, indisulam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117, INK-128, INSM-18, Ionaf Arnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, Kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuprorelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, Rootecan, LY-S6AKT1, LY-2780301, Mahosfamide, Marimastat, Mechloroethamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573,MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexafin gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 6-benzylguanine , oblimersen, omeprazole, Oncophage, OncoVEX, GM-CSF, ormiplatin, ortataxel, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-IBB antibody, oxatrazol, estrogen, panitumumab, patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-pa Clitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perillyl alcohol, pertuzumab, PI3K inhibitors, PI3K / mTOR inhibitors, PG-TXL, PG2, PLX-4032 / RO-5185426 (vemurafenib), PLX-360 3 / RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, fenoxodiol O, PKI166, previtrexed, plicamycin, polybutene, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY 869766, RDEA436, rebeccamycin analog, receptor tyrosine kinase (RTK) inhibitor, Revimid, 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 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabalubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, 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, tacedinaline, talaporfin, tarceva, tariquitar, tasisulam, taxotere, taxoplexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide Id, Theralux, Terarubicin, Thymalfasin, Timectacin, Tiazofurin, Tipifarnib, Tirapazamine, Tocladesine, Tomudex, Tremofin, Trabectedin, Trans MID-107, Trans Retinoic Acid, Trastuzumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Triciribine, Trimetrexate, TLK-286TXD 258, Tykerb / Tyverb, Urocidin, Valrubicin, Vatalanib, Vincristine, Vinflunine, Virulizine, 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, Zosuquidar, and combinations thereof.

[0247] In some embodiments of the method of treatment, the second therapeutic 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 some embodiments of the method of treatment, the second therapeutic agent is selected from the group consisting of, but not limited to, an LHRH agonist and an LHRH antagonist. In some embodiments, the LHRH agonist is selected from the group consisting of goserelin acetate, leuprolide acetate, triptorelin pamoate, and combinations thereof. In some embodiments, the second therapeutic agent includes an LHRH antagonist selected from the group consisting of degarelix, cetrorelix, abarelix, ozarelix, degarelix, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent comprises a growth factor inhibitor. In some embodiments, the growth factor inhibitor is selected from the group consisting of, but 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 of these inhibitors. In some embodiments, the human epidermal growth factor (HER) is selected from the group consisting of HER2, HER3, and HER4.

[0248] In some embodiments of the method of treatment, the second therapeutic agent comprises a tyrosine kinase inhibitor. In some embodiments of the method of treatment, the tyrosine kinase inhibitor is selected from the group consisting of, but not limited to, cetuximab, gefitinib, imatinib, lapatinib, and trastuzumab, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent comprises an aromatase inhibitor. In some embodiments of the method of treatment, the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, and combinations thereof.

[0249] In some embodiments of the method of treatment, the second therapeutic agent comprises an antimetabolite. In some embodiments of the method of treatment, the antimetabolite comprises an antifolate. In some embodiments of the method of treatment, the antifolate is selected from the group consisting of methotrexate, raltitrexed, a pyrimidine analog, and combinations thereof. In some embodiments of the method of treatment, the antimetabolite is a pyrimidine analog. In some embodiments of the method of treatment, the pyrimidine analog is selected from the group consisting of 5-fluorouracil, capecitabine, gemcitabine, and combinations thereof. In some embodiments of the method of treatment, the antimetabolite is a purine analog or an adenosine analog. In some embodiments of the method of treatment, the purine analog or adenosine analog is selected from the group consisting of mercaptopurine, thioguanine, cladribine, pentostatin, cytarabine, fludarabine, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent comprises an antitumor antibiotic. In some embodiments of the method of treatment, the antitumor antibiotic is selected from the group consisting of anthracyclines, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin, streptozocin, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent comprises a platinum derivative. In some embodiments of the method of treatment, the platinum derivative is selected from the group consisting of cisplatin, oxaliplatin, carboplatin, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent comprises an alkylating agent. In some embodiments of the method of treatment, the alkylating agent is selected from the group consisting of estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent comprises a nitrosourea. In some embodiments of the method of treatment, the nitrosourea is selected from the group consisting of carmustine, lomustine, thiotepa, and combinations thereof.The second therapeutic agent includes a mitotic inhibitor. In some embodiments of the method of treatment, the mitotic inhibitor is selected from the group consisting of a vinca alkaloid and a taxane. In some embodiments of the method of treatment, the taxane is selected from the group consisting of paclitaxel, docetaxel, and combinations thereof. In some embodiments of the method of treatment, the vinca alkaloid is selected from the group consisting of vinblastine, vindesine, vinorelbine, vincristine, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent includes a topoisomerase inhibitor. In some embodiments of the method of treatment, the topoisomerase inhibitor is an epipodophyllotoxin. In some embodiments of the method of treatment, the topoisomerase inhibitor is an epipodophyllotoxin selected from the group consisting of etoposide, etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, and combinations thereof. In some embodiments of the methods of treatment, the second therapeutic agent comprises a serine / threonine kinase inhibitor. In some embodiments of the methods of treatment, the serine / threonine kinase inhibitor is selected from the group consisting of a PDK1 inhibitor, a B-Raf inhibitor, an mTOR inhibitor, an mTORCl inhibitor, a PI3K inhibitor, an mTOR / PI3K dual inhibitor, an STK33 inhibitor, an AKT inhibitor, a PLK1 inhibitor, an inhibitor of a CDK, an Aurora kinase inhibitor, and combinations thereof. In some embodiments of the methods of treatment, the second therapeutic agent comprises a tyrosine kinase inhibitor. In some embodiments of the methods of treatment, the second therapeutic agent comprises a PTK2 / FAK inhibitor. In some embodiments of the methods of treatment, the second therapeutic agent comprises a protein-protein interaction inhibitor. In some embodiments of the methods of treatment, the protein-protein interaction inhibitor is selected from the group consisting of an IAP, Mcl-1, MDM2 / MDMX, and combinations thereof. In some embodiments of the methods of treatment, the second therapeutic agent comprises a rapamycin analog. In some embodiments of the method of treatment, the rapamycin analog is selected from the group consisting of everolimus, temsirolimus, ridaforolimus, sirolimus, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent is amifostine,In some embodiments of the method of treatment, the second therapeutic agent is selected from the group consisting of anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer, and combinations thereof. In some embodiments of the method of treatment, the second therapeutic agent is selected from the group consisting of 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-arretin, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, and apazidone. Quon, Apomin, Alanose, Arglavin, Arzoxifene, Atamestane, Atrasentan, Auristatin PE, AVLB, AZ10992, 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-736, ARQ 680, AS-703026 (pimasertib), Avastin, AZD-2014, azacitidine, azaepothilone B, azonafide, BAY-43-9006, BAY80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, bilirubin 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, bryostatin-1, bortezomib, brostallicin, busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, cefratonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655 / RO-4987655, chlorotrianisene, cilengitide, 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, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexate, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3, ethinylsiti gin, ethinyl estradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, Forfox, Forfox 4, forfili, formestane, fotemustine, galarubicin, gallium maltolate, gefitinib, gemtuzumab, gimatecan, glufosfamide, 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, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, Herceptin, Hexapro oxamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (cixutumumab), Immunol, indisulam, interferon alfa-2a, interferon alfa-2b, pegylated interferon alfa-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, Kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuprorelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, Rootecan, LY-S6AKT1, LY-2780301, Mahosfamide, Marimastat, Mechloroethamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, Midostaurin, Minodronic acid, Mitomycin, Mitomycin Bobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexafine gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole,Oncophage, OncoVEX GM-CSF, ormiplatin, ortataxel, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-IBB antibody, oxatrazol, estrogen, panitumumab, patupilone, pegfilgrastim, PCK-3145, gfilgrastim, 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, pelitinib, pemetrexed, pentrix, perifosine, perillyl 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, polybutene, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY 869766, RDEA436, rebeccamycin analog, receptor tyrosine kinase (RTK) inhibitor, Revimid, 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 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabalubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, stent, T 900607, T138067, TAK-733, TAS-103, tacedinaline, talaporfin, tarceva, tariquitar, tasisulam, taxotere, taxoplexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide Id, Theralux, Terarubicin, Thymalfasin, Timectacin, Tiazofurin, Tipifarnib, Tirapazamine, Tocladesine, Tomudex, Tremofin, Trabectedin, Trans MID-107, Trans Retinoic Acid, Trastuzumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Triciribine, Trimetrexate, TLK-286TXD 258, Tykerb / Tyverb, Urocidin, Valrubicin, Vatalanib, Vincristine, Vinflunine, Virulizine, 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, Zosuquidar, and combinations thereof.

[0250] In some embodiments, the other therapeutic agent includes a steroid. Steroids include, but are not limited to, dexamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazol. In some embodiments, the other therapeutic agent includes an antiemetic. Antiemetics include 5-HT3 receptor agonists (such as dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine), dopamine agonists (such as domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine, and metoclopramide), NK1 receptor antagonists (such as aprepitant and casopitant), antihistamines (such as cyclosporine, cyclosporine, and cyclosporine), and the like. These include, but are not limited to, lysine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine, cannabinoids (such as cannabis, dronabinol, nabilone, and Sativex), benzodiazepines (such as midazolam and lorazepam), anticholinergics (such as hyoscine), trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol, and ajwain.

[0251] The pharmaceutical composition may be administered to a subject by any suitable route of administration. In one embodiment, the pharmaceutical composition is administered to a subject orally, parenterally, transdermally, or transmucosally. In one embodiment, the pharmaceutical composition is administered to a subject parenterally. In one embodiment, the pharmaceutical composition is administered to a subject via a parenteral route selected from the group consisting of intravenous (IV), subcutaneous (SC), and intramuscular (IM). In one embodiment, the pharmaceutical composition is administered to a subject via a route of administration selected from rectal and transdermal. In one embodiment, the pharmaceutical composition is administered to a subject in a dosage form selected from the group consisting of a sterile solution, suspension, suppository, tablet, and capsule. In one embodiment, the pharmaceutical composition is administered to a subject in an oral dosage form selected from the group consisting of a tablet, caplet, capsule, lozenge, syrup, liquid, suspension, and elixir. In one embodiment, the pharmaceutical composition is administered to a subject in an oral dosage form selected from the group consisting of a tablet, hard-shell capsule, soft gelatin capsule, beads, granules, agglomerates, powders, gels, solids, and semisolids.

[0252] In some embodiments, the pharmaceutical composition is administered to the subject in a dosage form selected from the group consisting of a sustained release form, a controlled release form, a delayed release form, and a responsive release form.

[0253] In some embodiments, the pharmaceutical composition is administered to the subject once daily. In some embodiments, the pharmaceutical composition is administered to the subject by an infrequent dosing schedule (e.g., once per week or less frequently). In some embodiments, the pharmaceutical composition is administered to the subject by a frequent dosing schedule (e.g., administered twice per week or more frequently). In some embodiments, the pharmaceutical composition is administered to the subject once per week. In some embodiments, the pharmaceutical composition is administered to the subject once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject twice per week. In some embodiments, the pharmaceutical composition is administered to the subject once every two weeks. In some embodiments, the pharmaceutical composition is administered to the subject once every three weeks. In some embodiments, the pharmaceutical composition is administered to the subject in a repeating cycle of weekly, once every two weeks, once every three weeks, once every four weeks, or a combination thereof.

[0254] In one embodiment, the method of treatment comprises administering (i) a first therapeutic agent comprising a compound comprising Compound (1), Compound (10), an analog thereof, or a pharmaceutically acceptable salt thereof, in combination with (ii) a second therapeutic agent to a subject in need of such treatment, wherein the first and second therapeutic agents are administered simultaneously or sequentially, and further comprises assaying expression of an endoplasmic reticulum (ER) stress response gene in a biological sample. In some embodiments, the ER stress response gene is selected from the group including, but not limited to, C / EBP-homologous protein (CHOP), activating transcription factor 3 (ATF3), and both CHOP and ATF3. In some embodiments, the ER stress response gene is selected from the group including, but not limited to, ATF3, activating transcription factor 4 (ATF4), CHOP, IRE1, binding immunoglobulin protein (BiP), eukaryotic translation initiation factor 2A (eIF2a), and X-box binding protein 1 (XBP1). The biological sample may be a tumor, peripheral blood mononuclear cells, or skin biopsy. Biological samples may be obtained before, during, or after drug administration. In some embodiments, the method of treatment further comprises adjusting the dose of the first therapeutic agent to achieve about 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, or greater than 600% induction of one or more ER stress genes. In some embodiments, the method of treatment further comprises adjusting the dose of the first therapeutic agent to achieve about 50% to about 100%, about 100% to about 150%, about 150% to about 200%, about 200% to about 250%, about 250% to about 300%, about 300% to about 350%, about 350% to about 400%, about 400% to about 450%, about 450% to about 500%, about 500% to about 550%, about 550% to about 600%, or greater than 600% induction of an ER stress gene.In some embodiments, the method of treatment further comprises adjusting the dose of the first therapeutic agent to achieve about 50% to about 100%, about 100% to about 200%, about 200% to about 300%, about 300% to about 400%, about 400% to about 500%, about 500% to about 600%, or greater than 600% induction of the ER stress gene.

[0255] In one embodiment, the method of treatment comprises administering (i) a first therapeutic agent comprising a compound comprising Compound (1) or Compound (10), an analog thereof, or a pharmaceutically acceptable salt thereof, in combination with (ii) a second therapeutic agent to a subject in need of such treatment, wherein the first and second therapeutic agents are administered simultaneously or sequentially, and further comprises assaying for 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 method of treatment further comprises adjusting the dose to achieve 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% inhibition of proteasome activity. In some embodiments, the method of treatment further comprises adjusting the dose to achieve 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% inhibition of proteasome activity. In some embodiments, the treatment method further comprises adjusting the dose to achieve about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or greater than 90% inhibition of proteasome activity.

[0256] In one aspect, the present disclosure provides a method of treatment comprising administering to a subject in need of such treatment a combination of a first therapeutic agent comprising a compound of Formula (1) or Formula (10), or an analog thereof, or a pharmaceutically acceptable salt (e.g., a di- or tri-salt) thereof, and a second therapeutic agent, the method comprising: (i) administering a first therapeutic agent to a subject; (ii) waiting until a predetermined waiting period has elapsed after the time of administration of the first therapeutic agent to the subject and / or until the adverse event has resolved or is resolving; and (iii) administering a second therapeutic agent to the subject, wherein the predetermined waiting time is selected to achieve a delayed therapeutic effect of the first therapeutic agent without increasing the risk of potential combined toxic effects of the first and second therapeutic agents. In some embodiments of the treatment method, the predetermined waiting time is determined based on the clearance rate of the first therapeutic agent compound or a metabolite thereof. In some embodiments of the treatment method, the predetermined waiting time is determined by quantitative assessment of renal function and renal parameters. In some embodiments of the treatment method, the predetermined waiting time is determined by an assay for measuring renal function, the assay being selected from the group consisting of serum levels of the first therapeutic agent compound or a metabolite thereof, clearance rate of the first therapeutic agent compound or a metabolite thereof, and 24-hour urinary clearance of the first therapeutic agent compound or a metabolite thereof.

[0257] In one embodiment of the method of treatment, the predetermined waiting time is substantially equal to the time required for systemic clearance of the first therapeutic compound or its metabolites from the subject's body. In one embodiment of the method of treatment, the predetermined waiting time is substantially equal to the time required for renal clearance of the first therapeutic compound or its metabolites from the subject's body. In one embodiment of the method of treatment, the predetermined waiting time is substantially equal to the time required for hepatic clearance of the first therapeutic compound or its metabolites from the subject's body. In one embodiment of the method of treatment, the predetermined waiting time is substantially equal to the time required for total clearance of the first therapeutic compound or its metabolites from the subject's body. In one embodiment of the method of treatment, the predetermined waiting time is about 4 hours. In other embodiments, the waiting time is 1 day. In some embodiments, the waiting time is greater than or equal to the C of the first therapeutic compound. max In other embodiments, the waiting period is after the majority of adverse events have resolved or are in the process of being resolved. In one embodiment of the method of treatment, the predetermined waiting period is about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In one embodiment of the method of treatment, the predetermined waiting period is in the range of about 1-7 days, about 1-6 days, about 1-5 days, about 1-4 days, about 1-3 days, or about 1-2 days. In one embodiment, the waiting period is up to 3 weeks. The aforementioned periods are considered the "treatment period."

[0258] If the order of administration is reversed, the timing of administration of the first therapeutic agent should be adjusted to coincide with the C of the second therapeutic agent (i.e., the agent administered first). max In one embodiment, the administration of the first therapeutic agent can occur after most or substantially all of the originally administered drug has been cleared from the body or after the toxic effects of the originally administered drug have resolved or are being resolved.

[0259] In some embodiments, the treatment method further includes monitoring the level of a first therapeutic compound or a metabolite thereof in the subject using pharmacokinetic profiling. In some such embodiments, monitoring the level of a first therapeutic compound or a metabolite thereof in the subject using pharmacokinetic profiling includes constructing a pharmacokinetic profile of the first therapeutic compound or a metabolite thereof for the subject using the concentrations of the first therapeutic compound or a metabolite thereof in at least two samples obtained from the subject at time points suitable for constructing the pharmacokinetic profile. In some embodiments of methods that include monitoring the level of a first therapeutic compound or a metabolite thereof in the subject using pharmacokinetic profiling, the sample is collected from the subject at the point of care or point of use, by sampling or self-sampling on a matrix suitable for sample storage prior to laboratory quantification. In some embodiments of the treatment method, each of the point of care or point of use devices is capable of quantifying the first therapeutic compound or a metabolite thereof. In some embodiments of methods involving monitoring levels of a first therapeutic compound or its metabolite in a subject, one or more samples are collected from the subject by a biopsy device at the point of care or point of use for analysis at a point-of-care or point-of-use device or for storage prior to laboratory analysis. In some embodiments of the methods, the biopsy is obtained after a time interval of 3 to 8 hours after administration of the first therapeutic agent to the subject. In some embodiments of the methods, the biopsy is obtained after a time interval of 3 to 24 hours after administration of the first therapeutic agent to the subject. In some embodiments of the methods, the biopsy is obtained after a time interval of 8 to 24 hours after administration of the first therapeutic agent to the subject. In some embodiments of the methods, the biopsy is obtained after a time interval of 2 days after administration of the first therapeutic agent to the subject. In some embodiments of the methods, the biopsy is obtained after a time interval of 3 days after administration of the first therapeutic agent to the subject.In some embodiments of the method, the biopsy is obtained after a time interval of 4 days after administration of the first therapeutic agent to the subject. In some embodiments of the method, the biopsy is obtained after a time interval of 1 to 7 days after administration of the first therapeutic agent.

[0260] In some embodiments of the methods of treatment, the pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding administration of the first therapeutic agent for the subject being treated. ... max ") ranges from about 1000 ng / dL to 1500 ng / dL during the treatment period. In some embodiments, C max is less than 1500 ng / dL and greater than 85 ng / dL during the treatment period. In some embodiments of the treatment method, the maximum concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) following administration to the subject is max ") ranges from about 1000 ng / mL to 1500 ng / mL during the treatment period. In some embodiments, C max is less than 1500 ng / mL and more than 85 ng / mL during treatment.

[0261] In some embodiments, the maximum concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) following administration to the subject is measured. max") are approximately 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260 , 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490ng / dL to approximately 1500ng / dL; approximately 100 , 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135 C of 5, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng / dL to about 150 ng / dL; or C of about 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng / dL to about 15 ng / dL max is.

[0262] In some embodiments, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is measured. max") are approximately 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260 , 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490 ng / mL to approximately 1500 ng / mL; approximately 100 , 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135 a C of 5, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng / mL to about 150 ng / mL; or a C of about 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng / mL to about 15 ng / mL max is.

[0263] In some embodiments, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is measured. max ") are approximately 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, In some embodiments, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is selected from the group consisting of 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490 ng / dL.max ") is selected from about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng / dL. In some embodiments, the maximum concentration ("C") after administration of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is max ") is selected from about 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng / dL.

[0264] In some embodiments, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is measured. max ") are approximately 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, In some embodiments, the maximum concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) after administration is selected from the group consisting of 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490 ng / mL. max") is selected from about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng / mL. In some embodiments, the maximum concentration ("C") after administration of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is max ") is selected from about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5 ng / mL.

[0265] In some embodiments, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is measured. max") are approximately 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 475, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 765, 775, 785, 795, 805, 815, 825, 835, 845, 855, 865, 875, 885, 895, 905, 915, 925, 935, 945, 955, 965, 975, 985, 995, 1005, 1065, 1075, 1085, 1095, 1105, 1115, 1125, 75, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 765, 775, 785, 795, 805, 815, 825, 835, 845, 855, 865, 8 75, 885, 895, 905, 915, 925, 935, 945, 955, 965, 975, 985, 995, 1005, 1015, 1025, 1035, 1045, 1055, 1065, 1075, 1085, 1095, 1105, 1115, 1125, 1135, 1145, 1155, 1165, 1175, 1185, 1195, 1205, 1215 , 1225, 1235, 1245, 1255, 1265, 1275, 1285, 1295, 1305, 1315, 1325, 1335, 1345, 1355, 1365, 1375, 1385, 1395, 1405, 1415, 1425, 1435, 1445, 1455, 1465, 1475, 1485, 1495, or 1500 ng / dL. In some embodiments, the maximum concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) after administration is selected from the group consisting of: max") is approximately 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 9, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng / dL. In some embodiments, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is measured. max ") is selected from about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng / dL.

[0266] In some embodiments, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is measured. max") are approximately 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 475, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 765, 775, 785, 795, 805, 815, 825, 835, 845, 855, 865, 875, 885, 895, 905, 915, 925, 935, 945, 955, 965, 975, 985, 995, 1005, 1065, 1075, 1085, 1095, 1105, 1115, 1125, 75, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 765, 775, 785, 795, 805, 815, 825, 835, 845, 855, 865, 8 75, 885, 895, 905, 915, 925, 935, 945, 955, 965, 975, 985, 995, 1005, 1015, 1025, 1035, 1045, 1055, 1065, 1075, 1085, 1095, 1105, 1115, 1125, 1135, 1145, 1155, 1165, 1175, 1185, 1195, 1205, 1215 , 1225, 1235, 1245, 1255, 1265, 1275, 1285, 1295, 1305, 1315, 1325, 1335, 1345, 1355, 1365, 1375, 1385, 1395, 1405, 1415, 1425, 1435, 1445, 1455, 1465, 1475, 1485, 1495, or 1500 ng / mL. In some embodiments, the maximum concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) after administration is selected from the group consisting of: max") is approximately 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 , 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, or 149 ng / mL. In some embodiments, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is measured. max ") is selected from about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng / mL.

[0267] In some embodiments of the treatment methods, the maximum concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) after administration to the subject is determined. max In some embodiments, the maximum concentration ("C") after administration of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is in the range of about 85 ng / dL to 1500 ng / dL, about 8.5 ng / dL to 150 ng / dL, or about 0.85 ng / dL to 15 ng / dL. ... max") are approximately 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 47 5, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 765, 775, 785, 795, 805, 815, 825, 835, 845, 855, 865, 87 5, 885, 895, 905, 915, 925, 935, 945, 955, 965, 975, 985, 995, 1005, 1015, 1025, 1035, 1045, 1055, 1065, 1075, 1085, 1095, 1105, 1115, 1125, 1135, 1145, 1155, 1165, 1175, 1185, 1195, 1205, 1215, 1225, 1235, 1245, 1255, 1265, 1275, 1285, 1295, 1305, 1315, 1325, 1335, 1345, 1355, 1365, 1375, 1385, 1395, 1405, 1415, 1425, 1435, 1445, 1455, 1465, 1475, 1485, or 1495 ng / dL to approximately 1500 ng / dL;Approximately 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 ,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 1 08, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146 , 147, 148, or 149 ng / dL to about 150 ng / dL; or selected from about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng / dL to about 15 ng / dL;

[0268] In some embodiments of the treatment methods, the maximum post-administration concentration ("C") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is determined. max In some embodiments, the maximum concentration ("C") after administration of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) is in the range of about 85 ng / mL to 1500 ng / mL, about 8.5 ng / mL to 150 ng / mL, or about 0.85 ng / mL to 15 ng / mL. ... max") are approximately 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 475, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 765, 775, 785, 795, 805, 815, 825, 835, 845, 855, 865, 875, 885, 895, 905, 915, 925, 935, 945, 955, 965, 975, 985, 995, 1005, 1065, 1075, 1085, 1095, 1105, 1115, 1125, 75, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 765, 775, 785, 795, 805, 815, 825, 835, 845, 855, 865, 8 75, 885, 895, 905, 915, 925, 935, 945, 955, 965, 975, 985, 995, 1005, 1015, 1025, 1035, 1045, 1055, 1065, 1075, 1085, 1095, 1105, 1115, 1125, 1135, 1145, 1155, 1165, 1175, 1185, 1195, 1205, 1215 , 1225, 1235, 1245, 1255, 1265, 1275, 1285, 1295, 1305, 1315, 1325, 1335, 1345, 1355, 1365, 1375, 1385, 1395, 1405, 1415, 1425, 1435, 1445, 1455, 1465, 1475, 1485, or 1495 ng / mL to approximately 1500 ng / mL;Approximately 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 ,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 1 08, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146 , 147, 148, or 149 ng / mL to about 150 ng / mL; or selected from about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng / mL to about 15 ng / mL;

[0269] 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 versus time after drug administration, ranges from about 150 ng hr / mL to about 8000 ng hr / mL, from about 15 ng hr / mL to about 8000 ng hr / mL, or from about 1.5 ng hr / mL to about 80 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. In some embodiments, the AUC is less than 800 ng hr / mL and greater than or equal to 15 ng hr / mL. In some embodiments, the AUC is less than 800 ng hr / mL and greater than or equal to 1.5 ng hr / mL.

[0270] In some embodiments of the method, the total drug exposure over time is an AUC of about 100 ng hr / mL to about 8000 ng hr / mL, about 10 ng hr / mL to about 800 ng hr / mL, or about 1 ng hr / mL to about 80 ng hr / mL. In some embodiments, the total drug exposure over time is an AUC of about 150, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200, 4400, 4600, 4800, 5000, 5200, 5400, 5600, 5800, 6000, 6200, 6400, 6600, 6800, 7000, 7200, 7400, 7600, or 7800 ng hr / mL to about 8000 ng hr / mL. In some embodiments, the total drug exposure over time is an AUC of about 15, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, or 780 ng hr / mL to about 800 ng hr / mL. In some embodiments, the total drug exposure over time is an AUC of about 1.5, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, or 78 ng hr / mL to about 80 ng hr / mL.

[0271] In some embodiments of the method, the total drug exposure over time is an AUC of about 100 ng hr / mL to about 8000 ng hr / mL, about 10 ng hr / mL to about 800 ng hr / mL, or about 1 ng hr / mL to about 80 ng hr / mL. In some embodiments, the total drug exposure over time is an AUC of about 150 ng hr / mL to about 7800, 7600, 7400, 7200, 7000, 6800, 6600, 6400, 6200, 6000, 5800, 5600, 5400, 5200, 5000, 4800, 4600, 4400, 4200, 4000, 3800, 3600, 3400, 3200, 3000, 2800, 2600, 2400, 2200, 2000, 1800, 1600, 1400, 1200, 1000, 800, 600, 400, or 200 ng hr / mL. In some embodiments, the total drug exposure over time is an AUC of about 15 ng hr / mL to about 780, 760, 740, 720, 700, 680, 660, 640, 620, 600, 580, 560, 540, 520, 500, 480, 460, 440, 420, 400, 380, 360, 340, 320, 300, 280, 260, 240, 220, 200, 180, 160, 140, 120, 100, 80, 60, 40, or 20 ng hr / mL. In some embodiments, the total drug exposure over time is an AUC of about 1.5 ng hr / mL to about 78, 76, 74, 72, 70, 68, 66, 64, 62, 60, 58, 56, 54, 52, 50, 48, 46, 44, 42, 40, 38, 36, 34, 32, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 4, or 2 ng hr / mL. In some embodiments, the total drug exposure over time is an AUC of about 100 ng hr / mL to about 200 ng hr / mL, about 10 ng hr / mL to about 20 ng hr / mL, or about 1 ng hr / mL to about 2 ng hr / mL.

[0272] In some embodiments of the method, the total drug exposure over time is an AUC selected from about 100, 150, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200, 4400, 4600, 4800, 5000, 5200, 5400, 5600, 5800, 6000, 6200, 6400, 6600, 6800, 7000, 7200, 7400, 7600, 7800, and 8000 ng hr / mL. In some embodiments, the total drug exposure over time is an AUC selected from about 10, 15, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780, and 800 ng hr / mL. In some embodiments of the method, the total drug exposure over time is an AUC selected from about 1, 1.5, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, and 80 ng hr / mL.

[0273] In another aspect, provided by the present disclosure is a method of treatment or use of a composition to treat a condition comprising administering a combination of a first therapeutic agent and a second therapeutic agent to a subject in need of such treatment, the method comprising: (i) administering to a subject a first therapeutic agent comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; (ii) monitoring the level of the first therapeutic compound or a metabolite thereof in the subject using pharmacokinetic profiling; and (iii) administering a second therapeutic agent in response to the level of the first therapeutic agent in the subject. In some embodiments of the method, the monitoring step includes constructing a pharmacokinetic profile of the first therapeutic agent compound or its metabolite for the subject using concentrations of the first therapeutic agent compound or its metabolite in multiple samples obtained from the subject at time points suitable for constructing the pharmacokinetic profile. In some embodiments of the method, at least two samples are collected at the point of care or point of use by sampling or self-sampling at a point-of-care or point-of-use device or on a matrix suitable for sample storage prior to quantification of the compound or its metabolite in a laboratory. In some embodiments of the method, each of the point-of-care or point-of-use devices is capable of quantifying the compound or its metabolite. In some embodiments of the method, the pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding administration of the compound or its salt for the subject. In some embodiments of the method, the pharmacokinetic profile includes samples from 2 to 12 different samples. In some embodiments of the method, samples are collected over a period of up to 8 hours, 24 hours, 48 ​​hours, or 72 hours. In some embodiments of the method, the pharmacokinetic parameters are AUC, AUC inf , T max , C max, time above a threshold, steady-state concentration, absorption rate, clearance rate, distribution rate, terminal half-life, or a parameter derived from a compartmental pharmacokinetic (PK) analysis, including a non-compartmental PK analysis or a physiological model-based compartmental PK analysis. In some embodiments of the method, the treatment method further includes generating a report including the subject's pharmacokinetic profile. In some embodiments of the method, the report includes a dosing recommendation based on the subject's pharmacokinetic profile. In some embodiments of the method, a reduced dose of compound (1), its analog, or a pharmaceutically acceptable salt thereof is indicated to reduce the risk of toxicity based on the one or more pharmacokinetic parameters. In some embodiments of the method, a reduced dose of the compound or its salt is indicated based on the time above a threshold, the threshold being the drug concentration above which toxicity occurs, or the AUC, AUCs, or other parameters that adequately describe the pharmacokinetic profile. inf In some embodiments of the method, the one or more pharmacokinetic parameters are one or more of AUC, AUC infThe dose of the compound or its salt is increased based on one or more of the following: MRT, an index defining the pharmacokinetic profile, the volume of distribution at steady state (Vss), the volume of distribution at terminal phase (Vz), or a combination of pharmacokinetic variables. In some embodiments of the method, the dose of the compound or its salt is adjusted to within 5% to 25% of a desired target value. In some embodiments of the method, each sample is applied to a point-of-care or point-of-use device for determining the concentration of the compound or its metabolites, the point-of-care or point-of-use device including a lateral flow strip having a structure and composition such that application of one or more samples to the lateral flow strip binds a fraction of the drug in the sample to components of the lateral flow strip, generating a detectable signal proportional to the drug concentration in the applied sample. In some embodiments of the method, the sample is applied to a matrix suitable for sample storage prior to quantification in the laboratory. In some embodiments of the method, the sample is stored as a dried blood spot. In some embodiments of the method, the drug concentration is measured by ELISA, LC MS 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 terminal half-life. In some embodiments of the method, at least one sample is whole blood.

[0274] IX. Multidisciplinary therapy In one aspect, the present disclosure provides a multimodality therapy in which administration of a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment is supplemented with the administration of another therapy. In one embodiment, the multimodality therapy comprises administering to the subject a pharmaceutical composition comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof, in combination with radiation therapy or after it has been determined that radiation was ineffective. In one embodiment, the multimodality therapy comprises administering to the subject a pharmaceutical composition comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof, in combination with radiation therapy, wherein the pharmaceutical composition comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof and the radiation therapy are administered simultaneously or sequentially in any order. In one embodiment, the multimodality therapy comprises administering to a subject a pharmaceutical composition comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof, in a sequential sequence, in combination with radiation therapy. In one embodiment, the multimodality therapy comprises administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof, concurrently with radiation therapy. In one embodiment, the multimodality therapy is used to treat cancer. In one embodiment, the multimodality therapy comprises administering to a subject with cancer in need of such treatment a pharmaceutical composition comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof, and irradiating the cancer cells with a radiation beam. In one embodiment, the multimodality therapy uses conformal radiation therapy (CRT) techniques to deliver a prescribed dose-volume histogram (DVH) to the subject with cancer. In one embodiment, the multimodality therapy uses intensity-modulated radiation therapy (IMRT) techniques to deliver radiation to cancer cells. In one embodiment, the multimodality therapy uses techniques to compensate for tumor movement within the subject during treatment (e.g., when a dose of radiation must be administered to a breast tumor that moves as the patient breathes).For example, multimodality therapy adjusts the delivered radiation field using four-dimensional computed tomography (4D CT) scanning techniques to compensate for tumor motion over the respiratory cycle.

[0275] Any suitable type of radiation can be used in multimodality therapy, including fractionated gamma rays, IMRT (intensity-modulated radiation therapy), gamma knife, proton therapy, and brachytherapy. Administration of radiation therapy and a compound of Formula (1) or Formula (10), their analogs, or pharmaceutically acceptable salts thereof can treat brain metastases from brain tumors or lung cancer, such as glioblastoma. Multimodality therapy can be used to treat lung cancer, pancreatic cancer, rectal cancer, breast cancer, sarcoma, prostate cancer, gynecological malignancies, and lymphoma. Gamma knife is frequently used to treat brain metastases. In one embodiment, multimodality therapy includes the use of proton therapy to treat cancer, including brain tumors, prostate cancer, and any tumors in close proximity to vital organs, where minimizing toxicity to nearby normal tissue is critical.

[0276] In one embodiment, the multimodality therapy comprises administering a pharmaceutical composition comprising a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof, in conjunction with, simultaneously or in combination with, adoptive cell therapy (CAR-T (JCAR14, 15, 16, 17, KTE-C19, or CTL019); other T cells (AFM13); or NK (CDNO-109 or NK-92)) to a cancer subject in need of such treatment.

[0277] In one embodiment, the multimodality therapy eliminates minimal residual disease without increasing toxicity resulting from treatment with a compound of Formula (1) or Formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the multimodality therapy improves the prognosis of the subject being treated and / or reduces adverse side effects associated with a disease state or condition.

[0278] X. Additional Derivatives, Analogs, and Salts of Compound (1) and Related Compounds In one aspect, the present disclosure provides analogs and related salts of Compound (1) and methods for their preparation. Those skilled in the art will understand that the same general principles and concepts described above in connection with Compounds (1), (10) and their salts, including principles and concepts related to methods and pharmaceutical compositions, apply equally to derivatives and analogs and salts of Compound (1) and their salts.

[0279] In one embodiment, the analog has the structure of compound (25):

[0280] [ka]

[0281] wherein Y is NR or O, and R, R, R, and R are independently 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, R, R, R, and R are optionally substituted. In some embodiments, some or all of the hydrogen atoms in R, R, R, and R can be replaced with deuterium. In other embodiments, the analog has the structure of compound (25), wherein R, R, R, and R are independently selected from H, C, D, E, F, H, H, I ... 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, and C 1-4 alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4Alkyl phenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 and optionally substituted with alkyl, hydroxyl, or halo. In yet other embodiments, the analog has the structure of compound (25), wherein R, R, R, and R are independently selected from the group consisting of H, CH, CHPh, CH-((2-Cl)-Ph), CH-(2-thienyl), CHCHPh, CHCH(4-N-benzylpiperazine), CH-(2,4-diF-PH), CH-((2-CH)-Ph), CHCHOHPh, and (CH)CO-4F-Ph.

[0282] In one embodiment, the analog has the structure of compound (26):

[0283] [ka]

[0284] wherein R1 and R2 are independently 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 and R2 are independently selected from H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, and C 1-4 alkylthienyl, independently selected from the group consisting of C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 Alkyl, C1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, R is selected from the group consisting of H, CH, CHPh, CH-((2-Cl)-Ph), CH-(2-thienyl), CHCHPh, CHCH(4-N-benzylpiperazine), CH-(2,4-diF-Ph), CH-((2-CH)-Ph), CHCHOHPh, and (CH)CO-4F-Ph. In some embodiments, R2 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.

[0285] In some embodiments, R1 alone or in combination at the ortho, meta, and / or para positions of the benzyl ring may be one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1 where p is an integer from 2 to 20, and X is a halogen, including a fluorine, bromine, or iodine atom, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom. In some embodiments, R2 is selected from the group consisting of, alone or in combination at the ortho, meta, and / or para positions of the benzyl ring, one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1 where p is an integer of 2 to 20, and X is a halogen.

[0286] In some embodiments, R is hydrogen. In some embodiments, R is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 It is substituted with alkyl or halo.

[0287] In some embodiments, R2 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R2 is a substituted or unsubstituted heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or unsubstituted heteroarylalkyl, such as an isoxazolidinylmethyl or pyridylmethyl group. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, —CH 3 , —CF 3 , and —OCH 3 .

[0288] In one embodiment, the analog has the structure of compound (27):

[0289] [ka]

[0290] wherein R1 is 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 is H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, and C 1-4 alkylthienyl, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, R is selected from the group consisting of H, CH, CHPh, CH-((2-Cl)-Ph), CH-(2-thienyl), CHCHPh, CHCH(4-N-benzylpiperazine), CH-(2,4-diF-Ph), CH-((2-CH)-Ph), CHCHOHPh, and (CH)CO-4F-Ph.

[0291] In some embodiments, R1 alone or in combination at the ortho, meta, and / or para positions of the benzyl ring may be one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1wherein p is an integer from 2 to 20, and X is a halogen, including a fluorine, bromine, or iodine atom, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is a C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 It is substituted with alkyl or halo.

[0292] In one embodiment, the analog has the structure of compound (28):

[0293] [ka]

[0294] wherein R1 and R2 are independently 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 and R2 are independently selected from H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, and C 1-4 alkylthienyl, independently selected from the group consisting of C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 Alkyl, C1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, R is selected from the group consisting of H, CH, CHPh, CH-((2-Cl)-Ph), CH-(2-thienyl), CHCHPh, CH-(2,4-diF-Ph), CH-((2-CH)-Ph), CHCHOHPh, CHCH(4-N-benzylpiperazine), and (CH)CO-4F-Ph. In some embodiments, R2 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. In some embodiments, when R1 is CH2Ph, R2 is not CH2-((2-CH3)-Ph).

[0295] In some embodiments, R1 alone or in combination at the ortho, meta, and / or para positions of the benzyl ring may be one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1 where p is an integer from 2 to 20, and X is a halogen, including a fluorine, bromine, or iodine atom, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom. In some embodiments, R2 is selected from the group consisting of, alone or in combination at the ortho, meta, and / or para positions of the benzyl ring, one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1where p is an integer of 2 to 20, and X is a halogen.

[0296] In some embodiments, R is hydrogen. In some embodiments, R is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 It is substituted with alkyl or halo.

[0297] In some embodiments, R2 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R2 is a substituted or unsubstituted heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or unsubstituted heteroarylalkyl, such as an isoxazolidinylmethyl or pyridylmethyl group. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, —CH 3 , —CF 3 , and —OCH 3 .

[0298] In one embodiment, the analog has the structure of compound (29):

[0299] [ka]

[0300] wherein R1 and R2 are independently 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 and R2 are independently selected from H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, and C 1-4 alkylthienyl, independently selected from the group consisting of C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4In some embodiments, R is selected from the group consisting of H, CH, CHPh, CH-((2-Cl)-Ph), CH-(2-thienyl), CHCHPh, CHCH(4-N-benzylpiperazine), CH-(2,4-diF-Ph), CH-((2-CH)-Ph), CHCHOHPh, and (CH)CO-4F-Ph. In some embodiments, R2 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. In some embodiments, when R1 is CH2Ph, R2 is not CH2-((2-CH3)-Ph).

[0301] In some embodiments, R1 alone or in combination at the ortho, meta, and / or para positions of the benzyl ring may be one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1 where p is an integer from 2 to 20, and X is a halogen, including a fluorine, bromine, or iodine atom, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom. In some embodiments, R2 is selected from the group consisting of, alone or in combination at the ortho, meta, and / or para positions of the benzyl ring, one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1 where p is an integer of 2 to 20, and X is a halogen.

[0302] In some embodiments, R is hydrogen. In some embodiments, R is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 It is substituted with alkyl or halo.

[0303] In some embodiments, R2 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R2 is a substituted or unsubstituted heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or unsubstituted heteroarylalkyl, such as an isoxazolidinylmethyl or pyridylmethyl group. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, —CH 3 , —CF 3 , and —OCH 3 .

[0304] In one embodiment, the analog has the structure of compound (30):

[0305] [ka]

[0306] wherein R1 and R2 are independently 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 and R2 are independently selected from H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4 Benzylpiperazine, and C 1-4 alkylthienyl, independently selected from the group consisting of C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, R is selected from the group consisting of H, CH, CHPh, CH-((2-Cl)-Ph), CH-(2-thienyl), CHCHPh, CHCH(4-N-benzylpiperazine), CH-(2,4-diF-Ph), CH-((2-CH)-Ph), CHCHOHPh, and (CH)CO-4F-Ph. In some embodiments, R2 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. In some embodiments, when R1 is CH2Ph, R2 is not CH2-((2-CH3)-Ph).

[0307] In some embodiments, R1 alone or in combination at the ortho, meta, and / or para positions of the benzyl ring may be one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1 where p is an integer from 2 to 20, and X is a halogen, including a fluorine, bromine, or iodine atom, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom. In some embodiments, R2 is selected from the group consisting of, alone or in combination at the ortho, meta, and / or para positions of the benzyl ring, one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1 where p is an integer of 2 to 20, and X is a halogen.

[0308] In some embodiments, R is hydrogen. In some embodiments, R is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 It is substituted with alkyl or halo.

[0309] In some embodiments, R2 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R2 is a substituted or unsubstituted heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or unsubstituted heteroarylalkyl, such as an isoxazolidinylmethyl or pyridylmethyl group. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, —CH 3 , —CF 3 , and —OCH 3 .

[0310] In one embodiment, the analog has the structure of compound (31):

[0311] [ka]

[0312] wherein R1 and R2 are independently 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 and R2 are independently selected from H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketone, C 1-4Benzylpiperazine, and C 1-4 alkylthienyl, independently selected from the group consisting of C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketones, and C 1-4 Benzylpiperazine is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, R is selected from the group consisting of H, CH, CHPh, CH-((2-Cl)-Ph), CH-(2-thienyl), CHCHPh, CHCH(4-N-benzylpiperazine), CH-(2,4-diF-Ph), CH-((2-CH)-Ph), CHCHOHPh, and (CH)CO-4F-Ph. In some embodiments, R2 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. In some embodiments, when R1 is CH2Ph, R2 is not CH2-((2-CH3)-Ph).

[0313] In some embodiments, R1 alone or in combination at the ortho, meta, and / or para positions of the benzyl ring may be one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1where p is an integer from 2 to 20, and X is a halogen, including a fluorine, bromine, or iodine atom, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom. In some embodiments, R2 is selected from the group consisting of, alone or in combination at the ortho, meta, and / or para positions of the benzyl ring, one or more of the following substituents: -CH3, -NO2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -C p X 2p+1 , -OCX3, or -OC p X 2p+1 where p is an integer of 2 to 20, and X is a halogen.

[0314] In some embodiments, R is hydrogen. In some embodiments, R is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 It is substituted with alkyl or halo.

[0315] In some embodiments, R2 is a substituted or unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, arylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R2 is a substituted or unsubstituted heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or unsubstituted heteroarylalkyl, such as an isoxazolidinylmethyl or pyridylmethyl group. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is C 1-4 Alkyl, C 1-4 Alkoxyl, hydroxyl, perhalogenated C 1-4 In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, —CH 3 , —CF 3 , and —OCH 3 .

[0316] XI. Working Examples

[0317] It should be understood that the description and specific examples provided below are for illustrative purposes only and are not intended to limit the scope of the present disclosure. The following examples are intended to illustrate the disclosed embodiments and should not be construed as limiting thereof. Additional compounds other than those described below can be prepared according to the above reaction schemes or appropriate variations or modifications thereof.

[0318] Example 1. Synthesis of 2-chlorobenzylamino-2-imidazoline hydroiodide

[0319] To a stirred solution of 2-methylthio-2-imidazoline hydroiodide (244 mg, 1.00 mmol) in dry dioxane (2.0 mL) was added 2-chlorobenzylamine (141 mg, 1.0 mmol). The reaction mixture was stirred at 70 °C under argon for 90 min. The solution was cooled to room temperature, filtered through a sintered 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.

[0320] Example 2. Synthesis of 2-chlorobenzylamino-2-imidazoline

[0321] To a stirred solution of 2-chlorobenzylamino-2-imidazoline hydroiodide (242 mg, 0.72 mmol) in water (3 mL) at 7 °C was added 1.0 N sodium hydroxide (2 mL). The reaction mixture was stirred at 7 °C for 30 minutes under an argon atmosphere. Methylene chloride (5 mL) was then added, and the mixture was stirred for an additional 5 minutes. The reaction mixture was extracted with methylene chloride (2 × 2.5 mL). The organic layer was dried over anhydrous NaSO, 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).

[0322] Example 3. Synthesis of methyl-1-benzyl 4-oxo-3-piperidinecarboxylate (compound (6))

[0323] To stirred methyl-1-benzyl 4-oxo-3-piperidinecarboxylate hydrochloride (5.7 g, 20 mmol) in ethyl acetate (50 mL) was added triethylamine (6 mL) at 7 °C. The reaction mixture was stirred at 7 °C for 30 minutes under an argon atmosphere. The reaction mixture was extracted with ethyl acetate (2 × 50 mL) and washed with water (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and evaporated. The resulting free base residue (5, R = benzyl) as a viscous oil was used in the next reaction without further purification. MS (ESI) 248 (M + H).

[0324] Example 4. Synthesis of ONC902 (compound (14))

[0325] To a solution of 2-chlorobenzylamino-2-imidazoline (150 mg, 0.72 mmol) and methyl 1-benzyl 4-oxo-3-piperidinecarboxylate (5, R = benzyl) (195 mg, 0.79 mmol) in 1-butanol (2 mL) was added PPTS (10 mg), and the mixture was stirred at room temperature for 48 h. The reaction mixture was then refluxed at 125-130 °C for 2 h. The solvent was removed in vacuo, 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%-40% acetonitrile / water) to give ONC902 TFA salt (228 mg, 50% yield) as a white solid. MS (ESI) 407 (M+H).

[0326] Using the same process starting with different benzylamines, various analogs were prepared, e.g., ONC903, 904, 905, 906, 912, 210, 211, 212, 213, 214, 217, 218, 219, 220, 221, 222, 223, 224, 225, and 226.

[0327] Example 5. Synthesis of ONC907 (compound (19))

[0328] 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 h 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 over 1 h to the reaction mixture with stirring at 80 °C. The reaction mixture was stirred at the same temperature for 3 h, then cooled to 0 °C (ice bath), and the pH was adjusted to 6-6.5 with acetic acid. The resulting cooled mixture was diluted with water (10 mL) and adjusted to pH 8 with 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 vacuo to give methyl-1-tertbutoxycarbonyl-4-oxo-3-piperidinecarboxylate (5.0 g, 80%), which was used in the next reaction without further purification.

[0329] To 2-methylbenzylamino-2-imidazoline (190 mg, 1 mmol), methyl 1-tert-butoxycarbonyl-4-oxo-3-piperidinecarboxylate (315 mg, 1.1 mmol) in 1-butanol (2 mL) was added PPTS (10.0 mg), and the mixture was stirred at room temperature for 48 h. The reaction mixture was then refluxed at 125-130 °C for 2 h. The solvent was removed in vacuo, extracted with ethyl acetate (10 mL), and washed with saturated sodium bicarbonate solution (2 x 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%-40% acetonitrile / water) to give ONC907 (262 mg, 50%) as a TFA salt as a white solid. MS(ESI) 297(M+H).

[0330] Example 6. Synthesis of ONC909 (compound (21))

[0331] 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 h. The solvent was removed in vacuo, extracted with ethyl acetate (10 mL), and washed with water (5 mL). The organic layer was dried over anhydrous NaSO, filtered, and evaporated. The crude free base was purified by RP HPLC (10%-40% acetonitrile / water) to give ONC909 (62 mg, 50%) as the TFA salt as a white solid. MS (ESI) 401 (M+H).

[0332] Using the same process starting with different halides, ONC910 and 214 were obtained. Compounds 227, 228, 229, 230, 231, 232, 233, 234, 235, and 236 were prepared using processes similar to Examples 1 and 5, starting from different benzylamines.

[0333] Compound ONC911 was prepared from ONC910 by treatment with TFA.

[0334] Compound (72) was prepared by reacting the precursor NH compound prepared in the same manner as in Example 5 and treating it with styrene oxide.

[0335] Example 7. Synthesis of ONC908 (compound (20))

[0336] To a solution of 2-methylbenzylamino-2-imidazoline (190.0 mg, 1.0 mmol) and methyl 1-methyl 4-oxo-3-piperidinecarboxylate (185.0 mg, 1.0 mmol) in 1-butanol (2.0 mL) was added PPTS (10.0 mg), and the mixture was stirred at room temperature for 48 h. The reaction mixture was then refluxed at 125-130 °C for 2 h. The solvent was removed in vacuo, extracted with ethyl acetate (10 mL), and washed with saturated sodium bicarbonate solution (2 x 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 with 10%-40% acetonitrile and water to give ONC908 (270.0 mg, 50%) TFA salt as a white solid. MS (ESI) 311 (M+H).

[0337] Example 8. Synthesis of ONC201 (compound (1))

[0338] Compound (3) (239.7 g, 0.845 mol, 1.6 equiv.) was added portionwise to 800 mL of stirred saturated NaHCO3 in a 2 L round-bottom flask. n-Butanol (500 mL) was added to the resulting mixture, and the mixture was stirred for 30 min before being 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, a N2 inlet, a thermocouple, a condenser, and a Dean-Stark trap. Compound (5) (100 g, 0.528 mol, 1 equiv.) 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 to reflux for 6 h. Water in the reaction mixture was separated into the Dean-Stark trap as needed. The reflux temperature was increased from 93 °C to 118 °C. The reaction progress was monitored by HPLC. The reaction was stopped when the peak area of ​​compound (1) on HPLC remained constant with reaction time.

[0339] Example 9. Synthesis of ONC201 di-salt (compound (1)·2HCl)

[0340] 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 with water (500 mL x 2) and transferred to a 3 L three-necked round-bottom flask equipped with mechanical stirring, a N2 inlet, a thermocouple, a condenser, and a Dean-Stark trap. While stirring the reaction mixture, 1 N HCl in dioxane-MTBE solution was added dropwise until no solid precipitated from the reaction mixture upon addition of HCl (4 N HCl in dioxane: 300 mL, 1.2 mol, 2.27 equiv., MTBE: 1200 mL). The reaction mixture was heated to reflux at 60-65 °C for 2 h. Water was separated into the Dean-Stark trap as needed. Upon 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 (16 hours) in a vacuum oven at 65° C. to give 200 g of a yellow solid.

[0341] The above solid (200 g) was added to a 2 L three-necked round-bottom flask equipped with mechanical stirring, N2 inlet, thermocouple, and condenser, followed by ethanol (1000 mL). The mixture was heated to reflux at 78 °C for 2 hours. Upon cooling to room temperature, the solid was filtered through a sintered glass funnel and washed with ethanol (200 mL x 3). The wet solid was dried in a vacuum oven at 85 °C for 3 days until the residual solvent met specifications. 120 g of compound (2) was obtained as a white solid with a 49% yield and 99.7% HPLC purity.

[0342] Example 10. Activity of analogues of compound (1)

[0343] A number of representative analogs of compound (1) were prepared based on the synthetic methods of the present disclosure. For each of these compounds, the viability of human cancer cells was measured 72 hours after treatment with the compound. The change in potency (relative to ONC201) was measured and is shown in the table below.

[0344] TIFF2025186367000036.tif159169

[0345] Furthermore, single oral or intraperitoneal administration of compound 52 to mice bearing human colon cancer xenografts resulted in significant reductions in tumor volume compared to vehicle-treated control cohorts. Compound 52 was well tolerated in mice at doses up to at least 225 mg / kg, demonstrating a wide therapeutic window.

[0346] Example 11. Dosage regimen

[0347] Compound (1) is administered to tumor-bearing mice using repeated 7-day cycles according to the following dosing schedule: 1) Day 1: 200 mg / kg orally; 2) Day 1 / Day 4: 100 mg / kg orally per single dose; 3) Day 1 / Day 2: 100 mg / kg orally per single dose; or 4) Day 1: 100 mg / kg orally per single dose, given in two doses 6 hours apart. Evaluate and compare the efficacy of dosing regimens.

[0348] Example 12. Preliminary determination of interaction with compound (1)

[0349] The preliminary therapeutic spectrum of compound (1) in the human colon cancer cell line HCT116 was determined.

[0350] Briefly, compound (33) (ONC911) was immobilized on Sepharose beads at different immobilization densities. For quantitative mass spectrometry analysis, HCT116 human colon carcinoma cells were grown in medium containing different types of isotope-labeled amino acids (SILAC = stable isotope labeling by amino acids in cell culture). The corresponding proteomes could be distinguished by the introduced mass differences. Binding experiments were performed in duplicate using partial label switching to eliminate labeling artifacts. Bound proteins were completely eluted from the affinity matrix, separated by SDS-PAGE, and subjected to trypsin digestion. The recovered peptides were analyzed by LC-MS / MS using an LTQ Orbitrap Velos mass spectrometer (Thermo Fisher). The raw data generated by LC-MS / MS were processed with MaxQuant to obtain quantitative protein abundance data.

[0351] The quantified proteins were analyzed for protein enrichment relative to a control matrix and for competition of binding proteins by incubation with compound 1. Such binding and displacement patterns would be expected for a particular target protein.

[0352] (result)

[0353] First, HCT116 cells were cultured and metabolically labeled by SILAC. Efficient SILAC labeling was achieved, with incorporation rates of arginine and lysine isotope variants exceeding 95%. Sufficient cells were prepared for subsequent experiments. Cell extracts were generated by detergent-mediated cell lysis. Furthermore, to contain nuclear proteins, the remaining cell nuclei were extracted by lysis in the presence of 400 mM NaCl. The cytosol and nuclear extracts were mixed.

[0354] Linker compound 33 (ONC911) was immobilized to Sepharose beads via its amino group. Beads with four different immobilization densities were prepared: 6 mM, 3 mM, 1 mM, and 0.3 mM. These matrices were used to enrich proteins from HCT116 extracts, and the displacement of bound proteins by 50 μM compound 1 was investigated.

[0355] In total, approximately 3600 proteins were identified. Enrichment of specific proteins with immobilized compounds (33) was observed across all binding densities and replicates.

[0356] The number of target candidates increased with immobilization density. Table 3 summarizes the target candidates for compound (1). At the highest binding density (6 mM), enrichment by the affinity matrix and consistent displacement by compound (1) across two replicate experiments were observed for 14 proteins. At a binding density of 3 mM, two promising target candidates were identified, both of which were identical to the candidates at the high binding density. At lower binding densities (1 and 0.3 mM), two and one protein consistently behaved as targets, respectively.

[0357] Additionally, several proteins showed enrichment with the affinity matrix and displacement by compound (1), but displacement was observed in only one of two replicates per binding density. Such proteins are indicated in Table 3 as "OK (with outliers)."

[0358] In summary, the immobilized compound 33 (ONC911) appears to be functional and capable of specifically enriching proteins from cell lysates. Furthermore, clear competition with 50 μM compound 1 was observed.

[0359] [Table 3-1]

[0360] [Table 3-2]

[0361] Target classification: Evaluation of each protein at the indicated binding density of compound ONC216. "OK" indicates that each protein was consistently enriched and competed across two independent replicates. "OK (with outliers)" indicates enrichment by the affinity matrix and displacement by compound (1), but displacement was observed in only one of the two replicates.

[0362] Example 13. GPCR antagonistic effect of compound (1)

[0363] ONC201 was evaluated in a whole-cell functional assay of β-arrestin G protein-coupled receptor (GPCR) activity, which directly measures dopamine receptor activity by detecting the interaction of β-arrestin with activated GPCRs that can serve as reporters. Cell lines overexpressing reporter constructs for each dopamine receptor (DRD1, DRD2S, DRD2L, DRD3, DRD4, and DRD5) were grown from freezer stocks. A total volume of 20 μL of cells was plated into white-walled 384-well microplates and incubated at 37°C before EC201 assay, followed by agonist testing. 80 Cells were stimulated with a concentration of antagonist. A moderate dilution of the sample stock was performed to generate 5x samples in assay buffer. 3.5 μL of the 5x samples were added to the cells and incubated at 37°C or room temperature for 30 minutes. The vehicle concentration was 1%. 6xEC in 5 μL of assay buffer 80 Agonists were added to the cells and incubated at 37°C or room temperature for 90 or 180 minutes before the assay was read using the following formula: % Antagonism = 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (EC 80 Percent antagonism was calculated as the mean RLU of control minus the mean RLU of vehicle control.

[0364] Example 14. Evaluation of the interaction of compound (1) with efflux proteins and transport proteins

[0365] The ability of ONC201 to interfere with transport protein activity is assessed to determine the dosing regimen for ONC201 in combination with a substrate for the transport protein. The timing or dose level of ONC201 in combination with another therapeutic agent may be modified based on the results of these analyses. Transport proteins include solute carriers (SLCs) OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2.

[0366] The ability of ONC201 to interfere with efflux proteins was evaluated to determine whether ONC201 could inhibit the ability of these proteins to efflux small molecule substrates. Inhibition of these efflux proteins may enhance the efficacy of efflux protein substrates by binding to ONC201 and increasing their intracellular concentration or altering their biodistribution. Efflux proteins include MDR1 and BCRP.

[0367] The interaction of ONC201 with human MDR1 and BCRP transporters was investigated in vitro using MDR1- and BCRP-overexpressing Madin-Darby canine kidney (MDCKII-MDR1 and MDCKII-BCRP) and parental cells (MDCKII). To determine whether ONC201 is an inhibitor of MDR1 and BCRP, bidirectional permeability studies of the respective probe substrates in MDCKII-MDR1, MDCKII-BCRP, and MDCKII monolayers were performed. Digoxin and prazosin were used as probe substrates for MDR1 and BCRP, respectively.

[0368] The inhibition assay results are summarized in Table 4 below. ONC201 is an inhibitor of MDR1 and BCRP at 200 micromolar. Combining ONC201 with an MDR1 or BCRP substrate may increase the potency of the substrate by increasing the intracellular concentration or altering its biodistribution.

[0369] [Table 4]

[0370] Example 15. Inhibitory Potential of Compound (1) on P450 Enzymes

[0371] We evaluated the potential of ONC201 to induce human cytochrome P450 (CYP) enzymes using seedable human cryopreserved hepatocytes, focusing on the three major inducible drug-metabolizing enzymes, namely, CYP 1A2, 2B6, and 3A4.

[0372] The results of the CYP induction experiments with ONC201 are summarized in Table 5 below. ONC201 did not induce P450 to a degree greater than 20% of the potency of the positive control in this assay. Therefore, ONC201 can be used in combination with other drugs without altering CYP activity.

[0373] [Table 5]

[0374] The inhibitory potential of ONC201 against seven human cytochrome P450 (CYP) enzymes, namely CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, was investigated in vitro in pooled human liver microsomes (HLMs) using eight CYP isoform-specific marker substrate reactions: CYP1A2-mediated phenacetin O-deethylation, CYP2B6-mediated bupropion hydroxylation, CYP2C8-mediated amodiaquine N-deethylation, CYP2C9-mediated diclofenac 4'-hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated bufuralol 1'-hydroxylation, CYP3A4-mediated midazolam 1'-hydroxylation, and testosterone 6β-hydroxylation.

[0375] ONC201 inhibits CYP isoenzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) with IC values ​​ranging from 34.9 to 428.6 μM. 50 Value (9uM C maxand 40-480-fold above the mean plasma concentration of 0.9 uM at 24 hours), and the inhibition was not significantly time-dependent (see Table 6). These results indicate that ONC201 can be administered with most other drugs without safety concerns regarding drug-drug interactions.

[0376] [Table 6]

[0377] Example 16. Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

[0378] ONC201 induces tumor apoptosis at doses that trigger high levels of cell death in human cancer cells, but not in normal cells. The safety profile of ONC201 in rats and dogs in a GLP safety study was consistent with ONC201's selective cytotoxicity in tumors versus normal cells in vitro. Thus, ONC201's in vitro and in vivo profiles demonstrate a broad therapeutic window, highly desirable for a cancer therapeutic. Based on preclinical results demonstrating sustained tumor PD and in accordance with early pilot studies suggesting that more frequent dosing did not appear to substantially enhance in vivo efficacy, a full 21-day schedule was selected for clinical trials.

[0379] ONC201's remarkable efficacy and safety profile, as well as its novel involvement in signaling pathways important to many cancers, led to its clinical introduction in patients with advanced cancer. The primary objectives of this first-in-human, Phase 1 dose-escalation study were to determine the recommended Phase 2 dose (RP2D) of oral ONC201 in patients with advanced cancer and to evaluate the safety and tolerability of the drug. Secondary objectives included evaluation of ONC201's pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

[0380] Briefly, this phase 1, open-label study treated 10 patients with histologically confirmed advanced solid tumors during dose escalation. An additional 10 patients were enrolled in an ongoing expansion period to provide additional safety information. Patients received oral ONC201 at doses of 125 to 625 mg every 3 weeks using an accelerated titration design.

[0381] RP2D is a C of 1.5 to 7.5 mg / mL (approximately 3.9 to 19.4 mM). max The dose was determined to be 625 mg, which achieved a 9.6-h half-life and 25 h.μg / L AUC. Eight of the 10 patients achieved stable disease, one patient with prostate adenocarcinoma experienced long-term stable disease, and the remainder remained on study for 27 weeks. One additional patient with endometrial carcinoma had a mixed response.

[0382] ONC201 is very well tolerated, has a favorable PK profile including saturable absorption at micromolar plasma concentrations, and shows signs of clinical activity following oral dosing of 625 mg every three weeks.

[0383] Patients and methods

[0384] (ethics)

[0385] This study was conducted at Robert Wood Johnson University Hospital / Rutgers Cancer Institute of New Jersey (CINJ) in accordance with the Declaration of Helsinki and the International Conference on Harmonisation of Pharmaceuticals for Human Use guidelines, and was approved by the relevant regulatory committees and the CINJ Institutional Review Board. Patients provided written informed consent to participate in the study.

[0386] (Patient population)

[0387] Patients aged 18 years or older with advanced solid tumors who had not received or were resistant to standard therapy, had an ECOG performance status of 1 or greater, and had evaluable disease according to RECIST 1.1 criteria were eligible. If patients were receiving radiation therapy, they had to have one measurable lesion outside the irradiated field. Patients had to have completed all prior cytotoxic chemotherapy at least 4 weeks prior to the first dose, alkylating agents at least 6 weeks prior, targeted agents at least 28 days prior, and radiation therapy at least 14 days prior. All adverse events related to prior therapy, except for alopecia and neuropathy, of grade 2 or less, had to have resolved. Patients were required to demonstrate normal bone marrow and organ function as defined by the following parameters: absolute neutrophil count ≥ 1,500 / mcL; platelets ≥ 1,000,000 / mcL; hemoglobin ≥ 9.0 mg / dL without transfusion in the previous 2 weeks; total bilirubin within the normal range (for patients with liver metastases, serum bilirubin ≤ 1.5 x ULN); AST (SGOT) / ALT (SGPT) ≤ 2.5 x upper limit of normal; and for patients with creatinine levels above normal, measured or estimated creatinine clearance ≥ 40 mL / min / 1.73 m 2Exclusion criteria included symptomatic or asymptomatic brain metastases treated with steroids, previous bevacizumab treatment, previous allergic reaction to a compound similar to ONC201, difficult-to-control comorbidities, concomitant retroviral therapy for HIV, history of active cardiac disease / cardiac dysfunction, stroke or seizure within the previous 3 months, GI dysfunction that could alter ONC201 absorption, pregnancy, and treatment with hematopoietic colony-stimulating growth factors within 2 weeks before treatment initiation.

[0388] (Study design and toxicity evaluation)

[0389] The study was designed as an open-label, dose-escalation, phase 1 ONC201 single-agent trial in patients with advanced, refractory tumors who had exhausted or refused standard treatment options for their respective indications. ONC201 capsules (125 mg) were provided by Oncoceutics Inc. (Philadelphia, PA). ONC201 was administered orally once every 21-day cycle using an accelerated dose-escalation design. The oral starting dose was 125 mg (10% of the level at which no adverse events were observed in rats and dogs). The study was conducted with an individualized accelerated dose-escalation design, designed to stop if any patient experienced at least a grade 2 adverse event possibly related to ONC201. In this case, a conventional 3 + 3 dose-escalation design would have been used. Dose escalation would have occurred after the previously administered cohort completed one treatment cycle and met the criteria for progression to the next dose level. Enrollment at each subsequent dose level required all patients enrolled at the previous dose level to complete Cycle 1 dosing and be evaluated 21 days later for safety assessment. Dose levels progressed from 125 mg to 250 mg, 375 mg, 500 mg, and finally 625 mg.

[0390] After the RP2D was determined, an expansion period to 22 patients was initiated, and additional patients were enrolled at the RP2D to increase the robustness of the safety data generated in the trial.

[0391] All toxicities were assessed according to the Common Terminology Criteria for Adverse Events, version 4. DLTs were defined as drug-related adverse events or abnormal laboratory results that occurred during the first cycle of treatment and met any of the following criteria: grade 3 or higher nonhematologic toxicity; grade 3 nausea, vomiting, or diarrhea persisting for more than 72 hours despite optimal antiemetic or antidiarrheal therapy; grade 3 to 4 AST / ALT combined with a grade 2 elevation in bilirubin; grade 4 neutropenia lasting for 7 days; grade 4 neutropenia and fever >38.5°C; grade 3 neutropenia with >grade 3 infection; any grade of thrombocytopenia when associated with clinically significant bleeding; grade 4 thrombocytopenia; or grade 4 anemia assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medication; and those judged by the investigator to be "probably," "probably," or "definitely" related to ONC201 administration.

[0392] (Safety Assessment)

[0393] Safety assessments, including complete blood counts, blood chemistry, and toxicity, were performed at baseline, weekly during the first two cycles, and every three weeks thereafter. Electrocardiogram monitoring was performed immediately before ONC201 administration, and then 15 minutes, 1 hour, and 2 hours after drug administration. Adverse events were graded using CTCAE version 4.0. Tumor response was assessed every two cycles using RECIST.

[0394] (Pharmacokinetic analysis)

[0395] Plasma samples for PK were collected at baseline, 30 minutes, 2 hours, 4 hours, 6 hours, 24 hours, 48 ​​hours, and 168 hours after the first ONC201 dose, and before the pre-treatment dose for cycles 2 through 6. PK analysis was performed by LC-MS / MS using a validated GLP method to detect ONC201 in human plasma. PK analysis was performed using PHOENIX® WINNONLIN® version 6.3 (PHARSIGHT®, St. Louis, Missouri).

[0396] (statistical analysis)

[0397] Safety and tumor response data were analyzed using descriptive statistics.

[0398] (pharmacodynamic analysis)

[0399] Blood samples for PD were collected 6 hours, 2, 3, 8, and 15 days after ONC201 treatment in cycle 1, and before drug administration in cycles 2 and 3. Serum levels of cleaved cytokeratin 18 (cCK18) were assessed using the M30 assay, and serum levels of intact cytokeratin 18 (CK18) were assessed using the M65 assay (Perviva AB, Sweden). Assessment of other tumor-specific markers was also performed according to standard of care.

[0400] (In vitro sensitivity of tumor types)

[0401] The in vitro activity of ONC201 was evaluated in 1020 genetically annotated cell lines from the Genomic of Drug Sensitivity in Cancer (http: / / www.cancerrxgene.org) collection. As previously reported, IC was determined by cell viability assay 72 hours after treatment. 50 For each tumor type, estimated IC 50 Values ​​were averaged across multiple cell lines. Tumor types were assigned average IC 50 The ONC201 sensitivity range was determined by dividing the samples into three distinct groups representing tertiles of sensitivity. In Table 11, these groups are referred to as "high," "low," and "intermediate" based on their tertile classification within the ONC201 sensitivity range.

[0402] result

[0403] (Patient characteristics)

[0404] During the dose-escalation period, 10 evaluable patients were enrolled in the study. Patient characteristics are shown in Table 7. After completion of the dose-escalation period, an additional 10 patients were enrolled in the ongoing expansion period (Table 8).

[0405] [Table 7]

[0406] [Table 8]

[0407] (Dose escalation, RP2D and safety determination)

[0408] Dose cohorts are shown in Table 9. 625 mg was the maximum achieved dose and was determined as the RP2D. The only adverse event during the dose escalation period possibly attributable to ONC201 was low-grade fever in one patient. One patient enrolled in the maximum dose cohort was replaced due to rapid disease progression in cycle 1.

[0409] The only adverse event among the 10 enrolled patients during the expansion period that was possibly attributable to ONC201 was vomiting in one patient. Both of these adverse events were Grade 1 and resolved rapidly. Laboratory investigations and physical examinations revealed no drug-related abnormalities. Similarly, cardiovascular evaluations revealed no drug-related effects.

[0410] [Table 9]

[0411] (Pharmacokinetics)

[0412] Patients were analyzed for systemic exposure levels to ONC201 using plasma collected at consecutive time points (Figure 5). PK parameters were determined for all patients and summarized for the highest dose cohort (Table 10). While dose escalation included separate patient cohorts, systemic exposure to ONC201 was measured by AUC and C max Judging from the results, saturation appeared at the 375 mg dose (Figure 6). In the highest dose cohort, mean C max The mean V was 3312 (SD 2133) ng / mL, which occurred a mean of 1.8 hours after administration. Z The mean AUC was 26.3 (SD 10.8) h.μg / mL, and the mean CL / F was 27.19 (SD 10.95) L / h. 1 / 2 was 9.62 (SD 1.76) hours.

[0413] [Table 10]

[0414] In general, CL / F was observed to vary but was consistent across all dose groups. There was no apparent relationship between drug CL / F and patient gender or age. Of note, a superficial trend was observed with patient weight and BSA. An overall increase in CL / F was observed with increasing weight and BSA. CR Although a slight upward trend was observed between

[0415] Estimated volume of distribution (V Z A stronger correlation was observed between V and patient weight and BSA. Z From this trend, it was found that V increased significantly with an increas...

Claims

1. A pharmaceutical composition for treating or inhibiting cancer in a patient, comprising: (a) Compound or a pharmaceutically acceptable salt thereof; (b) one or more additional therapeutic agents; A pharmaceutical composition comprising:

2. The pharmaceutical composition according to claim 1, The pharmaceutical composition, wherein said one or more additional therapeutic agents are anti-cancer agents.

3. A pharmaceutical composition according to claim 1 or 2, The pharmaceutical composition, wherein the one or more additional therapeutic agents are either or both of an antimitotic agent and an antiangiogenic agent.

4. The pharmaceutical composition according to claim 1 or 2, The one or more additional therapeutic agents may be a flavanoid, an isoflavone, monothioglycerol, L-cysteine, thioglycolic acid, α-tocopherol, ascorbic acid 6-palmitate, dihydrolipoic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, propyl gallate, beta-carotene, ascorbic acid, a hormone analog, an antihormonal agent, an aromatase inhibitor, an LHRH agonist, an LHRH antagonist, an inhibitor of a growth factor, a growth factor antibody, a growth factor receptor antibody, or a tyrosine kinase inhibitor. , 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, RAF inhibitors, MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs, BTK inhibitors, CRM1 inhibitors, KPT185, p53 modulators, nutlin, angiogenesis inhibitors, axitinib, aflibercept, sorafenib, regorafenib, amifostine, anagreli d, clodronate, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, porfimer, 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-alethine, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, abiraterone, aldesleukin, alitretin Noin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomin, alanose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, 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-736, ARQ680, AS-703026, primasertib, Avastin, AZD-2014, azacitidine, azaepothilone B, azonafide, BAY-43-9006, BAY80-6946, BBR-3464, BBR-3 576, bevacizumab, BEZ-235, biricodar 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, bryostatin-1, bortezomib, brostallicin, busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1, cefixime, cefratonin, ceftriaxone, celecoxib B, cermoleukin, cemadotin, CH4987655 / RO-4987655, chlorotrianisene, cilengitide, 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, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole,DS-7423, E7010, E-6201, edatrexate, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3, ethinylcytidine, ethinyl estradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, Forfox, Forfox 4, Forfili, formestane, fotemustine, galarubicin, gallium maltolate, gefitinib, gemtuzumab, gimatecan, glufosfamide, 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, GSK-5126766, GSK-690693, GSK-1120212, trametinib, GSK-21 18436, dabrafenib, GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptin, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C1 1, IMC-A12, cixutumumab, Immunol, indisulam, interferon alfa-2a, interferon alfa-2b, pegylated interferon alfa-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, Kahalid F, ketoconazole, KW-2170, KW-2450,Lobaplatin, leflunomide, lenograstim, leuprolide, leuprorelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, Roototecan, LY-S6AKT1, LY-2780301, Mahosfamide, Marimastat, Mechloroethamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, Midostaurin, Minodronic acid, Mitomycin, Mibobulin, MK-2206, MK-0646, Dalotuzumab, MLN518, Motexafine gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 6-benzylguanine, oblimersen, omeprazole, Oncophage, OncoVEXGM-CSF, ormiplatin, ortataxel, OX44 antibody, OSI-027, OSI-906, linsitinib, 4-IBB antibody, oxatrazol, estrogen, panitumumab, patuximab 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, pelitinib, pemetrexed, Pentrix, perifosine, perilyl a Alcohol, pertuzumab, PI3K inhibitors, PI3K / mTOR inhibitors, 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, polybutene, porfiromycin,Prednisone, prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY 869766, RDEA436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, regorafenib, Revimid, 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 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabalubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, 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, tacedinaline, talaporfin, tarceva, tariquidar, tasisulam, taxotere, taxoplexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide Id, theralux, terarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, tremofine, trabectedin, trans MID-107, trans retinoic acid, trastuzumab, tremelimumab, tretinoin, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, Tykerb / Tyverb, Urocidine, valrubicin, vatalanib, vincristine, vinflunine, virudin, 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、ゾレドロネート、 , zosuquidar, and any combination thereof A pharmaceutical composition selected from:

5. A pharmaceutical composition according to claim 1 or 2, The one or more additional therapeutic agents may be: Tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide, LHRH agonists, LHRH antagonists, goserelin acetate, leuprolide acetate, triptorelin pamoate, degarelix, cetrorelix, abarelix, ozarelix, 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), tyrosine kinase inhibitors, Cetuximab, gefitinib, imatinib, lapatinib, trastuzumab, aromatase inhibitors, anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, antimetabolites, antifolates, methotrexate, raltitrexed, pyrimidine analogs, 5-fluorouracil, capecitabine, gemcitabine, purine analogs, adenosine analogs, mercaptopurine, thioguanine, cladribine, pentostatin, cytarabine, fludarabine, antitumor antibiotics, anthracyclines, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptomycin, Putozocin, platinum derivatives, cisplatin, oxaliplatin, carboplatin, alkylating agents, estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, carmustine, lomustine, thiotepa, antimitotic agents, vinca alkaloids, taxanes, paclitaxel, docetaxel, vinblastine, vindesine, vinorelbine, vincristine, topoisomerase inhibitors, epipodophyllotoxins, etoposide, etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, serine / threonine kinase inhibitors, PDK 1 inhibitor, B-Raf inhibitor, mTOR inhibitor, mTORCl inhibitor, PI3K inhibitor, mTOR / PI3K dual inhibitor, STK 33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors, PTK2 / FAK inhibitors, protein-protein interaction inhibitors, IAP, Mcl-1, MDM2 / MDMX, rapamycin analogs, everolimus, temsirolimus, ridaforolimus, sirolimus, amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, porfimer, 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-alesine, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin,16-Aza-epothilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, alanose, arglabin, arzoxifene, atamestane , atrasentan, auristatin PE, AVLB, AZ10992, 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-736, ARQ680, AS-703026 (pimasertib), Avastin, AZD-2014, azacitidine, azaepothilone B, azonafide, BAY-43-9006, BAY80-6946, BBR-3464, BBR-3576, Beva Cizumab, BEZ-235, biricodar 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 (valgatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycin acid, bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib, brostallicin, busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCL-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, cefratonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655 / RO-4987655, chlorotrianisene, cilengitide, 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, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxane, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexate, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin , enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3, ethinylcytidine, ethinylestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, Forfox, Forfox 4, forfili, formestane, fotemustine, galarubicin, gallium maltolate, gefitinib 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, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate, idenestor, IDN-5109, IGF-1R inhibitor, IMC-1C11,IMC-A12 (cixutumumab), Immunol, indisulam, interferon alfa-2a, interferon alfa-2b, pegylated interferon alfa-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, iso Tretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogens, Kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuprorelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, Roototecan, LY-S6AKT1, LY-2780301, Mahosfamide, Marimastat, Mechloroethamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, Midostaurin, Minodronic acid, My tomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexafine gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 6-benzylguanine, Brimersen, omeprazole, Oncophage, OncoVEXGM-CSF, olmiplatin, ortataxel, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-IBB antibody, oxatrazol, 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, pelitinib, pemetrexed, Pentrix, perifosine, perillyl 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, pivaloyloxymethyl butyrate, pixantrone, phenoxodiol O, PKI166, previtrexed, plicamycin, polybutene, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY 869766, RDEA436, rebeccamycin analog, receptor tyrosine kinase (RTK) inhibitor, Revimid, 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 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabalubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, 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, tacedinaline, talaporfin, tarceva, tariquidar, tasisulam, taxotere, taxaoplexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, telarux, telarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, tremofine, trabectedin, trans MID-107, trans retinoic acid, trastuzumab, tremelimumab, tretinoin,Triacetyluridine, Triapine, Triciribine, Trimetrexate, TLK-286TXD 258, Tykerb / Tyverb, Urocidin, Valrubicin, Vatalanib, Vincristine, Vinflunine, Virulizine, 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, zosuquidar, and any combination thereof. A pharmaceutical composition selected from:

6. A pharmaceutical composition according to claim 1 or 2, The one or more additional therapeutic agents may be steroids, dexamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, cortivazol, antiemetics, 5-HT3 receptor agonists, dolasetron, granisetron, ondansetron, tropisetron, palonosetron, mirtazapine, dopamine agonists, domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine The group consisting of ginger, metoclopramide, NK1 receptor antagonists, aprepitant, casopitant, antihistamines, cyclizine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine, cannabinoids, cannabis, dronabinol, nabilone, sativex, benzodiazepines, midazolam, lorazepam, anticholinergics, hyoscine, trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol, ajowan, and any combination thereof. A pharmaceutical composition selected from:

7. The pharmaceutical composition of claim 1 or 2, A pharmaceutical composition wherein the one or more additional therapeutic agents are a taxane, which is either or both of paclitaxel and docetaxel.

8. The pharmaceutical composition of claim 1 or 2, The one or more additional therapeutic agents may be acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, amethanthrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bevacizumab, bicalutamide, bisantrene, visnafide dimesylate, bizelesin, bleoma Isin, brequinar, bropirimine, busulfan, cactinomycin, calsterone, capecitabine, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefingol, celecoxib, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, droloxifene , dromostanolone, duazomycin, edatrexate, eflomitin, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin, elbrozole, esorubicin, estramustine, etanidazole, etoposide, etopurine, fadrozole, fazarabine, fenretinide, floxuridine, fludarabine, fluorouracil, flurocitabine, foskidone, fostriecin, fulvestrant, gemcitabine, hydroxyurea, idarubicin, ifosfamide, ilmofosine, interleukin II (I L-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, liarozole, lometrexol, lomustine, losoxantrone, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol, melengestrol acetate, melphalan, menogaril,Mercaptopurine, methotrexate, metoprine, meturedepa, mitindomide, mitocalicin, mitochromine, mitogillin, mitomarcine, mitomycin, mitospar, mitotane, mitoxantrone, mycophenolate, nelarabine, nocodazole, nogalamycin, omrnaplatin, oxlan, paclitaxel, pegaspargase, periomycin, pentamustine, peplomycin, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer, porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, ribopurine, rogletimide, safingol, semustine, simtrazene, sparfosate, sparsomycin, spirogermani the group consisting of cefotaxime, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talizomycin, tamoxifen, tecogalan, tegafur, tetoxantrone, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, topotecan, toremifene, trestron, triciribine, trimetrexate, triptorelin, tubrozole, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine, vinepidine, vinglisinate, vinleurosine, vinorelbine, vinrocidine, vinzolidine, vorozole, zeniplatin, zinostatin, zoledronate, zorubicin, and any combination thereof; A pharmaceutical composition selected from:

9. The pharmaceutical composition of claim 1, The pharmaceutical composition, wherein said one or more additional therapeutic agents is bevacizumab.

10. The pharmaceutical composition of claim 1 or 2, The one or more additional therapeutic agents may be aflibercept, axitinib, angiostatin, endostatin, 16 kDa prolactin fragment, laminin peptide, fibronectin peptide, tissue inhibitor of metalloproteinase (TIMP), or 1, 2, 3, 4), plasminogen activator inhibitors (PAI-1, PAI-2), tumor necrosis factor α, TGF-β1, interferons (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 protein, suramin, sorafenib, regorafenib, thalidomide, cortisone, linomide, fumagillin (AGM-1470, TNP-470), tamoxifen, retinoids, CM101, dexamethasone, leukemia inhibitory factor (LIF), hedgehog inhibitors, and any combination thereof. A pharmaceutical composition selected from:

11. The pharmaceutical composition of claim 1 or 2, The one or more additional therapeutic agents may be allopurinol, arsenic trioxide, azacitidine, bortezomib, bevacizumab, capecitabine, carboplatin, celecoxib, chlorambucil, clofarabine, cytarabine, dacarbazine, daunorubicin HCl, docetaxel, doxorubicin HCl, floxuridine, gemcitabine HCl, hydroxyurea, ifosfamide, mesylate The group consisting of imatinib, ixabepilone, lenalidomide, megestrol acetate, methotrexate, mitotane, mitoxantrone HCl, oxaliplatin, paclitaxel, pralatrexate, romidepsin, sorafenib, streptozocin, tamoxifen citrate, topotecan HCl, tretinoin, vandetanib, vismodegib, vorinostat, and any combination thereof. A pharmaceutical composition selected from:

12. The pharmaceutical composition of claim 1 or 2, The one or more additional therapeutic agents are selected from the group consisting of purine analogs, pyrimidine analogs, proteasome inhibitors, anti-angiogenic agents, platinum-based anti-neoplastic agents, COX-2 inhibitors, nitrogen mustards, alkylating agents, anthracyclines, taxanes, nucleotide synthesis inhibitors, Bcr-abl inhibitors, topoisomerase inhibitors, HDAC inhibitors, selective / multiple kinase inhibitors, hormone therapy agents, hedgehog signaling inhibitors, checkpoint inhibitors, BCL2 inhibitors, and any combination thereof. A pharmaceutical composition selected from:

13. The pharmaceutical composition of claim 1 or 2, The one or more additional therapeutic agents may be allopurinol, oxypurinol, clofarabine, tisopurine, 5-fluorouracil, floxuridine (FUDR), capecitabine, cytarabine, 6-azauracil (6-AU), gemcitabine (Gemzar), bortezomib, carfilzomib, cediranib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, ONCX0912, CEP-18770, ML N9708, epoxomicin, MG132, bevacizumab, aflibercept, sunitinib, sorafenib, pazopanib, vandetanib, cabozantinib, axitinib, ponatinib, regorafenib, ranibizumab, lapatinib, vandetanib, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, celecoxib, valdecoxib (Bextra), parecoxib (Dyna tat), lumiracoxib, etoricoxib, rofecoxib, cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan, bendamustine, mustine, cyclophosphamide, mechlorethamine or mustine (NH2) (trade name Mustargen), uramustine, uracil mustard, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, streptozocin, busul Fan, daunorubicin (daunomycin), daunorubicin (liposomal formulation), doxorubicin (adriamycin), doxorubicin (liposomal formulation), epirubicin, idarubicin, valrubicin, mitoxantrone, paclitaxel (Taxol), docetaxel (Taxotere), albumin-bound paclitaxel (Abraxane), methotrexate, pralatrexate, hydroxyurea, 5-fluorodeoxyuridine, 3,4-dihydroxybenzylamine, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, arsenic trioxide, thalidomide, Revlimid, mitotane, amsacrine, etoposide, etoposide phosphate, teniposide, doxorubicin, topotecan (Hycamtin), irinotecan (CAP-11, Camptosar), exatecan, raltotecan, ST1481, CKD602, ICRF-193, genistein, vorinostat (SAHA), romidepsin (Istodax), panobinostat (L BH589), valproic acid (as Mg valproic acid), belinstat (PXD101), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), SB939, resminostat (4SC-201), gibinostat, xinostat (JNJ-26481585), CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, quevetri ATRA, sorafenib, regorafenib, vandetanib, tamoxifen, toremifene, Arimidex (anastrozole), Aromasin (exemestane), Femara (letrozole), fulvestrant (Faslodex), vismodegib, BMS-833923, IPI-926, LDE-225, PF-04449913, LEQ506, TAK-441, Optivo (nivolumab), durvalumab (Medi4736), Keytruda (pembrolizumab, MK3475), BGB- the group consisting of A317, AMP-224, PDR001, REGN281, atezolizumab (MPDL3280A), pidilizumab (BMS-936559, CT-011, ONO-4538), avelumab (MSB0010718C), Yervoy (ipilimumab), tremelimumab, AT-101, Bcl-2 / xL inhibitors, navitoclax (ABT-263), venetoclax (ABT-199), avogossypol, PTN1258, obatoclax, G3139, and any combination thereof, A pharmaceutical composition selected from:

14. The pharmaceutical composition of claim 1 or 2, The pharmaceutical composition comprises a first therapeutic agent and a second therapeutic agent, wherein the ratio of the amount of the first therapeutic agent to the amount of the second therapeutic agent is: (i) a ratio of about 1:9 to about 9:1; (ii) a ratio of about 1:8 to about 8:1; (iii) a ratio of about 1:7 to about 7:1; (iv) a ratio of about 1:6 to about 6:1; (v) a ratio of about 1:5 to about 5:1; (vi) a ratio of about 1:4 to about 4:1; (vii) a ratio of about 1:3 to about 3:1; (viii) a ratio of about 1:2 to about 2:1, or (ix) a ratio of about 1:1 A pharmaceutical composition comprising:

15. The pharmaceutical composition according to any one of claims 1 to 14, A pharmaceutical composition, wherein (a) the compound, and (b) each of the one or more additional therapeutic agents, are provided as a combined composition containing the two in a fixed ratio.

16. The pharmaceutical composition according to any one of claims 1 to 14, A pharmaceutical composition, wherein (a) said compound, and (b) said one or more additional therapeutic agents are each provided as separate and distinct compositions.

17. The pharmaceutical composition according to any one of claims 1 to 16, A pharmaceutical composition, wherein (a) said compound, and (b) each of said one or more additional therapeutic agents are provided at dosage levels within the range of about 10% to 100% of the dose normally administered in a monotherapy regimen.

18. The pharmaceutical composition according to any one of claims 1 to 17, A pharmaceutical composition, wherein (a) said compound, and (b) each of said one or more additional therapeutic agents are provided at dosage levels within the range of about 10% to 80% of the dose normally administered in a monotherapy regimen.

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