WO2016123571A1 - 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 in therapy - Google Patents

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 in therapy Download PDF

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Publication number
WO2016123571A1
WO2016123571A1 PCT/US2016/015817 US2016015817W WO2016123571A1 WO 2016123571 A1 WO2016123571 A1 WO 2016123571A1 US 2016015817 W US2016015817 W US 2016015817W WO 2016123571 A1 WO2016123571 A1 WO 2016123571A1
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WO
WIPO (PCT)
Prior art keywords
compound
subject
pharmaceutically acceptable
cancer
acceptable salt
Prior art date
Application number
PCT/US2016/015817
Other languages
French (fr)
Inventor
Martin Stogniew
Joshua E. Allen
Richard S. Pottorf
Bhaskara Rao Nallaganchu
Gary L. Olson
Yanjun Sun
Original Assignee
Oncoceutics Inc.
Provid Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oncoceutics Inc., Provid Pharmaceuticals Inc. filed Critical Oncoceutics Inc.
Priority to CA2975476A priority Critical patent/CA2975476C/en
Priority to LTEP16744237.5T priority patent/LT3250208T/en
Priority to RS20201566A priority patent/RS61243B1/en
Priority to PL16744237T priority patent/PL3250208T3/en
Priority to MDE20170317T priority patent/MD3250208T2/en
Priority to MX2017009841A priority patent/MX2017009841A/en
Priority to SI201631003T priority patent/SI3250208T1/en
Priority to JP2017540230A priority patent/JP6802172B2/en
Priority to IL288525A priority patent/IL288525B/en
Priority to DK16744237.5T priority patent/DK3250208T3/en
Priority to KR1020237044537A priority patent/KR20240005186A/en
Priority to MX2021001096A priority patent/MX2021001096A/en
Priority to EA201791727A priority patent/EA037552B1/en
Priority to MA41434A priority patent/MA41434B1/en
Priority to EP16744237.5A priority patent/EP3250208B1/en
Priority to IL295286A priority patent/IL295286A/en
Priority to AU2016211243A priority patent/AU2016211243B2/en
Priority to BR112017016487-6A priority patent/BR112017016487B1/en
Priority to SG11201706062TA priority patent/SG11201706062TA/en
Priority to ES16744237T priority patent/ES2839401T3/en
Priority to CN201680008476.7A priority patent/CN107427516B8/en
Priority to EP20198062.0A priority patent/EP3805222A3/en
Priority to KR1020177022405A priority patent/KR102618971B1/en
Priority to US15/049,613 priority patent/US9845324B2/en
Publication of WO2016123571A1 publication Critical patent/WO2016123571A1/en
Priority to MX2018009227A priority patent/MX2018009227A/en
Priority to CN201780015327.8A priority patent/CN109311980B/en
Priority to SG11201806401YA priority patent/SG11201806401YA/en
Priority to EP17745078.0A priority patent/EP3408298A4/en
Priority to CN202211658374.3A priority patent/CN115844895A/en
Priority to PCT/US2017/015608 priority patent/WO2017132661A2/en
Priority to CA3013044A priority patent/CA3013044A1/en
Priority to MA043879A priority patent/MA43879A/en
Priority to KR1020187024948A priority patent/KR20180125460A/en
Priority to AU2017211423A priority patent/AU2017211423B2/en
Priority to BR112018015590A priority patent/BR112018015590A2/en
Priority to JP2018540011A priority patent/JP7030701B2/en
Priority to NZ745425A priority patent/NZ745425A/en
Priority to US16/073,228 priority patent/US11116771B2/en
Priority to SG10202108306UA priority patent/SG10202108306UA/en
Priority to IL253689A priority patent/IL253689B/en
Priority to US15/817,896 priority patent/US10266533B2/en
Priority to IL260815A priority patent/IL260815B/en
Priority to MX2023004443A priority patent/MX2023004443A/en
Priority to US16/287,195 priority patent/US20190194201A1/en
Priority to IL274135A priority patent/IL274135B/en
Priority to HRP20201949TT priority patent/HRP20201949T1/en
Priority to AU2020286168A priority patent/AU2020286168B8/en
Priority to CY20201101158T priority patent/CY1123616T1/en
Priority to US17/357,008 priority patent/US11976068B2/en
Priority to US17/388,551 priority patent/US20220072001A1/en
Priority to IL286923A priority patent/IL286923A/en
Priority to JP2021200772A priority patent/JP2022046528A/en
Priority to AU2022200583A priority patent/AU2022200583B2/en
Priority to AU2022228096A priority patent/AU2022228096A1/en

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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • G—PHYSICS
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Definitions

  • TNF -related apoptosis-inducing ligand is an endogenous protein that selectively induces apoptosis in cancer cells.
  • TRAIL is a powerful inducer of apoptosis in a wide range of human cancer cell lines via pro-apoptotic death receptor 4 (DR4; TRAIL-Rl ) and death receptor 5 (DR5; TRAIL-R2) at the cell surface through engagement of the extrinsic or intrinsic apoptotic pathways.
  • DR4 pro-apoptotic death receptor 4
  • DR5 death receptor 5
  • TRAIL plays a direct role in tumor suppression during immune surveillance but this anti-tumor mechanism is lost during the disease progression.
  • recombinant TRAIL has efficacy-limiting properties such as short serum half-life, stability, cost, and delivery. Delivery of recombinant TRAIL or TRAIL-agonist antibodies to the brain is limited by inability of recombinant TRAIL and TRAIL-agonist antibodies to cross the blood-brain barrier. Accordingly, there is a continuing need for anti-cancer compositions and methods.
  • pro vided herein are compounds of formula (10):
  • R3 ⁇ 4 and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylaikyl, alkoxyalkyl, alkoxycarbonyl, aralkoxy, araikylthio, and acyl, radicals, wherein when R; represents CH 2 Ph, R 2 does not represent CH 2 -((2-CH 3 )-Ph).
  • Ri and R 2 are independently selected from the group consisting of H, C h alky lthienyl,
  • Ci-dbenzyl-piperazine, Ci. 4 alkylthienyl, C j ⁇ alkylisoxazolidinyl, and Cj- 4 aikylpyrazinyl are optionally substituted with Ci-4alkyl, hydroxy!, perhalogenated Ci - 4 alkyl, or halo.
  • R; and'or R. 2 is a substituted or unsubstituted, arylalkyl or heteroarylalkyl.
  • the heteroarylalkyl is selected from Ci. 4 alkylfuryl,
  • Ci-4alkylquinolyl Ci_ 4 alkylisoquinolyl
  • Ri and'or R. 2 is a substituted or unsubstituted, benzyl or phenylethyl.
  • Ri and/or R 2 is a benzyl optionally substituted with one or more of the following substituents on the benzyl ring: X, -( ' I k -NO?, -QCH 3 , -C ⁇ . -CXH 2 , ⁇ X ⁇ .
  • R m and R are independently selected from hydrogen or a d -C4 alkyl
  • p is an integer from 2 to 20 and X represents a halogen.
  • R. 2 is as defined above, and wherein b2, R-bi' , b4, and Rbs are each independently selected from the group consisting of hydrogen, X, -CH 3 , -NO2, -OCH3, -CN, -CXH 2 , -CX 2 H, C 2 -C 4 alkyl, -CX 3 , -CH 2 (CX 3 ), ⁇ (. ' ! K C ' X : ) ⁇ . -C(CX 3 ) 3 , -C,,X Y . -OCX 3) -OC p H 2 p-H , -OC ⁇ ⁇ ⁇ . OR m , SR m , R m R n , NR ffi C(0)R n , SOR m , S0 2 R ra , C(0)R ra , and C(0)OR m ;
  • R m and R are independently selected from hydrogen or a C 1 -C4 alkyl
  • p is an integer from 2 to 20 and X represents a halogen.
  • compound (10) has the structure of compound (40)
  • R a j , R ri 2, a3, Ra4 5 and R a 5 are each independently selected from the group consisting of hydrogen, X, -CH 3> -NO?., -OCH3, -CN, -CXII2, -CX 2 H, C2-C4 alkyl, -CX 3 , -Cl MCX -CH(CX 3 ) 2 , -C(CX ) 3 , -CpX 2p -i !, -OCX 3 , - ( )( . ' ,.! : ⁇ ,. .
  • R m and R n are independently selected from hydrogen or a C1-C4 alkyl
  • p is an integer from 2 to 20 and X represents a halogen.
  • R b is selected from the group consisting of X, -CH 3 , -N0 2 , -OCH 3 , -CN, -CXH 2 , -CX 2 H, C 2 -C 4 alkyl, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX 2p ; 1 , -OCX 3 , -OC p H 2p+1 , -OC P X 2p +i, OR m , SR ra , NR n, R n , NR n, C(0)R n , SOR m , S0 2 R m , C(0)R m , and C(0)OR m ; and wherein R a!
  • R a2 , R a4 , and R a j are each independently selected from the group consisting of hydrogen, X, - CH 3 , -N0 2 , -QCH 3 , -CN, -CXII2, -CX 2 H, C2-C4 alkyl, -CX 3 , -C I t ⁇ ( ' X ⁇ . ⁇ .
  • R m and R n are independently selected from hydrogen or a C; -C4 alkyl
  • compound (10) has the structure of compound (80)
  • Rb2, b3, R b 4, and R- b are each independently selected from the group consisting of hydrogen, X, -CH 3 , -NO2, -OCH , -CN, -CXI-I2, -CX 2 H, C 2 -C 4 alkyl, -C ' X :.
  • RTM and R n are independently selected from hydrogen or a Ci-C 4 alkyl
  • the present invention provides a pharmaceutical composition, comprising a compound of formula (10) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises pharmaceutically acceptable salt of a compound of formula (10),
  • the salt is a pharmaceutically acceptable mono-salt of a compound of formula (10).
  • the salt is a pharmaceutically acceptable di-salt of a compound of formula (10).
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydrogensulphate, sulfates, phosphates, fumarates, succinates, oxalates and lactates, bisulfates, hydroxy!, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, acetate, and carboxylate.
  • the pharmaceutically acceptable salt is selected from the group consisting of p-toluene-sulfonate, benzenesulfonate, methanesuifonate, oxalate, succinate, tartrate, citrate, fumarate, glucuronate, ascorbate and maleate.
  • the pharmaceutically acceptable salt is selected from ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and/or with other counter-ions such as methylamino, dimethylamino, diethylamino and triethylamino counter-ions.
  • the pharmaceutical composition comprises a hydrochloride di-sait or hydrobromide di-sait of a compound of formula (10).
  • a pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
  • a pharmaceutical composition o the present invention includes a second therapeutic agent.
  • the second therapeutic agent is an anti-cancer agent.
  • the anti-cancer agent is a mitotic inhibitor.
  • the anti-cancer agent is selected from the group consisting of: paclitaxel, docetaxel and a combination thereof.
  • the second therapeutic agent is an a ti -angiogenic agent.
  • the a ti -angiogenic agent is bevacizumab.
  • the second therapeutic agent is administered as part of combination therapy to treat a patient. In one embodiment, details for the combination therapy- is included in a package insert for the compound of formula (10).
  • the pharmaceutical composition is formulated for oral administration.
  • the present in vention pro vides methods of treatment.
  • the method of treatment comprises administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (10) or a pharmaceutically acceptable salt thereof.
  • the method of treatment comprises 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 method of treatment comprises administering to the 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.
  • the method of treatment further comprises administering an additional therapeutic agent.
  • the additional therapeutic agent includes an anti-cancer agent.
  • the additional anti-cancer agent comprises an anti-mitotic agent.
  • the additional anti-cancer agent comprises paclitaxel, docetaxel, bevacizumab or a combination thereof.
  • 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.
  • TNF tumor necrosis factor
  • TRAIL apoptosis-inducing ligand
  • the subject undergoing treatment has, or is at risk of having, cancer.
  • the cancer is selected from the group consisting of colon cancer, breast cancer, glioblastoma multiforme, Mantle cell lymphoma, and colorectal cancer.
  • the cancer is selected from the group consisting of actinic keratosis, Barrett's esophagus, atrophic gastritis, dyskeratosis congenital, sideropenic dysphagia, lichen planus, oral submucous fibrosis, solar elastosis, cervical dysplasia, leukoplakia, and eiythroplakia.
  • the pharmaceutical composition is administered via an oral administration route.
  • the pharmaceutical composition is administered via an administration route selected from the group consisting of: intravenous, rectal, nasal, pulmonary, epidural, ocular, otic, mtra-arterial, topical, intracardiac, intracerebroventricular, intradermal, intramuscular, intraperitoneal, intraosseous, intrathecal, intravesical, subcutaneous, transdermal, transmucosal, sublingual, buccal, vaginal, and inhaiationai routes of administration.
  • the present invention provides a method of treating a subject having, or is at risk of having, brain cancer, the method comprising: administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount a compound of formula (10) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises a pharmaceutically acceptable carrier,
  • the present invention provides a method of treatment comprising administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (10) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable earner.
  • the present invention provides a method of treating a subject in need of such treatment, the method comprising:
  • the present invention provides a method of treating a subject in need of such treatment, the method comprising:
  • the present invention provides a method of, the method comprising:
  • the treatment method comprises administering to a subject a pharmaceutical composition, the composition comprising a pharmaceutically effective amount of a compound of formula (10) or of formula (1) or an analog therof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition includes a a pharmaceutically acceptable carrier.
  • the subject undergoing treatment has, or is at risk of having, cancer.
  • the subject is a human.
  • the present in vention provides a method of treating a subject in need of such treatment, the method comprising:
  • a first therapeutic agent including an analog of compound (1) (e.g., a compound of formula (10)) or a pharmaceutically acceptable salt thereof;
  • adverse events from the first therapeutic agent are related to the blood levels of that agent or metabolites thereof in the subject undergoing treatment.
  • the present invention provides a kit for monitoring of an analog of compound (1) (e.g., a compound of formula (10)) or a pharmaceutically acceptable salt thereof or a metabolite thereof in an individual treated with the analog of compound (1) or pharmaceutically acceptable salt thereof or metabolite thereof using pharmacokinetic profiling, the kit comprising a plurality of point-of-care devices or point of use devices capable of quantitating the drug in at least two samples or matrices suitable for storage of those samples prior to quantitation by a laboratory.
  • a kit further comprising instructions for collecting and/or storing the at least two samples.
  • the treatment method comprises administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring levels of the compound or a pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of the compound or salt thereof is selected to maintain a concentration of the compound or a metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject of at least about 400 ng/mL for a therapeutic time period within 4 hours post-treatment.
  • the subject undergoing treatment has, or is at risk of having, cancer.
  • the treatment method further comprises the step of waiting for 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).
  • the subject is a human.
  • the treatment method comprises administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring levels of the compound or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of the compound or salt thereof is selected to obtain an AUG of the compound or a metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject of at least about 3,500 hr-ng/mL with a time period of 2, 6, 12, 24, 48, 72 or greater than 72 hours post-treatment or extrapolated to infinity.
  • the treatment method comprises administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring levels of compound (1), the pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of the compound or salt thereof is selected to result in undetectable concentrations of the compound or a metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject at 3 days, 4 days, 5 days, 6 days, or 7 days post-treatment.
  • the treatment method comprises (i) administering, over a first time interval (e.g. , 7 days), a plurality of doses of a therapeutic agent including a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof, wherein the plurality of doses is administered over a second time interval (e.g., two to five consecutive days for a first time interval of a week) within the first time interval; and (ii) repeating step (i) one or more additional times.
  • the subject undergoing treatment has, or is at risk of having, cancer.
  • the treatment method further comprises the step of waiting for 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).
  • the subject is a human.
  • the pharmaceutical composition is administered to a subject once daily. In some embodiments, the pharmaceutical composition is administered to a subject accoridng to an infrequent dosing regimen (e.g., administered once per week or less frequently). In some embodiments, the pharmaceutical composition is administered to a subject accoridng to a frequent dosing regimen (e.g., administered more than once per week). In some embodiments, the pharmaceutical composition is administered to a subject once weekly. In some embodiments, the pharmaceutical composition is administered to a subject once every four weeks. In some embodiments, the pharmaceutical composition is administered to a subject twice a week. In some embodiments, the pharmaceutical composition is administered to a subject three times a week.
  • the pharmaceutical composition is administered to a subject four times a week. In some embodiments, the pharmaceutical composition is administered to a subject once ever ⁇ ' two weeks. In some embodiments, the pharmaceutical composition is administered to a subject once every three weeks. In some embodiments, the pharmaceutical composition is administered to a subject in a repeated cycle of once weekly, once ever ⁇ ' two weeks, once every three weeks, once every four weeks or combinations thereof.
  • the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring RNA
  • the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring RNA modifications levels and/or expression or activity levels of one or more of the proteins from Tables 1 and 3 and/or the presence or absence of one or more mutations in at least one gene encoding one or more proteins from Tables i and 3 in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining a prognosis for the subject, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
  • the subject has, or is at risk of having, cancer.
  • the treatment regimen comprises administering an effective amount of compound (1) or an analog thereof.
  • the RNA is mRNA.
  • the RNA is miRNA.
  • the RNA modification is methylation.
  • the RNA modification is N 6 -Methyladenosine (m 6 A).
  • the RNA modification is m b A mRNA methylation.
  • the subject is a human.
  • the subject is a domesticated pet, such as a cat or dog.
  • the protein is an RNA Reader, e.g. , YTHDF3.
  • the protein is an RNA Writer.
  • the protein is an RNA Eraser.
  • the method comprises (i) identifying whether a subject having a condition is likely to be responsive to a treatment regimen described herein; and (ii) treating with the treatment regimen a subject determined likely to be responsive to that treatment regimen.
  • the subject has, or is at risk of having, cancer.
  • the treatment regimen comprises administering an effective amount of compound (1) or an analog thereof.
  • the method comprises (i) obtaining a biological sample from the subject; (ii) measuring RNA modifications levels and/or expression or activity levels of one or more of the proteins from Tables 1 and 3 and/or the presence or absence of one or more mutations in at least one gene encoding one or more proteins from Tables 1 and 3 in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining whether the subject is responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
  • the subject has, or is at risk of having, cancer.
  • the treatment regimen comprises administering an effective amount of compound (1) or an analog thereof.
  • the RNA is mRNA.
  • the RNA is miRNA.
  • the RNA modification is methylation.
  • the RNA modification is A ⁇ -Methyladenosine (ni 6 A).
  • the RNA modification is m 6 A mRNA methylation.
  • the subject is a human.
  • the subject is a domesticated pet, such as a cat or dog.
  • the protein is an RNA Reader, e.g. , YTHDF3.
  • the protein is an RNA Writer.
  • the protein is an RNA Eraser.
  • the method comprises (i) contacting a protein from Tables 1 and 3 with a test compound suspected of being a therapeutic for the condition; (ii) measuring the binding affinity or interaction of the test compound to the protein; and (iii) comparing the binding affinity or interaction of test compound to a pre-determined threshold, wherein an affinity or interaction of the test compound comparable to or greater than the threshold is indicative of a therapeutic for the condition.
  • the condition is cancer.
  • the pre-determined threshold is the affinity or interaction of compound (1) or an analog thereof to the protein.
  • the pre-determined threshold is the affinity or interaction of compound (1) to the protein.
  • the protein is an RNA Reader, e.g. , YTHDF3.
  • the protein is an RNA Writer.
  • the protein is an RNA Eraser.
  • the method comprises (i) contacting a protein from Tables 1 and 3 with a reference compound under conditions where the reference compound binds to or interacts with the protein; (it) contacting the protein from Tables 1 and 3 with a test compound suspected of being a therapeutic for the condition; (iii) measuring the binding affinities or interactions of the reference and test compounds to the protein; and (iv) comparing the binding affinities or interactions 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 for the condition.
  • the reference compound is compound (1) or an analog thereof.
  • the reference compound is compound (I).
  • the condition is cancer.
  • the protein is an RNA Reader, e.g., YTHDF3.
  • the protein is an RN A Writer.
  • the protein is an RNA Eraser.
  • the method comprises (i) using a processor, modeling binding or interaction, if any, of a 3-dimensional structure of a test compound suspected of being a therapeutic for the condition to a 3-dimensional structure of a protein from Tables 1 and 3; (ii) using the processor, determining the binding affinity or interaction of the test compound structure to the protein structure; and (iii) using the processor, comparing the binding affinity or interaction of test compound to a pre-determined threshold, wherein an affinity or interaction of the test compound comparable to or greater than the threshold is indicati ve of a therapeutic for the condition.
  • the pre-determined threshold is the affinity or interaction of compound (1) or an analog thereof to the protein. In one embodiment, the pre-determined threshold is the affinity or interaction of compound (1) to the protein. In some embodiments, the condition is cancer. In one embodiment, the protein is an RNA Reader, e.g. , YTHDF3. In one embodiment, the protein is an RN A Writer. In one embodiment, the protein is an RNA Eraser.
  • the method comprises (i) using a computational docking method to model binding or interaction, of one or more 3-dimensional structures (conformations) of a test molecule suspected of being a therapeutic for the condition to a 3-dimensional structure or model of a protein from Tables 1 and 3; (ii) using the computational method to estimate the binding or interaction, if any, of a 3-dimensional structure of of the test molecule structure to the structure or model of the protein; and (iii) using the computational method to compare the binding affinities or interactions of the reference and test compounds to the protein; and (iv) using the processor, comparing the binding affinities or interactions of the reference and test compound structures, wherein a comparable or stronger affinity or interaction of the test compound relative to the reference compound is indicative of a therapeutic for the condition.
  • the reference compound structure is the structure compound (1) or an analog thereof. In some embodiments, the reference compound structure is the structure is compound (1). In some embodiments, the condition is cancer. In some embodiments, the protein is an RNA Reader, e.g., YTHDF3. In some embodiments, the protein is an R A Writer. In some embodiments, the protein is an RNA Eraser.
  • kits for treating a subject having a condition, such as cancer by administering agents that modulate the transcription, translation, or biological activity of YTHDF3 or other proteins in Tables 1 and 3 or nucleic acids encoding these proteins.
  • the agents include, but are not limited to siRNA, antisense nucleic acids, ribozymes, triple-helix-forming agents, antibodies, and polypeptides, as well as small molecule compounds.
  • the si RNA. antisense nucleic acids, ribozymes, triple-helix-forming agents inhibit the translation or transcription of one or more genes in Tables 1 and 3.
  • oligonucleotides used are designed on the basis of relevant sequences unique to the target gene.
  • a variety of gene therapy approaches may be used in accordance with the invention to modulate expression of the genes in Tables 1 and 3,
  • antisense DNA molecules may be engineered and used to block translation of YTHDF3 mRNA in vivo.
  • ribozyme molecules may be designed to cleave and destroy the YTHDF3 mRNAs in vivo.
  • oligonucleotides designed to hybridize to the 5' region of the YTHDF3 gene (including the region upstream of the coding sequence) and form triple helix structures block or reduce transcription of the YTHDF3 gene.
  • nucleic acid encoding the full length wild-type YTHDF3 message may be introduced in vivo into cells which otherwise would be unable to produce the wild-type YTHDF3 gene product in sufficient quantities or at all,
  • the pharmaceutical composition includes a pharmaceutically acceptable carrier.
  • the subject has, or is at risk of having, cancer.
  • the subject is, or is at risk of being, infected wth a virus.
  • the subject is a human.
  • the dose of compound (1) or a pharmaceutically acceptable salt thereof ranges from about 125 mg to about 625 mg.
  • a sample obtained from the subject is assayed for cleaved and/or total cytokeratin-18. determining whether the treatment regimen should continue based on the results of the cleaved and/or total cytokeratin-18 assays.
  • a treatment regiment described herein further comprises the step of administering a second therapeutic agent, wherein compound (1), the pharmaceutically acceptable salt thereof, or the analog thereof is administered before, simultaneously, or after the second therapeutic agent.
  • pro vided herein are methods of identifying whether a subject having a condition is likely to be responsive to a treatment regimen described herein.
  • the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, or DR5 in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining whether the subject is likely to be responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
  • the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, or DR5 in the sample in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining a prognosis or determining whether the subject is responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
  • 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 subject is, or is at risk of being, infected wth a virus. In some embodiments, the treatment regimen comprises administering an effective amount of compound (1 ), a pharmaceutically acceptable salt thereof, or an analog thereof.
  • the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining whether the subject is likely to be responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
  • the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining a prognosis or determining whether the subject is responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
  • 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 regimen comprises administering an effective amount of compound (1), a pharmaceutically acceptable salt thereof, or an analog thereof.
  • the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3. In some embodiments, the dopamine receptor is from the D2-3ike family of dopamine receptors.
  • the method comprises (i) contacting at least one G protein- coupled receptor (GPCR) with a test molecule suspected of being a therapeutic for a cond ition;
  • GPCR G protein- coupled receptor
  • the condition is cancer.
  • the pre-determined threshold is the GPCR antagonism or GPCR signaling antagonism of compound (1) or a pharmaceutically acceptable salt thereof, or an analog thereof.
  • the method comprises (i) contacting at least one dopamine receptor with a test molecule suspected of being a therapeutic for a condition; (ii) measuring the binding affinity or interaction of the test molecule to the at least one dopamine receptor; and
  • the condition is cancer.
  • the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3.
  • inhibition of the D2-like family of dopamine receptors is indicative of a therapeutic for the condition.
  • inhibition of both DRD2 and DRD3 dopamine receptors is indicative of a therapeutic for the condition.
  • the pre-determined threshold is the inhibition of the at least one dopamine receptor by compound (1) or a pharmaceutically acceptable salt thereof, or an analog thereof to the dopamine receptor.
  • the method comprises (i) using a computational docking method to model binding or interaction, if any, of one or more
  • the condition is cancer.
  • the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3.
  • inhibition of the D2--Iike family of dopamine receptors is indicative of a therapeutic for the condition. In one embodiment, inhibition of both DRD2 and DRD3 dopamine receptors is indicative of a therapeutic for the condition.
  • the pre-determined threshold is the inhibition of the at least one dopamine receptor by compound (1) or a pharmaceutically acceptable salt thereof, or an analog thereof to the dopamine receptor.
  • a pharmacophore modeling approach may be used to compare different dopamine antagonist compounds in three dimensions as described in Hogberg & Norinder, Chapter 3.
  • the method comprises (i) treating the subject according to a treatment method described herein (ii) assessing as decribed herein the treatment's effectiveness.
  • the subject has, or is at risk of having, cancer.
  • the treatment regimen comprises administering an effective amount of compound (1 ) or a pharmaceutically acceptable salt thereof or an analog thereof.
  • Figure 1 illustrates a dose response relation showing effects of various concentrations of compound (1) on viability of tumor and normal ceils
  • Figure 2 illustrates cell viability assay in human fetal lung fibroblast (MRC-5) cells following 72 hour treatment with compound (1 ).
  • Figure 3 illustrates antagonism by ONC201 of dopamine receptor (DRD1 , DRD2S, DRD2L, DRD3, DRD4, and DRD5).
  • Figure 4 illustrates soluble prolactin detected by an ELISA assay in the peripheral blood of advanced solid tumor patients at baseline and following a single ONC201 dose (PO 125-625 mg). Sampling time points post-treatment include 6 hours, 1, 2, 7, and 21 days post-treatment.
  • Figure 5 shows the mean ONC201 plasma concentrations versus time following the first dose of ONC201. Concentrations are shown as (A) the mean for each dose cohort, or (B) for individuals treated at 625 mg. Error bars indicate standard deviation.
  • Figure 6 illustrates individual measurements of ONC201 (A) AUC and (B) Cmax versus dose. * Anticipated dose proportionality line based on men for 625 mg dose group.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • any variable e.g., R 4
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 4 at each occurrence is selected independently from the definition of R ⁇
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • Ci_6 When an atom or chemical moiety is followed by a subscripted numeric range (e.g., Ci_6), it will be appreciated that this is meant to encompass each number within the range as well as all intermediate ranges.
  • "Ci-e alkyl” is meant to include alkyl groups with 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.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Cj _6 alkyl is intended to include Q, C 2 , C 3 , C 4 , Cs, and C alkyl groups.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl s-butyl, t-butyl, n-pentyl, s-pentyl, neopentyl and n-hexyl.
  • a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., Ci -Ce for straight chain, C 3 -C 6 for branched chain), and in another embodiment, a straight chain or branched chain alkyl has four or fewer carbon atoms.
  • cycloalkyls have from three to eight carbon atoms in their ring structure, and in other embodiments, cycloalkyls have five or six carbons in the ring structure.
  • (Cj -C6)alkyl particularly ethyl, methyl, isopropyi, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.
  • substituted aikyl means alk l as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, -M L. -N(CH 3 ) 2 , - ( ( ) ) ( ) ! I. trifluoromethyl, -C X.
  • substituted alky Is include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.
  • lower alkyl includes an alkyl group, as defined above, but having from one to six carbon atoms, preferably one to four, in its backbone structure.
  • Lower alkenyl and “lower alkynyl” have chain lengths of 2-6 carbon atoms and preferably 2-4 carbon atoms.
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyi), branched-chain alkenyl groups, cycloalkenyl (e.g., aiicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, eycloheptenyl, eyeiooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cvcloalkyl or cycloalkenyl substituted alkenyl groups.
  • a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C -Ce for straight chain, C3-C6 for branched chain).
  • cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and in some embodiments, cycloalkenyl groups have five or six carbons in the ring structure.
  • C 2 -Ce includes alkenyl groups containing two to six carbon atoms.
  • C 3 -C6 includes alkenyl groups containing three to six carbon atoms.
  • Alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, and cvcloalkyl or cycloalkenyl substituted alkynyl groups.
  • a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C3-C6 for branched chain).
  • C2-C6 includes alkynyl groups containing two to six carbon atoms.
  • C3-C 0 includes alkynyl groups containing three to six carbon atoms.
  • cycloalkyl refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • the cycioalkyl group is saturated or partially unsaturated.
  • the cycioalkyl group is fused with an aromatic ring.
  • Cycioalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycioalkyl groups include, but are not limited to, t
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyi, cyciobutyi, cyclopentyl, cyclohexyl, cycioheptyl, and cyclooctyi.
  • Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene.
  • Polycyclic cycloalkyls include adamantine and norbornane.
  • cycioalkyl includes "unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon carbon double bond or one carbon carbon triple bond.
  • cycloalkylalkyl refers to an alkyl group substituted by a cycioalkyl group.
  • Example cy cloalkylalky l groups include cyclopropylalkyl, cyclohexyialkyl, and the like.
  • heterocycloalkyi refers to a non-aromatic heterocycle where one or more of the ring-forming atoms can be a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
  • Example heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, ,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyi, oxazolidinvL thiazoiidinyl, imidazolidinyl, and the like.
  • heterocycloalkyl can be moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example quinolyl, isoquinolyl, and benzo derivatives of heterocycles.
  • a heterocycloalkyl group having one or more fused aromatic rings are attached though either the aromatic or non-aromatic portion.
  • Also included in the definition of heterocycloalkyl can be moieties where one or more ring-forming atoms can be substituted by 1 or 2 oxo or sulfide groups.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds, in some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
  • heterocycloalkylalkyi refers to an alkyl group substituted by a heterocycloalkyl group.
  • Example heterocycloalkylalkyi groups include morpholinoalkyl and piperazinylalkyl, and the like.
  • aryl refers to monocyclic or poly cyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like, in some embodiments, an aryl group has from 6 to about 20 carbon atoms.
  • arylalkyl refers to an alkyl group substituted by an aryl group.
  • Example arylalkyl groups include benzyl and phenylethyl.
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • heteroaryl groups include without limitation, pyridyl, " N-oxopyridyl, pyrimidinyl, pyrazinyi, pyridazinyi, triazinyl, furyl, quinoiyl, isoquinoiyl, thienyi, imidazolyl, thiazoiyi, indoiyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pvrazolyl, triazolvl, tetrazoiyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyi, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in farther embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, I to about 3, or I to 2 heteroatoms.
  • heteroarylalkyl refers to an alkyl group substituted by a heteroaryl group.
  • An example of a heteroarylalkyl group is pyridylmethyl.
  • halo or halogen refers to a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • perhalogenated refers to a moiety w erein all hydrogens are replaced by halogen atoms.
  • haloalkyl refers to alkyl moieties having a halogen atom replacing a hydrogen atom on one or more carbons of the hydrocarbon backbone.
  • Ci -Ce haloalkyl is intended to include a straight chain or branched alkyl having six or fewer carbon atoms in its backbone and a halogen atom replacing a hydrogen atom on one or more carbons of the hydrocarbon backbone.
  • alkoxy or "alkoxyl” includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • Cj-Ce alkoxy refers to moieties having six of few carbon atoms in the hydrocarbon backbone.
  • alkoxy groups or alkoxyl radicals
  • examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • Preferred are (Ci-C 3 ) alkoxy, particularly ethoxy and methoxy.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • hydroxy or "hydroxy! includes groups with an -OH or -0 ⁇ .
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to deri vatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • 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 in vention include the 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 which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the tree acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts can be found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, Journal of Pharmaceutical Science, 66, 2 (1977), and P. H.
  • suitable inorganic acids include hydrochloric acid, sulphuric acid, phosphoric acid, or hydrobromic acid
  • suitable organic acids can include carboxylic acid, sulpho acid, or sulphonic acid, 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, cirmamic 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, methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, ethane-1
  • suitable inorganic bases can include sodium hydroxide, potassium hydroxide and ammonia
  • suitable organic bases are amines, e.g., tertiary amines, such as trimethylamine, triethylamine, pyridine, NN-dimethylaniline, quinoiine, isoquinoiine, a-picoline, ⁇ -picoline, ⁇ -picoline, quinaldine, or pyrrolidine.
  • ONC201 compound (1)
  • compound (1) has broad anti-cancer activity, low toxicity including few, if any, adverse effects, low genotoxicity, and high bioavailability including oral bioavailability.
  • the present invention provides compound (1):
  • synthesis of a dihydrochloride salt of compound (1) starts with commercially available intermediary N-Benzyl-3-carbomethoxy-4-piperidone hydrochloride, compound (3).
  • the synthetic process includes neutralizing intermediary compound (3) with a base (Step 1) to produce compound (4), a free base.
  • the synthetic process includes neutralizing intermediary compound (3) with an inorganic base to produce compound (4).
  • the synthetic process includes neutralizing intermediary compound (3) with an organic base to produce compound (4).
  • intermediary compound (3) is neutralized in the presence of an alcohol.
  • intermediary compound (3) is neutralized in the presence of n-butanol.
  • intermediary compound (3) is neutralized in the presence of at least one organic solvent.
  • intermediary compound (3) is neutralized in the presence of n-butanol and/or ethyl acetate.
  • intermediary compound (3) is neutralized in the presence of a base and at least one organic solvent.
  • intermediary compound (3) is neutralized in the presence of NaHC0 3 and n-butanol.
  • intermediary compound (3) is neutralized in the presence of n-butanol and triethyl amine (Et 3 N).
  • the synthetic process includes reacting compound (4) with compound (5) (Step 2) to produce intermediary compound of (1).
  • the reaction in Step 2 includes heating compound (4) with compound (5).
  • the reaction in Step 2 includes refluxing heating compound (4) and compound (5) in the presence of a solvent.
  • the reaction in Step 2 includes use of Dean-stark trap to remove water and/or methanol (MeOH) formed in the reaction.
  • the synthetic process includes forming a dihydrochloride salt of compound (1) (Step 3).
  • the reaction in Step 3 includes treating compound (1) with HCl in dioxane.
  • the reaction in Step 3 includes treating compound (3) with 4N HCl in dioxane.
  • the synthetic process optionally includes recrystallization of the di-salt of compound (1).
  • the syn thetic process for the preparation of the di -hydrochloride salt of compound (1) is as illustrated in the following Scheme 2.
  • TRAIL protein can be assayed in a test sample obtained from a subject to detect TRAIL expression induced by the compounds and their salts described herein.
  • Immunoassays can be used to assay TRAIL in a sample, including, but not limited to, enzyme-linked immunosorbent assay (ELISA), enzyme- linked immunofiltration assay (ELIFA), flow cytometry, immunoblot, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescent immunoassay (LIA), fluorescent immunoassay (FIA), and radioimmunoassay. Assay methods may be used to obtain qualitative and/or quantitative results.
  • ELISA enzyme-linked immunosorbent assay
  • ELIFA enzyme- linked immunofiltration assay
  • flow cytometry immunoblot, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescent immunoassay (LIA), fluorescent immunoassay (FIA), and radioimmunoassay.
  • Assay methods may be used to obtain qualitative and/or
  • TRAIL assays are used to monitor a subject.
  • a test sample is obtained from the subject before treatment with a pharmaceutical composition and at one or more times during and/or following treatment in order to assess effectiveness of the treatment.
  • a test sample is obtained from the subject at various times in order to assess the course or progress of disease or healing.
  • death receptors can also be analyzed from circulating tumor cells to see if the administration of a compound or its salt described herein increases the amount or type of death receptors.
  • Cancers treated using methods and compositions described herein are characterized by abnormal cell proliferation including, but not limited to, pre- neoplastic hyperproliferation, cancer in-situ, neoplasms and metastasis. Methods and compositions described herein can be used for prophylaxis, as well as amelioration of signs and/or symptoms of cancer.
  • the terms “treating” and “treatment” used to refer to treatment of a cancer in a subject include:
  • cancers treated using methods and compositions described herein include, but are not limited to, breast cancer, CNS cancers, colon cancer, ovarian cancer, prostate cancer, leukemia, lung cancer, and lymphoma.
  • R3 ⁇ 4 and R? independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroc cloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxvcarbonvl, aralkoxy, aralkylthio, and acyl radicals, wherein when Rj represents CH 2 Ph, R 2 does not represent CH 2 -((2-CH3)-Ph.
  • Ri and R 2 are independently selected from the group consisting of H, Ci- 4 alkylphenyl, Ci-aalk
  • Ri and/or R 2 is a substituted or unsubstituted, arylalkyl or
  • heteroarylalkyl is selected from Ci- 4 alkylpyiTolyl, C h alky 1-1 ,2,4-thiadiazolyl, Ci- 4 alkylpyrimidyl,
  • Ci_4alkylisothiazoly] Chalk limidazolyl
  • Ri and/or R? is a benzyl optionally substituted with one or more of the following substituents on the benzyl ring: X, -CH 3 , -NO ? ., -OCH 3 , -CN, -CXH 2 , -CX 2 H, C 2 -C4 alkyl, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , ⁇ C(CX 3 ) 3 , -C P X 2p , -OCX 3 , -OC P H 2p i ! , -OCpX 2p+!
  • R iri and R" are independently selected from hydrogen or a C 1 -C4 alkyl; and where p is an integer from 2 to 20 and X represents a halogen, including a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • Ri is selected from the group consisting of H, CH 3 , CH 2 Ph,
  • R 2 is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -(4-CF -Ph), CH 2 -((2-Cl)-Ph), CH 2 -((2-F)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph,
  • Ri is a hydrogen. In some embodiments, Ri is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethvi group. In some embodiments, the arylalkyl is substituted with hydroxy!, perhalogenated C 4aikyi. or halo.
  • R 2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethvi group.
  • the arylalkyl is substituted with Ci -4 alkyl,
  • Ci- 4 alkoxyl, hydroxyl, perhalogenated or halo In one embodiment, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3 . In one embodiment, R 2 is a substituted or an unsubstituted
  • heterocycloalkylalkyl such as a morpholinoalkyl or piperazinylalkyl group.
  • R 2 is a substituted or an unsubstituted heteroarylalkyl, such as an
  • the heterocycloalkylalkyl or heteroarylalkyl is substituted with Cj ⁇ alkyl, Ci -4 alkoxyl, hydroxyl, perhalogenated Cj ⁇ alkyl, or halo.
  • the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, -Cl3 ⁇ 4, -CF 3 , and -OCH 3 .
  • compound (10) has the structure of compound (80):
  • Rb 2 , R b s, b 4, and Rbs are each independently selected from the group consisting of X, -CH 3 , -N0 2> -OCH 3 , -C , -CX13 ⁇ 4, -CX 2 H, ( ⁇ ( alkyl, -CX 3> -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -C p X 2p ; -i, -OCX 3 , -OC p H 2p+ 1 , -( )( r X v. ⁇ .
  • compound (10) has the structure of compound (90)
  • R? is as defined above, and wherein R b i,
  • Rb2, b3 , R b 4, and R 3 ⁇ 4 are each independently selected from the group consisting of X, -CH 3 , -N0 2 , -OCH3, -C , -CXH 2 , -CX 2 H, ( ⁇ - ( ., alkyl, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX 2p; -i, -OCX 3 , ⁇ OCpH 2 p + i, -OCpX 2p; -i, OR m , SR ' .
  • RTM and R n are independently selected from hydrogen or a Cj -C 4 alkyl; and where p is an integer from 2 to 20 and X represents a halogen.
  • compound (10) has the structure of compound (40)
  • R ai , R a2 , R a3 , R a4 , and R a s are each independently selected from the group consisting of hydrogen, X, -CH 3 , -N0 2 , -OCH 3 , -CN, -CXH 2 , -CX 2 H, C 2 -C 4 alkyl, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX ) 3 , -C p X 2p - , -OCX 3 , ⁇ ( )( . ⁇ ,.! 1 ⁇ ⁇ . -OC p X 2p - , OR ra , SR ra , NR ffi R n ,
  • RTM and R" are independently selected from hydrogen or a C1-C4 alkyl; and where p is an integer from 2 to 20 and X represents a halogen.
  • R3 ⁇ 4 is a hydrogen.
  • Ri is a substituted or an imsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • the arylaikyl is substituted with Ci -4 alkyl, C;_ 4 aikoxyl, hydroxyl, perhalogenated Ci_ 4 aikyi, or halo.
  • 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, --CH 3 , --CF 3 , and -OCH 3 . In one embodiment, the benzyl is substituted with one halogen substituent, e.g., a fluorine substituent at an ortho or para position. In one embodiment, the benzyl is substituted with two halogen substituents, e.g., fluorine substituents at both meta positions.
  • compound (40) has the structure of compound (45):
  • the benzy l is substituted with one or more halogens. In some embodiments, the benzyl is substituted with one or more substituents selected from the group consisting of halo, -CH , -CF , and -OCH 3 .
  • R a! or R a s is a halogen, e.g. , fluorine. In one embodiment, both R a2 or R a are halogen, e.g. , fluorine, substituents.
  • compound (10) has the structure of compound (50)
  • Ri is as defined above, and wherein is selected from the group consisting of X, -CH 3 , -N0 2 , -OCH3, -CN, -CXH 2 , -CX 2 H, Q2-C4 alkyl, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX 2 p+i, -OCX 3 , -OCpH 2p+i , -OCpX 2p ⁇ 1 , OR m , SR m , R m R n , NR m C(0)R n , SOR m , S0 2 R ffl , C(0)R ffl , and C(0)OR m ; R ffi and R n are independently selected from hydrogen or a C1-C4 alkyl; and where p is an integer from 2 to 20 and X represents a
  • R a2 , R a4 , and a s are each independently selected from the group consisting of hydrogen, X, -CH 3 , -NQ 2 , -OCH3, -CN, -CXH 2 , -CX 2 H, C2-C4 alkyl, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX 2p+1 , -OCX 3 , -OC p H 2p i ! , -OC p X 2pH , OR m , SRTM, XR. :r R. .
  • R m and R. are independently selected from hydrogen or a C1-C4 alkyl: and where p is an integer from 2 to 20 and X represents a halogen.
  • R is a hydrogen.
  • Ri is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In one embodiment, the arylalkyl is substituted with hydroxy!, periialogenated or halo.
  • b is selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3
  • one or more of R a i, R a2 , R a 4, and R a is selected from the group consisting ofhalo, -CH 3 , -CF 3 , and -OCH 3
  • R a! , R a2 , R_ a4 , and a s are hydrogen
  • R b is selected from the group consisting of alo, -CH 3 , -CF 3 , and -OCH 3
  • Rb is a halogen, e.g.
  • R is a fluorine or chlorine
  • R. a2 is a fluorine or chlorine
  • b is CF 3
  • R is -OCH 3
  • R3 ⁇ 4 is a chlorine and a j is a chlorine.
  • compound (50) has the structure of compound (55):
  • R ai , ]1 ⁇ 2, R a 4, R a s, a d R- b are as defined above.
  • R b is selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3 .
  • one or more of R a i, R a 2, a4, and R a ⁇ is selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3 .
  • R ai , R a2 , R a 4, and a 5 are hydrogen, and 3 ⁇ 4 is selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3 .
  • R 3 ⁇ 4 is a halogen, e.g. , fluorine, and R al is a methyl.
  • Rj, is fluorine or chlorine, and R a ? is a fluorine or chlorine.
  • R is CF .
  • R 3 ⁇ 4 is OCH .
  • R b is a chlorine and R a i is a chlorine.
  • compound (10) has the structure of compound (60)
  • i is a hydrogen.
  • i is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • Ri is a substituted or an unsubstituted heterocycloalkylalkyi. or a substituted or an unsubstituted heteroarylalkyl, such as an CH 2 -(2-thienyl), CH 2 -(3-thienyl), CH 2 -2-pyridinyl, CH 2 -3-pyridinyl, CH 2 -4-methyl-2-thiazolyl, CH 2 -2-pyrazinyl,
  • the arylalkyl is substituted with hydroxy!, perhaiogenated or halo.
  • the benzyl is substituted with one or more halogens.
  • the benzyl is substituted with one or more substituents selected from the group consisting of halo (e.g., fluorine) -CH 3 , -CF 3 , and -OCH 3 .
  • the benzyl is substituted at the para position with a substituent selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3 .
  • R ⁇ is
  • the crude products may be purified by column chromatography eluting with methylene chloride:methanol or by HPLC using acetonitrile:TFA:H 2 0 to produce the final products as either free bases or as TFA salts.
  • Treatment of the free bases with HCI in dioxane or lyophilization of the TFA salts generates the products (10) as HCI or TFA salts.
  • the free base may be treated with another inorganic or organic acid to form other salts, generally selected from those known to be pharmaceutically acceptable salts.
  • the salts of compound (10) are usually solids and examples have been crystallized from ethanol or other solvents to give high quality crystals.
  • the tricyclic structure has been definitively confirmed in the case of compound (1) by an X-ray cr stal structure and NMR.
  • Compound described herein can be used, with or without an aminoaikyi linker (e.g., compound (33)), to identify molecules (e.g., proteins) that interact with them in a cellular context.
  • the expression of these binding targets may be used to predict response to compound (1) (ONC201) or its analogs (i.e. serve as biomarkers).
  • these compounds can be used to screen for structurally unrelated anti-cancer compounds using competition assays known in the art to identify drugs able to outcompete the target interaction with a higher affinity.
  • these molecules may have drug properties that create therapeutic improvements or allow additional therapeutic applications by altering drag properties including but not limited to pharmacokinetics, potency, safety, biodistribution, or metabolism.
  • compound (1) with an aminoalkyl linker i.e., compound (33) was used to identify proteins that interact with compound (1). It has been found that compound (1) interacts with proteins involved with ⁇ -methyl- adenosine (tn 6 A) mRNA metiiylation. Proteins that are involved with m 6 A mRNA epigenetic modification include those in Table 1.
  • RNA Writers such as METTL3, METTL14, WTAP, and KIAA1429
  • demethylate m 6 A mRNA RNA Erasers
  • FTO and ALKBH5 RNA Erasers
  • RNA Readers such as YTHDF3, YTHDF2, YTHDF1 , YTHDC1 , and YTHDC2.
  • Measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, DR5, or cleaved or total cytokeratin 18 may be used to predict response or sensitivity to a method of treatment described herein and to identify subjects likely to be responsive to a method of treatment described herein, such as treatment with compound (1), a pharmaceutically acceptable salt thereof, or an analog thereof.
  • measuring expression, post-translational modifications, or activity levels of or mutations in eIF2 -alpha, ATF4, CHOP, DR5, or cleaved or total cytokeratin 18 can be used to assess the effectiveness of or monitor a method of treatment described herein.
  • measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, DR5, or cleaved or total cytokeratin 18 can be used to screen in vivo, in vitro, or in silico for structurally unrelated anti-cancer compounds.
  • competition and other assays known in the art may be used to identify drugs able to outcompete the target interaction with a higher affinity to compare changes in those levels to the respective changes produced by compound (1) or an analog thereof.
  • Assays can also be performed on li ving mammalian cells, which more closely approximate the effects of a particular serum level of drug in the body, or on microsomal extracts prepared from cultured cell lines.
  • the subject has, or is at risk of having, cancer.
  • the treatment regimen comprises administering an effective amount of compound (1) or compound (10) or an analog thereof.
  • the treatment regimen comprises administering an effective amount of compound (1).
  • the treatment regimen comprises administering an effective amount of a compound of formula (10).
  • the compound of formula (10) is a compound of formula (40), e.g. , a compound of formula (45).
  • a compound of formula (10) is a compound of formula (50), e.g., a compound formula (55).
  • the compound of formula (10) is a compound of formula (80).
  • 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, analogs of compound (1) have a structure selected from the structures of compound (25), compound (26), compound (27), compound (28), compound (29), compound (30), or compound (31).
  • Levels for a pre-deterrnined standard can be, e.g., the average or median levels measured in samples from subjects.
  • the levels for a pre-determined standard can be measured under the same or substantially similar experimental conditions as in measuring the sample from the subject.
  • the levels for the predetermined standard may be obtained from subjects who are responsive to treatment with compound (1) or compound (10) or an analog thereof.
  • the pre-determined standard is obtained from subjects who are responsive to treatment with the compound, and if the levels in the sample from the subject are similar to those in the standard, then the subject can be classified as likely to be responsive to treatment.
  • the levels for the pre-determined standard may be obtained from subjects who are not responsive to treatment with the compound.
  • the pre-determined standard is obtained from subjects who are not responsive to treatment with the compound, and if the levels in the sample from the subject are different (e.g., up- or down-regulated) than those in the pre-determined standard, then the subject can be classified as likely to be responsive to treatment.
  • the levels for the pre-determined standard may be obtained from normal healthy subjects.
  • 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 imm no filtration assay (ELIFA), flow cytometry, immunoblot, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescent immunoassay (LIA), fluorescent immunoassay (FIA), and radioimmunoassay, m°A rnR A methylation levels in a sample can be obtained by methylated RNA immunoprecipitation (Me-RIP) ) or other quantitative biochemical assays known in the art.
  • ELISA enzyme-linked immunosorbent assay
  • ELIFA enzyme-linked imm no filtration assay
  • flow cytometry immunoblot, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescent immunoassay (LIA), fluorescent immunoassay (FIA), and radioimmunoassay
  • Nucleic acid mutations can be determined by any of a number of known procedures.
  • a biologic sample from an individual can first be obtained.
  • biological samples include, but are not limited to, a bodily fluid (such as urine, saliva, plasma, or serum) or a tissue sample (such as a buccal tissue sample or buccal cell).
  • the biologic sample can then be sequenced or scanned using known methods.
  • DNA arrays can be used to analyze at least a portion of the subject's genomic sequence.
  • whole or partial genome sequence information can be used.
  • sequences can be determined using standard sequencing methods including chain-termination (Sanger dideoxynucleotide), dye-terminator sequencing, and SOLIDTM sequencing (Applied Biosystems).
  • DNA sequences can be cut by restriction enzymes or sheared (mechanically) into shorter fragments for sequencing.
  • DNA sequences can also be amplified using known methods such as PCR and vector-based cloning methods (e.g., Escherichia coif).
  • PCR and vector-based cloning methods e.g., Escherichia coif.
  • at least a portion of a subject's genetic material e.g. , DNA, RNA, mRNA, cDNA, other nucleotide bases or derivatives of these
  • a subject's genetic material e.g. , DNA, RNA, mRNA, cDNA, other nucleotide bases or derivatives of these
  • a subject's genetic material e.g. , DNA, RNA, mRNA, cDNA, other nucleotide bases or derivatives of these
  • the method comprises (i) identifying whether a subject having a condition is likely to be responsive to a treatment regimen described herein; and (ii) treating with the treatment regimen a subject determined likely to be responsive to that treatment regimen.
  • the subject has, or is at risk of having, cancer.
  • the trea tment regimen comprises administering an effective amount of compound (1) or compound (10) or an analog thereof.
  • the treatment regimen comprises administering an effective amount of compound (1).
  • the treatment regimen comprises administering an effective amount of a compound of formula (10).
  • the compound of formula (10) is a compound of formula (40), e.g. , a compound of formula (45). In some embodiments, a compound of formula (10) is a compound of formula (50), e.g. , a compound 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, analogs of compound (1) have a structure selected from the structures of compound (25), compound (26), compound (27), compound (28), compound (29), compound (30), or compound (31).
  • Levels for a pre-determined standard can be, e.g., the average or median levels measured in samples from subjects.
  • the levels for a pre-determined standard can be measured under the same or substantially similar experimental conditions as in measuring the sample from the subject.
  • the levels for the pre-determined standard may be obtained from subjects who are responsive to treatment with compound (1) or compound (10) or an analog thereof.
  • the pre-determined standard is obtained from subjects who are responsive to treatment with the compound, and if the levels in the sample from the subject are similar to those in the standard, then the subject can be classified as likely to be responsive to treatment.
  • the levels for the pre-determined standard may be obtained from subjects who are not responsive to treatment with the compound.
  • the pre-determined standard is obtained from subjects who are not responsive to treatment with the compound, and if the levels in the sample from the subject are different (e.g., up- or down-regulated) than those in the pre-determined standard, then the subject can be classified as likely to be responsive to treatment.
  • the levels for the pre-determined standard may be obtained from normal healthy subjects. Immunoassays can be used to assay protein levels in a sample.
  • the method comprises (i) treating the subject according to a method of treatment described herein (ii) assessing as decribed herein the effectiveness of the treatment.
  • the subject has, or is at risk of having, cancer.
  • the treatment regimen comprises administering an effective amount of compound (1) or compound (10) or an analog thereof.
  • the treatment regimen comprises administering an effective amount of compound (1 ).
  • the treatment regimen comprises administering an effective amount of a compound of formula (10).
  • the compound of formula (10) is a compound of formula (40), e.g.
  • a compound of formula (10) is a compound of formula (50), e.g. , a compound formula (55).
  • the compound of formula (10) is a compound of formula (80).
  • the compound of formula (10) is a compound of formula (90).
  • the compound of formula (10) is a compound of formula (60).
  • analogs of compound (1) have a structure selected from the structures of compound (25), compound (26), compound (27), compound (28), compound (29), compound (30), or compound (31).
  • Inflammation Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis; Cardiovascular diseases such as coronary artery disease, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, cardiac dysrhythmias, inflammatory heart disease, endocarditis, inflammatory cardiomegaly, myocarditis, valvular heart disease, cerebrovascular disease, peripheral arterial disease, congenital heart disease, rheumatic heart disease; Diabetes; and light chain amyloidosis.
  • Cardiovascular diseases such as coronary artery disease, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, cardiac dysrhythmias, inflammatory heart disease, endocarditis, inflammatory cardiomegaly, myocarditis, valvular heart disease, cerebrovascular disease, peripheral arterial disease, congenital heart disease, rheumatic heart disease; Diabetes; and light chain amyloidosis.
  • compositions comprising compounds of
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound.
  • the salt is a pharmaceutically acceptable mono-salt of the compound.
  • the salt is a pharmaceutically acceptable di-salt of the compound.
  • the salt is a pharmaceutically acceptable mono- or multi-salt (e.g. , a di-salt or tri-sait) thereof selected from the group consisting of hydrochloride, hydrobromide, hydrogensulphate, sulfates, phosphates, fumarates, succinates, oxalates and lactates, bisulfates, hydroxy!, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate, fumarate sulfonate, methylsuifonate, formate, acetate, and carboxylate.
  • the salt is a pharmaceutically acceptable salt selected from the group consisting of p-toluene- sulfonate, benzenesulfonate, citrate, methanesulfonate, oxalate, succinate, tartrate, fumarate and maleate.
  • the salt is a pharmaceutically acceptable salt selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and/or with counter-ions such as methylamino, dimethylammo, diethylamino and triethylamino counter-ions.
  • the salt is a. di-hydrochloride salt or a di-hydrobromide salt of the compound.
  • Compound (1) has the same chemical structure that would be revealed by structural analysis (e.g. , NMR, X-ray diffraction) of compound NSC 350625, available from the National Cancer Institute's Developmental Therapeutics Program Repository.
  • structural analysis e.g. , NMR, X-ray diffraction
  • the pharmaceutical composition includes 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- salts or tri-salts) of an analog of compound (1) can be prepared from an analog of compound (1), which can be synthesized as described herein, or using standard chemical synthetic methodology known to one of ordinary skill in the art.
  • the pharmaceutical composition includes at least one pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, those found in Handbook of Pharmaceutical Excipients, 7 ' edition, edited by Raymond C, Rowe et al , American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and earlier editions.
  • Exemplary pharmaceutically acceptable earners, methods for making pharmaceutical compositions and various dosage forms, as well as modes of administration are well-known in the art, for example as detailed in Pharmaceutical Dosage Forms: Tablets, edited by Larry L. Augsburger & Stephen W. Hoag., London: Informa Healthcare, 2008; and in L. V. Alien, Jr. et al, Ansel's Pharmaceutical
  • the pharmacuetical composition is formulated for ocular administration.
  • pharmaceutical compositions are formulated for topical administration.
  • the pharmaceutical compositions are formulated as drops, ointments, or liquids.
  • pharmaceutical compositions include conventional pharmaceutical earners such as aqueous, powdery or oily bases, thickeners or the like.
  • the pharmaceutical composition is a formulation for intravenous administration.
  • the intravenous formulation comprises a compound of formula (10), or a pharmaceutically acceptable salt thereof dissolved in a solvent.
  • the solvent comprises water.
  • the intravenous formulation includes the compound or its salt in a concentration of about 0.05, about 0,25, about 0,5, about 2.5, about 5, about 25, or about 50 mg mL.
  • the intravenous formulation includes the compound or its salt in a concentration of from about 0.05, 0.5, or 5 mg/mL to about 1 , 10, or 100 mg/mL.
  • the intravenous formulation includes from about 0.005% 0.05%, or 0.5 % to about 0.1 %, 1 %, or 10 % of the compound or its salt. In one embodiment, the intravenous formulation includes about 0.05%, 0.5 %, or 5 % of the compound or its salt. In some embodiments, the intravenous formulation includes a higher or a lower concentration of the compound or its salt.
  • the intravenous formulation has 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 includes dextrose or sodium chloride. In one embodiment, the intravenous formulation including the compound or its salt in a concentration of about 5 mg/mL and pH 3 and forms a stable solution. In one embodiment, the intravenous formulation includes the compound or its salt in a concentration of about 5 mg/mL and pH ⁇ 5 and forms a stable solution. In one embodiment, the intravenous formulation includes the compound or its salt and one or more antioxidants. In one embodiment, the intravenous formulation includes a mixture of mono- and di-hydrochloride salt of the compound.
  • the intravenous formulation includes the compound or its salt as a 1 % solution in a concentration of about 10 mg/mL.
  • the intravenous formulation is a solution having a pH of about 3.3. In one embodiment, the pH is less than 4.0.
  • the pharmaceutical composition further includes a
  • a suitable pharmaceutically acceptable carrier includes an oil.
  • a suitable pharmaceutically acceptable carrier includes sterile water.
  • a suitable pharmaceutically acceptable carrier includes an aqueous carrier.
  • the intravenous formulation includes dextrose and/or sodium. [00126] In one embodiment, the intravenous formulation comprises compound (1) or an analog thereof or a di -hydrochloride salt thereof dissolved in water at 25 mg/mL. In one embodiment, the intravenous formulation is adjusted to pH 3 with phosphate buffer. In one embodiment, the intravenous formulation includes dextrose or sodium chloride.
  • the intravenous formulation includes a higher or a lower concentration of the di-h drochloride salt of compound (1) or an analog thereof. In one embodiment, the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof in a concentration of about 5 mg/mL. In one embodiment, the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof in a
  • the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof in a concentration of about 5 mg/mL and pH ⁇ 5 and forms a stable solution.
  • the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof and one or more antioxidants.
  • the intravenous formulation includes a mixture of mono- and di-hydrochloride salt of compound (1) or an analog thereof.
  • the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof as a 1 % solution in a concentration of about 10 mg/mL.
  • the intravenous formulation is a solution having a pH of about 3.3. In one embodiment, the pH is less than 4.0.
  • the intravenous formulation includes from about 0.5 % to about
  • the intravenous formulation includes from about 5 % (or about 50 mg/mL) of compound (1) or an analog thereof or a di-salt thereof.
  • the intravenous infusion rate may be slowed to decrease side effects of compound (1) or an analog thereof or a di-salt thereof,
  • the pharmaceutical composition comprises about 0.1-99% of a salt of compound (1 ) or an analog thereof; and a pharmaceutically acceptable earner, e.g., an
  • the pharmaceutical composition comprises a mono or di-salt of compound (1) or an analog thereof in a range of from about 5% to about 50% for oral dosage forms.
  • the pharmaceutical composition includes an antioxidant.
  • Suitable antioxidants include: ascorbic acid derivatives such as ascorbic acid, erythorbic acid, sodium ascorbate, thiol derivatives such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione, tocopherols, butylated hydroxyanisole (BHA), butylated liydroxytoluene (BHT), sulfurous acid salts such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate, nordihydroguaiaretic acid.
  • ascorbic acid derivatives such as ascorbic acid, erythorbic acid, sodium ascorbate
  • thiol derivatives such as thiog
  • antioxidants used for aqueous formulations typically include: sodium sulphite, sodium metabisulphite, sodium formaldehyde sulphoxylate and ascorbic acid and combinations thereof, whereas antioxidants used in oil-based solutions, organic solvents, include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and propyl galiate and combinations thereof.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • an antioxidant can be one or more of a flavanoid, an isoflavone, monothioglyceroi, L-cysteine, thioglycolic acid, a-tocopherol, ascorbic acid 6-paimitate, dihydrolipoic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, propyl galiate, ⁇ -carotene, ascorbic acid.
  • Antioxidants can typically be used in about 0.1 % to 1.0% by weight, more typically about 0,2%.
  • the pharmaceutical composition includes compound (1) or compound (10) or an analog thereof or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent.
  • the other therapeutic agent is selected from the group consisting of 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; an ti tumour antibiotics; platinum derivatives; alkylation agents; antimitotic agents; tubuline 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, CRM!
  • inhibitors e.g., KPT185
  • P53 modulators e.g., Nutlins
  • antiangiogenics e.g., axitinib, aflibercept, sorafenib, and regorafenib
  • amifostin anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin,rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer
  • 2-chlorodesoxyadenosine 2-fluorodesoxy-cytidine
  • 2-methoxyoestradiol 2-methoxyoestradiol
  • 2C4,3-alethine 131- 1-TM-601 , 3 CPA, 7-ethyl-lO-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ 10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (selumetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988,
  • BBR-3576 bevacizuroab, 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, tomtovok), BIBF 1 120
  • BI 836845 (vargatei), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin- 1 , bortezomib, brostallicin, busulphan, BYL-71 , CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCl-779, CC-1 15, CC-223, CEP-701, CEP-751, CBT-1 eefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin,
  • CH4987655/RQ-4987655 chlorotrianisene, cilengitide, ciclosporin, CDA-XX, CDC-394, CKD-602, CKl-27, clofarabin, colchicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461 , CV-247, cyanornoipholinodoxombicin, cytarabine, D 24851 , decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanei, diethylstilbesirol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-74
  • GSK-1120212 (trametinib), GSK-21 18436 (dabrafenib), GSK-2126458, GSK-2132231 A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A 12 (cixutumumab), Immunol, indisulam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, I K-l 1 17, TNK-128, TNSM-18, ionafarnib,
  • isohomohalichondrin-B isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651 , lurtotecan, LY-S6AKT1 , LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK- 162, methyltestosteron, methylprednisolone, MEDI-573, MEN- 10755, MDX-H210, MDX-447, MDX-1379, MGV,
  • PI3K/mTOR inhibitors PG-TXL, PG2, PLX-4032/RO-5185426 (vemurafenib),
  • pivaloyloxymethylbutyrate pixantrone, phenoxodiol O, PKI166, plevitrexed, plicamyein, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, qumupristin, Rl 15777, RAF-265, ramosetron, ranpimase, RDEA-119/BAY 869766, RDEA-436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, regorafenib, revirnid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb, rinfabate, risedronate,rituximab, robatumumab, rofecoxib, RO-31 -7453, RO-5126766, RO-5068760, RPR
  • the other therapeutic agent comprises a hormone analog, an antihornione 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, medroxy-progesterone, octreotide, and combinations thereof.
  • a hormone analog selected from the group consisting of tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medr
  • the other therapeutic agent comprises one or more LHRH agonists and/or antagonists selected from the group consisting of goserelin acetate, iuproiide acetate, triptorelin pamoate and combinations thereof and wherein the LHRH antagonists are selected from the group consisting of Degarelix, Cetrorelix, Abarelix, Ozarelix, Degarelix combinations thereof.
  • 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), insuline-like growth factors (IGF), human epidermal growt factor (HER) and hepatocyte growth factor (HGF).
  • the other therapeutic agent comprises one or more inhibitors of the human epidermal growth factor selected from the group consisting of HER2, HER3, and HER4.
  • 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.
  • 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.
  • the other therapeutic agent comprises one or more antimetabolites which are antifolates selected from the group consisting of methotrexate, raititrexed, and pyrimidine analogs.
  • the other therapeutic agent comprises one or more antimetabolites which are pyrimidine analogs selected from the group consisting of 5-fluorouracil, capecitabin and gemcitabin.
  • the other therapeutic agent comprises one or more antimetabolites which are purine and/or adenosine analogs selected from the group consisting of mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine, and combinations thereof.
  • the other therapeutic agent comprises one or more antitumour antibiotics selected from the group consisting of anthraeyclins, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin and combinations thereof.
  • the other therapeutic agent comprises one or more platinum derivatives selected from the group consisting of cisplatin, oxalipiatin, carboplatin and combinations thereof.
  • the other therapeutic agent comprises one or more alkylation agents selected from the group consisting of estramustin, meclorethamine, melphaian, chlorambucil, busulphan, dacarbazin,
  • the other therapeutic agent comprises nitrosoureas selected from the group consisting of carmustin, lomustin, thiotepa, and combinations thereof.
  • the other therapeutic agent comprises antimitotic agents selected from the group consisting of Vinea alkaloids and taxanes.
  • the other therapeutic agent comprises one or more taxanes selected from the group consisting of paclitaxel, docetaxel, and combinations thereof.
  • the other therapeutic agent comprises one or more Vinca alkaloids selected from the group consisting of vinblastine, vindesin, vinorelbin, vincristine, and combinations thereof.
  • the other therapeutic agent comprises one or more topoisomerase inhibitors which are epipodophyllotoxins.
  • the other therapeutic agent comprises one or more epipodophyllotoxins selected from the group consisting of etoposide and etopophos, tenyposide, amsacrin, topotecan, irinotecan, mitoxantron, and combinations thereof.
  • the other therapeutic agent comprises one or more serine/threonine kinase inhibitors selected from the group consisting of PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mXORC l inhibitors, PBK inhibitors, dual niTOR/PB inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors, and combinations thereof.
  • the other therapeutic agent comprises one or more tyrosine kinase inhibitors which are PT 2/FAK inhibitors.
  • the other therapeutic agent comprises one or more protein protein interaction inhibitors selected from the group consisting of IAP, Mcl-1 ,
  • the other therapeutic agent comprises one or more rapamycin analogs selected from the group consisting of everolimus, temsirolimus, ridaforolimus, sirolimus, and combinations thereof.
  • the other therapeutic agent comprises one or more therapeutic agents selected from the group consisting of amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin,rituximab, procarbazine, levamisole, rnesna, rnitotane, pamidronate and porfimer, and combinations thereof.
  • the other therapeutic agent comprises one or more therapeutic agents selected from the group consisting of 2-chlorodesoxyadenosine, 2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine, 131 -1-TM-601, 3CPA, 7-ethyl- 10-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, A VLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 4381
  • earboxyphthalatoplatin CCl-779, CC-1 15, CC-223, CEP-701 , CEP-751 , CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RQ-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-XI, CDC-394, CKD-602, CKI-27, clofarabin, coichicin, com retastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247,
  • FOLFOX4, FOLFXRL formestane, fotemustine, galarubicin, gallium maltolate, gefinitib, 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, gplOO-peptide vaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametmib), GSK-21 18436 (dabrafe ib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid,
  • 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, perillylaieohol, pertuzumab, PI3K inhibitors, PDK/mTOR inhibitors, PG-TXL, PG2, PLX-4032/RO-51 85426 (vemurafenib), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKI166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed
  • tremelimumab tretinoin
  • triacetyluridine triapine
  • triciribine trimetrexate
  • TLK-286TXD 258, tykerb/tyverb urocidin
  • valrubicin vatalanib
  • vincristine vmflunme
  • virulizin WX-UKl , WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281 , XL-518/R-7420/GDC-0973, XL-765, YM-51 , YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331 , ZD 1839, ZSTK-474, zoledronat, zosuquidar, and combinations thereof.
  • the other therapeutic agent comprises a steroid.
  • Steroids include, but are not limited to, dexamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazol.
  • the other therapeutic agent comprises an anti-emetic.
  • Anti-emetics include, but are not limited to, 5-HT3 receptor agonists (e.g. , dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine), dopamine agonists (e.g.
  • NK1 receptor antagonists e.g. , aprepitant and casopitant
  • antihistamines such as cyclizine, diphenhydramine, dinienhydrinate, doxylamine, meclizine, promethazine, hydroxyzine
  • cannabinoids e.g., cannabis, dronabinol, nabilone, and sativex
  • benzodiazepines e.g.
  • anticholinergics e.g., hyoscine
  • trimethobenzamide ginger, emetrol, propofol, peppermint, muscimol, and ajwain.
  • the other therapeutic agent comprises an anti-cancer agent, which includes a mitotic inhibitor.
  • the mitotic inhibitor includes a taxane.
  • the mitotic inhibitor includes a taxane selected from the group consisting of paclitaxel and docetaxel.
  • the pharmaceutical composition includes compound (1) or compound (10) or an analog thereof!, or a pharmaceutically acceptable salt thereof; and at least one anti-cancer agent, which includes, without limitation, one or more of acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, ailopurmol, altretamine, ambomycin, ametantrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperiin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bevacizumab, bicalutamide, bisantrene, bisnafide dimesylate, bizelesin, bleomycin, brequinar, bropirimine, busulfan,
  • anti-cancer agent which
  • Suitable anti-cancer agents include, but are not limited to, those described Goodman and Oilman's The Pharmacological Basis of Therapeutics, 12 th Ed., edited by Laurence Brunton, Brace Chabner, Bjorn KnoUman, McGraw Hill Professional, 2010.
  • the pharmaceutical composition includes 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.
  • the anti-angiogenic agent is bevacizumab.
  • the anti-angiogenic agent is selected from the group consisting of aflibercept, axitinib, angiostatin, endostatin, 16kDa prolactin fragment, laminin peptides, fibronectin peptides, tissue metalloproteinase inhibitors (TIMP 1 , 2, 3, 4), plasminogen activator inhibitors (PAI-1 , -2), tumor necrosis factor a, (high dose, invitro), TGF- ⁇ , interferons (IFN- , - ⁇ , ⁇ ), ELR-CXC chemokines, IL-12; SDF-1; MIG; platelet factor 4 (PF-4); IP- 10, thrombospondin (TSP), SPARC, 2-methoxyoestradiol, proliferin-related protein, suramin, sorafenib, regorafenib, thalidomide, cortisone, linomide, fumagillin (AGM-1470;
  • a pharmaceutical combination can include first and second therapeutic agents in any desired proportions provided that the synergistic or cooperative effect still occurs.
  • the synergistic pharmaceutical combination preferably contains the first and second therapeutic agents in a ratio of from about 1 :9 to about 9: 1.
  • the synergistic pharmaceutical combination pontains the first and second therapeutic agents in a ratio of from about 1 :8 to about 8: 1 , from about 1 :7 to about 7: 1 , from about 1 :6 to about 6: 1 , from, about 1 :5 to about 5: 1 , from about 1 :4 to about 4: 1, from about 1 :3 to about 3: 1 , or from about 1 :2 to about 2: 1.
  • the synergistic pharmaceutical combination contains the first and second therapeutic agents in a ratio of approximately 1 : 1.
  • the second therapeutic agent is selected from the group consisting of Allopurinol, Arsenic Trioxide, Azacitidine, Bortezomib, Bevacizumab, Capecitabine, Carboplatm, Celecoxib, Chlorambucil, Ciofarabine, Cytarabine, dacarbazine, Daunorubicin HC1, Docetaxel, Doxorubicin HC1, Floxuridine, Gemcitabine HC1, Hydroxyurea, Ifosfamide, Imatinib Mesylate, Ixabepilone, Lenalidomide, Megestrol acetate, Methotrexate, Mitotane, Mitoxantrone HCi, Oxaliplatin, Paclitaxel, Pralatrexate, Romidepsin, Sorafersib, Streptozocra, Tamoxifen Citrate, Topotecan HCI, Tretinoin, Vandetanib,
  • the second therapeutic agent comprises a small molecule multi-kinase inhibitor, e.g., sorafenib or regorafenib.
  • the second therapeutic agent comprises a Hedgehog Pathway Inhibitor, e.g., vismodegib.
  • the second therapeutic agent includes drugs selected from Table 2 below.
  • Proteasome inhibitors bortezomib, carfiizomib, cediranib, disulfiram,
  • epigallocatechin-3-gallate salinosporamide A, ONCX 0912, CEP-18770, MLN9708, epoxomicin, and MG132.
  • Platinum-based antineoplastic cisplatin carboplatin, oxaliplatm, satraplatin, picoplatin, drugs nedapiatin, and triplatin.
  • COX-2 inhibitors celecoxib, valdecoxib (Bextra), parecoxib (Dynastat), iimiiracoxib, etoricoxib, and rofecoxib.
  • Doxorubicin (Adriamycin), Doxorubicin (liposomal), Epirubicin, Idarubicin, Valrubicin, and Mitoxantrone.
  • Taxanes Paclitaxel (Taxol), Docetaxel (Taxotere), and
  • Bcr-abl inhibitors imatinib, nilotinib, dasatinib, bosutinib and ponatinib.
  • arsenic trioxide thalidomide, revlimid, and mitotane.
  • Topoisomerase inhibitor amsacrine, etoposide, etoposide phosphate, teniposide, doxorubicin, Topotecan (Hycamtin), Iriiiotecan (CPT- 11 , Camptosar), Exatecan, Lurtotecan, ST 1481, CKD 602, ICRF-193, and genistein.
  • HDAC inhibitors Vorinostat (SAHA), Romidepsin (Istodax), Panobinostat
  • Multi-kinase inhibitors sorafenib, regorafenib, and vandetanib are Multi-kinase inhibitors sorafenib, regorafenib, and vandetanib.
  • Hedgehog signaling Inhibitors vismodegib, BMS-833923, IPI-926, LDE-225,
  • pembrolizumab MK3475
  • BGB-A317 BGB-A317
  • AMP-224 PDR001
  • REGN 281 Atezoiizumab (MPDL3280A)
  • Pidilizumab BMS-936559, CT-01 1, ONO-4538
  • Avelumab MSB0010718 C
  • Yervoy ipilimumab
  • BCL2 Inhibitors AT- 101 Bcl-2/xL inhibitor, Navitoclax (ABT-263),
  • Venetociax (ABT-199), Apogossypol, PTN1258, obatoclax, G3139
  • the second therapeutic agent includes drugs that target tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors.
  • the second therapeutic agent includes a recombinant TRAIL or an agonistic antibody that activates one or more TRA I L receptors.
  • the second therapeutic agent includes one or more antibodies or recombinant TRAIL that activate signaling by DR4, DR5 or both.
  • the second therapeutic agent includes one or more of AMG-655, LBY-135, mapatumumab, lexatumumab, Apomab, and rhApo2L/TRAIL.
  • the second therapeutic agent includes an active agent selected from the group consisting of Carnptothecin, 5-FU, capecitabine, cisplatin, doxorubicin, irinotecan, paclitaxel, cisplatin, bortezomib, BH3I-2, rituximab, radiation, triterpenoids, sorafenib, gemcitabine, HDAC inhibitors, carboplatin, T- 101 (a gossypol derivate), ABT-263, ABT-737, and GX- 15-070 (obatoclax), vorinostat, cetuxirnab, panitumumab, bevacizumab, ganitumab, interferon gamma, sorafenib, XIAP antagonists, Bcl-2 antagonists, and Smac mimetics.
  • an active agent selected from the group consisting of Carnptothecin, 5-FU, capecitabine, c
  • a 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 where the weight can be based on the compound in its free base form.
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 50 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800,
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 40 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; from about 4 mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 1 80, 190, or 200 mg; or from about 0.4 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, and 20 mg.
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 60 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 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, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about 0.6 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg.
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 100 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 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, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about ! mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg.
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging 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, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or 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, based on the compound in its free base form.
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose 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, 1 10, 120, 130, 140, 150, 160, 170, 1 80, 190, or 200 mg; or from about 4 mg to about 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg based on the compound in its free base form.
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof th ereof in a dose level ranging 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 mg 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 10 mg; from about 9 mg to about 10 mg; from about 0.5 mg to about 0.6, 0.7, 0.
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose ranging from about 1 mg kg to about 40 mg/kg; 0.1 mg/kg to about 4 mg/kg; or 0.0! mg/kg to about 0.40 mg/kg.
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging 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, 1 1 , 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; from about 30, 31 , 32, 33, 34, 35, 36, 37, 38, or 39 mg/kg to about 40 mg/kg; from 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; from about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,
  • a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 37.5 mg/m " to about 1500 mg/m 2 ; from about 3.75 mg/m 2 to about 150 mg/m 2 ; or from about 0.4 mg/m 2 to about 15 mg/m 2
  • a pharmaceutical composition comprises comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 1 15, 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
  • Suitable pharmaceutical compositions for use with the methods described herein can be formulated into a dosage form that can be administered to a patient.
  • the pharmaceutical composition is in the form of an oral dosage unit or parenteral dosage unit.
  • the pharmaceutical composition is in the form of an oral dosage unit.
  • an oral dosage unit is fractionated into several, smaller doses, which are administered to a subject over a predetermined period of time in order to reduce toxicity of the therapeutic agent being administered.
  • an oral dosage unit is administered by a tablet or capsule comprising a controlled release formulation that can include a plurality of particles, granules, pellets, minitablets or tablets.
  • the pharmaceutical composition is in the form of a parenteral dosage unit.
  • the pharmaceutical composition is in the form of a parenteral dosage unit selected from the group consisting of intravenous (IV), subcutaneous (SC), and intramuscular (M), rectal (PR) and transdermal dosage units.
  • the pharmaceutical composition is in a dosage form selected from the group consisting of sterile solutions, suspensions, suppositories, tablets and capsules.
  • the composition is an oral dosage form selected from the group consisting of a tablet, caplet, capsule, lozenge, syrup, liquid, suspension and elixir.
  • the composition is in an oral dosage form selected from the group consisting of tablets, hard shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids and semi-solids.
  • suitable forms of pharmaceutical compositions for use in the methods described herein include dermatological compositions adapted for cutaneous topical administration.
  • dermatological compositions include a cosmetically or pharmaceutically acceptable medium.
  • the dermatological compositions for topical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, skin enhancers and the like can be necessary or desirable and therefore can be used.
  • Suitable enhancers include, but are not limited to, ethers such as diethylene glycol monoethyl ether (available commercially as TRANSCUTOL®) and di ethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231 , 182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Patent No.
  • ethers such as diethylene glycol monoethyl ether (available commercially as TRANSCUTOL®) and di ethylene glycol monomethyl ether
  • surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231 , 182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Patent No.
  • alcohols such as ethanol, propanol, octanoi, benzyl alcohol, and the like
  • polyethylene glycol and esters thereof such as polyethylene glycol monolaurate
  • amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylforniamide (DMF), 2-pyrrolidone,
  • 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.
  • the pharmaceutical composition is in a dosage form selected from the group consisting of sustained release forms, controlled release forms, delayed release forms and response release forms. VIII. METHODS OF USE
  • compositions and methods described herein have utility in treating many disease conditions, including cancer (e.g., colorectal, brain, and glioblastoma).
  • cancer e.g., colorectal, brain, and glioblastoma
  • the compositions and methods described herein are used to treat diseases such as ocular melanoma, desmoplastic round cell tumor, chondrosarcoma, leptomengial disease, diffuse large B-cell lymphoma, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, AIDS-Related Lymphoma, Anal or Rectal Cancer, Appendix Cancer, Astrocytomas, and Atypical Teratoid Rhabdoid Tumor.
  • diseases such as ocular melanoma, desmoplastic round cell tumor, chondrosarcoma, leptomengial disease, diffuse large B-cell lymphoma
  • compositions and methods described herein 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 Cance, Bronchial Tumors, Burkitt Lymphoma, and Spinal Cord Tumors.
  • 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 Cance, Bronchial Tumors, Burkitt Lymphoma, and Spinal Cord Tumors.
  • compositions and methods described herein are used to treat diseases such as Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Leptomeningeal Disease, Central Nervous System Embryonal Tumors, Central Nervous System Lymphoma, 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, Sezary syndrome and mycosis fungoides (MF)).
  • compositions and methods described herein are used to treat cdiseases such as Embryonal Tumors of Central Nervous System, Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, and Eye Cancer.
  • cdiseases such as Embryonal Tumors of Central Nervous System, Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, and Eye Cancer.
  • the compositions and methods described herein are used to treat diseases such as Gallbladder Cancer, Gastric (Stomach) Cancer,
  • compositions and methods described herein are used to treat a cancer selected from the group consisting of Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Hodgkin Lymphoma, and Hypopharyngeal Cancer.
  • compositions and methods described herein are used to treat cdiseases such as Kaposi Sarcoma, and Kidney (Renal Cell) Cancer.
  • compositions and methods described herein are used to treat diseases such as Langerhans Cell Histiocytosis, Laryngeal Cancer, Lip and Oral Cavity- Cancer, Liver Cancer, Lung Cancer, Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma.
  • diseases such as Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Metastatic
  • compositions and methods described herein are used to treat cancer.
  • compositions and methods described herein are used to treat diseases such as Nasal Cavity and Paranasal Sinus Cancer,
  • compositions and methods described herein are used to treat diseases such as Oral 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.
  • the compositions and methods described herein are used to treat diseases such as Pancreatic Cancer, Papillomatosis, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pineal
  • compositions and methods described herein are used to treat a cancer selected from the group consisting of Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15,
  • compositions and methods described herein are used to treat high grade prostate cancer. In one embodiment, the compositions and methods described herein are used to treat medium grade prostate cancer. In one embodiment, the compositions and methods described herein are used to treat low grade prostate cancer. In one embodiment, the compositions and methods described herein are used to treat castration-resistant prostate cancer.
  • ONC20.1 compound (1)
  • These features allows ONC 201 and various analogs to be particularly well suited for pediatric patients.
  • These features also make ONC 201 and various analogs particularly well suited for chronic therapy, for high risk patients, and to ensure long-lasting responses or stable disease or to prevent disease recurrence.
  • compositions and methods described herein are used to treat a pediatric cancer (e.g. , pediatric solid tumors, pediatric sarcomas, pediatric Ewing's sarcomas, pediatric gliomas, pediatric central nervous system cancers, pediatric neuroblastoma pediatric leukemia and pediatric lymphoma).
  • a pediatric cancer e.g. , pediatric solid tumors, pediatric sarcomas, pediatric Ewing's sarcomas, pediatric gliomas, pediatric central nervous system cancers, pediatric neuroblastoma pediatric leukemia and pediatric lymphoma.
  • compositions and methods described herein are used to treat a proliferative skin disorder such as psoriasis.
  • a proliferative skin disorder such as psoriasis.
  • the compositions and methods described herein are used to treat a cancer selected from the group consisting of Salivary Gland Cancer, Sarcoma, Sezary Syndrome, Skin Cancer, Ocular Cancer, Skin Carcinoma, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinom,
  • compositions and methods described herein are used to treat a cancer selected from the group consisting of T-Ceil Lymphoma, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, and Gestational Trophoblastic Tumor.
  • compositions and methods described herein are used to treat a cancer selected from the group consisting of Carcinoma of Unknown Primary Site, Cancer of Unknown Primary Site, Unusual Cancers of Childhood, Transitional Cell Cancer of the Renal Pelvis and Ureter, Urethral Cancer, and Uterine Sarcoma.
  • the compositions and methods described herein are used to treat cancer selected from the group consisting of Vaginal Cancer and Vulvar Cancer.
  • the compositions and methods described herein are used to treat a cancer selected from the group consisting of Wilms Tumor and Women's Cancers.
  • the compositions and methods described herein are used as a first-line therapy (sometimes called primary therapy). In some embodiments, the compositions and methods described herein are used as a second-line therapy. In some embodiments, the compositions and methods described herein are used as a third-line therapy. In some embodiments, the compositions and methods described herein are used as a salvage therapy.
  • the term "salvage therapy" as used herein means a therapeutic agent that can be taken with any regimen after a subject's initial treatment regimen has failed or after the subject's condition has not responded to an initial treatment. In some embodiments, the compositions and methods described herein are used as a rescue therapy.
  • the compositions are used as a rescue agent to counteract the action of an initial treatment.
  • the compositions are used as rescue agent which is administered to a subject who has developed resistance to a standard or an initial treatment.
  • the compositions and methods described herein are used as a neoadjuvant therapy.
  • the neoadjuvant therapy comprises administration of one or more of the therapeutic agents described herein to a subject before a main or first line treatment.
  • the neoadjuvant therapy reduces the size or extent of the cancer being treated before a main or first line treatment is administered to the subject undergoing treament.
  • compositions and methods described herein are used as an adjuvant therapy.
  • the adjuvant therapy comprises administration of one or more therapeutic agents described herein to a subject, wherein the one or more therapeutic agent that modif the effect of other therapeutic agents that are already administered to the subject or are concurrently administered to the subject or subsequently administered to the subject,
  • compositions and methods described herein exhibit reduced chance of drug-drag interactions.
  • compound (1) or compound (10) or an analog thereof are eliminated from the patient's body before it can interact with another pharmaceutically active agent.
  • compositions and methods of described herein exhibit toxicity levels that facilitates combinations with other pharamaceutical agents.
  • a subject treated according to methods and using compositions described herein can be mammalian or non-mammalian.
  • a mammalian subject mammal includes, but is not limited to, a human; a non-human primate; a rodent such as a mouse, rat, or guinea pig; a domesticated pet such as a cat or dog; a horse, cow, pig, sheep, goat, or rabbit.
  • a non-mammalian subject includes, but is not limited to, a bird such as a duck, goose, chicken, or turkey.
  • the subject is a human.
  • subjects can be either gender and any age.
  • the composition and methods can also be used to prevent cancer.
  • the composition and methods can also be used to stimulate the immune system.
  • compositions described herein are not limited to a particular age of the subject.
  • a subject treated according to methods and using compositions described herein can be over the age of 50 years, over the age of 55 years, over the age of 60 years, or over the age of 65 years.
  • a subject treated according to methods and using compositions described herein can be under the age of 50 years, under the age of 55 years, under the age of 60 years, or under the age of 65 years.
  • a subject treated according to methods and using compositions described herein can be a pediatric patient.
  • the pediatric patient ct 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, wherein is 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.
  • the pediatric patient is younger than 12 months old, younger than 1 1 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, is 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 younger than
  • the pediatric patient is younger than 7 days old, younger than 6 days old, younger than 5 days old, younger than 4 days old, younger than 3 days old, younger than 2 days old, or younger than 1 day old.
  • the pediatric patient is a neonate. In one embodiment, the pediatric patient is prematurely born. In one embodiment, the pediatric patient is a neonate.
  • the patient is less than 45 kg in weight, less than 40 kg in weight, less than 35 kg in weight, less than 30 kg in weight, less than 25 kg in weight, less than 20 kg in weight, less than 15 kg in weight, less than 14 kg in weight, less than 10 kg in weight, less than
  • 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.
  • the prior therapeutic agent is ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, cytarabine, cispiatin, rituximab, 5-fluorouracil, oxaliplatin, leucovorin, or lenalidomide,
  • the subject has been treated with radiation. In one embodiment, the subject has been treated with surgery. In one embodiment, the subject has been treated with adoptive T-cell therapy.
  • the cancer no longer responds to treatment with ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide,
  • the compositions and methods described herein have a dose response relation in cancer cells that is different from the dose response relation of the same compositions and methods in normal cells.
  • Figure 1 illustrates the dose response relation of compound (1) on proliferation and cell death in normal and tumor cells.
  • Figure 1 shows cell viability following treatment with compound (1) at indicated concentrations for 72 hours.
  • the tumors tested included a human colon cancer cell line (HCTl 16), breast tumor cell line (MDA-MB-231), and a human primary glioblastoma cell line (U87).
  • normal cells tested included human foreskin fibroblasts ⁇ I I FF ;, human fetal lung fibroblast (MRC-5) cells, and a human lung fibroblast cell line (WI-38), Doxorubicin was used as a positive control at 1 Ltg/mL in normal fibroblasts.
  • cell viability of normal cells tested is at least about 75% at about 1 -5 mg/niL concentration of compound (1), whereas viability of tumor cells is significantly lower (e.g., at or below 50%) at the same concentration of compound (1).
  • concentration of compound (1) increases beyond about 5 mg/niL viability of tumor cells falls to below 25%, whereas viability of normal cells remains at about 75%.
  • Figure 2 illustrates cell viability assays in human fetal lung fibroblast (MRC-5) cells following 72 hour treatment with compound (1 ) (5 ⁇ ) or DMSO and the indicated recovery- period in complete drug-free media after treatment. The time points are given as time following removal of compound (1) after 72 hour treatment. As shown in Figure 2, cell recovery was seen with compound (1), but not with DMSO.
  • compositions and methods described herein have utility in treating cancer in a subject.
  • compositions and methods described herein have utility in treating cancer in a human subject.
  • the treatment method comprises administering to a subject in need of such treatment, a pharmaceutically effective amount of compound (1 ) or compound (10) or an analog thereof, or a
  • the treatment method comprises administering to a subject in need of such treatment: (i) a first therapeutic agent including compound (1 ) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in combination with (ii) a second therapeutic agent, wherein the first and the second therapeutic agents are administered either simultaneously or sequentially.
  • the second therapeutic agent can be any suitable therapeutic agent, including any pharmaceutically active agent disclosed herein.
  • pharmaceutically acceptable salt of compound (1) includes the di-hydrochloride salt below:
  • the treatment method comprises administering a synergistic pharmaceutical combination, either simultaneously or sequentially, to a subject in need of such treatment, wherein 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.
  • the treatment method comprises administering to a subject in need of such treatment, either simultaneously or sequentially, therapeutically synergistic effective amounts of the first therapeutic agent in combination with the second therapeutic agent.
  • the treatment method 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, wherein the combination provides a synergistic effect in the in vivo treatment of a cancer sensitive to the combination, and wherein the first and the second therapeutic agents are administered either simultaneously or sequentially.
  • the treatment method 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 a second therapeutic agent, wherein the combination provides a synergistic effect in the in vivo treatment of a minimal residual disease sensitive to the combination, and wherein the first and second therapeutic agents are administered either simultaneously or sequentially.
  • the second therapeutic agent can be given before or prior to the first therapeutic agent.
  • the treatment method targets a cancer selected from the group consisting of solid tumors, liquid tumors, lymphomas, leukemias, or myelomas.
  • the treatment method targets a solid tumor, wherein the solid tumor is selected from the group consisting of: Cervical Cancer, Endometrial Cancer, Extracranial Germ Cell Tumor; Extragonadal Germ Cell Tumor; Germ Cell Tumor;
  • Gestational Trophoblastic Tumor Ovarian Cancer, Ovarian Germ Cell Tumor, Ovarian Epithelial Cancer, and Ovarian Low Malignant Potential Tumor; Penile Cancer, Prostate Cancer; Pregnancy and Breast Cancer; high grade prostate cancer; medium grade prostate cancer; low grade prostate cancer; castration-resistant prostate cancer; Breast Cancer; Bile Duct Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; 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, Melanoma, Merkel Cell Carcinoma, Papillomatosis, Multiple Endocrine Neoplasia Syndrome; Pancreatic Cancer, Parathyroid Cancer, ocular melanoma; Eye Cancer; Retinoblastoma;
  • Tumor Craniopharyngioma, Glioma, Brain cancer, Medullobiastoma, Medulloepithelioma, Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor (GIST), Bladder Cancer, Anal or Rectal Cancer, Appendix Cancer, Esophageal Cancer, Hypopharyngeal Cancer; Laryngeal Cancer, Lip and Oral Cavity Cancer, Metastatic Squamous Neck Cancer with Occult Primary, Mouth Cancer, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Oral Cancer, Lip and Oral Cavity Cancer, Oropharyngeal Cancer, Paranasal Sinus and Nasal Cavity Cancer, Pharyngeal Cancer; Head and Neck Cancer, and Mesothelioma.
  • the treatment method targets a lymphoma selected from the group consisting of: diffuse large B-cell lymphoma, AIDS-Reiated Lymphoma, Cutaneous T-Cell Lymphoma, Sezary syndrome, mycosis fungoides (MF); Histiocytosis; Burkitt Lymphoma, and Central Nervous System Lymphoma; Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma, Hodgkin Lymphoma, Waldenstrom's
  • lymphoplasmacytic lymphoma and Primary Central Nervous System Lymphoma.
  • 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, lyphoplasmacytic NHL, Waldenstrom's macroglobulinaemia, and skin lymphomas.
  • NHL Non-Hodgkin' s lymphoma
  • the treatment method targets a leukemia selected from the group consisting of: Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloproliferative Disorders; Hairy Cell Leukemia; Acute Myeloid Leukemia (AML); Chronic Myelogenous Leukemia (CML); and Langerhans Ceil Histiocytosis.
  • ALL Acute Lymphoblastic Leukemia
  • CLL Chronic Lymphocytic Leukemia
  • Chronic Myeloproliferative Disorders Chronic Hairy Cell Leukemia
  • AML Acute Myeloid Leukemia
  • CML Chronic Myelogenous Leukemia
  • Langerhans Ceil Histiocytosis Langerhans Ceil Histiocytosis
  • the treatment method targets an acute leukemia selected from the group consisting of: acute lymphotyte leukemia, acute myeloid leukemia, chronic
  • lymphoblastic leukemia chronic myeloid leukemia, myelodysplastic syndrome, and myeloproliferative disease.
  • the treatment 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 Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, and Myeloproliferative Disorders.
  • 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
  • the treatment method targets a cancer selected from the group consisting of: Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, AIDS-Reiated Lymphoma, Anal or Rectal Cancer, Appendix Cancer, Astrocytomas, and Atypical Teratoid/Rhabdoid Tumor.
  • a cancer selected from the group consisting of: Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, AIDS-Reiated Lymphoma, Anal or Rectal Cancer, Appendix Cancer, Astrocytomas, and Atypical Teratoid/Rhabdoid Tumor.
  • the treatment method targets a cancer selected from the group consisting of: 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 Cance, Bronchial Tumors, Burkitt Lymphoma, and Spinal Cord Tumors.
  • a cancer selected from the group consisting of: 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 Cance, Bronchial Tumors, Burkitt Lymphoma, and Spinal Cord Tumors.
  • the treatment method targets a cancer selected from the group consisting of: Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Atypical Teratoid Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Central Nervous System Lymphoma, 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, Sezary syndrome and mycosis fungoides).
  • a cancer selected from the group consisting of: Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Atypical Teratoid Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Central Nervous System Lymphoma, Cervical Cancer, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelog
  • the treatment method targets a cancer selected from the group consisting of: Embryonal Tumors of Central Nervous System, Endometrial Cancer,
  • Ependymoblastoma Ependymoma, Esophageal Cancer, Ewing Sarcoma Family of Tumors, Desmoplastic Round Cell Tumor, Chondrosarcoma, Extracranial Germ Cell Tumor,
  • Extragonadal Germ Cell Tumor Extrahepatic Bile Duct Cancer, and Eye Cancer, including Intraocular Melanoma and Retinoblastoma.
  • the treatment 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.
  • 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.
  • the treatment method targets a cancer selected from the group consisting of: Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Hodgkin Lymphoma, and Hypopharyngeal Cancer.
  • a cancer selected from the group consisting of: Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Hodgkin Lymphoma, and Hypopharyngeal Cancer.
  • the treatment method targets a cancer selected from the group consisting of Kaposi Sarcoma and Kidney (Renal Cell) Cancer.
  • the treatment method 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 Cance, Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma.
  • 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 Cance, Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma.
  • the treatment method targets a cancer selected from the group consisting of: Waldenstrom's maeroglobulinemia (lymphoplasmacytic lymphoma), Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Multiple Endocrine Neoplasia Syndrome, Mouth Cancer, Multiple
  • Myeloma/Plasma Cell Neoplasm Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Multiple Myeloma, and Myeloproliferative
  • the treatment method is useful for treating a cancer selected from the group consisting of: Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, and Neuroblastoma.
  • the treatment method is useful for treating a cancer selected from the group consisting of: Oral 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.
  • a cancer selected from the group consisting of: Oral 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.
  • the treatment method is useful for treating a cancer selected from the group consisting of: Pancreatic Cancer, Papillomatosis, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Pleuropulmonary Blastema, Pregnancy and Breast Cancer, Primary Central Nervous System Lymphoma, and Prostate Cancer.
  • a cancer selected from the group consisting of: Pancreatic Cancer, Papillomatosis, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Pleuropulmonary Blastema, Pregnancy and Breast Cancer
  • the treatment method is useful for treating a cancer selected from the group consisting of Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma, and Rhabdomyosarcoma.
  • the treatment method is useful for treating a cancer selected from the group consisting of: Salivary Gland Cancer, Sarcoma, Sezary Syndrome, Skin Cancer, Skin Carcinoma, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinom, Squamous Neck Cancer with Occult Primary, and Supratentorial Primitive Neuroectodermal Tumors.
  • a cancer selected from the group consisting of: Salivary Gland Cancer, Sarcoma, Sezary Syndrome, Skin Cancer, Skin Carcinoma, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinom, Squamous Neck Cancer with Occult Primary, and Supratentorial Primitive Neuroectodermal Tumors.
  • the treatment method 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 Cancer of the Renal Pelvis and Ureter, and Gestational Trophoblastic Tumor.
  • a cancer selected from the group consisting of: T-Cell Lymphoma, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, and Gestational Trophoblastic Tumor.
  • the treatment method is useful for treating a cancer selected from the group consisting of: Carcinoma of Unknown Primary Site, Cancer of Unknown Primary Site, Unusual Cancers of Childhood, Transitional Cell Cancer Of the Renal Pelvis and Ureter, Urethral Cancer, and Uterine Sarcoma.
  • the treatment method is useful for treating a cancer selected from the group consisting of: Vaginal Cancer and Vulvar Cancer.
  • the treatment method is useful for treating a cancer selected from the group consisting of: Wilms Tumor and Women's Cancers.
  • treatment of cancer comprises prevention of tumor growth in a cancer subject. In some embodiments, treatment of cancer comprises prevention of formation of cancer metastases in a cancer subject. In some embodiments, treatment of cancer comprises targeted treatment of minimal residual disease in a cancer subject known to have the minimal residual disease in a cancer or a subject at risk for having minimal residual disease,
  • minimal residual disease denotes a small number of cancer cells that remain in a subject during treatment or after treatment when the subject is in remission (exhibiting no symptoms or signs of the disease).
  • the methods described herein are preterably applied to a form of the diseases listed herein, including adult and childhood forms of these diseases.
  • the treatment method is useful for treating an autoimmune disease.
  • Autoimmune diseases include, but are not limited to alopecia areata, antiphospholipid, autoimmune hepatits, celiac disease, diabetes type 1, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, inflammatory myopathies, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, and vitiligo.
  • the treatment method is useful for treating autoimmune and inflammatory disorders of the peripheral nerve system such as amyotrophic lateral sclerosis (Lou Gehrig's disease), based on various causes such as metabolic disorders that include diabetes, B12 and folate vitamin deficiencies, chemotherapy medications and medicines used to treat HIV, poisons that cause peripheral nerve damage, cancers that develop peripheral neuropathies as well as paraneoplastic syndromes, alcohol abuse, chronic kidney disease, injuries that cause compression on nerves and other lesions, infections such as Lyme disease, Guillain Barre syndrome, connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, certain inflammatory conditions such as sarcoidosis, coeliac disease, hereditary diseases such as Charcot marie tooth syndrome, Friedreich's ataxia, and/or idiopathic where no specific cause is found but inflammatory and/or autoimmune mechanisms are the cause of onset.
  • diseases such as sarcoidosis, coeliac disease, heredit
  • the treatment method is useful for treating autoimmune and inflammatory disorders with ocular manifestations.
  • ocular manifestations 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, Behcet'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 ulceration, and less common entities such as choroiditis, retinal vasculitis, episcle
  • the treatment method is useful for treating acute allograft rejection in transplant patients.
  • the treatment method is useful for treating ischemic stroke.
  • the treatment method is useful for treating inflammatory diseases including, but not limited to, arthritis, psoriasis, asthma, and colitis.
  • a therapeutic agent includes a pharmaceutically acceptable mono-salt of compound (1) or an analog thereof (e.g., a compound of formula (10)).
  • a therapeutic agent includes a pharmaceutically acceptable di-salt of compound (1) or an analog thereof (e.g. , a compound of formula (10)).
  • some of the analogs can be tri-salts
  • a therapeutic agent includes compound (1) or an analog thereof (e.g.
  • a therapeutic agent includes compound (1) or an analog thereof in the form of a pharmaceutically acceptable mono- or di-salt selected from p-toluene-sulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate and maieate.
  • a therapeutic agent includes compound (1) or an analog thereof in the form of a pharmaceutically acceptable mono- or di-salt having a counter ion selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and/or with counter-ions such as methylamino, dimethylamino, diethylamino, triethylamino counter-ions, and combinations thereof.
  • a therapeutic agent includes compound described herein in the form of a halide di-salt, such as a di-hydrochloride salt or a di-hydrobromide salt.
  • the second therapeutic agent includes an anti-cancer agent.
  • the second therapeutic agent is selected, without limitation, from acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, ametantrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bevaeizumab, bicalutamide, bisantrene, bisnafide dimesylate, bizelesin, bleomycin, brequinar, bropirimine, busuifan, cactinomycin, calusterone, capecitabine, caracemide, carbetimer, carboplatin,
  • the second therapeutic agent is selected, without limitation, from 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; anti tumour antibiotics; platinum derivatives; alkylation agents; antimitotic agents; tubuline inhibitors; PARP inhibitors, topoisomerase inhibitors, serine/threonine kinase inhibitors, tyrosine kinase inhibitors, protein protein interaction inhibitors, MEK inhibitors, ER inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs, amifostin, anagrelid, clodronat, filgrastim, interferon, interferon alpha, leucovorin,rituximab, procarbazine, levamisole, mesna, mitotane, pamidron
  • AZD-6244 ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY -4 -9006.
  • carboxyphthalatoplatin CCl-779, CC-1 15, CC-223, CEP-701 , CEP-751 , CBT-1 cefixirne, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-II, CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247,
  • PCK-3145 pegfiigrastim, PBI-1402, PBI-05204, PDO325901 , PD-1 antibodies
  • 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, periilylalcohol, perruzumab, P13K inhibitors, PI3K/mTOR inhibitors, PG-TXL, PG2, PLX-4032/RO-51 85426 (vemurafenib), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKJ166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed
  • tremelimumab tretinoin
  • triacetyluridine triapine
  • triciribine trimetrexate
  • TLK-286TXD 258, tykerb/tyverb urocidin
  • valrubicin vatalanib
  • vincristine vinfiunine
  • virulizin WX-UK1, WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-51 1 , YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331 , ZD 1839, ZSTK-474, zoledronat, zosuquidar, and combinations thereof.
  • 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, medroxy-progesterone, octreotide, and combinations thereof.
  • the second therapeutic agent is selected, without limitation, from, the group consisting of LHRH agonists and LHRH antagonists.
  • a LHRH agonist is selected from the group consisting of goserelm acetate, luprohde acetate, triptorelin pamoate and combinations thereof.
  • the second therapeutic agent includes a LHRH antagonist is selected from the group consisting of Degarelix, Cetrorelix, Abareiix, Ozarelix, Degarelix combinations thereof.
  • the second therapeutic agent includes an inhibitor of a growth factor.
  • the inhibitor of a growth factor is selected, without limitation, 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), insuline-like growth factors (IGF), human epidermal growth factor (HER), hepatocyte growth factor (HGF), and combinations thereof.
  • PDGF platelet derived growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • IGF insuline-like growth factors
  • HER human epidermal growth factor
  • HGF hepatocyte growth factor
  • the human epidermal growth factor (HER) is selected from the group consisting of HER2, HER3, and HER4.
  • the second therapeutic agent includes a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is selected, without limitation, from the group consisting of cetuximab, gefitinib, imatinib, lapatinib and trastuzumab, and combinations thereof.
  • the second therapeutic agent includes an aromatase inhibitor.
  • the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, and combinations thereof.
  • the second therapeutic agent includes an antimetabolite.
  • the antimetabolite comprises an antifolate.
  • the antifolate is selected from the group consisting of methotrexate, raltitrexed, pyrimidine analogs, and combinations thereof.
  • the antimetabolite is a pyrimidine analog.
  • the pyrimidine analog is selected from the group consisting of 5-fluorouracil, capecitabin, gemcitabin, and combination thereof.
  • the antimetabolite is a purine analog or an adenosine analog.
  • the purine analog or adenosine analog is selected from the group consisting of mereaptopurme, thioguanine, cladribine and pentostatin, cytarabine, fludarabine, and combinations thereof.
  • the second therapeutic agent includes an antitumour antibiotic.
  • the antitumor antibiotic is selected from the group consisting of anthracyclins, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin and
  • the second therapeutic agent includes a platinum derivative.
  • the platinum derivative is selected from the group consisting of cisplatin, oxaliplatin, carboplatin and combinations thereof.
  • the second therapeutic agent includes an alkylation agent.
  • the alkylation agent is selected from the group consisting of estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide,
  • the second therapeutic agent includes a nitrosourea.
  • the nitrosourea is selected from the group consisting of carmustin, lomustin, thiotepa, and combinations thereof.
  • the second therapeutic agent includes an antimitotic agent.
  • the antimitotic agent is selected from the group consisting of Vinca alkaloids and taxanes.
  • the taxane is selected from the group consisting of paciitaxel, docetaxel, and combinations thereof.
  • the Vinca alkaloids are selected from the group consisting of vinblastine, vindesm, vinorelbin, vincristine, and combinations thereof.
  • the second therapeutic agent includes a topoisomerase inhibitor.
  • the topoisomerase inhibitor is an epipodophyllotoxin.
  • the topoisomerase inhibitor which is an epipodophyllotoxin selected from the group consisting of etoposide, etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron, and combinations thereof
  • the second therapeutic agent includes a serine/threonine kinase inhibitor.
  • the serine/threonine kinase inhibitor is selected from the group consisting of PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORCl inhibitors, PDK inhibitors, dual mTOR/PDK inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors, and combinations thereof.
  • the second therapeutic agent includes a tyrosine kinase inhibitor.
  • the second therapeutic agent includes a PTK2/FAK inhibitor.
  • the second therapeutic agent includes a protein protein interaction inhibitor.
  • the protein protein interaction inhibitor is selected from the group consisting of LAP, Mcl-1 , MDM2/MDMX and combinations thereof.
  • the second therapeutic agent includes a rapamycin analog.
  • the rapamycin analog is selected from the group consisting of everoiimus, temsirolimus, ridaforolimus, sirolimus, and combinations thereof.
  • the second therapeutic agent is selected from the group consisting of amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, and combinations thereof.
  • the second therapeutic agent is selected from the group consisting of 2-chlorodesoxyadenosine,
  • ARRY-704/AZD-8330 AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, 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, B1BW 2992 (afatinib, tomtovok), BIBF 1 120 (vargatef
  • FOLFOX4, FOLFIRI formes tane, fotemustine, galarubicin, gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide, GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-lOO, gpl OO-peptide vaccines, GSK-5126766, GSK-690693, GSK- 1 120212 (trametinib), GSK-21 18436 (dabrafenib), GSK-2126458, GSK-2132231 A, GSK-2334470, GSK-21 10183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyal
  • PCK-3145 PCK-3145, pegfilgrastim, PBI-1402, ⁇ -05204, PDO325901 , PD-1 antibodies,
  • PEG-paclitaxel albumin-stabilized paclitaxel
  • PEP-005 PF-05197281, PF-05212384
  • tremelimumab tretinoin
  • triacetyluridine triapine
  • triciribine trimetrexate
  • TLK-286TXD 258, tykerb/tyverb urocidin
  • valrubicin vatalanib
  • vincristine vinflunine
  • virulizin WX-UK1 , WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281, XL-518 R-7420/GDC-0973, XL-765, YM-51 1 , YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331 , ZD 1839, ZSTK-474, zoledronat, zosuquidar, and combinations thereof.
  • the other therapeutic agent comprises a steroid.
  • Steroids include, but are not limited to, dexamethasone, prednisolone, methy l prednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazol.
  • the other therapeutic agent comprises an anti-emetic.
  • Anti-emetics include, but are not limited to, 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), NKl receptor antagonists (such as aprepitant and casopitant), antihistamines (such as cyclizine.
  • 5-HT3 receptor agonists such as dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine
  • dopamine agonists such as domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, pro
  • cannabinoids such as cannabis, dronabinol, nabiione, and sativex
  • benzodiazepines such as midazolam and lorazepam
  • anticholinergics such as hyoscine
  • trimethobenzamide ginger, emetrol, propofol, peppermint, muscimol, and ajwain.
  • compositions may be administered to a subject via any suitable route of administration.
  • the pharmaceutical composition is administered to a subject orally, parenterally, transdermally or transmucosally.
  • the pharmaceutical composition is administered to a subject parenterally.
  • the pharmaceutical composition is administered to a subject via a parenteral route of
  • the pharmaceutical composition is administered to a subject via a route of administration selected from rectal and transdermal.
  • the pharmaceutical composition is administered to a subject in a dosage form selected from the group consisting of sterile solutions, suspensions, suppositories, tablets and capsules.
  • 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.
  • the pharmaceutical composition is administered to a subject in an oral dosage form selected from the group consisting of tablets, hard shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids and semi-solids.
  • the pharmaceutical composition is administered to a subject as a dosage form selected from the group consisting of sustained release forms, controlled release forms, delayed release forms and response release forms.
  • the pharmaceutical composition is administered to a subject once daily. In some embodiments, the pharmaceutical composition is administered to a subject accoridng to an infrequent dosing regimen (e.g., administered once per week or less frequently). In some embodiments, the pharmaceutical composition is administered to a subject accoridng to a frequent dosing regimen (e.g., administered more than once per week). In some embodiments, the pharmaceutical composition is administered to a subject once weekly . In some embodiments, the pharmaceutical composition is administered to a subject once every four weeks. In some embodiments, the pharmaceutical composition is administered to a subject twice a week. In some embodiments, the pharmaceutical composition is administered to a subject once every two weeks. In some embodiments, the pharmaceutical composition is administered to a subject once every three weeks. In some embodiments, the pharmaceutical composition is administered to a subject in a repeated cycle of once weekly, once every two weeks, once every three weeks, once ever ⁇ ' four weeks or combinations thereof.
  • the treatment method comprises administering to a subject in need of such treatment: (i) a first therapeutic agent including a compound comprising compound (1), compound (10) an analog thereof, or a pharmaceutically acceptable salt thereof in combination with (ii) a second therapeutic agent, wherein the first therapeutic agent and the second therapeutic agent are administered either simultaneously or sequentially; and further comprises assaying the expression of an endoplasmic reticulum (ER) stress response gene in a biological sample.
  • a first therapeutic agent including a compound comprising compound (1), compound (10) an analog thereof, or a pharmaceutically acceptable salt thereof in combination with (ii) a second therapeutic agent, wherein the first therapeutic agent and the second therapeutic agent are administered either simultaneously or sequentially; and further comprises assaying the expression of an endoplasmic reticulum (ER) stress response gene in a biological sample.
  • ER endoplasmic reticulum
  • the endoplasmic reticulum stress response gene is selected from the group that includes, but is not limited to, C/EBP-Homologous Protein (CHOP), Activating Transcription Factor 3 (ATF3) and both CHOP and ATF3,
  • the endoplasmic reticulum stress response gene is selected from the group that includes, but is not limited to, ATF3, Activating Transcription Factor 4 (ATF4) CHOP, IREl , Binding immunoglobulin protein (BiP), Eukaryotic translation initiation factor 2A (eIF2a), X-box binding protein 1 (XBP1).
  • the biological sample may be tumor, peripheral blood mononuclear cells, or skin biopsy.
  • the biological sample may be obtained before, during, or after drug administration.
  • the treatment method further comprises adjusting a dose of the first therapeutic agent to achieve induction of 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% of one or more ER stress gene.
  • the treatment method further comprises adjusting a dose of the first therapeutic agent to achieve induction of 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% of ER stress genes.
  • the treatment method further comprises adjusting a dose of the first therapeutic agent to achieve induction of 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% of ER stress genes.
  • the treatment method comprises administering to a subject in need of such treatment: (i) a first therapeutic agent including 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, wherein the first therapeutic agent and the second therapeutic agent are administered either simultaneously or sequentially: and further comprises assaying the expression of proteasomal activity in a biological sample.
  • the proteasomal activity may be chymotrysin-like, trypsin-like, and/or caspase-like activity.
  • the biological sample may be tumor, peripheral blood mononuclear cells, or skin cells. The biological sample may be obtained before, during, or after drug administration.
  • the treatment method further comprises adjusting the dose to achieve inhibition of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of the proteasomal activity.
  • the treatment method further comprises adjusting the dose to achieve inhibition of at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the proteasomal activity.
  • the treatment method further comprises adjusting the dose to achieve inhibition of 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% of the proteasomal activity.
  • methods of treatment which comprises administering to a subject in need of such treatment a combination of a first therapeutic agent including a compound of formula (1) or of formula (10), an analog thereof, or a
  • the predetermined waiting time is chosen so as to obtain a delayed therapeutic effect of the first therapeutic agent without an increased risk of possible combined toxic effects of the first and second therapeutic agents.
  • the predetermined waiting time is determined based on the clearance rate of the compound of the first therapeutic agent or a metabolite thereof.
  • the predetermined waiting time is determined by a quantitative assessment of renal function and parameters of renal.
  • the predetermined waiting time is determined by an assay for the determination of renal fanction, wherein the assay is selected from the group consisting of serum level the compound of the first therapeutic agent or a metabolite thereof; clearance rate of the compound of the first therapeutic agent or a metabolite thereof; 24-hour urinary clearance of the compound of the first therapeutic agent or a metabolite thereof.
  • the predetermined waiting time substantialiy equals the time required for systemic clearance of the compound of the first therapeutic agent or a metabolite thereof from the subject's body.
  • the predetermined waiting time substantially equals the time required for renal clearance of the compound of the first therapeutic agent or a metabolite thereof from the subject's body. In one embodiment of the treatment method, the predetermined waiting time substantially equals the time required for hepatic clearance of the compound of the first therapeutic agent or a metabolite thereof from the subject's body. In one embodiment of the treatment method, the predetermined waiting time substantially equals the time required for total clearance of the compound of the first therapeutic agent or a metabolite thereof from the subject's body. In one embodiment of the treatment method, the predetermined waiting time is about 4 hours. In other embodimens the waiting time is 1 day. In some embodiments, the waiting time is until Cmax of the compound of the first therapeutic agent has passed.
  • the waiting time is after most of the adverse events are resolved or are resolving.
  • the predetermined waiting time is about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.
  • the predetermined waiting time is a 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 to 2 days.
  • the waiting time is up to 3 weeks.
  • the preceeding are considered "therapeutic time periods," [00214] When the order of administration is reversed, timing for the administration of the first therapeutic agent can be after the C raax of the second therapeutic agent (i.e., the first administered drug) has passed. In one embodiment, administration of the first therapeutic agent can be after most or substantialiy all of the first administered drag has been eliminated from the body or the toxicity effects for the first administered drug are resolved or are resolving.
  • the treatment method further comprises monitoring levels of the compound of the first therapeutic agent or a metabolite thereof in the subject using pharmacokinetic profiling.
  • monitoring levels of the compound of the first therapeutic agent or a metabolite thereof in the subject using pharmacokinetic profiling comprises constructing a pharmacokinetic profile of the compound of the first therapeutic agent or a metabolite thereof for the subject using concentrations of the compound of the first therapeutic agent or a metabolite thereof in at least two samples obtained from the subject at time points suitable to construct a pharmacokinetic profile.
  • samples are collected from the subject at point-of-care or point of use by sampling or self-sampling on point-of-care devices or point of use devices or on matrices suitable for storage of the samples prior to quantitation in a laboratory.
  • each of the point-of-care devices or point of use devices is capable of quantitating the compound of the first therapeutic agent or a metabolite thereof.
  • one or more samples are collected from the subject at point-of-care or point of use by biopsy device for analysis at the point-of-care or point of use devices or for storage prior to analysis by a laboratory.
  • a biopsy is taken after a time interval of 3-8 hours following administration the first therapeutic agent to the subject.
  • a biopsy is taken after a time interval of 3-24 hours following administration of the first therapeutic agent to the subject.
  • a biopsy is taken after a time interval of 8-24 hours following administration of the first therapeutic agent thereof to the subject.
  • a biopsy is taken after a time interval of 2 days following administration of the first therapeutic agent to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 3 days following administration of the first therapeutic agent to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 4 days following administration of the first therapeutic agent to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 1 -7 days following administration of the first therapeutic agent.
  • the pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding dosing of the first therapeutic agent for the subject being treated.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“C max ") of the subject following its administration to the subject ranges from about 1000 ng/dL to 1500 ng/dL for a therapeutic time period. In some embodiments, C max is less than 1500 ng/dL and greater than 85 ng/dL for a therapeutic time period.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“Cmax") of the subject following its administration to the subject ranges from about 1000 ng/niL to 1500 ng/mL for a therapeutic time period. In some embodiments, C max is less than 1500 ng/mL and greater than 85 ng/mL for a therapeutic time period.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) is a C» ja x of from about 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1 100, 11 10, 1 120, 1130, 1140, 1 150, 1 160, 1 170, 1 1 80, 1 190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 13 10, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490ng/dLto about 1500ng/dL; from about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) is a C max offrom about 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 about 1500 ng/mL; from about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“Cmax") of the subject following its administration is selected from about 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/dL.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“Cmax") of the subject following its administration is selected from aboutlOO, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, ill, 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.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“C max ") of the subject following its administration is selected from aboutlO, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5 ng/dL.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“Cmax") of the subject following its administration is selected from about 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.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“Cmax") of the subject following its administration is selected from about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, ill, 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.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“C max ") of the subject following its administration is selected from about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5 ng/mL.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“Cmax") of the subject following its administration is selected from about 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, 45, 555, 65, 575, 85, 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, 845, 8
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“C max ") of the subject following its administration is selected from about 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
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“Cmax") of the subject following its administration is selected from about 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
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“C max ") of the subject following its administration is selected from about 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
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“C max ") of the subject following its administration 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, 1 1, 1 1.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng/mL.
  • the maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("C max ") of the subject following its administration to the subject ranges from about 85 ng/dL to 1500 ng/dL; from about 8,5 ng/dL to 150 ng/dL; or from about 0.85 ng/dL to 15 ng/dL.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“C max ") of the subject following its administration is selected from about 85, 95, 105, 1 15, 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,
  • the maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("C max ") of the subject following its administration ranges from about 85 ng/mL to 1500 ng/mL; from about 8.5 ng/mL to 150 ng/mL; or from about 0.85 ng/mL to 15 ng/mL.
  • maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“C max ") of the subject following its administration is selected from about 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
  • the total drug exposure over time measured as the area under the curve ("AUC") of a plot of the concentration of the drug in blood (whole blood, plasma, or serum) of the subject following administration of the drug against time after administration of the drug ranges from about 150 ng hr/mL to about 8000 ng hr/mL; from about 15 ng hr/mL to about 800 ng hr/mL; or from about 1.5 ng hr/mL to about 80 ng hr/mL.
  • AUC is less than 8000 ng hr/mL and is greater than or equal to 150 ng hr/mL.
  • AUC is less than 800 ng hr/mL and is greater than or equal to 15 ng hr/mL. In some embodiments, AUC is less than 80 ng hr/mL and is greater than or equal to 1.5 ng hr/mL.
  • the total drug exposure over time is an AUC of from about 100 ng hr/mL to about 8000 ng hr/mL; from about 10 ng hr/mL to about 800 ng hr/mL; or from about 1 ng hr/mL to about 80 ng hr/mL.
  • the total drug exposure over time is an AUC of from about from 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.
  • the total drug exposure over time is an AUC of from 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.
  • the total drug exposure over time is an AUC of from about from 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.
  • the total drag exposure over time is an AUC of from about 100 ng hr/mL to about 8000 ng hr/mL, from about 10 ng hr/mL to about 800 ng hr/mL; or from about 1 ng hr/mL to about 80 ng hr/mL.
  • the total drug exposure over time is an AUC of from about from 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
  • the total drug exposure over time is an AUC of from about from 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,
  • the total drag exposure over time is an AUC of from about from 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,
  • the total drag exposure over time is an AUC of from about 100 ng hr/mL to about 200 ng hr/mL; from about 10 ng hr/mL to about 20 ng hr/mL; or from about 1 ng hr/mL to about 2 ng hr/mL, [00228]
  • the total drag exposure over time is an AUC selected from about 100, 150, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400,
  • the total drug exposure over time is an AUC selected from about 10, 15, 20, 40, 60, 80, 100, 120, 140, 160, 1 80, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 4600, 480, 500, 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780, and 800 ng hr/mL.
  • the total drug exposure over time is an AUC selected from about 1, 15, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 460, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, and 80 ng hr/mL.
  • compositions to treat a disease state which comprises administering to a subject in need of such treatment a combination of a first therapeutic agent and a second therapeutic agent, the method comprising:
  • the monitoring step includes constructing a pharmacokinetic profile of the compound of the first therapeutic agent or a metabolite thereof for the subject using concentrations of the compound of the first therapeutic agent or a metabolite thereof in a plurality of samples obtained from the subject at time points suitable to construct a pharmacokinetic profile.
  • at least two samples are collected at point-of-care or point of use by sampling or self-sampling on point-of-care devices or point of use devices or on matrices suitable for storage of the samples prior to quantitation of the compound or a metabolite thereof by a laboratory.
  • each point-of-care devices or point of use devices is capable of quantitating the compound or a metabolite thereof.
  • the pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding dosing of the compound or a salt thereof for the subject.
  • the samples include from 2-12 samples. In some embodiments of the method, the samples are collected over a time period of up to 8 hours, up to 24 hours, up to 48 hours, or up to 72 hours.
  • the pharmacokinetic parameters include at least one parameter selected from the group consisting of AUC, AUCin , T max , ⁇ ⁇ » time above threshold, steady state concentration, absorption rate, clearance rate, distribution rate, terminal T-l/2 or parameters drawn from noncompartmental pharmacokinetic (PK) or compartmental PK analysis, including physiological model-based compartmental PK analysis.
  • the treatment method further comprises generating a report including the pharmacokinetic profile of the subject.
  • the report includes a recommendation regarding dosing based on the pharmacokinetic profile of the subject.
  • a reduction in dosage of compound (1), the analog thereof, or the pharmaceutically acceptable salt thereof is indicated to reduce risk of toxicity based on one or more pharmacokinetic parameters.
  • the reduction in dosage of the compound or salt thereof is indicated based on time above threshold, wherein the threshold is the drug concentration above which toxicity occurs, or one or more of AUC, AUCmf, mean residence time (MRT), exponentials defining the pharmacokinetic profile, volume of distribution at steady state (Vss), volume of distribution during the terminal phase (Vz) or combination of a group of pharmacokinetic variable to adequately describe the pharmacokinetic profile.
  • a dose adjustment of the compound or salt thereof is indicated to increase efficacy based on one or more pharmacokinetic parameters.
  • an increase in dosage of the compound or salt thereof is indicated based on one or more of AUC, AUC mf , MRT, exponentials defining the pharmacokinetic profile, steady state volume (Vss) of distribution, volume of distribution during the terminal phase (Vz) or combination of a group of pharmacokinetic variables to adequately describe the pharmacokinetic profile.
  • the dose of the compound or salt thereof is adjusted to within 5% to 25% of a desired target value.
  • each of the samples is applied to the point-of-care device or the point of use device for determining the concentration of the compound or a metabolite thereof, wherein the point-of-care device or the point of use device comprises a lateral flow strip having a construction and composition such that an application of one or more of the samples to the lateral flow strip causes a fraction of the drug in the sample to bind to with a component of the lateral flow strip such that a detectable signal proportional to the concentration of the drug in the applied sample is produced .
  • the samples are applied to matrices suitable for storage of the samples prior to quantitation by a laboratory.
  • the samples are stored as dried blood spots.
  • drug concentrations are measured by ELISA, LC MS MS, LC UV or LCMS.
  • the pharmacokinetic parameters include at least one of steady state concentration, absorption, and terminal Ti/ 2 .
  • at least one of the samples is whole blood.
  • multimodal therapeutic methods in which administration of a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment is supplemented by administration of other therapeutic modalities.
  • the multimodal therapeutic method comprises administering to a subject a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a
  • the multimodal therapeutic method comprises administering to a subject a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof in conjunction with radiation therapy, wherein the pharmaceutical composition comprising the compound of formula (1 ) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof and the radiation therapy are administered concurrently or sequentially in any order, in one embodiment, the multimodal therapeutic method comprises administering to a subject a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof in conjunction with radiation therapy in a sequential arrangement.
  • the multimodal therapeutic method comprises administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of formula (! or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof thereof concurrently with radiation therapy.
  • the multimodal therapeutic method is used for the treatment of cancer.
  • the multimodal therapeutic method includes administering to a cancer subject in need of such treatment a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof and irradiating cancer cells with a radiation beam.
  • the multimodal therapeutic method uses the technique of conformal radiotherapy (CRT) to deliver a dose volume histogram (DVH) prescribed to a cancer subject.
  • CTR conformal radiotherapy
  • DVDH dose volume histogram
  • the multimodal therapeutic method uses the technique of intensity modulated radiation therapy (IMRT) to deliver radiation to cancer ceils.
  • IMRT intensity modulated radiation therapy
  • the multimodal therapeutic method uses techniques that compensate for motion of tumors in the subject during treatment (e.g., where doses of radiation must be administered to a thoracic tumor which moves as the patient breathes).
  • the multimodal therapeutic method use Four Dimensional Computed Tomography (4D CT) scanning techniques to adjust the delivered radiation field to compensate for tumor motion over the breathing cycle.
  • 4D CT Four Dimensional Computed Tomography
  • any suitable type of radiation including gamma radiation which is given fractionated, IMRT (intensity modulated radiation therapy), gamma knife, proton therapy and brachytherapy can be used with the multimodal therapeutic method.
  • Radiation therapy and administering a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof can be used to treat brain tumors such as glioblastoma or disease that has metastasized to the brain from lung cancer.
  • the multimodal therapeutic method can be used to treat lung cancer, pancreatic cancer, rectal cancer, breast cancer, sarcoma, prostate cancer, gynecological malignancies, and lymphoma.
  • the gamma knife is used frequently to treat brain metastases.
  • the multimodal therapeutic method includes use of proton therapy to treat cancer, including brain tumors, prostate cancer and any tumor proximate vital organs where it is very important to minimize toxicity to nearby normal tissue.
  • the multimodal therapeutic method includes administering to a cancer subject in need of such treatment a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof in combination with adoptive cell therapy (e.g., CAR-T (JCAR 14, 15, 16, 17, KTE-C19, or CTL019); other T Cell (ATM 13); or NK (CDNO-109 orNK-92)) either simultaneously or in combination.
  • adoptive cell therapy e.g., CAR-T (JCAR 14, 15, 16, 17, KTE-C19, or CTL019
  • ATM 13 T Cell
  • NK CDNO-109 orNK-92
  • the multimodal therapeutic method eliminates minimal residual disease without adding to toxicity resu lting from treatment by a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the multimodal therapeutic method improves prognosis and/or reduces adverse side-effects associated with a disease state or condition in a subject undergoing treatment.
  • compositions apply with equal force to derivatives and analogs of and salts of compound (1) and salts thereof.
  • the analogs have the structure of compound (25):
  • R4 independently represent hydrogen, alkyl, cycloalkyl, cycioalkylalkyl, carboxyi, haioalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, araikyl, hydroxyalky], alkoxy, aryloxy, alkoxyalkyl, aikoxycarbonyi, araikoxy, aralkylthio, aikanoyi, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaiyi, acyl, and heterocycie radicals.
  • Ri , R 2 , R 3 , and R 4 are optionally substituted In some embodiments, some or all hydrogens in Ri , R 2 , R 3 , and R4 may be substituted by deuterium . Irs other embodiments, the analogs have the structure of compound (25), wherein Rj , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, C1. 4 alkylph.enyl,
  • Ci_ 4 alkyl Ci- 4 alkylphenyl
  • the analogs have the structure of compound (25), wherein Ri, R 2 , R 3 , and R 4 are independently selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzyl-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (CH 2 ) 3 CO-4F-Ph.
  • Ri, R 2 , R 3 , and R 4 are independently selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzyl-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph),
  • analogs have the structure of compound (26):
  • Rj and R 2 independently represent hydrogen, alkyl, cycloalkyl, cycioalkylalkyl, carboxyi, haioalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, araikyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, aikoxycarbonyi, araikoxy, aralkylthio, aikanoyi, mercapto, alkylthio, arylthio, alkylsulfinyi, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaiyi, acyl, and heterocycie radicals.
  • Rj and R 2 are independently selected from the group consisting of H, C h alk 1, Ci -4 alkylphenyl, Ci -4 alkylphenylketone,
  • Ci_ 4 alkylphenylketone, and Ci_ 4 benzy3 ⁇ piperazine are optionally substituted with Ci -4 alkyl,
  • Ci Ci -4 alkoxyl, hydroxyi, perhalogenated or halo.
  • Ri is selected from the group consisting of H, CH 3) CH 2 Ph, CH 2 -((2-Cl)-Ph) s CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzyl-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (CH 2 ) 3 CO-4F ⁇ Ph
  • R 2 is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzyl-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (
  • Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , -NG 2 , -OCH 3s -CXH 2) --CX 2 H, -CX 3 , -CH 2 (CX 3 ), ⁇ ( ' ! Si CX : ⁇ ⁇ .
  • X represents a halogen including a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • R 2 is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , - 0 2 , -OCH 3 , -CXH 2 , -CX 2 H, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX 2p +i, ⁇ OCX 3 , or -OCpX 2p+ i, where p is an integer from 2 to 20 and where X represents a halogen.
  • Rj is a hydrogen.
  • R is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • the arylalkyl is Ci_ 4 alkoxyl, hydroxy!, perhalogenated C] - 4 alkyl, or halo.
  • R 2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • the arylalkyl is substituted with Ci- 4 alkoxyl, hydroxy!, perhalogenated C j ⁇ alkyl, or halo.
  • the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3 .
  • R 2 is a substituted or an unsubstituted
  • heterocycloalkylalkyl such as a morpholinoalkyl or piperazinylalkyl group.
  • R 2 is a substituted or an unsubstituted heteroarylalkyl, such as an
  • the heterocycloalkylalkyl or heteroarylalkyl is substituted with hydroxyl, perhalogenated Ci- 4 alkyl, or halo.
  • 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 .
  • the analogs have the structure of compound (27):
  • R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haioalkyl, alkenyl, cycloalkeiiyl, alkynyl, ar l, aralkyl,
  • Ri is selected from the group consisting of H, Ci- 4 alkyl, Ci. 4 benzyl-piperazine, and
  • Ci-4alkylthienyi wherein Cj- 4 alkylphenyl, Cj_ 4 alkyiphenyiketone, and
  • Ci-4benzyl-piperazine are optionally substituted with C h alky 1, Ci_ 4 a3koxyl, hydroxy!, perhaiogenated Ci.. 4 aikyl, or halo.
  • Ri is selected from the group consisting of H, CH , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl) s CH 2 CH 2 Ph,
  • Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meia, and/or para positions of the benzyl ring: -CH 3 , -N0 2 , -OC ' l .
  • j is a hydrogen.
  • Ri is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • the arylalkyl is substituted with C h alk 1,
  • Ci_4alkoxyl hydroxyl, perhaiogenated or halo.
  • analogs have the structure of compound (28):
  • Ri and R 2 independently represent hydrogen, alkyl, cycloalkyl, cvcloalkylalkvl, carboxyl, haioalkyl, alkenyl, cycloalkeiiyl, alkynyl, aryl, aralkyl, hydroxvalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arvlthio, alkylsu!finy!, arylsuliinyl, alkylsuifonyl, arylsulfonyl, heteroaxyi, acyl, and heterocycle radicals.
  • Ri and R 2 are independently selected from the group consisting of H, Chalk lphenyl, Ci -4 alkylphenylketone,
  • Rj is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 - 2 » thienyI), CH 2 CH 2 Ph, CH 2 -(2,4-di I- -Ph ).
  • R 2 is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzy1-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (CH 2 ) 3 CO-4F-Ph.
  • Ri represents CH 2 Ph
  • R 2 does not represent CH 2 -((2-CH 3 )-Ph.
  • Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , -N0 2 , -OC ' l . -CXH 2 , -CX 2 H, -CX 3> -C13 ⁇ 4(CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3> -CpX 2p ; -i, -OCXs, or -OCpX 2p ; !
  • X represents a halogen including a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • R is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , -NQ 2 , -OCH 3 , -CXH 2 , -CX 2 H, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX 2p+! , -OCX 3 , or -QCpX 2p+ i, where p is an integer from 2 to 20 and where X represents a halogen.
  • Ri is a hydrogen.
  • R i is a substituted or an unsubstituted arylalkyl, suc as a benzyl or phenylethyl group.
  • the arylalkyl is substituted with or halo.
  • R 2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • the arylalkyl is substituted with Ci -4 alkyl, Ci-4alkoxyl, hydroxy!, perhalogenated Cj ⁇ alkyl, or halo.
  • the arylalkyl is substituted with one or more substituents selected from the group consisting of ha!o, -CH 3 , -CF 3 , and -OCH 3 .
  • R 2 is a substituted or an unsubstituted
  • R 2 is a substituted or an unsubstituted heteroarylalkyl, such as an
  • the heterocycloaikylalkyi or heteroarylalkyl is substituted with C 1-4 alkoxyl, hydroxy!, perhalogenated Ci_ 4 alkyl, or halo.
  • the heterocycioalkylaikyl or heteroarylalkyi is substituted with one or more substituents selected from the group consisting of halo, -C!3 ⁇ 4, -CF 3 , and -OCH 3 -
  • the analogs have the structure of compound (29):
  • Ri and R 2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl,
  • Ri and R2 are independently selected from the group consisting of H,
  • Rj is selected from the group consisting of H, CH 3 , C i l -Ph. CH 2 -((2-Cl)-Ph), Ci ] - ⁇ 2-ihien i ).
  • R 2 is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cf)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzyl-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (CH 2 ) 3 CO-4F-Ph.
  • Ri represents CH 2 Ph
  • R 2 does not represent CH 2 -((2-CH 3 )-Ph.
  • Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , -N0 2 , -OCH 3 , -CXH 2 , -CX 2 H, -CX , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) , ⁇ CpX 2p H , -OCX3, or -OCpX 2p - ; -1, where p is an integer from 2 to 20 and where X represents a halogen including refers to a fluorine, chlorine, bromine, or iodine atom, preferably , fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • R 2 is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , -N0 2 , -OCH 3 , -CXH 2 , -CX 2 H, -CX 3 , -C13 ⁇ 4(CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX pH , -OCX 3 , or ( ⁇ ' ⁇ ⁇ - ⁇ . where p is an integer from 2 to 20 and where X represents a halogen.
  • Rj is a hydrogen.
  • R is a substituted, or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • the arvialkyl is substituted with C h alk 1, Ci.4alkoxyl, hydroxyl, perhalogenated or halo.
  • R 2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • the arylalkyl is substituted with Ci- 4 alkyi, Ci-4alkoxyl, hydroxyl, perhalogenated or halo. In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3 . In some embodiments, R2 is a substituted or an unsubstituted
  • R 2 is a substituted or an unsubstituted heteroaryialkyl, such as an
  • the heterocycloalkylalkyl or heteroaryialkyl is substituted with hydroxyl, perhalogenated Ci-4alky], or halo.
  • the heterocycloalkylalkyl or heteroaryialkyl is substituted with one or more substituents selected from the group consisting of halo, -CH 3 , - ( . ' ! ' :. ami ⁇ ( )(. ' ! I ;.
  • the analogs have the structure of compound (30):
  • Ri and R2 independently represent hydrogen, aikyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkyithio, alkanoyl, mercapto, alkylthio, aiylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryi, acyl, and heterocycle radicals.
  • Rj and R2 are independently selected from the group consisting of H, C h alky 1, Cj ⁇ alkylphenyl, Cj ⁇ alkyiphenyiketone,
  • Ci- 4 alkoxyl, hydroxyl, perhalogenated is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4- -benzy]-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (CH 2 ) 3 CO-4F-Ph.
  • R 2 is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzyl-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (CH 2 ) 3 CO-4F-Ph.
  • Ri represents CH 2 Ph
  • R 2 does not represent CH 2 -((2-CH 3 )-Ph.
  • Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , -N0 2 , -OCH 3 , -CXH 2 , -CX 2 H, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , "CpX pt-i, -OCX 3 , or OCpX v. ⁇ .
  • p is an integer from 2 to 20 and where X represents a halogen including refers to a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • R 2 is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH , -N0 2 , -OCH 3 , -CXH 2 , -CX 2 H, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -C P X 2P -H , -OCX 3 , or ( ⁇ ⁇ ⁇ - ⁇ . where p is an integer from 2 to 20 and where X represents a halogen.
  • Ri is a hydrogen. In some embodiments, Ri is a substituted or an unsubstituted ar lalkyl, such as a benzyl or phenylethyl group. In some embodiments, the ar lalkyl is substituted with Ci. 4 alkyl, Ci- 4 alkoxyl, hydroxy], perhalogenated or halo.
  • R 2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group.
  • the arylalkyl is substituted with Ci-4alkoxyl, hydroxy!, perhalogenated Ci_ 4 alkyl, or halo.
  • the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH 3 , -CF 3 , and -OCH 3 .
  • R 2 is a substituted or an unsubstituted
  • R 2 is a substituted or an unsubstituted heteroarylalkyi, such as an
  • the heterocycloalkyialkyl or heteroarylalkyi is substituted with hydroxyl, perhalogenated Ci-4alkyl, or halo.
  • the heterocycloalkyialkyl or heteroarylalkyi is substituted with one or more substituents selected from the group consisting of halo, -CH 3 , -CF 3 , and -QU I
  • the analogs have the structure of compound (31):
  • Ri and R 2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyi, haloalkyl, alkenyl, cycloalkenyl, alkynyl, ar l, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, aikylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaiyl, acyl, and heterocycle radicals.
  • Rj and R? are independently selected from the group consisting of H, Cj
  • Ci- 4 alkylphenylketone are optionally substituted with
  • Ri is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzyl-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (CH 2 ) 3 CO-4F-Ph.
  • R 2 is selected from the group consisting of H, CH 3 , CH 2 Ph, CH 2 -((2-Cl)-Ph), CH 2 -(2-thienyl), CH 2 CH 2 Ph, CH 2 CH 2 (4-N-benzyI-piperazine), CH 2 -(2,4-di F-Ph), CH 2 -((2-CH 3 )-Ph), CH 2 CHOHPh, and (CH 2 ) 3 CO-4F-Ph.
  • Rj represents CH Ph
  • R 2 does not represent CH 2 -((2-CH 3 )-Ph.
  • Rj is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , -N0 2 , -OCH 3s -CXH 2 , -CX 2 H, -CX 3 , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX 2p +; , -OCX 3 , or -OCpX 2p +; , where p is an integer from 2 to 20 and where X represents a halogen including refers to a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • R 2 is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH 3 , -NO?, -OCH 3 , -CXH 2 , -CX 2 H, -CX , -CH 2 (CX 3 ), -CH(CX 3 ) 2 , -C(CX 3 ) 3 , -CpX 2p ⁇ i, -OCX 3 , or -OC p X 2p - H , where p is an integer from 2 to 20 and where X represents a halogen.
  • Rj is a hydrogen.
  • R is a substituted or an unsubsiituted arylalkyi, such as a benzyl or phenylethyl group.
  • the arvlalkyl is substituted with hydroxyl, perhalogenated or halo.
  • R 2 is a substituted or an unsubsiituted arylalkyi, such as a benzyl or phenylethyl group.
  • the arylalkyi is substituted with Cj ⁇ aikyi, Ci-4alkoxyl, hydroxyl, perhalogenated C ⁇ alkyl, or halo.
  • the arylalkyi is substituted with one or more substituents selected from the group consisting of halo, -CH 3 , -CF 3 , and -GCH 3 .
  • R 2 is a substituted or an unsubsiituted
  • R 2 is a substituted or an unsubsiituted heteroarylalkyl, such as an
  • the heterocycloalkylalkyl or heteroarylalkyl is substituted with hydroxyl, perhalogenated Ci-4alkyl, or halo.
  • the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, -C33 ⁇ 4, -CF 3 , and -OCH 3 .
  • the reaction mixture was stirred for 3 h at the same temperature and then cooled to 0 °C (ice bath) and adjusted to pH 6-6.5 with acetic acid.
  • the resulting cold mixture was diluted with water (lOmL) 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 layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure
  • the compound was dried in vacuum to give methyl-l-tert-butoxycarbonyl- 4-oxo-3-piperidine earboxylate (5.0 g, 80%).
  • the compound obtained was carried to next reaction without any further purification.
  • Compound ONC91 1 was prepared from ONC910 by treatment with TFA.
  • Compound (72) was prepared by reacting the precursor NH compound prepared in analogy to Example 5 and treating it with styrene oxide.
  • the reaction mixture from Example 8 was washed with 500 mL of water and diluted with methyl tert-butyl ether (MTBE) (800 mL).
  • MTBE methyl tert-butyl ether
  • the organic phase was washed with water (500 mL x 2) and transferred to a 3 L three-neck round bottom flask equipped with mechanical stirring, N 2 inlet, a thermocouple, a condenser and a Dean-Stark trap.
  • Compound (1) is administerd to tumor-bearing mice, according to one of the following dosing regimens using a 7 day recurring cycle.
  • compound (33) (ONC911) was immobilized at different immobilization densities to sepharose beads.
  • the corresponding proteomes can be distinguished by the introduced mass difference.
  • Binding experiments were performed in duplicate with a partial switch of labels to exclude labeling artifacts. Bound proteins were completely eluted from the affinity matrices, separated by SDS-PAGE and subjected to tryptic digestion. Recovered peptides were analyzed by LC-MS/MS on an LTQ Orbitrap Velos mass spectrometer (Thermo Fisher). Raw data generated by LC-MS/MS were processed by MaxQuant to obtain quantitative protein abundance data.
  • Quantified proteins were analyzed for enrichment of proteins compared to the control matrix and competition of bound protein by incubation with compound (1). Such a binding and displacement pattern would be expected of a specific target protein.
  • HCTl 16 cells were cultivated and metabolically labeled by SILAC. Efficient SILAC encoding with incorporation rates of the isotopic variants of arginine and lysine exceeding 95% was achieved. Sufficient cells were prepared for subsequent experiments. Cell extracts were generated by detergent mediated cell lysis. In addition, remaining cell nuclei were extracted by lysis in the presence of 400 mM NaCl in order to include nuclear proteins. The cytosolic and nuclear extracts were combined.
  • the linker compound (33) (ONC.911) was immobilized via its amino group to sepharose beads. Bead with four different immobilization densities of 6 mM, 3 mM, 1 mM and 0,3 mM were prepared. These matrices w r ere used to enrich proteins from HCT116 extracts and to investigate displacement of bound proteins by 50 ⁇ of compound (1).
  • immobilized compound (33) appears to be functional and is able to specifically enrich proteins from a cell lysate. Additionally, distinct competition with 50 ⁇ of compound (1) was observed.
  • Uniprot ID Best Uniprot identifier
  • Protein name Protein name according to Uniprot.
  • Target classification Evaluation of the respective protein at the indicated coupling density of compound ONC216. "OK” indicates that the respective protein was consistently enriched and competed over 2 independent replicate experiments. “OK (with outlier)” indicates enrichment by the affinity matrix and displacement by Compound (1), but displacement was observed in only one of the two replicates.
  • ONC201 was evaluated in a whole cell, functional assay of a ⁇ -Arrestin G protein- coupled receptor (GPCR) activity that directly measure dopamine receptor activity by detecting the interaction of ⁇ -Arrestin with the activated GPCR that can serve as a reporter.
  • GPCR G protein- coupled receptor
  • DRD1 , DRD2S, DRD2L, DRD3, DRD4, and DRD5 dopamine receptor
  • cell lines overexpressing the reporter constructs were expanded from freezer stocks. Cells were seeded in a total volume of 20 ⁇ , into white walled, 38 -well microplates and incubated at 37°C prior to testing, with antagonist followed by agonist challenge at the ECso concentration.
  • % Antagonism 100% x (1— (mean RLU of test sample— mean RLU of vehicle control) / (mean RLU of ECso control — mean RLU of vehicle control).
  • Example 14 Assessing Compound (1 ) interactions with Efflux and transporter proteins
  • ONC201 The ability of ONC201 to interfere with transporter protein activity is evaluated to determine the dosing regimens for ONC201 in combination with substrates on transporter proteins.
  • the timing or dose level of ONC201 in combination with another therapeutic agent may be modified based on these assay results.
  • Transporter proteins include OATP1B1 , OATP1B3, OAT1, OAT3, OCT! , OCT2, MATE1 and MATE2-f solute earners (SLC).
  • ONC20 to interfere with the efflux proteins was evaluated to determine if ONC201 could inhibit the ability of these proteins to efflux small molecule substrates. Inhibiting these efflux proteins could increase the efficacy of efflux protein substrates by combining with ONC201 to increase its intracellular concentrations or to alter its biodistribution.
  • Efflux proteins include MDR1 and BCRP.
  • ONC201 The interaction of ONC201 with the human MD 1 and BCRP transporter was investigated in vitro using MDR1 and BCRP over-expressing Madin-Darby canine kidney (MDCKll-MDRl and MDCKIl-BCRP) and the parental cells (MDCKII).
  • MDCKll-MDRl and MDCKIl-BCRP Madin-Darby canine kidney
  • MDCKII the parental cells
  • ONC20.1 is an inhibitor for MDR1 and BCRP
  • Digoxin and prazosin were used as the probe substrates for MDRl and BCRP, respectively.
  • ONC201 is an inhibitor of MDR 1 and BCRP at 200 micrornolar.
  • the combination of ONC201 with substrates of MDR l or BCRP may increase the efficacy of the substrate by increasing intracellular concentrations of the substrate or altering its biodistribution.
  • A-B apical-to-basolateral
  • B-A basolateral-to-apical
  • PC positive control
  • ONC201 did not induce P450 to an effect that was >20% of positive controls in this assay. Therefore can be used in combination of other drugs with out changing the activity of CYP enzymes.
  • CYP mRNA induction fold values were calculated using a standard AACj method with ⁇ 8S gene as the reference gene and target (C YP) gene expression of hepatocytes treated with vehicle control as the baseline.
  • Negative control - flumazenil 25 ⁇ was used as the negative control treatment
  • CYP i.e. CYP1A2, 2B6, 2C8, 2C9, 2C 19, 2D6, and 3A4
  • HLM human liver microsomes
  • CYP2C9-mediated diclofenac 4' hydroxylation CYP2C 19 mediated S mephenytoin 4' hydroxylation
  • CYP2D6-mediated bufuralol ⁇ hydroxylation CYP3A4 mediated midazolam
  • ONC201 inhibited CYP isozymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) with ICso values ranging from 34.9 to 428.6 ⁇ (4 to 48-fold above Cmax of 9uM; 40-480-fold above average plasma concentration at 24-hours of 0.9uM) 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 related to drug-drug interactions. Table 6:
  • ONC201 induces apoptosis in tumor, but not normal, cells at doses that trigger high levels of cell death in human cancer cells.
  • the safely profile of ONC201 in GLP safety studies in rats and dogs was consistent with the preferential cytotoxicity of ONC201 in tumor over normal cells in vitro.
  • the in vitro and in vivo profiles of ONC201 indicate a wide therapeutic window that is highly desirable for cancer therapeutics.
  • a schedule of every 21 days was selected for the clinical studies based on preclinical results that indicate sustained PD in tumors and after initial preliminary experiments suggesting that more frequent dosing did not appear to substantially increase the in vivo efficacy.
  • this phase I open-label study treated 10 patients during dose escalation with histologically-confirmed advanced solid tumors. An additional 10 patients have been accrued in an ongoing expansion phase to increase the safety experience. Patients received GNC2Q1 orally every 3 weeks at closes from 125 to 625 mg using an accelerated titration design.
  • the RP2D was defined as 625 mg that achieved a C max of 1 .5 - 7.5 rng/mL (-3.9-19.4 DiM). Plasma concentrations saturated at 375 mg, suggesting dose escalation above 625 mg was not warranted. No Grade >1 drag-related adverse events occurred.
  • the mean number of cycles (21 days) was 3.1 .
  • the expansion phase with 10 patients confirmed the safety of ONC201 at the RP2D.
  • PK analysis revealed a half-life of 9.6 hours and an AUC of 25 h ⁇ g/L. Prolonged induction of serum caspase-cleaved keratin 18 and induction of TRAIL was observed. Eight of 10 patients had stable disease and one patient with prostate adenocarcinoma experienced prolonged stable disease, remaining on study for 27 weeks. One additional patient with endometrial cancer underwent a mixed response.
  • QNC2Q1 is extremely well tolerated, possesses a favorable PK profile with saturable absorption of micromolar plasma concentrations, and exhibits signs of clinical activity when orally administered at 625 mg every 3 weeks.
  • Exclusion criteria included symptomatic brain metastases or asymptomatic brain metastases treated with steroids, prior bevacizumab treatment, prior allergic reactions to compounds similar to ONC201, uncontrolled intercurrent illnesses, combination retroviral therapy for HIV, active cardiac disease/history of cardiac dysfunction, stroke or seizures in the last 3 months, impairment of GI function that may alter absorption of ONC201 , pregnancy and treatment with hematopoietic colony-stimulating growth factor ⁇ 2 weeks prior to beginning treatment. Study Design, and Toxicity Assessment
  • the design was an open-label, dose- escalation phase I trial of monoagent ONC201 in patients with advanced, refractory tumors who had exhausted or refused standard treatment options for their respective indications.
  • Capsules (125 mg) of ONC201 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 no-observed-adverse-event-level in rats and dogs).
  • the study was conducted with a single patient accelerated dose escalation design that was designed to stop if any patient experienced a Grade > 2 adverse event that was at least possibly related to ONC201.
  • Dose escalation could proceed after the previously dosed cohort completed one treatment cycle and met the criteria to proceed with the next dose level. Enrollment at each subsequent dose level required that all patients enrolled at the prior dose level completed Cycle 1 dosing and were evaluated 21 days later to assess safety. Dose levels proceeded from 125 mg to 250 mg, 375 mg, 500 mg and finally to 625 mg.
  • Plasma samples for PK were collected at baseline, 30 minutes, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, and 168 hours following the first dose of ONC201 and before doses prior to treatment in cycles 2-6.
  • PK was analyzed 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).
  • Blood samples for PD were collected at 6 hours, days 2, 3, 8, and 15 after ONC201 treatment for cycle 1 , and pre-dose on the day of drug administration for cycle 2 and 3.
  • Serum levels of cleaved cytokeratin 18 (cCK18) were assessed using the M30 assay and serum levels of total cytokeratin 18 (CK18) were assessed using the M65 assay (Perviva A.B., Sweden). Assessments of other tumor-specific markers were also evaluated per standard of care.
  • ONC201 The in vitro activity of ONC201 was evaluated in 1020 genetically annotated cell lines that from the Genomic of Dr g Sensitivity in Cancer (http://www.cancerrxgene.org) collection.
  • IC5 0 values were determined by cell viability assays at 72 hours post-treatment as reported previously.
  • the estimated IC5 0 values were averaged across multiple cell lines for each tumor type.
  • Tumor types were categorized into three different groups that represented tertiles of average IC5 0 values. These groups are referred to as "high”, “low” and “medium” in Table 11 based on their textile classification within the ONC201 sensitivity spectrum.
  • ONC201 RP2D (625mg every t rs ;e weeks).
  • Dose cohorts are listed in Table 9. 625 mg was the highest dose reached and was determined to be the P2D. The only adverse event during the dose escalation phase that was possibly attributed to ONC201 was a low grade fever in one patient. One patient enrolled in the top dose cohort was replaced due to rapid disease progression in cycle 1.
  • Table 9 Dose-escalation and expansion cohorts with ONC201 dosed every 3 weeks.
  • Plasma collected at serial time points was used to analyze the systemic exposure levels of ONC201 in patients (Figure 5).
  • PK parameters were determined for all patients and summarized for the top-dose cohort (Table 10). While dose escalation involved single patient cohorts, systemic exposure to ONC201 , as determined by AUC and C max , appeared to saturate at a dose of 375 mg ( Figure 6).
  • the mean C max was 3312 (SD 2133) ng/niL, which occurred on average 1.8 hours following administration.
  • the mean V z was 381 (SD 164) L, consistent with a large distributive volume.
  • CL/F was observed to be variable but consistent across all the dose groups. There were no apparent relationships between drug CL/F and patient sex and age. Noticeable, shallow trends were observed with patient weight and BSA. An overall increase in CL/F was observed as weight and BSA increased. Although a slight upward trend was observed, there was no strong correlation between CL/F and CL C R.
  • Table 11 lists patient outcomes for the 10 evaluable patients enrolled in the dose escalation phase. Out of 10 evaluable patients completed at least 2 cycles, 4 patients completed at least 4 cycles, and 1 patient received 8 cycles and remains on therapy. On average, patients received 3, 1 doses of ONC201. Among the 10 patients enrolled in the expansion phase, 6 patients remain on therapy.
  • the serum M30 assay is able to detect a caspase-cleaved form of cytokeratin- 18 that occurs during apoptosis, which is useful in a heterogeneous study of solid tumors because most solid tumors express cytokeratin- 18.
  • the M30 sandwich ELISA has been used extensively in clinical trials as biomarkers of cell death induced by a variety of different cancer chemotherapeutic agents in a spectrum of different solid tumors.
  • the M65 sandwich ELISA assay which has also been used in clinical studies to detect increases in total cytokeratin 18 that can occur with tumor necrosis and disease progression, was used to differentiate tumor apoptosis from necrosis.
  • This Example is the first study of ONC201 , an investigational cancer therapy, in humans.
  • the primary objective of the study was to determine the RP2D of oral O C201 administered every 3 weeks to patients with solid tumors who have exhausted all treatment options.
  • no drug-related > grade 1 toxicities were observed at micromolar plasma concentrations that are effective in preclinical models in any patient. Due to the excellent safety profile of the drug, the study allowed progression to the next dose levels without requiring additional patient enrollments and was completed without digressing from the accelerated titration design.
  • This study determined 625 mg administered once every 3 w r eeks as the RP2D on the absence of toxicity and the fact that this dose achieves therapeutic plasma concentration.
  • This RP2D exceeds the saturation threshold observed at 375mg and thus does not require adjustment for body-surface-area to consistently achievable target blood levels. The RP2D has been confirmed in an expansion phase with an additional 10 patients evaiuable for safety.
  • the pharmacokinetic profile of ONC201 indicates significant absorption of the drug with oral administration that was rapid, as indicated by the 1.8 hour mean.
  • the PK parameters such as C ma x and AUC in the top dose cohort treated at the RP2D exceeded those associated with the NOAEL in GLP toxicology studies.
  • the observation that systemic exposure to ONC201 saturated at 2 dose levels below the RP2D is suggestive of saturation of absorption. Since saturation of absorption occurs at a dose that yields therapeutic plasma concentrations that are apparently well tolerated, this may function as a safety feature.
  • ONC201 is very well tolerated at the RP2D of 625 mg and exhibits signs of biological activity in patients with advanced solid tumors.

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Abstract

This disclosure relates to methods of treatment using compound (1) or analogs thereof, and pharmaceutically acceptable salts thereof. Also disclosed are compounds of formula (10): as defined in the specification, and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the same. Methods of treatment, such as for cancer, are provided that comprise administering the compounds and their salts to a subject in need of such treatment.

Description

7-BENZYL-4-(2-METHYLBENZYL)-2,4,6!7,8,9-HEXAHYDR01MlDAZO [l ,2-a]PYRIDQ[3,4-e]PYRIMIDIN-5( liT)-QNE, ANALOGS THEREOF, AND SALTS THEREOF AND METHODS FOR THEIR USE IN THERAPY
BACKGROUND OF THE INVENTION
[0001] TNF -related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that selectively induces apoptosis in cancer cells. TRAIL is a powerful inducer of apoptosis in a wide range of human cancer cell lines via pro-apoptotic death receptor 4 (DR4; TRAIL-Rl ) and death receptor 5 (DR5; TRAIL-R2) at the cell surface through engagement of the extrinsic or intrinsic apoptotic pathways. TRAIL plays a direct role in tumor suppression during immune surveillance but this anti-tumor mechanism is lost during the disease progression. The ability of TRAIL to initiate apoptosis selectively in cancer cells has led to ongoing clinical trials with administration of recombinan t TRAIL and the longer-li ved TRAIL- agonist antibodies targeting either of its two pro-apoptotic death receptors.
[0002] Despite its potency, recombinant TRAIL has efficacy-limiting properties such as short serum half-life, stability, cost, and delivery. Delivery of recombinant TRAIL or TRAIL-agonist antibodies to the brain is limited by inability of recombinant TRAIL and TRAIL-agonist antibodies to cross the blood-brain barrier. Accordingly, there is a continuing need for anti-cancer compositions and methods.
BRIEF SUMMARY OF THE INVENTION
[0003 In one aspect, pro vided herein are compounds of formula (10):
Figure imgf000002_0001
, wherein R¾ and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylaikyl, alkoxyalkyl, alkoxycarbonyl, aralkoxy, araikylthio, and acyl, radicals, wherein when R; represents CH2Ph, R2 does not represent CH2-((2-CH3)-Ph). In some embodiments, Ri and R2 are independently selected from the group consisting of H,
Figure imgf000002_0002
Figure imgf000002_0003
Chalky lthienyl,
Chalky lpyridinyl, and C1_4alkylpyrazinyl
Figure imgf000002_0004
Ci-dbenzyl-piperazine, Ci.4alkylthienyl,
Figure imgf000002_0005
C j ^alkylisoxazolidinyl,
Figure imgf000003_0001
and Cj-4aikylpyrazinyl are optionally substituted with Ci-4alkyl, hydroxy!, perhalogenated Ci -4alkyl, or halo. In some embodiments, R; and'or R.2 is a substituted or unsubstituted, arylalkyl or heteroarylalkyl. In some embodiments, the heteroarylalkyl is selected from
Figure imgf000003_0002
Ci.4alkylfuryl,
Cj -4alkyl-l ,2,4-thiadiazolyl,
Figure imgf000003_0003
Ci-4alkylisothiazolyl, Ci-4alkylimidazolyl,
Figure imgf000003_0004
Chalk Ipyrazinyl, Chalk Ipyrimidyl,
Ci-4alkylquinolyl, Ci_4alkylisoquinolyl,
Figure imgf000003_0005
Figure imgf000003_0006
Chalky lpurinyl,
Ci-4alkylcarbazolyl,
Figure imgf000003_0007
and Ci_4aIkylisoxazolyl. In some embodiments, Ri and'or R.2 is a substituted or unsubstituted, benzyl or phenylethyl. In some embodiments, Ri and/or R2 is a benzyl optionally substituted with one or more of the following substituents on the benzyl ring: X, -( 'I k -NO?, -QCH3, -C\. -CXH2, ί X Π. C2-C4 alkyl, -CX , -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p+i, -OCX3> -OCpU2pn, -Oi. rX.-r . ORm, SRffi, NR ,
NRmC(0)Rn, SORm, SO - R ' . C(0)Rm, and C(0)ORm;
Rm and R are independently selected from hydrogen or a d -C4 alkyl;
where p is an integer from 2 to 20 and X represents a halogen.
the structure of compound (90)
Figure imgf000003_0008
R.2 is as defined above, and wherein b2, R-bi' , b4, and Rbs are each independently selected from the group consisting of hydrogen, X, -CH3, -NO2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), ·(.'! K C' X : ) ··. -C(CX3)3, -C,,X Y . -OCX3) -OCpH2p-H , -OC ΓΧ γ . ORm, SRm, RmRn, NRffiC(0)Rn, SORm, S02Rra, C(0)Rra, and C(0)ORm;
Rm and R are independently selected from hydrogen or a C1 -C4 alkyl;
where p is an integer from 2 to 20 and X represents a halogen.
[0005] In one embodiment, compound (10) has the structure of compound (40)
Figure imgf000003_0009
as defined above, and wherein Raj , Rri2, a3, Ra45 and Ra5 are each independently selected from the group consisting of hydrogen, X, -CH3> -NO?., -OCH3, -CN, -CXII2, -CX2H, C2-C4 alkyl, -CX3, -Cl MCX -CH(CX3)2, -C(CX )3, -CpX2p-i !, -OCX3, -( )(.',.! : ·,. . -OCpX2p-i !, ORm, SRra, NRmRn, NRffiC(0)Rn, SORra, S02Rm, C(0)Rm, and C(0)ORm;
Rm and Rn are independently selected from hydrogen or a C1-C4 alkyl;
where p is an integer from 2 to 20 and X represents a halogen.
as the stmcture of compound (50):
Figure imgf000004_0001
rein Ri is as defined above, and wherein Rb is selected from the group consisting of X, -CH3, -N02, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p ; 1, -OCX3, -OCpH2p+1, -OCPX2p+i, ORm, SRra, NRn,Rn, NRn,C(0)Rn, SORm, S02Rm, C(0)Rm, and C(0)ORm; and wherein Ra!, Ra2, Ra4, and Raj are each independently selected from the group consisting of hydrogen, X, - CH3, -N02, -QCH3, -CN, -CXII2, -CX2H, C2-C4 alkyl, -CX3, -C I t ·( 'X ·. }. -CH(CX3)2, -C(CX3)3, -CPX2p 1, -OCX3, -OCpH2p H, -OCpX2p+i, ORm, SRm, NRmRn, RmC(0)Rn, SORra, S02Rm, C(0)Rm, and C(0)ORm;
Rm and Rn are independently selected from hydrogen or a C; -C4 alkyl;
where p is an integer from 2 to 20 and X represents a halogen,
[0007] In one embodiment, compound (10) has the structure of compound (80)
Figure imgf000004_0002
wherein Rai, Ra2, Ra3, Ra4, Ra5, Rbi,
Rb2, b3, Rb4, and R-b are each independently selected from the group consisting of hydrogen, X, -CH3, -NO2, -OCH , -CN, -CXI-I2, -CX2H, C2-C4 alkyl, -C'X :. -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p-K , -OCX :, -OCPH2p÷;, -OCpX2p- , ORm, SRra, NRmRn, RffiC(0)Rn, S0Rra, S02Rm, C(0)Rm, and C(0)ORm;
R™ and Rn are independently selected from hydrogen or a Ci-C4 alkyl;
where p is an integer from 2 to 20 and X represents a halogen. [0008] 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 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, hydrogensulphate, sulfates, phosphates, fumarates, succinates, oxalates and lactates, bisulfates, hydroxy!, 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-toluene-sulfonate, benzenesulfonate, methanesuifonate, 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 counter-ions such as methylamino, dimethylamino, diethylamino and triethylamino counter-ions. In one embodiment, the pharmaceutical composition comprises a hydrochloride di-sait or hydrobromide di-sait of a compound of formula (10). In some embodiments, a pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
10009] In some embodiments, a pharmaceutical composition o the present invention includes 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 a combination thereof. In an alternative embodiment, the second therapeutic agent is an a ti -angiogenic agent. In one embodiment, the a ti -angiogenic agent is bevacizumab. In one embodiment, the second therapeutic agent is administered as part of combination therapy to treat a patient. In one embodiment, details for the combination therapy- is included in a package insert for the compound of formula (10).
[0010] In some embodiments, the pharmaceutical composition is formulated for oral administration.
[0011 ] In another aspect, the present in vention pro vides methods of treatment. In one embodiment, the method of treatment comprises administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (10) or a pharmaceutically acceptable salt thereof.
[0012] In one embodiment, the method of treatment comprises 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 method of treatment comprises administering to the 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.
[0013] In some embodiments, the method of treatment further comprises administering an additional therapeutic agent. In one embodiment, the additional therapeutic agent includes 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 a combination thereof.
[0014] 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.
[0015] In one embodiment of the method of treatment, the subject undergoing treatment 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 congenital, sideropenic dysphagia, lichen planus, oral submucous fibrosis, solar elastosis, cervical dysplasia, leukoplakia, and eiythroplakia.
[0016] In one embodiment of the method of treatment, the pharmaceutical composition is administered via an oral administration route. In one embodiment, the pharmaceutical composition is administered via an administration route selected from the group consisting of: intravenous, rectal, nasal, pulmonary, epidural, ocular, otic, mtra-arterial, topical, intracardiac, intracerebroventricular, intradermal, intramuscular, intraperitoneal, intraosseous, intrathecal, intravesical, subcutaneous, transdermal, transmucosal, sublingual, buccal, vaginal, and inhaiationai routes of administration.
[0017] In one embodiment, the present invention provides a method of treating a subject having, or is at risk of having, brain cancer, the method comprising: administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount a compound of formula (10) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier,
[0018] In one embodiment, the present invention provides a method of treatment comprising administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (10) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable earner. [0019] 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 q first therapeutic agent including a compound of formula (10) or a pharmaceutically acceptable salt thereof;
(ii) waiting until a predetermined waiting time has elapsed after the time of administration of the first therapeutic agent to the subject; and
(iii) administering a second therapeutic agent to the subject, wherein the predetermined waiting time is chosen so as to obtain a delayed therapeutic effect of the first therapeutic agent without an increased risk or with a reduced risk of possible combined toxic effects of the first and second therapeutic agents.
|0020] 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 including a compound of formula (10) or a pharmaceutically acceptable salt thereof;
(ii) monitoring the level of the compound of formula (10) or a salt thereof or a metabolite thereof in the subject using pharmacokinetic profiling; and
(iii) administering a second therapeutic agent conditional on the level of the first therapeutic agent in the subject.
|0021] In another aspect, the present invention provides a method of, the method comprising:
(i) administering to the subject a first therapeutic agent including a compound of formula (10) or a pharmaceutically acceptable salt thereof; and
(ii) administering a second therapeutic agent conditional on the expected half life of the compound of formula (10) in the subject undergoing treatment.
[0022 In another aspect, provided herein are analogs of compounds of formula (10):
Figure imgf000007_0001
or of formula (1): (1) and their pharmaceutically acceptable salts, as well as processes of making the same. In one aspect, provided herein are methods of treatment. In one embodiment, the treatment method comprises administering to a subject a pharmaceutical composition, the composition comprising a pharmaceutically effective amount of a compound of formula (10) or of formula (1) or an analog therof, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition includes a a pharmaceutically acceptable carrier. In one embodiment, the subject undergoing treatment has, or is at risk of having, cancer. In one embodiment, the subject is a human.
[0023] Irs another aspect, the present in vention provides a method of treating a subject in need of such treatment, the method comprising:
(i) administering to the subject a first therapeutic agent including 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 conditional on adverse events from the first therapeutic agent having resolved or are resolving. In some embodiments, adverse events from the first therapeutic agent are related to the blood levels of that agent or metabolites thereof in the subject undergoing treatment.
[0024] In another aspect, the present invention provides a kit for monitoring of an analog of compound (1) (e.g., a compound of formula (10)) or a pharmaceutically acceptable salt thereof or a metabolite thereof in an individual treated with the analog of compound (1) or pharmaceutically acceptable salt thereof or metabolite thereof using pharmacokinetic profiling, the kit comprising a plurality of point-of-care devices or point of use devices capable of quantitating the drug in at least two samples or matrices suitable for storage of those samples prior to quantitation by a laboratory. In some embodiments, a kit further comprising instructions for collecting and/or storing the at least two samples.
[0025] In some embodiments, the treatment method comprises administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring levels of the compound or a pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of the compound or salt thereof is selected to maintain a concentration of the compound or a metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject of at least about 400 ng/mL for a therapeutic time period within 4 hours post-treatment. In some embodiments, the subject undergoing treatment has, or is at risk of having, cancer. In some embodiments, the treatment method further comprises the step of waiting for 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 a human.
[0026] In some embodiments, the treatment method comprises administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring levels of the compound or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of the compound or salt thereof is selected to obtain an AUG of the compound or a metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject of at least about 3,500 hr-ng/mL with a time period of 2, 6, 12, 24, 48, 72 or greater than 72 hours post-treatment or extrapolated to infinity.
[0027] In some embodiments, the treatment method comprises administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof; and (ii) monitoring levels of compound (1), the pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of the compound or salt thereof is selected to result in undetectable concentrations of the compound or a metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject at 3 days, 4 days, 5 days, 6 days, or 7 days post-treatment.
[0028] In some embodiments, the treatment method comprises (i) administering, over a first time interval (e.g. , 7 days), a plurality of doses of a therapeutic agent including a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof, wherein the plurality of doses is administered over a second time interval (e.g., two to five consecutive days for a first time interval of a week) within the first time interval; and (ii) repeating step (i) one or more additional times. In some embodiments, the subject undergoing treatment has, or is at risk of having, cancer. In some embodiments, the treatment method further comprises the step of waiting for 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 a human.
[0029] In some embodiments, the pharmaceutical composition is administered to a subject once daily. In some embodiments, the pharmaceutical composition is administered to a subject accoridng to an infrequent dosing regimen (e.g., administered once per week or less frequently). In some embodiments, the pharmaceutical composition is administered to a subject accoridng to a frequent dosing regimen (e.g., administered more than once per week). In some embodiments, the pharmaceutical composition is administered to a subject once weekly. In some embodiments, the pharmaceutical composition is administered to a subject once every four weeks. In some embodiments, the pharmaceutical composition is administered to a subject twice a week. In some embodiments, the pharmaceutical composition is administered to a subject three times a week. In some embodiments, the pharmaceutical composition is administered to a subject four times a week. In some embodiments, the pharmaceutical composition is administered to a subject once ever}' two weeks. In some embodiments, the pharmaceutical composition is administered to a subject once every three weeks. In some embodiments, the pharmaceutical composition is administered to a subject in a repeated cycle of once weekly, once ever}' two weeks, once every three weeks, once every four weeks or combinations thereof.
[0030] In one aspect, provided herein are methods of identifying whether a subject having a condition is likely to be responsive to a treatment regimen. In some embodiments, the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring RNA
modifications levels and/or expression or activity levels of one or more of the proteins from Tables 1 and 3 and/or the presence or absence of one or more mutations in at least one gene encoding one or more proteins from Tables 1 and 3 in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining whether the subject is likely to be responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard. In one aspect, provided herein are methods of providing a prognosis for a subject with a condition. In some embodiments, the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring RNA modifications levels and/or expression or activity levels of one or more of the proteins from Tables 1 and 3 and/or the presence or absence of one or more mutations in at least one gene encoding one or more proteins from Tables i and 3 in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining a prognosis for the subject, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
[0031] 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 N6-Methyladenosine (m6A). In one embodiment, the RNA modification is mbA mRNA methylation. In one embodiment, the subject is a human. In one embodiment, the subject is a domesticated pet, such as a cat or dog. 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.
[0032] In one aspect, provided herein are methods of identifying and treating a subject having a condition and who is likely to be responsive to a treatment regimen described herein. In some embodiments, the method comprises (i) identifying whether a subject having a condition is likely to be responsive to a treatment regimen described herein; and (ii) treating with the treatment regimen a subject determined likely to be responsive to that treatment regimen. 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.
[0033] In one aspect, provided herein are methods of assessing the effectiveness of or monitoring a subject having a condition and undergoing treatment according to a treatment regimen described herein. In some embodiments, the method comprises (i) obtaining a biological sample from the subject; (ii) measuring RNA modifications levels and/or expression or activity levels of one or more of the proteins from Tables 1 and 3 and/or the presence or absence of one or more mutations in at least one gene encoding one or more proteins from Tables 1 and 3 in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining whether the subject is responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
[0034] 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 A^-Methyladenosine (ni6A). In one embodiment, the RNA modification is m6A mRNA methylation. In one embodiment, the subject is a human. In one embodiment, the subject is a domesticated pet, such as a cat or dog. 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.
[0035] In one aspect, provided herein are methods for screening a potential therapeutic for a condition. In some embodiments, the method comprises (i) contacting a protein from Tables 1 and 3 with a test compound suspected of being a therapeutic for the condition; (ii) measuring the binding affinity or interaction of the test compound to the protein; and (iii) comparing the binding affinity or interaction of test compound to a pre-determined threshold, wherein an affinity or interaction of the test compound comparable to or greater than the threshold is indicative of a therapeutic for the condition. In some embodiments, the condition is cancer. In some embodiments, the pre-determined threshold is the affinity or interaction of compound (1) or an analog thereof to the protein. In some embodiments, the pre-determined threshold is the affinity or interaction of compound (1) to 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.
[0036] In one aspect, provided herein are methods for screening a potential therapeutic for a condition. In some embodiments, the method comprises (i) contacting a protein from Tables 1 and 3 with a reference compound under conditions where the reference compound binds to or interacts with the protein; (it) contacting the protein from Tables 1 and 3 with a test compound suspected of being a therapeutic for the condition; (iii) measuring the binding affinities or interactions of the reference and test compounds to the protein; and (iv) comparing the binding affinities or interactions 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 for the condition. In one embodiment, the reference compound is compound (1) or an analog thereof. In one embodiment, the reference compound is compound (I). In one embodiment, the condition is cancer. In one embodiment, the protein is an RNA Reader, e.g., YTHDF3. In one embodiment, the protein is an RN A Writer. In one embodiment, the protein is an RNA Eraser.
[0037] In one aspect, provided herein are methods for screening a potential therapeutic for a condition. In some embodiments, the method comprises (i) using a processor, modeling binding or interaction, if any, of a 3-dimensional structure of a test compound suspected of being a therapeutic for the condition to a 3-dimensional structure of a protein from Tables 1 and 3; (ii) using the processor, determining the binding affinity or interaction of the test compound structure to the protein structure; and (iii) using the processor, comparing the binding affinity or interaction of test compound to a pre-determined threshold, wherein an affinity or interaction of the test compound comparable to or greater than the threshold is indicati ve of a therapeutic for the condition. In one embodiment, the pre-determined threshold is the affinity or interaction of compound (1) or an analog thereof to the protein. In one embodiment, the pre-determined threshold is the affinity or interaction of compound (1) to the protein. In some embodiments, the condition is cancer. In one embodiment, the protein is an RNA Reader, e.g. , YTHDF3. In one embodiment, the protein is an RN A Writer. In one embodiment, the protein is an RNA Eraser.
[0038] In one aspect, provided herein are methods for screening a potential therapeutic for a condition. In some embodiments, using a processor, the method comprises (i) using a computational docking method to model binding or interaction, of one or more 3-dimensional structures (conformations) of a test molecule suspected of being a therapeutic for the condition to a 3-dimensional structure or model of a protein from Tables 1 and 3; (ii) using the computational method to estimate the binding or interaction, if any, of a 3-dimensional structure of of the test molecule structure to the structure or model of the protein; and (iii) using the computational method to compare the binding affinities or interactions of the reference and test compounds to the protein; and (iv) using the processor, comparing the binding affinities or interactions of the reference and test compound structures, wherein a comparable or stronger affinity or interaction of the test compound relative to the reference compound is indicative of a therapeutic for the condition. In one embodiment, the reference compound structure is the structure compound (1) or an analog thereof. In some embodiments, the reference compound structure is the structure is compound (1). In some embodiments, the condition is cancer. In some embodiments, the protein is an RNA Reader, e.g., YTHDF3. In some embodiments, the protein is an R A Writer. In some embodiments, the protein is an RNA Eraser.
[0039] In one aspect, provided herein are methods of treating a subject having a condition, such as cancer, by administering agents that modulate the transcription, translation, or biological activity of YTHDF3 or other proteins in Tables 1 and 3 or nucleic acids encoding these proteins. The agents include, but are not limited to siRNA, antisense nucleic acids, ribozymes, triple-helix-forming agents, antibodies, and polypeptides, as well as small molecule compounds. Preferrably, the si RNA. antisense nucleic acids, ribozymes, triple-helix-forming agents inhibit the translation or transcription of one or more genes in Tables 1 and 3. To accomplish this, oligonucleotides used are designed on the basis of relevant sequences unique to the target gene. A variety of gene therapy approaches may be used in accordance with the invention to modulate expression of the genes in Tables 1 and 3, For example, antisense DNA molecules may be engineered and used to block translation of YTHDF3 mRNA in vivo. Alternatively, ribozyme molecules may be designed to cleave and destroy the YTHDF3 mRNAs in vivo. Alternatively, oligonucleotides designed to hybridize to the 5' region of the YTHDF3 gene (including the region upstream of the coding sequence) and form triple helix structures block or reduce transcription of the YTHDF3 gene. In yet another alternative, nucleic acid encoding the full length wild-type YTHDF3 message may be introduced in vivo into cells which otherwise would be unable to produce the wild-type YTHDF3 gene product in sufficient quantities or at all,
[0040] In one embodiment, the pharmaceutical composition includes a pharmaceutically acceptable carrier. In some embodiments, the subject has, or is at risk of having, cancer. In some embodiments, the subject is, or is at risk of being, infected wth a virus. In some embodiments, the subject is a human. In some embodiments, the dose 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 total cytokeratin-18. determining whether the treatment regimen should continue based on the results of the cleaved and/or total cytokeratin-18 assays. In some embodiments, a treatment regiment described herein further comprises the step of administering a second therapeutic agent, wherein compound (1), the pharmaceutically acceptable salt thereof, or the analog thereof is administered before, simultaneously, or after the second therapeutic agent.
[0041] In one aspect, pro vided herein are methods of identifying whether a subject having a condition is likely to be responsive to a treatment regimen described herein. In some embodiments, the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, or DR5 in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining whether the subject is likely to be responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard. In another aspect, provided herein are methods of assessing the effectiveness of a treatment regimen described herein, monitoring, or providing a prognosis for a subject with a condition. In some embodiments, the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, or DR5 in the sample in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining a prognosis or determining whether the subject is responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard. 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 subject is, or is at risk of being, infected wth a virus. In some embodiments, the treatment regimen comprises administering an effective amount of compound (1 ), a pharmaceutically acceptable salt thereof, or an analog thereof.
[0042] In one aspect, provided herein are methods of identifying whether a subject having a condition is likely to be responsive to a treatment regimen described herein. In some embodiments, the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining whether the subject is likely to be responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard. In another aspect, provided herein are methods of assessing the effectiveness of a treatment regimen described herein, monitoring, or providing a prognosis for a subject with a condition. In some embodiments, the methods comprises (i) obtaining a biological sample from the subject; (ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample; (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining a prognosis or determining whether the subject is responsive to the treatment regimen, based on the levels measured and/or mutations found in the sample to those for the pre-determined standard. 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 regimen comprises 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 D2-3ike family of dopamine receptors.
[0043] In one aspect, provided herein are methods for screening a potential therapeutic for a condition. In some embodiments, the method comprises (i) contacting at least one G protein- coupled receptor (GPCR) with a test molecule suspected of being a therapeutic for a cond ition;
(ii) measuring the binding affinity, interaction or GPCR signalling of the test compound to the GPCR; and (iii) comparing the binding affinity or interaction of test molecule to a pre-determined threshold, wherein GPCR antagonism or GPCR signaling antagonism of the test molecule comparable to or greater than the threshold is indicative of a therapeutic for the condition. In one embodiment, the condition is cancer. In one embodiment, the pre-determined threshold is the GPCR antagonism or GPCR signaling antagonism of compound (1) or a pharmaceutically acceptable salt thereof, or an analog thereof.
[0044] In one aspect, provided herein are methods for screening a potential therapeutic for a condition. In some embodiments, the method comprises (i) contacting at least one dopamine receptor with a test molecule suspected of being a therapeutic for a condition; (ii) measuring the binding affinity or interaction of the test molecule to the at least one dopamine receptor; and
(iii) comparing the binding affinity or interaction of the test molecule to a pre-determined threshold, wherein inhibition of the at least one dopamine receptor by the test molecule comparable to or greater than the threshold is indicative of a therapeutic for the condition. In some embodiments, the condition is cancer. In some embodiments, the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3. In some embodiments, inhibition of the D2-like family of dopamine receptors is indicative of a therapeutic for the condition. In some embodiments, inhibition of both DRD2 and DRD3 dopamine receptors is indicative of a therapeutic for the condition. In some embodiments, the pre-determined threshold is the inhibition of the at least one dopamine receptor by compound (1) or a pharmaceutically acceptable salt thereof, or an analog thereof to the dopamine receptor.
[0045] In one aspect, provided herein are methods for screening a potential therapeutic for a condition. In some embodiments, using a processor, the method comprises (i) using a computational docking method to model binding or interaction, if any, of one or more
3 -dimensional structures (conformations) of a test molecule suspected of being a therapeutic for the condition to a 3-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 structure to the structure or model of the at least one dopamine receptor; and (iii) using the computational method to compare the binding affinity or interaction of the test molecule to a pre-determined threshold, wherein inhibition of the at least one dopamine receptor by the test molecule comparable to or greater than the threshold is indicative of a therapeutic for the condition, one embodiment, the condition is cancer. In some embodiments, the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3. one embodiment, inhibition of the D2--Iike family of dopamine receptors is indicative of a therapeutic for the condition. In one embodiment, inhibition of both DRD2 and DRD3 dopamine receptors is indicative of a therapeutic for the condition. In one embodiment, the pre-determined threshold is the inhibition of the at least one dopamine receptor by compound (1) or a pharmaceutically acceptable salt thereof, or an analog thereof to the dopamine receptor. In one embodiment, a pharmacophore modeling approach may be used to compare different dopamine antagonist compounds in three dimensions as described in Hogberg & Norinder, Chapter 3. Theoretical and Experimental Methods in Drug Design applied on 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.
[0046] In one aspect, provided herein are meth ods of treating and assessing the effectiveness of a treatment in a subject having a condition. In some embodiments, the method comprises (i) treating the subject according to a treatment method described herein (ii) assessing as decribed herein the treatment's effectiveness. In some embodiments, the subject has, or is at risk of having, cancer. In one embodiment, the treatment regimen comprises administering an effective amount of compound (1 ) or a pharmaceutically acceptable salt thereof or an analog thereof.
[0047] The foregoing summary, as well as the following detailed description of embodiments of the compositions and methods of treatment, 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 DESCRIPTION OF THE DRAWINGS
[0048] The foregoing summary, as well as the following detailed description of embodiments of the present invention, will be better understood when read in conjunction with the appended drawings of an exemplary embodiment. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.
[0049] In the drawings:
[0050] Figure 1 illustrates a dose response relation showing effects of various concentrations of compound (1) on viability of tumor and normal ceils; and
[0051 ] Figure 2 illustrates cell viability assay in human fetal lung fibroblast (MRC-5) cells following 72 hour treatment with compound (1 ).
[0052] Figure 3 illustrates antagonism by ONC201 of dopamine receptor (DRD1 , DRD2S, DRD2L, DRD3, DRD4, and DRD5).
[0053] Figure 4 illustrates soluble prolactin detected by an ELISA assay in the peripheral blood of advanced solid tumor patients at baseline and following a single ONC201 dose (PO 125-625 mg). Sampling time points post-treatment include 6 hours, 1, 2, 7, and 21 days post-treatment.
[0054] Figure 5 shows the mean ONC201 plasma concentrations versus time following the first dose of ONC201. Concentrations are shown as (A) the mean for each dose cohort, or (B) for individuals treated at 625 mg. Error bars indicate standard deviation.
[0055] Figure 6 illustrates individual measurements of ONC201 (A) AUC and (B) Cmax versus dose. * Anticipated dose proportionality line based on men for 625 mg dose group.
DETAILED DESCRIPTION OF THE INVENTION
[0056] Scientific and technical terms used herein are intended to have the meanings commonly understood by those of ordinary skill in the art. Such terms are found defined and used in context in various standard references illustratively including J. Sambrook and D. W. Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press; 3rd Ed., 2001 ; F. M. Ausubel, Ed,, Short Protocols in Molecular Biology, Current Protocols; 5th Ed., 2002; B. Alberts et al, Molecular Biology of the Cell, 4th Ed., Garland, 2002; D. L. Nelson and M. M. Cox, Lehninger Principles of Biochemistry, 4th Ed., W.H, Freeman & Company, 2004; Engelke, D. R„ RNA Interference (RNAi): Nuts and Bolts of RNAi
Technology, DNA Press LLC, Eagleville, Pa., 2003; Herdewijn, P. (Ed.), Oligonucleotide Synthesis: Methods and Applications, Methods in Molecular Biology, Humana Press, 2004; A. Nag}'', M. Gertsenstein, K. Vintersten, R. Behringer, Manipulating the Mouse Embryo: A Laboratory Manual, 3rd edition, Cold Spring Harbor Laboratory Press; Dec. 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, as well as U.S. Patent No. 8,673,923. The content of each of the foregoing references is hereby incorporated by reference in its entirety .
[0057] The singular terms "a," "an," and "the"' are not intended to be limiting and include plural referents unless explicitly stated or the context clearly indicates otherwise.
[0058] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).
[0059] When any variable (e.g., R4) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R4 moieties, then the group may optionally be substituted with up to three R4 moieties and R4 at each occurrence is selected independently from the definition of R \ Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
[0060] When an atom or chemical moiety is followed by a subscripted numeric range (e.g., Ci_6), it will be appreciated that this is meant to encompass each number within the range as well as all intermediate ranges. For example, "Ci-e alkyl" is meant to include alkyl groups with 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.
[0061 ] 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, Cj _6 alkyl is intended to include Q, C2, C3, C4, Cs, and C alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl s-butyl, t-butyl, n-pentyl, s-pentyl, neopentyl and n-hexyl. In certain embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., Ci -Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched chain alkyl has four or fewer carbon atoms. Likewise, cycloalkyls have from three to eight carbon atoms in their ring structure, and in other embodiments, cycloalkyls have five or six carbons in the ring structure. Most preferred is (Cj -C6)alkyl, particularly ethyl, methyl, isopropyi, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl. [0062] As used herein, the term "substituted aikyl" means alk l as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, -M L. -N(CH3)2, - ( ( ))( )! I. trifluoromethyl, -C X. -C'( ( ))( )( ( ' -( .,'Hi!k i. -C(=0)NH2, -SO2 H2, -C(=NH)NH2, and -N02, preferably containing one or two substituents selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)0H, more preferably selected from halogen, alkoxy and -OH. Examples of substituted alky Is include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.
[0063] Unless the number of carbons is otherwise specified, "lower alkyl" includes an alkyl group, as defined above, but having from one to six carbon atoms, preferably one to four, in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of 2-6 carbon atoms and preferably 2-4 carbon atoms.
[0064] "Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain 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, decenyi), branched-chain alkenyl groups, cycloalkenyl (e.g., aiicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, eycloheptenyl, eyeiooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cvcloalkyl or cycloalkenyl substituted alkenyl groups. In certain embodiments, a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C -Ce for straight chain, C3-C6 for branched chain). Likewise, cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and in some embodiments, cycloalkenyl groups have five or six carbons in the ring structure. The term "C2-Ce" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.
[0065] "Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, and cvcloalkyl 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-C6for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C0" includes alkynyl groups containing three to six carbon atoms.
[0066] As used herein, "cycloalkyl" refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In one embodiment, the cycioalkyl group is saturated or partially unsaturated. In another embodiment, the cycioalkyl group is fused with an aromatic ring. Cycioalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycioalkyl groups include, but are not limited to, t
Figure imgf000020_0001
Monocyclic cycloalkyls include, but are not limited to, cyclopropyi, cyciobutyi, cyclopentyl, cyclohexyl, cycioheptyl, and cyclooctyi. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbornane. The term cycioalkyl includes "unsaturated nonaromatic carbocyclyl" or "nonaromatic unsaturated carbocyclyl" groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon carbon double bond or one carbon carbon triple bond.
|0068] As used herein, "cycloalkylalkyl" refers to an alkyl group substituted by a cycioalkyl group. Example cy cloalkylalky l groups include cyclopropylalkyl, cyclohexyialkyl, and the like.
[0069] As used herein, "heterocvcloalkyi" refers to a non-aromatic heterocycle where one or more of the ring-forming atoms can be a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles. Example heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, ,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyi, oxazolidinvL thiazoiidinyl, imidazolidinyl, and the like. Also included in the definition of heterocycloalkyl can be moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example quinolyl, isoquinolyl, and benzo derivatives of heterocycles. A heterocycloalkyl group having one or more fused aromatic rings are attached though either the aromatic or non-aromatic portion. Also included in the definition of heterocycloalkyl can be moieties where one or more ring-forming atoms can be substituted by 1 or 2 oxo or sulfide groups. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds, in some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
[0070] As used herein, 'heterocycloalkylalkyi" refers to an alkyl group substituted by a heterocycloalkyl group. Example heterocycloalkylalkyi groups include morpholinoalkyl and piperazinylalkyl, and the like.
[0071] As used herein, "aryl" refers to monocyclic or poly cyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like, in some embodiments, an aryl group has from 6 to about 20 carbon atoms.
[0072] As used herein, "arylalkyl" refers to an alkyl group substituted by an aryl group. Example arylalkyl groups include benzyl and phenylethyl.
[0073] As used herein, a "heteroaryl" group refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) 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 without limitation, pyridyl, "N-oxopyridyl, pyrimidinyl, pyrazinyi, pyridazinyi, triazinyl, furyl, quinoiyl, isoquinoiyl, thienyi, imidazolyl, thiazoiyi, indoiyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pvrazolyl, triazolvl, tetrazoiyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyi, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in farther embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, I to about 3, or I to 2 heteroatoms.
[0074] As used herein, a "heteroarylalkyl" group refers to an alkyl group substituted by a heteroaryl group. An example of a heteroarylalkyl group is pyridylmethyl.
[0075] As used herein, "halo" or "halogen" refers to a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. The term "perhalogenated" refers to a moiety w erein all hydrogens are replaced by halogen atoms.
[0076] The term "haloalkyl" refers to alkyl moieties having a halogen atom replacing a hydrogen atom on one or more carbons of the hydrocarbon backbone. Ci -Ce haloalkyl is intended to include a straight chain or branched alkyl having six or fewer carbon atoms in its backbone and a halogen atom replacing a hydrogen atom on one or more carbons of the hydrocarbon backbone.
[0077] The term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Cj-Ce alkoxy refers to moieties having six of few carbon atoms in the hydrocarbon backbone. Examples of alkoxy groups (or alkoxyl radicals) include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Preferred are (Ci-C3) alkoxy, particularly ethoxy and methoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups.
[0078] The term "hydroxy" or "hydroxy!" includes groups with an -OH or -0~.
[0079] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to deri vatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to 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 in vention include the 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 which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the tree acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are 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, Selectio and Use, 2na Revised edition, Weirmeim/Zurich:Wiley-VCH/VHCA (2011), each of which is incorporated herein by reference in its entirety.
[0080] Examples of suitable inorganic acids include hydrochloric acid, sulphuric acid, phosphoric acid, or hydrobromic acid, while examples of suitable organic acids can include carboxylic acid, sulpho acid, or sulphonic acid, 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, cirmamic 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, methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, ethane-1 ,2- disulphonic acid, benzenesulphonic acid, 4-methylbenzenesulphonic acid or naphthalene-2-sulphonic acid. Examples of suitable inorganic bases can include sodium hydroxide, potassium hydroxide and ammonia, while examples of suitable organic bases are amines, e.g., tertiary amines, such as trimethylamine, triethylamine, pyridine, NN-dimethylaniline, quinoiine, isoquinoiine, a-picoline, β-picoline, γ-picoline, quinaldine, or pyrrolidine.
L COMPOUND (1 ), SALTS THEREOF AND SYNTHESES THEREOF
[0081] The inventors have found in in vitro models, in animal models, and in human clinical trials that ONC201 (compound (1)) has broad anti-cancer activity, low toxicity including few, if any, adverse effects, low genotoxicity, and high bioavailability including oral bioavailability. These features allows ONC 201 and various analogs to be particularly well suited for a variety of applications.
|0082 In one aspect, the present invention provides compound (1):
Figure imgf000023_0001
, analogs thereof, and pharmaceutically acceptable salts thereof, as well as processes of making the same. Compound (1) can be prepared by the synthetic process illustrated in Scheme 1 below.
Figure imgf000023_0002
I
Figure imgf000023_0003
if)
[0083] In one embodiment, synthesis of a dihydrochloride salt of compound (1) starts with commercially available intermediary N-Benzyl-3-carbomethoxy-4-piperidone hydrochloride, compound (3). In one embodiment, the synthetic process includes neutralizing intermediary compound (3) with a base (Step 1) to produce compound (4), a free base. In one embodiment, the synthetic process includes neutralizing intermediary compound (3) with an inorganic base to produce compound (4). In one embodiment, the synthetic process includes neutralizing intermediary compound (3) with an organic base to produce compound (4). In one embodiment, intermediary compound (3) is neutralized in the presence of an alcohol. For example, intermediary compound (3) is neutralized in the presence of n-butanol. In one embodiment, intermediary compound (3) is neutralized in the presence of at least one organic solvent. For example, intermediary compound (3) is neutralized in the presence of n-butanol and/or ethyl acetate. In one embodiment, intermediary compound (3) is neutralized in the presence of a base and at least one organic solvent. For example, intermediary compound (3) is neutralized in the presence of NaHC03 and n-butanol. In one embodiment, intermediary compound (3) is neutralized in the presence of n-butanol and triethyl amine (Et3N).
[0084] In one embodiment, the synthetic process includes reacting compound (4) with compound (5) (Step 2) to produce intermediary compound of (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 refluxing heating compound (4) and compound (5) in the presence of a solvent. In one embodiment, the reaction in Step 2 includes use of Dean-stark trap to remove water and/or methanol (MeOH) formed in the reaction.
[0085] 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).
[0086] In one preferred embodiment, the syn thetic process for the preparation of the di -hydrochloride salt of compound (1) is as illustrated in the following Scheme 2.
Figure imgf000025_0001
31
Figure imgf000025_0002
II. TNF-RELATED APOPTOSIS-JL DUCI1NG LIGAND ("TRAIL")
[0087] TRAIL protein can be assayed in a test sample obtained from a subject to detect TRAIL expression induced by the compounds and their salts described herein. Immunoassays can be used to assay TRAIL in a sample, including, but not limited to, enzyme-linked immunosorbent assay (ELISA), enzyme- linked immunofiltration assay (ELIFA), flow cytometry, immunoblot, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescent immunoassay (LIA), fluorescent immunoassay (FIA), and radioimmunoassay. Assay methods may be used to obtain qualitative and/or quantitative results. Specific details of suitable assay methods for both qualitati ve and quantitative assays of a sample are described in standard references, illustratively including 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 Deri vatives, Basics: From Background to Bench, BIOS Scientific Publishers, 2000; B. K. C. Lo, Antibody
Engineering: Methods and Protocols, Methods in Molecular Biology, Humana Press, 2003; F. M. Ausubei et al, Eds., Shoxt Protocols in Molecular Biology, Current Protocols, Wiley, 2002; S. Klussman, Ed., The Aptarner Handbook: Functional Oligonucleotides and Their
Applications, Wiley, 2006; Ormerod, M. G., Flow Cytometry: a practical approach, Oxford University Press, 2000: Givan, A. L., Flow Cytometry: first principles, W ley, New York, 2001 ; Gorczyca, W., Flo Cytometry in Neoplastic Hematology:
morphologic-immunophenotypic correlation, Taylor & Francis, 2006; Crowther, J. R., The ELISA Guidebook (Methods in Molecular Biology), Humana Press, 2000; Wild, D., The Immunoassay Handbook, 3'"d Edition, Elsevier Science, 2005, and J. Sambrook and D. W. Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 3rt ed„ 2001.
[0088] Examples of protocols for assaying and analyzing a sample for TRAIL for the purpose of detection of an effect of a pharmaceutical composition are described in U.S. Patent 8,673,923 to Wafik S. El-deiry et a!., which is incorporated by reference herein in its entirety.
[0089] In one embodiment, TRAIL assays are used to monitor a subject. Thus, for example, a test sample is obtained from the subject before treatment with a pharmaceutical composition and at one or more times during and/or following treatment in order to assess effectiveness of the treatment. In a further example, a test sample is obtained from the subject at various times in order to assess the course or progress of disease or healing. In one embodiment, death receptors can also be analyzed from circulating tumor cells to see if the administration of a compound or its salt described herein increases the amount or type of death receptors.
[0090] Cancers treated using methods and compositions described herein are characterized by abnormal cell proliferation including, but not limited to, pre- neoplastic hyperproliferation, cancer in-situ, neoplasms and metastasis. Methods and compositions described herein can be used for prophylaxis, as well as amelioration of signs and/or symptoms of cancer. The terms "treating" and "treatment" used to refer to treatment of a cancer in a subject include:
preventing, inhibiting or ameliorating the cancer in the subject, such as slowing progression of the cancer and/or reducing or ameliorating a sign or symptom of the cancer. Examples of cancers treated using methods and compositions described herein include, but are not limited to, breast cancer, CNS cancers, colon cancer, ovarian cancer, prostate cancer, leukemia, lung cancer, and lymphoma.
III. COMPOUND (10) AND SALTS THEREOF
[0091 ] In one aspect, provided herein are compounds and related salts of compound (10) and processes of making the same. Persons skilled in the art will understand that the general principles and concepts described herein in conjunction with compound (1 ) and salts thereof, including principles and concepts related to methods and pharmaceutical compositions, apply with equal force to compounds of formula (10) and salts thereof. In some embodiments, provided herein are compounds represented by formula (10)
Figure imgf000027_0001
, wherein R¾ and R? independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroc cloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxvcarbonvl, aralkoxy, aralkylthio, and acyl radicals, wherein when Rj represents CH2Ph, R2 does not represent CH2-((2-CH3)-Ph.
[0093] Irs some embodiments, Ri and R2 are independently selected from the group consisting of H, Ci-4alkylphenyl, Ci-aalk
Chalky lthienyl, Chalky lisoxa
Figure imgf000027_0002
C1-4alkylphenylketone,
Figure imgf000027_0003
Ci_4alkylpyridinyl,
Cj.ialkylisoxazolidinyl,
Figure imgf000027_0004
are optionally substituted with
Figure imgf000027_0005
hydroxyl, perhalogenated or halo. In some embodiments, Ri and/or R2 is a substituted or unsubstituted, arylalkyl or
heteroarylalkyl. In some embodiments, the heteroarylalkyl is selected from Ci-4alkylpyiTolyl,
Figure imgf000027_0006
Chalky 1-1 ,2,4-thiadiazolyl, Ci-4alkylpyrimidyl,
Figure imgf000027_0007
Ci_4alkylisothiazoly], Chalk limidazolyl,
Ci-aalkylpyrazinyl, Chalky lpyrimidyl, Ci.dalkylquinolyl, Chalk lisoquinolyl,
C i -ialkylthiophenyl, C j.4a3kylbenzothienyi,
Figure imgf000027_0008
C i-4alky ipyrazolyl, Ci-4a3kylindolyl, C
Figure imgf000027_0009
and
Figure imgf000027_0010
[0094] In some embodiments, Ri and/or R? is a benzyl optionally substituted with one or more of the following substituents on the benzyl ring: X, -CH3, -NO?., -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, ~C(CX3)3, -CPX2p , -OCX3, -OCPH2p i !, -OCpX2p+!, ORm, SRm, NRraR", RmC(0)Rn, SORm, S02Rm, C(0)Rm, and C(0)ORra; Riri and R" are independently selected from hydrogen or a C1 -C4 alkyl; and where p is an integer from 2 to 20 and X represents a halogen, including a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
[0095] In some embodiments, Ri is selected from the group consisting of 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-pyridiny3, CH2-4-methyl-2-thiazolyl,
CH2-2-pyrazinyl, CH2CH2Ph, CH2CH2(4-N-benzyl-piperazine), CH2-(2,4-di F-Ph), C! l - ί -..4- di Cl-Ph), CH2-(3,4-di F-Ph), CH2-(3,5-di F-Ph), CH2 »((2-CH3)»Ph),
CH2CH(OH)Ph, (4-F-Ph)-4-oxobut l, CH2CH2NHCOOC(CH3)3, CH2CH2CH2NH2, and
CD i (.1 ) . In some embodiments, R2 is selected from the group consisting of H, CH3, CH2Ph, CH2-(4-CF -Ph), CH2-((2-Cl)-Ph), CH2-((2-F)-Ph), CH2-(2-thienyl), CH2CH2Ph,
CH2CH2(4-N-benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-(2,4-di F-Ph), CH2-(2,4-di Cl-Ph), CH2-(3,4-di Cl-Ph), CH2-(3,4-di F-Ph), CH2-(3,5-di F-Ph), CH2-((2-CH )-Ph), CH2(2-CH3, 4-F-Ph), CH2-((4-OCH3)-Ph), CH2-(3-pyridinyl), CH2-(3-isoxazolidinyl),
CH2CH2-(4-morpholinyI), CH2-(2-F, 4-CF3-Ph), CH2CH(OH)Ph, (CH2)3CO-4F-Ph, ,
(4-F-Ph)-4-oxobutyl, CH2CH2NHCOOC(CH3)3> CH2CH2CH2NH2, and CD2C6D5.
[0096] In some embodiments, Ri is a hydrogen. In some embodiments, Ri is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethvi group. In some embodiments, the arylalkyl is substituted with
Figure imgf000028_0001
hydroxy!, perhalogenated C 4aikyi. or halo.
[0097] In one embodiment, R2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethvi group. In one embodiment, the arylalkyl is substituted with Ci-4alkyl,
Ci-4alkoxyl, hydroxyl, perhalogenated
Figure imgf000028_0002
or halo. 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 an unsubstituted
heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In one embodiment, R2 is a substituted or an unsubstituted heteroarylalkyl, such as an
isoxazolidinylmethyl or pyridylmethyl group. In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is substituted with Cj ^alkyl, Ci-4alkoxyl, hydroxyl, perhalogenated Cj ^alkyl, or halo. In one embodiment, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, -Cl¾, -CF3, and -OCH3.
[0098] In one embodiment, compound (10) has the structure of compound (80):
Figure imgf000028_0003
wherein Rai, Ra2, R^, Ra4, Ra5, Rbi,
Rb2, Rbs, b4, and Rbs are each independently selected from the group consisting of X, -CH3, -N02> -OCH3, -C , -CX1¾, -CX2H, ( ···( alkyl, -CX3> -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p ;-i, -OCX3, -OCpH2p+ 1, -( )( rX v. · . ORm, SRrs, NRmRn, NRmC(0)Rn, SORm, S02Rrs, C(0)Rm, and C(0)OR™; R™ and R" are independently selected from hydrogen or a C1 -C4 alkyl; and where p is an integer from 2 to 20 and X represents a halogen. [0099] In one embodiment, compound (10) has the structure of compound (90)
Figure imgf000029_0001
wherein R? is as defined above, and wherein Rbi,
Rb2, b3, Rb4, and R ¾ are each independently selected from the group consisting of X, -CH3, -N02, -OCH3, -C , -CXH2, -CX2H, ( ·-( ., alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p;-i, -OCX3, ~OCpH2p+i, -OCpX2p;-i, ORm, SR ' . NRmRn, NRmC(0)Rn, SORm, S02Rm, C(0)Rm, and C(0)ORm; R™ and Rn are independently selected from hydrogen or a Cj -C4 alkyl; and where p is an integer from 2 to 20 and X represents a halogen.
[00100] In one embodiment, compound (10) has the structure of compound (40)
Figure imgf000029_0002
(40), wherein i is as defined above, and wherein Rai, Ra2, Ra3, Ra4, and Ras are each independently selected from the group consisting of hydrogen, X, -CH3, -N02, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX )3, -CpX2p- , -OCX3, ·()(.·,.! 1 ·Γ . -OCpX2p- , ORra, SRra, NRffiRn,
NRraC(0)R" SORm, S02R"', C(0)Rm, and C(0)ORm; R™ and R" are independently selected from hydrogen or a C1-C4 alkyl; and where p is an integer from 2 to 20 and X represents a halogen. In one embodiment, R¾ is a hydrogen. In one embodiment, Ri is a substituted or an imsubstituted arylalkyl, such as a benzyl or phenylethyl group. In one embodiment, the arylaikyl is substituted with Ci-4alkyl, C;_4aikoxyl, hydroxyl, perhalogenated Ci_4aikyi, 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, e.g., a fluorine substituent at an ortho or para position. In one embodiment, the benzyl is substituted with two halogen substituents, e.g., fluorine substituents at both meta positions.
[OOlOlf In one embodiment, compound (40) has the structure of compound (45):
Figure imgf000030_0001
are as defined above. In one embodiment, the benzy l is substituted with one or more halogens. In some embodiments, the benzyl is substituted with one or more substituents selected from the group consisting of halo, -CH , -CF , and -OCH3. In one embodiment, Ra! or Ras is a halogen, e.g. , fluorine. In one embodiment, both Ra2 or Ra are halogen, e.g. , fluorine, substituents.
[00102] In one embodiment, compound (10) has the structure of compound (50)
Figure imgf000030_0002
wherein Ri is as defined above, and wherein is selected from the group consisting of X, -CH3, -N02, -OCH3, -CN, -CXH2, -CX2H, Q2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p+i, -OCX3, -OCpH2p+i, -OCpX2p÷1, ORm, SRm, RmRn, NRmC(0)Rn, SORm, S02Rffl, C(0)Rffl, and C(0)ORm; Rffi and Rn are independently selected from hydrogen or a C1-C4 alkyl; and where p is an integer from 2 to 20 and X represents a halogen and wherein Ra-. , Ra2, Ra4, and as are each independently selected from the group consisting of hydrogen, X, -CH3, -NQ2, -OCH3, -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p+1, -OCX3, -OCpH2p i !, -OCpX2pH, ORm, SR™, XR.:rR. . N R:Ti O)R: . SOR™, S( ),R !:. '(t ) ! , and C(0)ORra; Rm and R. are independently selected from hydrogen or a C1-C4 alkyl: and where p is an integer from 2 to 20 and X represents a halogen. In one embodiment, R; is a hydrogen. In one embodiment, Ri is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In one embodiment, the arylalkyl is substituted with
Figure imgf000030_0003
hydroxy!, periialogenated or halo. In one embodiment, b is selected from the group consisting of halo, -CH3, -CF3, and -OCH3, In one embodiment, one or more of Rai, Ra2, Ra4, and Ra is selected from the group consisting ofhalo, -CH3, -CF3, and -OCH3. In one embodiment, Ra!, Ra2, R_a4, and as are hydrogen, and Rb is selected from the group consisting of alo, -CH3, -CF3, and -OCH3. In one embodiment, Rb is a halogen, e.g. , fluorine, and Rai is a methyl. In one embodiment, R is a fluorine or chlorine, and R.a2 is a fluorine or chlorine. In one embodiment, b is CF3. In one embodiment, R is -OCH3. In one embodiment, R¾ is a chlorine and aj is a chlorine. [00103] In one embodiment, compound (50) has the structure of compound (55):
Figure imgf000031_0001
Rai, ]½, Ra4, Ras, a d R-b are as defined above. In one embodiment, Rb is selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, one or more of Rai, Ra2, a4, and Ra< is selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, Rai, Ra2, Ra4, and a5 are hydrogen, and ¾ is selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R¾ is a halogen, e.g. , fluorine, and Ral is a methyl. In one embodiment, Rj, is fluorine or chlorine, and Ra? is a fluorine or chlorine. In one embodiment, R is CF . In one embodiment, R¾ is OCH . In one embodiment, Rb is a chlorine and Rai is a chlorine.
[00104] In one embodiment, compound (10) has the structure of compound (60)
Figure imgf000031_0002
i is a hydrogen. In some embodiments, i is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, Ri is a substituted or an unsubstituted heterocycloalkylalkyi. or a substituted or an unsubstituted heteroarylalkyl, such as an CH2-(2-thienyl), CH2-(3-thienyl), CH2-2-pyridinyl, CH2-3-pyridinyl, CH2-4-methyl-2-thiazolyl, CH2-2-pyrazinyl,
CH2CH2(4-N-benzyl-piperazine), CH2-(3-isoxazolidinyl),
Figure imgf000031_0003
In one embodiment, the arylalkyl is substituted with
Figure imgf000031_0004
hydroxy!, perhaiogenated
Figure imgf000031_0005
or halo. In one embodiment, the benzyl is substituted with one or more halogens. In some embodiments, the 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, the benzyl is substituted at the para position with a substituent selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In one embodiment, R \ is
fluoroplienyloxobutyi or hydroxyphenylethyl Scheme 3 illustrates the synthesis of compounds of formula (10):
Figure imgf000032_0001
Methods: a. NaH, dimethyl carbonate, toluene, 80°C 4 h; b. 1 N NaOH/CH2CI2 to convert to free base, then heat in dioxane 70 °C; c. 1 -butanol/reflux 3-6 h (Dean-Stark trap) PPTS; d. dioxane 70 °C; e. HCI in dioxane -25 °C - RT to give HCI salt ; f. Na2C03, DIEA 80 °C; g. NaOH/CH2CI2 to make free base, then MeOH reflux, 3.5 h
Scheme 3
[00105] Compounds of formula (10) are synthesized starting from a substituted piperidone, which is converted by reaction with a substitued aminoimidazoline to give the core compound (10). There are two routes, one in which the Ri substituent is present in the piperidone (e.g., 68). In that route, (68) is acylated with dimethyl carbonate using sodium hydride in toluene at 80 °C to form piperidone ester (69). Commercially available methylthioimidazoline HI salt
(63) is reacted with an amine in dioxane at 70 °C to afford the R2-substituted aminoimidazoline
(64) as its HI salt. Direct reaction of (64) with piperidone ester (69) in 1-butanol at reflux with removal of water via a Dean-Stark trap over 3-6 h gives the tricylic compound (10). In a variant of this scheme, N-BOC protected piperidone (61) is converted by the same methods to BOC protected compound (65), which is treated with HCI in dioxane to remove the BOC group and then converted to the free base of (66) with IN NaOH with extraction with methylene chloride. Subsequent treatment of (66) with a halide (67) or epoxide (70) affords desired compound (10).
[00106] The crude products may be purified by column chromatography eluting with methylene chloride:methanol or by HPLC using acetonitrile:TFA:H20 to produce the final products as either free bases or as TFA salts. Treatment of the free bases with HCI in dioxane or lyophilization of the TFA salts generates the products (10) as HCI or TFA salts. Alternatively, the free base may be treated with another inorganic or organic acid to form other salts, generally selected from those known to be pharmaceutically acceptable salts. The salts of compound (10) are usually solids and examples have been crystallized from ethanol or other solvents to give high quality crystals. The tricyclic structure has been definitively confirmed in the case of compound (1) by an X-ray cr stal structure and NMR.
[00107] Compound described herein can be used, with or without an aminoaikyi linker (e.g., compound (33)), to identify molecules (e.g., proteins) that interact with them in a cellular context. The expression of these binding targets may be used to predict response to compound (1) (ONC201) or its analogs (i.e. serve as biomarkers). In addition, these compounds can be used to screen for structurally unrelated anti-cancer compounds using competition assays known in the art to identify drugs able to outcompete the target interaction with a higher affinity. In addition, these molecules may have drug properties that create therapeutic improvements or allow additional therapeutic applications by altering drag properties including but not limited to pharmacokinetics, potency, safety, biodistribution, or metabolism. EXAMPLES OF COMPOUND (10)
C Number Mi ¾
ONC201 CH2Ph CH2-((2-CH3)-Ph)
CH2Ph CH3
O C902 CH2Ph CH2-((2-Cl)-Ph)
O C903 CH2Ph CH2-(2-thienyl)
O C904 CH2Ph i t C ! ! -Pf=
ONC905 CH2Ph CH2CH2(4-N-benzyl-piperazine)
ONC906 CH2Ph CH2-(2,4-di F-Ph)
ONC907 H CH2-((2-CH3)-Ph)
ONC908 CH3 CH2-((2-CH3)-Ph)
ONC909 CH2CH2Ph CH2-((2-CH3)-Ph)
CH2CH2-(4-N-benzyl-piperizine) CH2-((2-CH3)-Ph)
CH CHOHPh CH2-((2-CH3)-Ph)
(CH2)3CO-4F-Ph CH2-((2-CH3)-Ph)
ONC910 CH2CH2NHCOOC(CH3)3 CH2-((2-CH3)-Ph)
ONC911 C ! I 1 1 C I i N i l - CH2-((2-CH3)-Ph)
ONC210 CH2Ph CH2-(3,5-di F-Ph)
ONC211 CH2Ph CH2-(3,4-di Cl-Ph)
ONC212 CH2Ph CH2-(4-CF3-Ph)
ONC213 CH2Ph CH2-(3,4-di F-Ph)
ONC214 CD2C6D5 CH2-((2-CH3)-Ph)
ONC217 CH2Ph CH2-(2-F-Ph)
ONC218 Cl¾Ph CH2(2-CH3> 4-F-Ph)
ONC219 CH2Ph Ci¾-(2,4-di Cl-Ph)
O C220 CH2Ph CH2-((4-OCH3)-Ph)
ONC226 CH2Ph CH2-(3 -pyridinyl)
ONC222 CH2Ph CH2-(3-isoxazolidinyl)
ONC224 CH2Ph C'l i -CI 1 -{4-nH)rpiioi i ny! )
ONC223 CH2Ph CH2-(4-CH3-Ph)
ONC221 H CH2-(4-CF3-Ph)
ONC227 CH2-(4-CF3-Ph) CH2-(4-CF3-Ph)
ONC225 CH2Ph CH2-(2-F, 4-CF3-Ph)
ONC228 CH2-(4-F-Ph) CH2-(4-CF3-Ph)
ONC229 CH2-(OCH3-Ph) CH2-(4-CF3-Ph) No. ONC Number Ri ¾
76 QNC230 (4-F-Ph)-4-oxobutyl CH2-(4-CF3-Ph)
QNC231 CH2-3-pyridyl CH2-(4-CF3-Ph)
78 QNC232 CH2-4-methyl"2-thiazoiy3 CH2-(4-CF3-Ph)
79 ONC233 CH2-2-pyrazinyl CH2-(4-CF3-Ph)
81 ONC234 CH2-(3,4-di Cl-Ph) ! . (4 I : h )
82 QNC235 CH2-(4-Cl-Ph) CH2-(4-CF3-Ph)
83 QNC236 CH2-3-thienyl CH2-(4-CF3-Ph)
84 ONC237 CH2CH(OH)Ph CH2-(4-CF3-Ph)
|00108] As described in Example 12 below, compound (1) with an aminoalkyl linker (i.e., compound (33)) was used to identify proteins that interact with compound (1). It has been found that compound (1) interacts with proteins involved with Νό-methyl- adenosine (tn6A) mRNA metiiylation. Proteins that are involved with m6A mRNA epigenetic modification include those in Table 1. These proteins include those that methylate mRNA (RNA Writers), such as METTL3, METTL14, WTAP, and KIAA1429; those that demethylate m6A mRNA (RNA Erasers), such as FTO and ALKBH5; as well as those that specifically recognize m6A RNA (RNA Readers), such as YTHDF3, YTHDF2, YTHDF1 , YTHDC1 , and YTHDC2.
Table 1: mf>A mRNA methylation proteins
RNA Readers
YTHDF3
YTHDF2
YTHDF 1
YTHDC1
YTHDC2
RNA Writers
METTL3
METTL14
WTAP KIAA1429
RNA Erasers
FTO IV. ASSESSING SENSITIVITY AND EFFICACY OF TREATMENT REGIMENS [00109] Measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, DR5, or cleaved or total cytokeratin 18 may be used to predict response or sensitivity to a method of treatment described herein and to identify subjects likely to be responsive to a method of treatment described herein, such as treatment with compound (1), a pharmaceutically acceptable salt thereof, or an analog thereof. In addition, measuring expression, post-translational modifications, or activity levels of or mutations in eIF2 -alpha, ATF4, CHOP, DR5, or cleaved or total cytokeratin 18 can be used to assess the effectiveness of or monitor a method of treatment described herein. Furthermore, measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, DR5, or cleaved or total cytokeratin 18 can be used to screen in vivo, in vitro, or in silico for structurally unrelated anti-cancer compounds. For example, competition and other assays known in the art may be used to identify drugs able to outcompete the target interaction with a higher affinity to compare changes in those levels to the respective changes produced by compound (1) or an analog thereof. Assays can also be performed on li ving mammalian cells, which more closely approximate the effects of a particular serum level of drug in the body, or on microsomal extracts prepared from cultured cell lines.
[00110] 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, a compound of formula (10) is a compound of formula (50), e.g., a compound 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, analogs of compound (1) have a structure selected from the structures of compound (25), compound (26), compound (27), compound (28), compound (29), compound (30), or compound (31).
[00111] Levels for a pre-deterrnined standard can be, e.g., the average or median levels measured in samples from subjects. The levels for a pre-determined standard can be measured under the same or substantially similar experimental conditions as in measuring the sample from the subject. The levels for the predetermined standard may be obtained from subjects who are responsive to treatment with compound (1) or compound (10) or an analog thereof In one embodiment, the pre-determined standard is obtained from subjects who are responsive to treatment with the compound, and if the levels in the sample from the subject are similar to those in the standard, then the subject can be classified as likely to be responsive to treatment. The levels for the pre-determined standard may be obtained from subjects who are not responsive to treatment with the compound. In one embodiment, the pre-determined standard is obtained from subjects who are not responsive to treatment with the compound, and if the levels in the sample from the subject are different (e.g., up- or down-regulated) than those in the pre-determined standard, then the subject can be classified as likely to be responsive to treatment. The levels for the pre-determined standard may be obtained from normal healthy subjects.
[00112] 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 imm no filtration assay (ELIFA), flow cytometry, immunoblot, immunoprecipitation, immunohistochemistry, immunocytochemistry, luminescent immunoassay (LIA), fluorescent immunoassay (FIA), and radioimmunoassay, m°A rnR A methylation levels in a sample can be obtained by methylated RNA immunoprecipitation (Me-RIP) ) or other quantitative biochemical assays known in the art.
[00113] Nucleic acid mutations can be determined by any of a number of known procedures. For example, a biologic sample from an individual can first be obtained. Such biological samples include, but are not limited to, a bodily fluid (such as urine, saliva, plasma, or serum) or a tissue sample (such as a buccal tissue sample or buccal cell). The biologic sample can then be sequenced or scanned using known methods. For example, DNA arrays can be used to analyze at least a portion of the subject's genomic sequence. Furthermore, whole 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). Whole genome sequences can be cut by restriction enzymes or sheared (mechanically) into shorter fragments for sequencing. DNA sequences can also be amplified using known methods such as PCR and vector-based cloning methods (e.g., Escherichia coif). In one embodiment, at least a portion of a subject's genetic material (e.g. , DNA, RNA, mRNA, cDNA, other nucleotide bases or derivatives of these) is scanned or sequenced using, e.g., conventional DNA sequencers or chip-based technologies, to identify the presence or absence of mutations or copy number variations. [00114] In one aspect, provided herein are methods of identifying and treating a subject having a condition and who is likely to be responsive to a treatment regimen described herein. In one embodiment, the method comprises (i) identifying whether a subject having a condition is likely to be responsive to a treatment regimen described herein; and (ii) treating with the treatment regimen a subject determined likely to be responsive to that treatment regimen. In one embodiment, the subject has, or is at risk of having, cancer. In one embodiment, the trea tment 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, a compound of formula (10) is a compound of formula (50), e.g. , a compound 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, analogs of compound (1) have a structure selected from the structures of compound (25), compound (26), compound (27), compound (28), compound (29), compound (30), or compound (31).
|00115] Levels for a pre-determined standard can be, e.g., the average or median levels measured in samples from subjects. The levels for a pre-determined standard can be measured under the same or substantially similar experimental conditions as in measuring the sample from the subject. The levels for the pre-determined standard may be obtained from subjects who are responsive to treatment with compound (1) or compound (10) or an analog thereof In one embodiment, the pre-determined standard is obtained from subjects who are responsive to treatment with the compound, and if the levels in the sample from the subject are similar to those in the standard, then the subject can be classified as likely to be responsive to treatment. The levels for the pre-determined standard may be obtained from subjects who are not responsive to treatment with the compound. In one embodiment, the pre-determined standard is obtained from subjects who are not responsive to treatment with the compound, and if the levels in the sample from the subject are different (e.g., up- or down-regulated) than those in the pre-determined standard, then the subject can be classified as likely to be responsive to treatment. The levels for the pre-determined standard may be obtained from normal healthy subjects. Immunoassays can be used to assay protein levels in a sample.
[00116] In one aspect, provided herein are methods of treating and assessing the effectiveness of a treatment in a subject having a condition. In some embodiments, the method comprises (i) treating the subject according to a method of treatment described herein (ii) assessing as decribed herein the effectiveness of the treatment. 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, a compound of formula (10) is a compound of formula (50), e.g. , a compound 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, analogs of compound (1) have a structure selected from the structures of compound (25), compound (26), compound (27), compound (28), compound (29), compound (30), or compound (31).
[00117] Other conditions that may be suitable for the methods described herein include, but are not limited to, Attention Deficit Disorder; Addiction; Epilepsy; Viral infection;
Inflammation; Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis; Cardiovascular diseases such as coronary artery disease, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, cardiac dysrhythmias, inflammatory heart disease, endocarditis, inflammatory cardiomegaly, myocarditis, valvular heart disease, cerebrovascular disease, peripheral arterial disease, congenital heart disease, rheumatic heart disease; Diabetes; and light chain amyloidosis.
ZD
|00118] In one as ect, pharmaceutical compositions are provided, comprising compounds of
Figure imgf000039_0001
formula (10): ' or of formula (1):
(1) and their pharmaceutically acceptable salts. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound. In one
30 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. , a di-salt or tri-sait) thereof selected from the group consisting of hydrochloride, hydrobromide, hydrogensulphate, sulfates, phosphates, fumarates, succinates, oxalates and lactates, bisulfates, hydroxy!, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate, fumarate sulfonate, methylsuifonate, formate, acetate, and carboxylate. In one embodiment In one embodiment, the salt is a pharmaceutically acceptable salt selected from the group consisting of p-toluene- sulfonate, benzenesulfonate, citrate, methanesulfonate, oxalate, succinate, tartrate, fumarate and maleate. In one embodiment, the salt is a pharmaceutically acceptable salt selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and/or with counter-ions such as methylamino, dimethylammo, diethylamino and triethylamino counter-ions. In one embodiment, the salt is a. di-hydrochloride salt or a di-hydrobromide salt of the compound.
[00119] Compound (1) has the same chemical structure that would be revealed by structural analysis (e.g. , NMR, X-ray diffraction) of compound NSC 350625, available from the National Cancer Institute's Developmental Therapeutics Program Repository.
[00120] In one embodiment, the pharmaceutical composition includes 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- salts or tri-salts) of an analog of compound (1) can be prepared from an analog of compound (1), which can be synthesized as described herein, or using standard chemical synthetic methodology known to one of ordinary skill in the art.
[00121] In one embodiment, the pharmaceutical composition includes at least one pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers, include, but are not limited to, those found in Handbook of Pharmaceutical Excipients, 7' edition, edited by Raymond C, Rowe et al , American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and earlier editions. Exemplary pharmaceutically acceptable earners, methods for making pharmaceutical compositions and various dosage forms, as well as modes of administration are well-known in the art, for example as detailed in Pharmaceutical Dosage Forms: Tablets, edited by Larry L. Augsburger & Stephen W. Hoag., London: Informa Healthcare, 2008; and in L. V. Alien, Jr. et al, Ansel's Pharmaceutical
Dosage Forms and Dmg 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 & Oilman's The Pharmacological Basis of Therapeutics, McGraw-Hill Professional, 10th ed., 2001. [00122] In one embodiment, the pharmacuetical composition is formulated for ocular administration. In one embodiment, pharmaceutical compositions are formulated for topical administration. In one embodiment, the pharmaceutical compositions are formulated as drops, ointments, or liquids. In one embodiment, pharmaceutical compositions include conventional pharmaceutical earners such as aqueous, powdery or oily bases, thickeners or the like.
[00123] 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 includes the compound or its salt in 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 includes the compound or its salt in a concentration of from about 0.05, 0.5, or 5 mg/mL to about 1 , 10, or 100 mg/mL. In one embodiment, the intravenous formulation includes from about 0.005% 0.05%, or 0.5 % to about 0.1 %, 1 %, or 10 % of the compound or its salt. In one embodiment, the intravenous formulation includes about 0.05%, 0.5 %, or 5 % of the compound or its salt. In some embodiments, the intravenous formulation includes a higher or a lower concentration of the compound or its salt.
[00124] In some embodiments, the intravenous formulation has 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 includes dextrose or sodium chloride. In one embodiment, the intravenous formulation including the compound or its salt in a concentration of about 5 mg/mL and pH 3 and forms a stable solution. In one embodiment, the intravenous formulation includes the compound or its salt in a concentration of about 5 mg/mL and pH < 5 and forms a stable solution. In one embodiment, the intravenous formulation includes the compound or its salt and one or more antioxidants. In one embodiment, the intravenous formulation includes a mixture of mono- and di-hydrochloride salt of the compound. In one embodiment, the intravenous formulation includes the compound or its salt as a 1 % solution in 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.
[00125] In one embodiment, the pharmaceutical composition further includes a
pharmaceutically acceptable carrier. In one embodiment, a suitable pharmaceutically acceptable carrier includes an oil. In one embodiment, a suitable pharmaceutically acceptable carrier includes sterile water. In one embodiment, a suitable pharmaceutically acceptable carrier includes an aqueous carrier. In some embodiments, the intravenous formulation includes dextrose and/or sodium. [00126] In one embodiment, the intravenous formulation comprises compound (1) or an analog thereof or a di -hydrochloride salt thereof dissolved in water at 25 mg/mL. In one embodiment, the intravenous formulation is adjusted to pH 3 with phosphate buffer. In one embodiment, the intravenous formulation includes dextrose or sodium chloride. In one embodiment, the intravenous formulation includes a higher or a lower concentration of the di-h drochloride salt of compound (1) or an analog thereof. In one embodiment, the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof in a concentration of about 5 mg/mL. In one embodiment, the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof in a
concentration of about 5 mg/mL and pH 3 forms a stable solution. In one embodiment, the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof in a concentration of about 5 mg/mL and pH < 5 and forms a stable solution. In one embodiment, the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof and one or more antioxidants. In one embodiment, the intravenous formulation includes a mixture of mono- and di-hydrochloride salt of compound (1) or an analog thereof. In one embodiment, the intravenous formulation includes compound (1) or an analog thereof or a di-hydrochloride salt thereof as a 1 % solution in 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.
[00127] In one embodiment, the intravenous formulation includes from about 0.5 % to about
10 % (or from about 5 mg/mL to about 100 mg/mL) of compound (1) or an analog thereof or a di-salt thereof. In one embodiment, the intravenous formulation includes from about 5 % (or about 50 mg/mL) of compound (1) or an analog thereof or a di-salt thereof. In one embodiment, the intravenous infusion rate may be slowed to decrease side effects of compound (1) or an analog thereof or a di-salt thereof,
[00128] 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 earner, e.g., an
011 or a sterile water or other aqueous carriers. In one embodiment, the pharmaceutical composition comprises a mono or di-salt of compound (1) or an analog thereof in a range of from about 5% to about 50% for oral dosage forms.
[00129] In some embodiments, the pharmaceutical composition includes an antioxidant. Suitable antioxidants include: ascorbic acid derivatives such as ascorbic acid, erythorbic acid, sodium ascorbate, thiol derivatives such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione, tocopherols, butylated hydroxyanisole (BHA), butylated liydroxytoluene (BHT), sulfurous acid salts such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate, nordihydroguaiaretic acid. It should be noted that antioxidants used for aqueous formulations typically include: sodium sulphite, sodium metabisulphite, sodium formaldehyde sulphoxylate and ascorbic acid and combinations thereof, whereas antioxidants used in oil-based solutions, organic solvents, include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and propyl galiate and combinations thereof. In yet other embodiments, an antioxidant can be one or more of a flavanoid, an isoflavone, monothioglyceroi, L-cysteine, thioglycolic acid, a-tocopherol, ascorbic acid 6-paimitate, dihydrolipoic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, propyl galiate, β-carotene, ascorbic acid. Antioxidants can typically be used in about 0.1 % to 1.0% by weight, more typically about 0,2%.
[00130] In one embodiment, the pharmaceutical composition includes 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 is selected from the group consisting of 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; an ti tumour antibiotics; platinum derivatives; alkylation agents; antimitotic agents; tubuline 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, CRM! inhibitors (e.g., KPT185), P53 modulators (e.g., Nutlins), antiangiogenics (e.g., axitinib, aflibercept, sorafenib, and regorafenib), amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin,rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, 2-chlorodesoxyadenosine, 2-fluorodesoxy-cytidine, 2-methoxyoestradiol,
2C4,3-alethine, 131- 1-TM-601 , 3 CPA, 7-ethyl-lO-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ 10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (selumetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY -43-9006, BAY 80-6946, BBR-3464,
BBR-3576, bevacizuroab, 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, tomtovok), BIBF 1 120
(vargatei), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin- 1 , bortezomib, brostallicin, busulphan, BYL-71 , CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCl-779, CC-1 15, CC-223, CEP-701, CEP-751, CBT-1 eefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin,
CH4987655/RQ-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-XX, CDC-394, CKD-602, CKl-27, clofarabin, colchicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461 , CV-247, cyanornoipholinodoxombicin, cytarabine, D 24851 , decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanei, diethylstilbesirol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexat, edotreotide, efaproxiral, eflomithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratiizumab, ER-86526, erlotinib, ET-18-0CH3, ethynylcytidine, ethynvloestradiol, exaiecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4, FOLFIRI, formestane, foternisstine, galarubicin, gallium maltolate, gefinitib, 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, gplOO-peptide vaccines, GSK-5126766, GSK-690693,
GSK-1120212 (trametinib), GSK-21 18436 (dabrafenib), GSK-2126458, GSK-2132231 A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A 12 (cixutumumab), Immunol, indisulam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, I K-l 1 17, TNK-128, TNSM-18, ionafarnib, ipilimumab, iproplatin, irofulven,
isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651 , lurtotecan, LY-S6AKT1 , LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK- 162, methyltestosteron, methylprednisolone, MEDI-573, MEN- 10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN 18, motexaf in 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, 0X44 antibodies, OSI-027, OSI-906 (linsitinib), 4-1 BB antibodies, oxantrazole, oestrogen, panitumumab, patupilorse, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibodies, PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281 , PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PT-88, pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol, 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, plevitrexed, plicamyein, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, qumupristin, Rl 15777, RAF-265, ramosetron, ranpimase, RDEA-119/BAY 869766, RDEA-436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, regorafenib, revirnid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb, rinfabate, risedronate,rituximab, robatumumab, rofecoxib, RO-31 -7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubiteean, R-flurbiprofen, RX-0201 , S-9788, sabarubiein, SAHA, sargramostim, satrapiatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101 , semustin, seocalcitoL SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR- 13668, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS-103, tacedinaline, talaporf in, Tarceva, tariquitar, tasisulam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab, tremelimumab, tretinoin, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin, valrubicin, vatalanib, vincristine, vinflunine, virulizin, VVX-UKL VVX-554, A'ectibix, 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, zoledronat, zosuquidar, and combinations thereof.
[001311 In one embodiment, the other therapeutic agent comprises a hormone analog, an antihornione 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, medroxy-progesterone, 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, iuproiide acetate, triptorelin pamoate and combinations thereof and wherein the LHRH antagonists are selected from the group consisting of Degarelix, Cetrorelix, Abarelix, Ozarelix, Degarelix 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), insuline-like growth factors (IGF), human epidermal growt factor (HER) and hepatocyte growth factor (HGF). In one embodiment, the other therapeutic agent comprises one or more inhibitors of the 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 which are antifolates selected from the group consisting of methotrexate, raititrexed, and pyrimidine analogs. In one embodiment, the other therapeutic agent comprises one or more antimetabolites which are pyrimidine analogs selected from the group consisting of 5-fluorouracil, capecitabin and gemcitabin. In one embodiment, the other therapeutic agent comprises one or more antimetabolites which are purine and/or adenosine analogs selected from the group consisting of mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more antitumour antibiotics selected from the group consisting of anthraeyclins, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more platinum derivatives selected from the group consisting of cisplatin, oxalipiatin, carboplatin and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more alkylation agents selected from the group consisting of estramustin, meclorethamine, melphaian, chlorambucil, busulphan, dacarbazin,
cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, and combinations thereof. In one embodiment, the other therapeutic agent comprises nitrosoureas selected from the group consisting of carmustin, lomustin, thiotepa, and combinations thereof. In one embodiment, the other therapeutic agent comprises antimitotic agents selected from the group consisting of Vinea 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, vindesin, vinorelbin, vincristine, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more topoisomerase inhibitors which are epipodophyllotoxins. In one embodiment, the other therapeutic agent comprises one or more epipodophyllotoxins selected from the group consisting of etoposide and etopophos, tenyposide, amsacrin, topotecan, irinotecan, mitoxantron, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more serine/threonine kinase inhibitors selected from the group consisting of PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mXORC l inhibitors, PBK inhibitors, dual niTOR/PB inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more tyrosine kinase inhibitors which are PT 2/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 amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin,rituximab, procarbazine, levamisole, rnesna, rnitotane, pamidronate and porfimer, and combinations thereof. In one embodiment, the other therapeutic agent comprises one or more therapeutic agents selected from the group consisting of 2-chlorodesoxyadenosine, 2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine, 131 -1-TM-601, 3CPA, 7-ethyl- 10-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, A VLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (selumetinib),
ARRY-704/AZD-8330, AR-I2, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, biricodar dicitrate, BCX-1777, BKM-120, bleocin, BLP-25, BMS- 184476, BMS-247550, BMS-188797, BMS-275291 , BMS-663513, BMS-7548Q7, BNP-1350, BNP-7787, BIBW 2992 (afatinib, tomtovok), BIBF 1 120 (vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin-1 , bortezomib, brostallicin, busulphan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine,
earboxyphthalatoplatin, CCl-779, CC-1 15, CC-223, CEP-701 , CEP-751 , CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RQ-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-XI, CDC-394, CKD-602, CKI-27, clofarabin, coichicin, com retastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247,
cyanomorpholinodoxorubicin, cytarabine, D 24851 , decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstiibestroi, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexat, edotreotide, efaproxiral, efloniithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epraiuzumab, ER-86526, erlotinib, ET-18-0CH3, ethyrsylcytidirse, ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX,
FOLFOX4, FOLFXRL formestane, fotemustine, galarubicin, gallium maltolate, gefinitib, 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, gplOO-peptide vaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametmib), GSK-21 18436 (dabrafe ib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate, idenestrol, lD'N-5109, IGF- 1R inhibitors, IMC-1C 1 1 , IMC-A12 (cixutumumab), immunol, indisulam, interferon aipha-2a, interferon alpha- 2b, pegylated interferon alpha-2b, interleukin-2, INK- 1117, INK-128, INSM-18, ionafaraib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, ,1 Si - 1 54. J- 107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, Ieflunomide, lenograstim, leuprolide, Ieuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1 , LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162, methyltestosteron, methylprednisolone, MEDI-573, MEN- 10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf in gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzyiguanine, oblimersen, omeprazole, oncophage, oncoVEXGM-CSF, ormiplatin, ortataxel, 0X44 antibodies, OSI-027, OSI-906 (linsitinib), 4- IBB antibodies, oxantrazole, oestrogen, panitumumab, parupilone, pegfiigrastim,
PC -3145, pegfiigrastim, PBI-1402, PBI-05204, PDQ325901 , PD-1 antibodies,
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, perillylaieohol, pertuzumab, PI3K inhibitors, PDK/mTOR inhibitors, PG-TXL, PG2, PLX-4032/RO-51 85426 (vemurafenib), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKI166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, R l 15777, RAF-265, ramosetron, ranpirnase, RDEA-1 19 BAY 869766, RDEA-436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb, rinfabate, risedronate,rituximab, robatumumab, rofecoxib, RO-31 -7453, RO-5126766, RO-5068760, RPR 109881 A, rubidazone, rubitecan, R-ffurbiprofen, RX-0201 , S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015/Ve-015, Si .54 1 , SU6668, SDX-101 , semustin, seocalcitol, SM-1 1355, S -38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS- 103, tacedinaline, talaporf in, Tarceva, tariquitar, tasisuiam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab,
tremelimumab, tretinoin, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin, valrubicin, vatalanib, vincristine, vmflunme, virulizin, WX-UKl , WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281 , XL-518/R-7420/GDC-0973, XL-765, YM-51 , YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331 , ZD 1839, ZSTK-474, zoledronat, zosuquidar, and combinations thereof.
[00132] In one embodiment, the other therapeutic agent comprises a steroid. Steroids include, but are not limited to, dexamethasone, prednisolone, methyl prednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazol. In one embodiment, the other therapeutic agent comprises an anti-emetic. Anti-emetics include, but are not limited to, 5-HT3 receptor agonists (e.g. , dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine), dopamine agonists (e.g. , domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, pi chlorperazine, alizapride, prochiorperazine, and metoclopramide), NK1 receptor antagonists (e.g. , aprepitant and casopitant), antihistamines (such as cyclizine, diphenhydramine, dinienhydrinate, doxylamine, meclizine, promethazine, hydroxyzine), 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.
[00133] In some embodiments, the other therapeutic agent comprises an anti-cancer agent, which includes a mitotic inhibitor. In one embodiment, the mitotic inhibitor includes a taxane. In one embodiment, the mitotic inhibitor includes a taxane selected from the group consisting of paclitaxel and docetaxel.
[00134] In one embodiment, the pharmaceutical composition includes compound (1) or compound (10) or an analog thereof!, or a pharmaceutically acceptable salt thereof; and at least one anti-cancer agent, which includes, without limitation, one or more of acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, ailopurmol, altretamine, ambomycin, ametantrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperiin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bevacizumab, bicalutamide, bisantrene, bisnafide dimesylate, bizelesin, bleomycin, brequinar, bropirimine, busulfan, cactinomycin, calusterone, capecitabine, caracemide, carbetimer, carboplatin, carmustine, cambicin, carzelesin, cedefingol, celecoxib, chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, droioxifene, dromostanoione, duazomycin, edatrexate, eflomi thine, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin, erbulozole, esorubicin, estramustine, etanidazole, etoposide, etoprine, fadrozole, fazarabine, fenretinide, floxuridine, fludarabine, fluorouracil, flurocitabine, fosquidone, fostriecin, fulvestrant, gemcitabine, hydroxyurea, idarubicin, ifosfamide, ilmofosine, interleukin II (IL-2, including recombinant interleukin II or rIL2), interferon alfa-2a, interferon alfa-2b, interferon alfa-nl , interferon alfa-n3, interferon beta-la, interferon gamma-lb, iproplatin, irinotecan, lanreotide, letrozole, leuprolide, liarozole, lometrexol, lomustine, losoxantrone, masoprocol, maytansine, mechlorethamine hydrochlride, megestrol, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, metoprine, meturedepa, mitindomide, mitocarcin, mitocromin, mitogiilin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone, mycophenolic acid, nelarabine, nocodazole, nogalamycin, ormnaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer, porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, riboprine, rogletimide, safingol, semustine, simtrazene, sparfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tamoxifen, tecogalan, tegafur, teloxantrone, temoporfm, teniposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, topotecan, toremifene, trestolone, triciribine, trimetrexate, triptorelin, tubulozole, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine, vinepidine, vinglycinate, vinleurosine, vinorelbine, vinrosidine, vinzolidine, vorozole, zeniplatin, zinostatin, zoledronate, zorubicin and combinations thereof.
[00135] Examples of suitable anti-cancer agents include, but are not limited to, those described Goodman and Oilman's The Pharmacological Basis of Therapeutics, 12 th Ed., edited by Laurence Brunton, Brace Chabner, Bjorn KnoUman, McGraw Hill Professional, 2010.
[00136] In some exemplary embodiments, the pharmaceutical composition includes 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 selected from the group consisting of aflibercept, axitinib, angiostatin, endostatin, 16kDa prolactin fragment, laminin peptides, fibronectin peptides, tissue metalloproteinase inhibitors (TIMP 1 , 2, 3, 4), plasminogen activator inhibitors (PAI-1 , -2), tumor necrosis factor a, (high dose, invitro), TGF-βΙ, interferons (IFN- , -β, γ), ELR-CXC chemokines, IL-12; SDF-1; MIG; platelet factor 4 (PF-4); IP- 10, thrombospondin (TSP), SPARC, 2-methoxyoestradiol, proliferin-related protein, suramin, sorafenib, regorafenib, thalidomide, cortisone, linomide, fumagillin (AGM-1470; TNP-470), tamoxifen, retinoids, CM101 , dexamethasone, leukemia inhibitory factor (LIF), hedgehog inhibitor and
combinations thereof.
[00137] A pharmaceutical combination can include first and second therapeutic agents in any desired proportions provided that the synergistic or cooperative effect still occurs. The synergistic pharmaceutical combination preferably contains the first and second therapeutic agents in a ratio of from about 1 :9 to about 9: 1. In one embodiment, the synergistic pharmaceutical combination pontains the first and second therapeutic agents in a ratio of from about 1 :8 to about 8: 1 , from about 1 :7 to about 7: 1 , from about 1 :6 to about 6: 1 , from, about 1 :5 to about 5: 1 , from about 1 :4 to about 4: 1, from about 1 :3 to about 3: 1 , or from 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 approximately 1 : 1.
[00138] In one embodiment, the second therapeutic agent is selected from the group consisting of Allopurinol, Arsenic Trioxide, Azacitidine, Bortezomib, Bevacizumab, Capecitabine, Carboplatm, Celecoxib, Chlorambucil, Ciofarabine, Cytarabine, Dacarbazine, Daunorubicin HC1, Docetaxel, Doxorubicin HC1, Floxuridine, Gemcitabine HC1, Hydroxyurea, Ifosfamide, Imatinib Mesylate, Ixabepilone, Lenalidomide, Megestrol acetate, Methotrexate, Mitotane, Mitoxantrone HCi, Oxaliplatin, Paclitaxel, Pralatrexate, Romidepsin, Sorafersib, Streptozocra, Tamoxifen Citrate, Topotecan HCI, Tretinoin, Vandetanib,
Vismodegib, Vorinostat, and combinations thereof,
[00139] In one embodiment, the second therapeutic agent comprises a small molecule multi-kinase inhibitor, e.g., sorafenib or regorafenib. In one embodiment, the second therapeutic agent comprises a Hedgehog Pathway Inhibitor, e.g., vismodegib. In one embodiment, the second therapeutic agent includes drugs selected from Table 2 below.
Table 2: Classes Of Drags
Classes of drugs Examples
Purine analogs allopurinol, oxypurinol, clofarabine, and tisopurine
Pyrimidine analogs 5-fluorouracii, Floxuridine (FUDR), capecitabine,
cytarabine, 6-azauracil (6-AU), and gemcitabine (Gemzar)
Proteasome inhibitors bortezomib, carfiizomib, cediranib, disulfiram,
epigallocatechin-3-gallate, salinosporamide A, ONCX 0912, CEP-18770, MLN9708, epoxomicin, and MG132.
Anti-angiogenic bevacizumab, aflibercept, sunitinib, sorafenib, pazopanib, vandetanib, cabozantinib, axitinib, ponatinib, regorafenib, ranibizumab, lapatinib, and vandetanib.
Platinum-based antineoplastic cisplatin, carboplatin, oxaliplatm, satraplatin, picoplatin, drugs nedapiatin, and triplatin.
COX-2 inhibitors celecoxib, valdecoxib (Bextra), parecoxib (Dynastat), iimiiracoxib, etoricoxib, and rofecoxib.
Nitrogen mustards cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan, bendamustine, and mustine.
Alkylating agents cyclophosphamide, mechlorethamine or mustine (HN2)
(trade name Mustardgen), uramustine or uracil mustard, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, streptozocin, and busulfan.
Anthracyclines Daunorubicin (Daunomycin), Daunorubicin (liposomal),
Doxorubicin (Adriamycin), Doxorubicin (liposomal), Epirubicin, Idarubicin, Valrubicin, and Mitoxantrone.
Taxanes Paclitaxel (Taxol), Docetaxel (Taxotere), and
albumin-bound paclitaxel (Abraxane). Classes of drags Examples
Nucleotide synthesis inhibitor methotrexate, pralatrexate, hydroxyurea, and
5-fluorod.eoxyuridine, 3,4-dihydroxybenzylamine.
Bcr-abl inhibitors imatinib, nilotinib, dasatinib, bosutinib and ponatinib.
Other arsenic trioxide, thalidomide, revlimid, and mitotane.
Topoisomerase inhibitor amsacrine, etoposide, etoposide phosphate, teniposide, doxorubicin, Topotecan (Hycamtin), Iriiiotecan (CPT- 11 , Camptosar), Exatecan, Lurtotecan, ST 1481, CKD 602, ICRF-193, and genistein.
HDAC inhibitors Vorinostat (SAHA), Romidepsin (Istodax), Panobinostat
(LBH589), Valproic acid (as Mg valproate), Belinostat (PXDIOI), Mocetinostat (MGCD0103), Abexinostat (PCT-24781 ), Entinostat (MS-275), SB939, Resminostat (4SC-201 ), Givinostat, Quisinostat (JNJ-26481585), CUDC- 101 , AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, Kevetrin, and ATRA.
Multi-kinase inhibitors sorafenib, regorafenib, and vandetanib.
Hormone therapies tamoxifen, toremiiene, Arimidex (anastrozole), Aromasin
(exemestane), Femara (letrozole), and Fulvestrant (Faslodex).
Hedgehog signaling Inhibitors vismodegib, BMS-833923, IPI-926, LDE-225,
PF-04449913, LEQ 506, and TAK-441,
Checkpoint Inhibitors Opdivo (nivolumab), Durvalumab (Medi4736), Keytmda
(pembrolizumab, MK3475), BGB-A317, AMP-224, PDR001, REGN 281 , Atezoiizumab (MPDL3280A), Pidilizumab (BMS-936559, CT-01 1, ONO-4538), Avelumab (MSB0010718 C), Yervoy (ipilimumab), tremelimumab
BCL2 Inhibitors AT- 101 , Bcl-2/xL inhibitor, Navitoclax (ABT-263),
Venetociax (ABT-199), Apogossypol, PTN1258, obatoclax, G3139
[00140] In some embodiments, the second therapeutic agent includes drugs that target tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. In one embodiment, the second therapeutic agent includes a recombinant TRAIL or an agonistic antibody that activates one or more TRA I L receptors. In one embodiment, the second therapeutic agent includes one or more antibodies or recombinant TRAIL that activate signaling by DR4, DR5 or both. In one embodiment, the second therapeutic agent includes one or more of AMG-655, LBY-135, mapatumumab, lexatumumab, Apomab, and rhApo2L/TRAIL. In one embodiment, the second therapeutic agent includes an active agent selected from the group consisting of Carnptothecin, 5-FU, capecitabine, cisplatin, doxorubicin, irinotecan, paclitaxel, cisplatin, bortezomib, BH3I-2, rituximab, radiation, triterpenoids, sorafenib, gemcitabine, HDAC inhibitors, carboplatin, T- 101 (a gossypol derivate), ABT-263, ABT-737, and GX- 15-070 (obatoclax), vorinostat, cetuxirnab, panitumumab, bevacizumab, ganitumab, interferon gamma, sorafenib, XIAP antagonists, Bcl-2 antagonists, and Smac mimetics.
VI. DOSE
|00141] In one embodiment, a 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 where the weight can be based on the compound in its free base form. In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 50 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 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, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, and 200 mg; or from about 0.5 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, and 20 mg. In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 40 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg; from about 4 mg to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 1 80, 190, or 200 mg; or from about 0.4 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, and 20 mg. In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 60 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 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, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about 0.6 mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg. In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 100 mg to about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1 100, 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, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or from about ! mg to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg. In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging 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, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg; or 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, based on the compound in its free base form. In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose 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, 1 10, 120, 130, 140, 150, 160, 170, 1 80, 190, or 200 mg; or from about 4 mg to about 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg based on the compound in its free base form. In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof th ereof in a dose level ranging 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 mg 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 10 mg; from about 9 mg to about 10 mg; from about 0.5 mg to about 0.6, 0.7, 0. 8, 0.9, or 1 mg; from about 0.6 mg to about 0.7, 0.8, 0,9, or 1 mg; from about 0.7 mg to about 0.8, 0.9 or 1 mg, from about 0.8 mg to about 0,9 or 1 mg; or from about 0.9 mg to about 1 mg.
[00142] In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose ranging from about 1 mg kg to about 40 mg/kg; 0.1 mg/kg to about 4 mg/kg; or 0.0! mg/kg to about 0.40 mg/kg. In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging 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, 1 1 , 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; from about 30, 31 , 32, 33, 34, 35, 36, 37, 38, or 39 mg/kg to about 40 mg/kg; from 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; from about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,
I .8, or 1.9 mg/kg to about 2, 3, or 4 mg/kg; from 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 from 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; from 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; from about 0.10, 0.1 1, 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; from about 0.20, 0.21 , 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, or 0.29 mg/kg to about 0.30 or 0.40 O.mg/kg; or from 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.
[00143] In one embodiment, a pharmaceutical composition comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 37.5 mg/m" to about 1500 mg/m2; from about 3.75 mg/m2 to about 150 mg/m2; or from about 0.4 mg/m2 to about 15 mg/m2 In one embodiment, a pharmaceutical composition comprises comprises compound (1) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in a dose level ranging from about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 1 15, 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, 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, 910, 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, 1 100, 1 105, 11 10, 1 115, 1 120, 1125, 1 130, 1135, 1 140, 1145, 1150, 1 155, 1160, 1 165, 1 170, 1 175, 1 180, 1185, 1 190, 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, 1495 mg/m2 to about 1500 mg/m2; from about 4, 5, 6, 7, 8, 9, 10,
I I, 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, 1 10, 1 1 1 , 1 12, 113, 1 14, 1 15, 116, 117, 1 18, 1 19, 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/m2 to about 150 mg m2;or from 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, 1 1 , 1 1 1 , 1 1.5, 12, 12.5, 13, 13.5, 14, or 14.5 mg/m2 to about 15 mg/mz.
VII. DOSAGE FORMS
[00144] Suitable pharmaceutical compositions for use with the methods described herein 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 parenteral dosage unit. In one embodiment, the pharmaceutical composition is in the form of an oral dosage unit. In some embodiments, an oral dosage unit is fractionated into several, smaller doses, which are administered to a subject over a predetermined period of time in order to reduce toxicity of the therapeutic agent being administered. In some embodiments, an oral dosage unit is administered by a tablet or capsule comprising a controlled release formulation that can include a plurality of particles, granules, pellets, minitablets 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), and 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, caplet, capsule, lozenge, syrup, liquid, suspension and elixir. In one embodiment, the composition is in an oral dosage form selected from the group consisting of tablets, hard shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids and semi-solids.
[00145] In some embodiments, suitable forms of pharmaceutical compositions for use in the methods described herein include dermatological compositions adapted for cutaneous topical administration. For example, dermatological compositions include a cosmetically or pharmaceutically acceptable medium. The dermatological compositions for topical administration can 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 can be necessary or desirable and therefore can be used. Examples of suitable enhancers include, but are not limited to, ethers such as diethylene glycol monoethyl ether (available commercially as TRANSCUTOL®) and di ethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231 , 182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Patent No. 4,783,450); alcohols such as ethanol, propanol, octanoi, benzyl alcohol, and the like; polyethylene glycol and esters thereof such as polyethylene glycol monolaurate; amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylforniamide (DMF), 2-pyrrolidone,
l-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.
[00146] In some embodiments, the pharmaceutical composition is in a dosage form selected from the group consisting of sustained release forms, controlled release forms, delayed release forms and response release forms. VIII. METHODS OF USE
[00147] The compositions and methods described herein have utility in treating many disease conditions, including cancer (e.g., colorectal, brain, and glioblastoma). In one embodiment, the compositions and methods described herein are used to treat diseases such as ocular melanoma, desmoplastic round cell tumor, chondrosarcoma, leptomengial disease, diffuse large B-cell lymphoma, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, AIDS-Related Lymphoma, Anal or Rectal Cancer, Appendix Cancer, Astrocytomas, and Atypical Teratoid Rhabdoid Tumor. In one embodiment, the compositions and methods described herein 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 Cance, Bronchial Tumors, Burkitt Lymphoma, and Spinal Cord Tumors. In one embodiment, the compositions and methods described herein are used to treat diseases such as Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Leptomeningeal Disease, Central Nervous System Embryonal Tumors, Central Nervous System Lymphoma, 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, Sezary syndrome and mycosis fungoides (MF)). In one embodiment, the compositions and methods described herein are used to treat cdiseases such as Embryonal Tumors of Central Nervous System, Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, and Eye Cancer. In one embodiment, the compositions and methods described herein 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 described herein are used to treat a cancer selected from the group consisting of Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Hodgkin Lymphoma, and Hypopharyngeal Cancer. In one embodiment, the compositions and methods described herein are used to treat cdiseases such as Kaposi Sarcoma, and Kidney (Renal Cell) Cancer. In one embodiment, the compositions and methods described herein are used to treat diseases such as Langerhans Cell Histiocytosis, Laryngeal Cancer, Lip and Oral Cavity- Cancer, Liver Cancer, Lung Cancer, Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma. In one embodiment, the compositions and methods described herein are used to treat diseases such as Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Metastatic
Squamous Neck Cancer with Occult Primary, Multiple Endocrine Neoplasia Syndrome, Mouth Cancer, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic Myeloproliferative Neoplasms, Multiple Myeloma, and Myeloproliferative Disorders. In one embodiment, the compositions and methods described herein are used to treat cancer. In one embodiment, the compositions and methods described herein are used to treat diseases such as Nasal Cavity and Paranasal Sinus Cancer,
Nasopharyngeal Cancer, and Neuroblastoma. In one embodiment, the compositions and methods described herein are used to treat diseases such as Oral 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 described herein are used to treat diseases such as Pancreatic Cancer, Papillomatosis, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pineal
Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System Lymphoma, and Prostate Cancer. In one embodiment, the compositions and methods described herein are used to treat a cancer selected from the group consisting of Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15,
Retinoblastoma, and Rhabdomyosarcoma. In one embodiment, the compositions and methods described herein are used to treat high grade prostate cancer. In one embodiment, the compositions and methods described herein are used to treat medium grade prostate cancer. In one embodiment, the compositions and methods described herein are used to treat low grade prostate cancer. In one embodiment, the compositions and methods described herein are used to treat castration-resistant prostate cancer.
[001481 The inventors have found in in vitro models, in animal models, and in human clinical trials that ONC20.1 (compound (1)) has broad anti-cancer activity, low toxicity including few, if any, adverse effects, low genotoxicity, and high bioavailability including oral bioavailability. These features allows ONC 201 and various analogs to be particularly well suited for pediatric patients. These features also make ONC 201 and various analogs particularly well suited for chronic therapy, for high risk patients, and to ensure long-lasting responses or stable disease or to prevent disease recurrence.
[00149] In one embodiment, the compositions and methods described herein are used to treat a pediatric cancer (e.g. , pediatric solid tumors, pediatric sarcomas, pediatric Ewing's sarcomas, pediatric gliomas, pediatric central nervous system cancers, pediatric neuroblastoma pediatric leukemia and pediatric lymphoma).
[00150] In one embodiment, the compositions and methods described herein are used to treat a proliferative skin disorder such as psoriasis. In one embodiment, the compositions and methods described herein are used to treat a cancer selected from the group consisting of Salivary Gland Cancer, Sarcoma, Sezary Syndrome, Skin Cancer, Ocular Cancer, Skin Carcinoma, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinom,
Squamous Neck Cancer with Occult Primary, and Supratentorial Primitive Neuroectodermal Tumors. In one embodiment, the compositions and methods described herein are used to treat a cancer selected from the group consisting of T-Ceil Lymphoma, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, and Gestational Trophoblastic Tumor. In one embodiment, the compositions and methods described herein are used to treat a cancer selected from the group consisting of Carcinoma of Unknown Primary Site, Cancer of Unknown Primary Site, Unusual Cancers of Childhood, Transitional Cell Cancer of the Renal Pelvis and Ureter, Urethral Cancer, and Uterine Sarcoma. In one embodiment, the compositions and methods described herein are used to treat cancer selected from the group consisting of Vaginal Cancer and Vulvar Cancer. In one embodiment, the compositions and methods described herein are used to treat a cancer selected from the group consisting of Wilms Tumor and Women's Cancers.
[00151] In some embodiments, the compositions and methods described herein are used as a first-line therapy (sometimes called primary therapy). In some embodiments, the compositions and methods described herein are used as a second-line therapy. In some embodiments, the compositions and methods described herein are used as a third-line therapy. In some embodiments, the compositions and methods described herein are used as a salvage therapy. The term "salvage therapy" as used herein means a therapeutic agent that can be taken with any regimen after a subject's initial treatment regimen has failed or after the subject's condition has not responded to an initial treatment. In some embodiments, the compositions and methods described herein are used as a rescue therapy. In one embodiment of the rescue therapy, the compositions are used as a rescue agent to counteract the action of an initial treatment. In one embodiment of the rescue therapy, the compositions are used as rescue agent which is administered to a subject who has developed resistance to a standard or an initial treatment. In some embodiments, the compositions and methods described herein are used as a neoadjuvant therapy. In one embodiment, the neoadjuvant therapy comprises administration of one or more of the therapeutic agents described herein to a subject before a main or first line treatment. In one embodiment, the neoadjuvant therapy reduces the size or extent of the cancer being treated before a main or first line treatment is administered to the subject undergoing treament. In some embodiments, the compositions and methods described herein are used as an adjuvant therapy. In one embodiment, the adjuvant therapy comprises administration of one or more therapeutic agents described herein to a subject, wherein the one or more therapeutic agent that modif the effect of other therapeutic agents that are already administered to the subject or are concurrently administered to the subject or subsequently administered to the subject,
[00152] In some embodiments, the compositions and methods described herein exhibit reduced chance of drug-drag interactions. In some embodiments, compound (1) or compound (10) or an analog thereof are eliminated from the patient's body before it can interact with another pharmaceutically active agent.
[00153] In some embodiments, the compositions and methods of described herein exhibit toxicity levels that facilitates combinations with other pharamaceutical agents.
[00154] The methods and compositions described herein are not limited to a particular animal species. In one embodiment, a subject treated according to methods and using compositions described herein, can be mammalian or non-mammalian. In one embodiment, a mammalian subject mammal includes, but is not limited to, a human; a non-human primate; a rodent such as a mouse, rat, or guinea pig; a domesticated pet such as a cat or dog; a horse, cow, pig, sheep, goat, or rabbit. In one embodiment, a non-mammalian subject includes, but is not limited to, a bird such as a duck, goose, chicken, or turkey. In some embodiments, the subject is a human. In one embodiment, subjects can be either gender and any age. The composition and methods can also be used to prevent cancer. The composition and methods can also be used to stimulate the immune system.
[00155] The methods and compositions described herein are not limited to a particular age of the subject. In one embodiment, a subject treated according to methods and using compositions described herein can be over the age of 50 years, over the age of 55 years, over the age of 60 years, or over the age of 65 years. In one embodiment, a subject treated according to methods and using compositions described herein can be under the age of 50 years, under the age of 55 years, under the age of 60 years, or under the age of 65 years.
[00156] . In one embodiment, a subject treated according to methods and using compositions described herein can be a pediatric patient. In one embodiment, the pediatric patient ct 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, wherein is 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 1 1 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, is 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 younger than
4 weeks old, younger than 3 weeks old, younger than 2 weeks old, younger than 1 weeks old. In one embodiment, the pediatric patient is younger than 7 days old, younger than 6 days old, younger than 5 days old, younger than 4 days old, younger than 3 days old, younger than 2 days old, or younger than 1 day old. In one embodiment, the pediatric patient is a neonate. In one embodiment, the pediatric patient is prematurely born. In one embodiment, the pediatric patient is a neonate.
[001571 In one embodiment, the patient is less than 45 kg in weight, less than 40 kg in weight, less than 35 kg in weight, less than 30 kg in weight, less than 25 kg in weight, less than 20 kg in weight, less than 15 kg in weight, less than 14 kg in weight, less than 10 kg in weight, less than
5 kg in weight, less than 4 kg in weight, less than 3 kg in weight, less than 2 kg in weight, or less than 1 kg in weight. [00158] 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, cispiatin, rituximab, 5-fluorouracil, oxaliplatin, leucovorin, or lenalidomide,
[00159] In one embodiment, the subject has been treated with radiation. In one embodiment, the subject has been treated with surgery. In one embodiment, the subject has been treated with adoptive T-cell therapy.
[00160] In some embodiments, the cancer no longer responds to treatment with ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide,
hydroxydaunorubicin, vincristine, prednisone, cytarabine, cispiatin, rituximab, 5-fluorouracil, oxaliplatin, leucovorin, lenalidomide, radiation, surgery, or a combination thereof.
[00161] In some embodiments, the compositions and methods described herein have a dose response relation in cancer cells that is different from the dose response relation of the same compositions and methods in normal cells. Figure 1, for example, illustrates the dose response relation of compound (1) on proliferation and cell death in normal and tumor cells. Figure 1 shows cell viability following treatment with compound (1) at indicated concentrations for 72 hours. The tumors tested included a human colon cancer cell line (HCTl 16), breast tumor cell line (MDA-MB-231), and a human primary glioblastoma cell line (U87). And the normal cells tested included human foreskin fibroblasts ί I I FF ;, human fetal lung fibroblast (MRC-5) cells, and a human lung fibroblast cell line (WI-38), Doxorubicin was used as a positive control at 1 Ltg/mL in normal fibroblasts. As shown in Figure 1 , cell viability of normal cells tested is at least about 75% at about 1 -5 mg/niL concentration of compound (1), whereas viability of tumor cells is significantly lower (e.g., at or below 50%) at the same concentration of compound (1). Moreover, as the concentration of compound (1) increases beyond about 5 mg/niL viability of tumor cells falls to below 25%, whereas viability of normal cells remains at about 75%.
[00162] Figure 2 illustrates cell viability assays in human fetal lung fibroblast (MRC-5) cells following 72 hour treatment with compound (1 ) (5 μΜ) or DMSO and the indicated recovery- period in complete drug-free media after treatment. The time points are given as time following removal of compound (1) after 72 hour treatment. As shown in Figure 2, cell recovery was seen with compound (1), but not with DMSO.
[00163] In some embodiments, the compositions and methods described herein have utility in treating cancer in a subject. In one embodiment, the compositions and methods described herein have utility in treating cancer in a human subject. In some embodiments, the treatment method comprises administering to a subject in need of such treatment, 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,
[00164] In one embodiment, the treatment method comprises administering to a subject in need of such treatment: (i) a first therapeutic agent including compound (1 ) or compound (10) or an analog thereof, or a pharmaceutically acceptable salt thereof in combination with (ii) a second therapeutic agent, wherein the first and the second therapeutic agents are administered either simultaneously or sequentially. The second therapeutic agent can be any suitable therapeutic agent, including any pharmaceutically active agent disclosed herein. A
pharmaceutically acceptable salt of compound (1) includes the di-hydrochloride salt below:
Figure imgf000064_0001
[00165] It is understood that a di-hydrochloride salt of compound (1) or an analog thereof (including, but not limited to, a compound of formula (10)), or an alternative di-salt thereof apparent from the teaching of this disclosure, can be substitued for compound (1) or an analog thereof in a composition or dosing regimen described hererin.
[00166] In some embodiments, the treatment method comprises administering a synergistic pharmaceutical combination, either simultaneously or sequentially, to a subject in need of such treatment, wherein 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 treatment method comprises administering to a subject in need of such treatment, either simultaneously or sequentially, therapeutically synergistic effective amounts of the first therapeutic agent in combination with the second therapeutic agent. In one embodiment, the treatment method 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, wherein the combination provides a synergistic effect in the in vivo treatment of a cancer sensitive to the combination, and wherein the first and the second therapeutic agents are administered either simultaneously or sequentially. In one embodiment, the treatment method 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 a second therapeutic agent, wherein the combination provides a synergistic effect in the in vivo treatment of a minimal residual disease sensitive to the combination, and wherein the first and second therapeutic agents are administered either simultaneously or sequentially.
[00167] In some embodiments, the second therapeutic agent can be given before or prior to the first therapeutic agent.
[00168] In one embodiment, the treatment method targets a cancer selected from the group consisting of solid tumors, liquid tumors, lymphomas, leukemias, or myelomas.
[00169] In one embodiment, the treatment method targets a solid tumor, wherein the solid tumor is selected from the group consisting of: Cervical Cancer, Endometrial Cancer, Extracranial Germ Cell Tumor; Extragonadal Germ Cell Tumor; Germ Cell Tumor;
Gestational Trophoblastic Tumor; Ovarian Cancer, Ovarian Germ Cell Tumor, Ovarian Epithelial Cancer, and Ovarian Low Malignant Potential Tumor; Penile Cancer, Prostate Cancer; Pregnancy and Breast Cancer; high grade prostate cancer; medium grade prostate cancer; low grade prostate cancer; castration-resistant prostate cancer; Breast Cancer; Bile Duct Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; 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, Melanoma, Merkel Cell Carcinoma, Papillomatosis, Multiple Endocrine Neoplasia Syndrome; Pancreatic Cancer, Parathyroid Cancer, ocular melanoma; Eye Cancer; Retinoblastoma;
Malignant Fibrous Histiocytoma; Ewing Sarcoma Family of Tumors; desmoplastic round cell tumor; chondrosarcoma, Kaposi Sarcoma, Rhabdomyosarcoma; Spinal Cord Tumors, Leptomeningeal Disease, Central Nervous System Embry onal Tumors, Chordoma, Embryonal Tumors of Central Nervous System, Ependymoblastoma, Ependymoma, Neuroblastoma; Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma; Adrenocortical Carcinoma; Bone Cancer, Osteosarcoma; Malignant Fibrous Histiocytoma of Bone and Osteosarcoma; Osteosarcoma and Malignant Fibrous Histiocytoma of Bone; Carcinoid Tumor, Carcinoma of Unknown Primary, Bronchial Tumors, Lung Cancer, Pleuropulmonary
Blastema; Respiratory Tract Carcinoma Involving the N UT Gene on Chromosome 15, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor; Central Nervous System Atypical
Teratoid Rhabdoid Tumor, Craniopharyngioma, Glioma, Brain cancer, Medullobiastoma, Medulloepithelioma, Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor (GIST), Bladder Cancer, Anal or Rectal Cancer, Appendix Cancer, Esophageal Cancer, Hypopharyngeal Cancer; Laryngeal Cancer, Lip and Oral Cavity Cancer, Metastatic Squamous Neck Cancer with Occult Primary, Mouth Cancer, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Oral Cancer, Lip and Oral Cavity Cancer, Oropharyngeal Cancer, Paranasal Sinus and Nasal Cavity Cancer, Pharyngeal Cancer; Head and Neck Cancer, and Mesothelioma.
[00170] In one embodiment, the treatment method targets a lymphoma selected from the group consisting of: diffuse large B-cell lymphoma, AIDS-Reiated Lymphoma, Cutaneous T-Cell Lymphoma, Sezary syndrome, mycosis fungoides (MF); Histiocytosis; Burkitt Lymphoma, and Central Nervous System Lymphoma; Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma, Hodgkin Lymphoma, Waldenstrom's
macroglobuiinemia; Mycosis Fungoides; Primary Central Nervous System Lymphoma;
lymphoplasmacytic lymphoma, and Primary Central Nervous System Lymphoma.
[00171] 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, lyphoplasmacytic NHL, Waldenstrom's macroglobulinaemia, and skin lymphomas.
[00172] In one embodiment, the treatment method targets a leukemia selected from the group consisting of: Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloproliferative Disorders; Hairy Cell Leukemia; Acute Myeloid Leukemia (AML); Chronic Myelogenous Leukemia (CML); and Langerhans Ceil Histiocytosis.
[00173] In one embodiment, the treatment method targets an acute leukemia selected from the group consisting of: acute lymphotyte leukemia, acute myeloid leukemia, chronic
lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and myeloproliferative disease.
[00174] In one embodiment, the treatment 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 Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, and Myeloproliferative Disorders.
[00175] 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 Cancers, AIDS-Reiated Lymphoma, Anal or Rectal Cancer, Appendix Cancer, Astrocytomas, and Atypical Teratoid/Rhabdoid Tumor.
[00176] In one embodiment, the treatment method targets a cancer selected from the group consisting of: 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 Cance, Bronchial Tumors, Burkitt Lymphoma, and Spinal Cord Tumors.
[00177] In one embodiment, the treatment method targets a cancer selected from the group consisting of: Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Atypical Teratoid Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Central Nervous System Lymphoma, 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, Sezary syndrome and mycosis fungoides).
[00178] In one embodiment, the treatment method targets a cancer selected from the group consisting of: Embryonal Tumors of Central Nervous System, Endometrial Cancer,
Ependymoblastoma, Ependymoma, Esophageal Cancer, Ewing Sarcoma Family of Tumors, Desmoplastic Round Cell Tumor, Chondrosarcoma, Extracranial Germ Cell Tumor,
Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, and Eye Cancer, including Intraocular Melanoma and Retinoblastoma.
[00179] In one embodiment, the treatment 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.
[00180] In one embodiment, the treatment method targets a cancer selected from the group consisting of: Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Hodgkin Lymphoma, and Hypopharyngeal Cancer.
[00181 ] In one embodiment, the treatment method targets a cancer selected from the group consisting of Kaposi Sarcoma and Kidney (Renal Cell) Cancer.
[00182] In one embodiment, the treatment method 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 Cance, Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma.
[00183] In one embodiment, the treatment method targets a cancer selected from the group consisting of: Waldenstrom's maeroglobulinemia (lymphoplasmacytic lymphoma), Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Multiple Endocrine Neoplasia Syndrome, Mouth Cancer, Multiple
Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Multiple Myeloma, and Myeloproliferative
Disorders.
[00184] In one embodiment, the treatment method is useful for treating a cancer selected from the group consisting of: Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, and Neuroblastoma.
[00185] In one embodiment, the treatment method is useful for treating a cancer selected from the group consisting of: Oral 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.
[00186] In one embodiment, the treatment method is useful for treating a cancer selected from the group consisting of: Pancreatic Cancer, Papillomatosis, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Pleuropulmonary Blastema, Pregnancy and Breast Cancer, Primary Central Nervous System Lymphoma, and Prostate Cancer.
[00187] In one embodiment, the treatment method is useful for treating a cancer selected from the group consisting of Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma, and Rhabdomyosarcoma.
[00188] In one embodiment, the treatment method is useful for treating a cancer selected from the group consisting of: Salivary Gland Cancer, Sarcoma, Sezary Syndrome, Skin Cancer, Skin Carcinoma, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinom, Squamous Neck Cancer with Occult Primary, and Supratentorial Primitive Neuroectodermal Tumors.
[00189] In one embodiment, the treatment method 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 Cancer of the Renal Pelvis and Ureter, and Gestational Trophoblastic Tumor.
[00190] In one embodiment, the treatment method is useful for treating a cancer selected from the group consisting of: Carcinoma of Unknown Primary Site, Cancer of Unknown Primary Site, Unusual Cancers of Childhood, Transitional Cell Cancer Of the Renal Pelvis and Ureter, Urethral Cancer, and Uterine Sarcoma.
[00191] In one embodiment, the treatment method is useful for treating a cancer selected from the group consisting of: Vaginal Cancer and Vulvar Cancer. [00192] In one embodiment, the treatment method is useful for treating a cancer selected from the group consisting of: Wilms Tumor and Women's Cancers.
[001 3] In some embodiments, treatment of cancer comprises prevention of tumor growth in a cancer subject. In some embodiments, treatment of cancer comprises prevention of formation of cancer metastases in a cancer subject. In some embodiments, treatment of cancer comprises targeted treatment of minimal residual disease in a cancer subject known to have the minimal residual disease in a cancer or a subject at risk for having minimal residual disease,
[00194] This might be indicated after treatment of the primary tumor by surgery and/or after chemotherapy (radiotherapy) has been initiated or determined to be effieaceous. Disseminated tumor cells may be in their dormant state and often cannot be attacked by chemotherapy
(radiotherapy). A thus treated patient seemingly is in a healed state, and refered to as "minimal residual disease." Nevertheless, the dormant tumor cells have a potential to form metastases if they become metastasising cells due to a growth stimulus after a longer dormant state.
[00195] As used herein, "minimal residual disease" denotes a small number of cancer cells that remain in a subject during treatment or after treatment when the subject is in remission (exhibiting no symptoms or signs of the disease). The methods described herein are preterably applied to a form of the diseases listed herein, including adult and childhood forms of these diseases.
[00196] In one embodiment, the treatment method is useful for treating an autoimmune disease. Autoimmune diseases include, but are not limited to alopecia areata, antiphospholipid, autoimmune hepatits, celiac disease, diabetes type 1, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, inflammatory myopathies, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, and vitiligo.
[00197] In one embodiment, the treatment method is useful for treating autoimmune and inflammatory disorders of the peripheral nerve system such as amyotrophic lateral sclerosis (Lou Gehrig's disease), based on various causes such as metabolic disorders that include diabetes, B12 and folate vitamin deficiencies, chemotherapy medications and medicines used to treat HIV, poisons that cause peripheral nerve damage, cancers that develop peripheral neuropathies as well as paraneoplastic syndromes, alcohol abuse, chronic kidney disease, injuries that cause compression on nerves and other lesions, infections such as Lyme disease, Guillain Barre syndrome, connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, certain inflammatory conditions such as sarcoidosis, coeliac disease, hereditary diseases such as Charcot marie tooth syndrome, Friedreich's ataxia, and/or idiopathic where no specific cause is found but inflammatory and/or autoimmune mechanisms are the cause of onset.
[001 8] In one embodiment, the treatment method is useful for treating autoimmune and inflammatory disorders with ocular manifestations. Such ocular manifestations 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, Behcet'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 ulceration, and less common entities such as choroiditis, retinal vasculitis, episcleral nodules, retinal detachments, and/or macular edema.
[00199] In one embodiment, the treatment method is useful for treating acute allograft rejection in transplant patients. In one embodiment, the treatment method is useful for treating ischemic stroke. In one embodiment, the treatment method is useful for treating inflammatory diseases including, but not limited to, arthritis, psoriasis, asthma, and colitis.
[00200] In one embodiment, a therapeutic agent includes a pharmaceutically acceptable mono-salt of compound (1) or an analog thereof (e.g., a compound of formula (10)). In one embodiment, a therapeutic agent includes a pharmaceutically acceptable di-salt of compound (1) or an analog thereof (e.g. , a compound of formula (10)). As described herein, some of the analogs can be tri-salts In one embodiment, a therapeutic agent includes 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, hydrogensulphate, sulfates, phosphates, fumarates, succinates, oxalates and lactates, bisulfates, hydroxyl, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maieate, fumarate sulfonate, methylsulfonate, formate, acetate, and carboxylate. In one embodiment, a therapeutic agent includes compound (1) or an analog thereof in the form of a pharmaceutically acceptable mono- or di-salt selected from p-toluene-sulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate and maieate. In one embodiment, a therapeutic agent includes compound (1) or an analog thereof in the form of a pharmaceutically acceptable mono- or di-salt having a counter ion selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and/or with counter-ions such as methylamino, dimethylamino, diethylamino, triethylamino counter-ions, and combinations thereof. In one embodiment, a therapeutic agent includes compound described herein in the form of a halide di-salt, such as a di-hydrochloride salt or a di-hydrobromide salt. [00201] In some embodiments of the treatment method, the second therapeutic agent includes an anti-cancer agent. In some embodiments of the treatment method, the second therapeutic agent is selected, without limitation, from acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, ametantrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bevaeizumab, bicalutamide, bisantrene, bisnafide dimesylate, bizelesin, bleomycin, brequinar, bropirimine, busuifan, cactinomycin, calusterone, capecitabine, caracemide, carbetimer, carboplatin, carmustine, carabicin, carzelesin, cedefingol, celecoxib, chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinornycin, daimorubicin, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, droioxifene, dromostanoione, duazomycin, edatrexate, eflomithine, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin, erbulozole, esorubicin, estramustine, etanidazole, etoposide, etoprine, fadrozole, fazarabine, fenretinide, fioxuridine, fludarabine, fluorouracil, flurocitabine, fosquidone, fostriecin, fulvestrant, gemcitabine, hydroxyurea, idarubicin, ifosfamide, ilmofosine, interleukin II (IL-2, including recombinant interleukin II or rIL2), interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-la, interferon gamma-lb, iproplatin, irinotecan, lanreotide, letrozole, leuprolide, liarozole, lometrexol, lomustine, losoxantrone, masoprocol, maytansine, mec lorethamine hydrochlride, megestrol, meiengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, metoprine, meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone, mycophenoiic acid, nelarabine, nocodazole, nogalamycin, ormnaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplornycin, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer, porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, riboprine, rogietimide, safingoi, semustine, simtrazene, sparfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tamoxifen, tecogalan, tegafur, teloxantrone, temoporfin, tenyposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, topotecan, toremifene, trestolone, triciribine, trimetrexate, triptorelin, tubulozole, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine, vinepidine, vinglycinate, vinleurosine, vinorelbine, vinrosidine, vinzolidine, vorozole, zeniplatin, zinostatin, zoledronate, zorabicin and combinations thereof.
[00202] In some embodiments of the treatment method, the second therapeutic agent is selected, without limitation, from 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; anti tumour antibiotics; platinum derivatives; alkylation agents; antimitotic agents; tubuline inhibitors; PARP inhibitors, topoisomerase inhibitors, serine/threonine kinase inhibitors, tyrosine kinase inhibitors, protein protein interaction inhibitors, MEK inhibitors, ER inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs, amifostin, anagrelid, clodronat, filgrastim, interferon, interferon alpha, leucovorin,rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, 2-chlorodesoxyadenosine, 2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine, 131-1-TM-601, 3CPA,
7-ethyl- 1 O-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, abiraterone, aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, A VLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (selunietinib),
ARRY-704/AZD-8330, AR-I2, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363,
AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY -4 -9006. BAY 80-6946, BBR-3464, BBR-3576, 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, torntovok), BIBF 1 120 (vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin-1 , bortezomib, brostallicin, busulphan, BYL-719, CA-4 prodrug, CA-4, CapCeli, calcitriol, canertinib, canfosfamide, capecitabine,
carboxyphthalatoplatin, CCl-779, CC-1 15, CC-223, CEP-701 , CEP-751 , CBT-1 cefixirne, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-II, CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247,
cyanomorpholinodoxorubicin, cytarabine, D 24851 , decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstiibestroi , diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexat, edotreotide, efaproxiral, efloniithine, EGF'R inhibitors, EKB-569, 1 K B- 09. enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER- 86526, erlotinib, ET-18-0CH3, ethynylcytidine, ethynyloestradioi, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4, FOLFXRI, formestane, fotemustine, galarubicin, gallium maltolate, gefinitib, 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, gplOO-peptide vaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametmib), GSK-21 18436 (dabrafenib), GSK-2126458, GSK-2132231 A, GSK-2334470, GSK-21 10183, GSK-2141795, GW2016, granisetron, herceptin, hexamethylmeiamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate, idenestroi, IDN-5109, IGF- 1R inhibitors, 1MC-1C1 1, IMC-A12 (cixutumumab), immunol, indisulam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha- 2b, interleukin-2, INK- 11 17, INK-128, I SM-18, ionafarnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J- 107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, Ieflunomide, lenograstim, leuprolide, Ieuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1 , LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162, methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), ML 518, motexaf in 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, 0X44 antibodies, OSI-027, OSI-906 (linsitinib), 4- IBB antibodies, oxantrazole, oestrogen, panitumumab, parupilone, pegfiigrastim,
PCK-3145, pegfiigrastim, PBI-1402, PBI-05204, PDO325901 , PD-1 antibodies,
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, periilylalcohol, perruzumab, P13K inhibitors, PI3K/mTOR inhibitors, PG-TXL, PG2, PLX-4032/RO-51 85426 (vemurafenib), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKJ166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, Rl 15777, RAF-265, ramosetron, ranpirnase, RDEA-1 19 BAY 869766, RDEA-436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb, rinfabate, risedronate,rituximab, robatumumab, rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881 A, rubidazone, mbitecan, R-flurbiprofen, RX-0201 , S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015A'"e-015, Si . 4 1 , SU6668, SDX-101 , semustin, seocalcitol, SM--1 1355, S -38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS- 103, tacedinaline, talaporf in, Tarceva, tariquitar, tasisulam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubiein, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab,
tremelimumab, tretinoin, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin, valrubicin, vatalanib, vincristine, vinfiunine, virulizin, WX-UK1, WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-51 1 , YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331 , ZD 1839, ZSTK-474, zoledronat, zosuquidar, and combinations thereof.
[00203] In some embodiments of the treatment method, 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, medroxy-progesterone, octreotide, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent is selected, without limitation, from, the group consisting of LHRH agonists and LHRH antagonists. In some embodiments, a LHRH agonist is selected from the group consisting of goserelm acetate, luprohde acetate, triptorelin pamoate and combinations thereof. In some embodiments, the second therapeutic agent includes a LHRH antagonist is selected from the group consisting of Degarelix, Cetrorelix, Abareiix, Ozarelix, Degarelix combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes an inhibitor of a growth factor. In some embodiments, the inhibitor of a growth factor is selected, without limitation, 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), insuline-like growth factors (IGF), human epidermal growth factor (HER), hepatocyte growth factor (HGF), and combinations thereof. In some embodiments, the human epidermal growth factor (HER) is selected from the group consisting of HER2, HER3, and HER4.
[00204] In some embodiments of the treatment method, the second therapeutic agent includes a tyrosine kinase inhibitor. In some embodiments of the treatment method, the tyrosine kinase inhibitor is selected, without limitation, from the group consisting of cetuximab, gefitinib, imatinib, lapatinib and trastuzumab, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes an aromatase inhibitor. In some embodiments of the treatment method, the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, and combinations thereof.
[00205] In some embodiments of the treatment method, the second therapeutic agent includes an antimetabolite. In some embodiments of the treatment method, the antimetabolite comprises an antifolate. In some embodiments of the treatment method, the antifolate is selected from the group consisting of methotrexate, raltitrexed, pyrimidine analogs, and combinations thereof. In some embodiments of the treatment method, the antimetabolite is a pyrimidine analog. In some embodiments of the treatment method, the pyrimidine analog is selected from the group consisting of 5-fluorouracil, capecitabin, gemcitabin, and combination thereof. In some embodiments of the treatment method, the antimetabolite is a purine analog or an adenosine analog. In some embodiments of the treatment method, the purine analog or adenosine analog is selected from the group consisting of mereaptopurme, thioguanine, cladribine and pentostatin, cytarabine, fludarabine, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes an antitumour antibiotic. In some embodiments of the treatment method, the antitumor antibiotic is selected from the group consisting of anthracyclins, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin and
combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes a platinum derivative. In some embodiments of the treatment method, the platinum derivative is selected from the group consisting of cisplatin, oxaliplatin, carboplatin and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes an alkylation agent. In some embodiments of the treatment method, the alkylation agent is selected from the group consisting of estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide,
temozolomide, nitrosoureas, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes a nitrosourea. In some embodiments of the treatment method, the nitrosourea is selected from the group consisting of carmustin, lomustin, thiotepa, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes an antimitotic agent. In some embodiments of the treatment method, the antimitotic agent is selected from the group consisting of Vinca alkaloids and taxanes. In some embodiments of the treatment method, the taxane is selected from the group consisting of paciitaxel, docetaxel, and combinations thereof. In some embodiments of the treatment method, the Vinca alkaloids are selected from the group consisting of vinblastine, vindesm, vinorelbin, vincristine, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes a topoisomerase inhibitor. In some
embodiments of the treatment method, the topoisomerase inhibitor is an epipodophyllotoxin. In some embodiments of the treatment method, the topoisomerase inhibitor, which is an epipodophyllotoxin selected from the group consisting of etoposide, etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron, and combinations thereof In some embodiments of the treatment method, the second therapeutic agent includes a serine/threonine kinase inhibitor. In some embodiments of the treatment method, the serine/threonine kinase inhibitor is selected from the group consisting of PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORCl inhibitors, PDK inhibitors, dual mTOR/PDK inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes a tyrosine kinase inhibitor. In some embodiments of the treatment method, the second therapeutic agent includes a PTK2/FAK inhibitor. In some embodiments of the treatment method, the second therapeutic agent includes a protein protein interaction inhibitor. In some embodiments of the treatment method, the protein protein interaction inhibitor is selected from the group consisting of LAP, Mcl-1 , MDM2/MDMX and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent includes a rapamycin analog. In some embodiments of the treatment method, the rapamycin analog is selected from the group consisting of everoiimus, temsirolimus, ridaforolimus, sirolimus, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent is selected from the group consisting of amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, and combinations thereof. In some embodiments of the treatment method, the second therapeutic agent is selected from the group consisting of 2-chlorodesoxyadenosine,
2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine, 131 -1 -TM-601, 3CPA,
7-ethyl-lO-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, abiraterone, aldesleukin, alitretmoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (selumetinib),
ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, 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, B1BW 2992 (afatinib, tomtovok), BIBF 1 120 (vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin-1 , bortezomib, brostallicin, busulphan, BYL-7.19, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capeciiabine,
carboxyphthalatoplatin, CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, eeflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-IL CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461 , CV-247,
cyanomorpholinodoxorubicin, cytarabine, D 24851 , decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201 , edatrexat, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET- 18-0CH3, ethynylcytidine, ethynyloestradioi, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX,
FOLFOX4, FOLFIRI, formes tane, fotemustine, galarubicin, gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide, GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-lOO, gpl OO-peptide vaccines, GSK-5126766, GSK-690693, GSK- 1 120212 (trametinib), GSK-21 18436 (dabrafenib), GSK-2126458, GSK-2132231 A, GSK-2334470, GSK-21 10183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate, ideiiestrol, ID -5109, IGF- 1R inhibitors, IMC-1C11, IMC-A12 (cixutumumab), immunol, indisulam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-11 17, 1NK- 128, fNSM-18, ionafarnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J- 107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrm, lometrexol, losoxantrone, LU 223651 , iurtotecan, LY-S6AKT1 , LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162, methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotnzumab), MLN518, motexaf in 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, 0X44 antibodies, OSI-027, OSI-906 (linsitinib), 4-1 BB antibodies, oxantrazole, oestrogen, panitumurnab, patupilone, pegfilgrastim,
PCK-3145, pegfilgrastim, PBI-1402, ΡΒΪ-05204, PDO325901 , PD-1 antibodies,
PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384,
PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosme, perillylalcohol, pertuzumab, PI3K inhibitors, PDK/mTOR inhibitors, PG-TXL, PG2, PLX-4032/RG-5185426 (vemurafenib), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, Pis. I I 66.
pievitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristm, R l 15777, RAF-265, ramosetron, ranpimase, RDEA- 19/B AY 869766, RDEA-436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG-7304, RG-7421 , RG-7321 , RG 7440, rhizoxin, rhu-MAb, rinfabate, risedronatejituximab, robatumimiab, rofecoxib, RO-31 -7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015/Ve-015, SU5416, SI .'6668. SDX-101 , semustin, seocalcitol, SM-1 1355, SN-38, SN-4071 , SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS-103, tacedinaline, talaporf in, Tarceva, tariquitar, tasisulam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab,
tremelimumab, tretinoin, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin, valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1 , WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281, XL-518 R-7420/GDC-0973, XL-765, YM-51 1 , YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331 , ZD 1839, ZSTK-474, zoledronat, zosuquidar, and combinations thereof.
[00206] In some embodiments, the other therapeutic agent comprises a steroid. Steroids include, but are not limited to, dexamethasone, prednisolone, methy l prednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazol. In some embodiments, the other therapeutic agent comprises an anti-emetic. Anti-emetics include, but are not limited to, 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), NKl receptor antagonists (such as aprepitant and casopitant), antihistamines (such as cyclizine. diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine), cannabinoids (such as cannabis, dronabinol, nabiione, and sativex), benzodiazepines (such as midazolam and lorazepam), anticholinergics (such as hyoscine), trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol, and ajwain.
[00207] Pharmaceutical compositions may be administered to a subject via 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 of
administration 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 sterile solutions, suspensions, suppositories, tablets and capsules. 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 tablets, hard shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids and semi-solids.
[00208] In some embodiments, the pharmaceutical composition is administered to a subject as a dosage form selected from the group consisting of sustained release forms, controlled release forms, delayed release forms and response release forms.
[00209] In some embodiments, the pharmaceutical composition is administered to a subject once daily. In some embodiments, the pharmaceutical composition is administered to a subject accoridng to an infrequent dosing regimen (e.g., administered once per week or less frequently). In some embodiments, the pharmaceutical composition is administered to a subject accoridng to a frequent dosing regimen (e.g., administered more than once per week). In some embodiments, the pharmaceutical composition is administered to a subject once weekly . In some embodiments, the pharmaceutical composition is administered to a subject once every four weeks. In some embodiments, the pharmaceutical composition is administered to a subject twice a week. In some embodiments, the pharmaceutical composition is administered to a subject once every two weeks. In some embodiments, the pharmaceutical composition is administered to a subject once every three weeks. In some embodiments, the pharmaceutical composition is administered to a subject in a repeated cycle of once weekly, once every two weeks, once every three weeks, once ever}' four weeks or combinations thereof.
[002101 In one embodiment, the treatment method comprises administering to a subject in need of such treatment: (i) a first therapeutic agent including a compound comprising compound (1), compound (10) an analog thereof, or a pharmaceutically acceptable salt thereof in combination with (ii) a second therapeutic agent, wherein the first therapeutic agent and the second therapeutic agent are administered either simultaneously or sequentially; and further comprises assaying the expression of an endoplasmic reticulum (ER) stress response gene in a biological sample. In some embodiments, the endoplasmic reticulum stress response gene is selected from the group that includes, but is not limited to, C/EBP-Homologous Protein (CHOP), Activating Transcription Factor 3 (ATF3) and both CHOP and ATF3, In some embodiments, the endoplasmic reticulum stress response gene is selected from the group that includes, but is not limited to, ATF3, Activating Transcription Factor 4 (ATF4) CHOP, IREl , Binding immunoglobulin protein (BiP), Eukaryotic translation initiation factor 2A (eIF2a), X-box binding protein 1 (XBP1). The biological sample may be tumor, peripheral blood mononuclear cells, or skin biopsy. The biological sample may be obtained before, during, or after drug administration. In some embodiments, the treatment method further comprises adjusting a dose of the first therapeutic agent to achieve induction of 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% of one or more ER stress gene. In some embodiments, the treatment method further comprises adjusting a dose of the first therapeutic agent to achieve induction of 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% of ER stress genes. In some embodiments, the treatment method further comprises adjusting a dose of the first therapeutic agent to achieve induction of 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% of ER stress genes.
[00211] In one embodiment, the treatment method comprises administering to a subject in need of such treatment: (i) a first therapeutic agent including 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, wherein the first therapeutic agent and the second therapeutic agent are administered either simultaneously or sequentially: and further comprises assaying the expression of proteasomal activity in a biological sample. In some embodiments the proteasomal activity may be chymotrysin-like, trypsin-like, and/or caspase-like activity. In some embodiments, the biological sample may be tumor, peripheral blood mononuclear cells, or skin cells. The biological sample may be obtained before, during, or after drug administration. In some embodiments, the treatment method further comprises adjusting the dose to achieve inhibition of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of the proteasomal activity. In some embodiments, the treatment method further comprises adjusting the dose to achieve inhibition of at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the proteasomal activity. In some embodiments, the treatment method further comprises adjusting the dose to achieve inhibition of 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% of the proteasomal activity.
[00212] In an aspect, provided herein are methods of treatment, which comprises administering to a subject in need of such treatment a combination of a first therapeutic agent including a compound of formula (1) or of formula (10), an analog thereof, or a
pharmaceutically acceptable salt thereof (e.g., a di-salt or tri-salt) and a second therapeutic agent, the method comprising:
(i) administering to the subject the first therapeutic agent;
(ii) waiting until a predetermined waiting time has elapsed after the time of administration of the first therapeutic agent to the subject; and/or until adverse events are resolved or resolving; and
(iii) administering the second therapeutic agent to the subject, wherein the predetermined waiting time is chosen so as to obtain a delayed therapeutic effect of the first therapeutic agent without an increased risk of possible 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 compound of the first therapeutic agent or a metabolite thereof. In some embodiments of the treatment method, the predetermined waiting time is determined by a quantitative assessment of renal function and parameters of renal. In some embodiments of the treatment method, the predetermined waiting time is determined by an assay for the determination of renal fanction, wherein the assay is selected from the group consisting of serum level the compound of the first therapeutic agent or a metabolite thereof; clearance rate of the compound of the first therapeutic agent or a metabolite thereof; 24-hour urinary clearance of the compound of the first therapeutic agent or a metabolite thereof. [00213] In one embodiment of the treatment method, the predetermined waiting time substantialiy equals the time required for systemic clearance of the compound of the first therapeutic agent or a metabolite thereof from the subject's body. In one embodiment of the treatment method, the predetermined waiting time substantially equals the time required for renal clearance of the compound of the first therapeutic agent or a metabolite thereof from the subject's body. In one embodiment of the treatment method, the predetermined waiting time substantially equals the time required for hepatic clearance of the compound of the first therapeutic agent or a metabolite thereof from the subject's body. In one embodiment of the treatment method, the predetermined waiting time substantially equals the time required for total clearance of the compound of the first therapeutic agent or a metabolite thereof from the subject's body. In one embodiment of the treatment method, the predetermined waiting time is about 4 hours. In other embodimens the waiting time is 1 day. In some embodiments, the waiting time is until Cmax of the compound of the first therapeutic agent has passed. In other embodiments, the waiting time is after most of the adverse events are resolved or are resolving. In one embodiment of the treatment method, the predetermined waiting time 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 treatment method, the predetermined waiting time is a 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 to 2 days. In one embodiment, the waiting time is up to 3 weeks. The preceeding are considered "therapeutic time periods," [00214] When the order of administration is reversed, timing for the administration of the first therapeutic agent can be after the Craax of the second therapeutic agent (i.e., the first administered drug) has passed. In one embodiment, administration of the first therapeutic agent can be after most or substantialiy all of the first administered drag has been eliminated from the body or the toxicity effects for the first administered drug are resolved or are resolving.
[00215] In some embodiments, the treatment method further comprises monitoring levels of the compound of the first therapeutic agent or a metabolite thereof in the subject using pharmacokinetic profiling. In some such embodiments, monitoring levels of the compound of the first therapeutic agent or a metabolite thereof in the subject using pharmacokinetic profiling comprises constructing a pharmacokinetic profile of the compound of the first therapeutic agent or a metabolite thereof for the subject using concentrations of the compound of the first therapeutic agent or a metabolite thereof in at least two samples obtained from the subject at time points suitable to construct a pharmacokinetic profile. In some embodiments of the method, which include monitoring levels of the compound of the first therapeutic agent or a metabolite thereof in the subject using pharmacokinetic profiling, samples are collected from the subject at point-of-care or point of use by sampling or self-sampling on point-of-care devices or point of use devices or on matrices suitable for storage of the samples prior to quantitation in a laboratory. In some embodiments of the treatment method, each of the point-of-care devices or point of use devices is capable of quantitating the compound of the first therapeutic agent or a metabolite thereof. In some embodiments of the method, which include monitoring levels of the compound of the first therapeutic agent or a metabolite thereof in the subject, one or more samples are collected from the subject at point-of-care or point of use by biopsy device for analysis at the point-of-care or point of use devices or for storage prior to analysis by a laboratory. In some embodiments of the method, a biopsy is taken after a time interval of 3-8 hours following administration the first therapeutic agent to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 3-24 hours following administration of the first therapeutic agent to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 8-24 hours following administration of the first therapeutic agent thereof to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 2 days following administration of the first therapeutic agent to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 3 days following administration of the first therapeutic agent to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 4 days following administration of the first therapeutic agent to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 1 -7 days following administration of the first therapeutic agent.
[00216] In some embodiments of the treatment method, the pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding dosing of the first therapeutic agent for the subject being treated. In some embodiments of the treatment method, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration to the subject ranges from about 1000 ng/dL to 1500 ng/dL for a therapeutic time period. In some embodiments, Cmax is less than 1500 ng/dL and greater than 85 ng/dL for a therapeutic time period. In some embodiments of the treatment method, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration to the subject ranges from about 1000 ng/niL to 1500 ng/mL for a therapeutic time period. In some embodiments, Cmax is less than 1500 ng/mL and greater than 85 ng/mL for a therapeutic time period.
[00217] In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration to the subject is a C»jax of from about 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1 100, 11 10, 1 120, 1130, 1140, 1 150, 1 160, 1 170, 1 1 80, 1 190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 13 10, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, or 1490ng/dLto about 1500ng/dL; 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 ngdL to about 150 ng/dL; or from about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5 ng/dL to about 15 ng/dL.
[00218] In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is a Cmax offrom about 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 about 1500 ng/mL; 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 to about 150 ng/mL; or from about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5 ng/mL to about 15 ng/mL.
[0021 ] In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 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/dL. In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from aboutlOO, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, ill, 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, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from aboutlO, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5 ng/dL.
[00220] In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 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. In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, ill, 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, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 10, 10.5, 11, 11.5, 120, 12.5, 13, 13.5, 14, or 14.5 ng/mL.
[00221] In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 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, 45, 555, 65, 575, 85, 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, 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, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 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 ng/dL, In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cma ") of the subject following its administration 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.
|00222] In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 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, 1015, 1025, 1035, 1045, 1055, 1065, 1075, 1085, 1095, 1 105, 1 115, 1125, 1 135, 1 145, 1155, 1 165, 1175, 1 185, 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, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 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, 11 1, 1 12, 1 13, 1 14, 1 15, 1 16, 1 17, 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, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration 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, 1 1, 1 1.5, 12, 12.5, 13, 13.5, 14, or 14.5 ng/mL.
[00223] In some embodiments of the treatment method, the maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration to the subject ranges from about 85 ng/dL to 1500 ng/dL; from about 8,5 ng/dL to 150 ng/dL; or from about 0.85 ng/dL to 15 ng/dL. In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 85, 95, 105, 1 15, 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, 1015, 1025, 1035, 1045, 1055, 1065, 1075, 1085, 1095, 1 105, 11 15, 1 125, 1135, 1145, 1 155, 1165, 1 175, 1 185, 1 195, 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 about 1500 ng/dL; from about 8, 9, 10, 1 1 , 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 ng/dL to about 150 ngdL; or 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.
[00224] In some embodiments of the treatment method, the maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration ranges from about 85 ng/mL to 1500 ng/mL; from about 8.5 ng/mL to 150 ng/mL; or from about 0.85 ng/mL to 15 ng/mL. In some embodiments, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) ("Cmax") of the subject following its administration is selected from about 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, 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 about 1500 ng/mL; from about 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 ngmL to about 150 ngmL; or 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.
[00225] In some embodiments of the method, the total drug exposure over time, measured as the area under the curve ("AUC") of a plot of the concentration of the drug in blood (whole blood, plasma, or serum) of the subject following administration of the drug against time after administration of the drug ranges from about 150 ng hr/mL to about 8000 ng hr/mL; from about 15 ng hr/mL to about 800 ng hr/mL; or from about 1.5 ng hr/mL to about 80 ng hr/mL. In some embodiments, AUC is less than 8000 ng hr/mL and is greater than or equal to 150 ng hr/mL. In some embodiments, AUC is less than 800 ng hr/mL and is greater than or equal to 15 ng hr/mL. In some embodiments, AUC is less than 80 ng hr/mL and is greater than or equal to 1.5 ng hr/mL.
[00226] In some embodiments of the method, the total drug exposure over time is an AUC of from about 100 ng hr/mL to about 8000 ng hr/mL; from about 10 ng hr/mL to about 800 ng hr/mL; or from about 1 ng hr/mL to about 80 ng hr/mL. In some embodiments, the total drug exposure over time is an AUC of from about from 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 from 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 from about from 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.
|00227] In some embodiments of the method the total drag exposure over time is an AUC of from about 100 ng hr/mL to about 8000 ng hr/mL, from about 10 ng hr/mL to about 800 ng hr/mL; or from about 1 ng hr/mL to about 80 ng hr/mL. In some embodiments, the total drug exposure over time is an AUC of from about from 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 from about from 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 drag exposure over time is an AUC of from about from 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 drag exposure over time is an AUC of from about 100 ng hr/mL to about 200 ng hr/mL; from about 10 ng hr/mL to about 20 ng hr/mL; or from about 1 ng hr/mL to about 2 ng hr/mL, [00228] In some embodiments of the method, the total drag 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, 46000, 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, 1 80, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 4600, 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, 15, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 460, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, and 80 ng hr/mL.
[00229] In another aspect, provided herein are methods of treatment, or use of a composition to treat a disease state, which comprises administering to a subject in need of such treatment a combination of a first therapeutic agent and a second therapeutic agent, the method comprising:
(i) administering to the subject the first therapeutic agent including a compound of formula
(1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof;
(ii) monitoring levels of the compound of the first therapeutic agent or a metabolite thereof in the subject using pharmacokinetic profiling; and
(iii) administering the second therapeutic agent conditional on 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 compound of the first therapeutic agent or a metabolite thereof for the subject using concentrations of the compound of the first therapeutic agent or a metabolite thereof in a plurality of samples obtained from the subject at time points suitable to construct a pharmacokinetic profile. In some embodiments of the method, at least two samples are collected at point-of-care or point of use by sampling or self-sampling on point-of-care devices or point of use devices or on matrices suitable for storage of the samples prior to quantitation of the compound or a metabolite thereof by a laboratory. In some embodiments of the method, each point-of-care devices or point of use devices is capable of quantitating the compound or a metabolite thereof. In some embodiments of the method, the pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding dosing of the compound or a salt thereof for the subject. In some embodiments of the method, the samples include from 2-12 samples. In some embodiments of the method, the samples are collected over a time period of up to 8 hours, up to 24 hours, up to 48 hours, or up to 72 hours. In some embodiments of the method, the pharmacokinetic parameters include at least one parameter selected from the group consisting of AUC, AUCin , Tmax, ΟΒ» time above threshold, steady state concentration, absorption rate, clearance rate, distribution rate, terminal T-l/2 or parameters drawn from noncompartmental pharmacokinetic (PK) or compartmental PK analysis, including physiological model-based compartmental PK analysis. In some embodiments of the method, the treatment method further comprises generating a report including the pharmacokinetic profile of the subject. In some embodiments of the method, the report includes a recommendation regarding dosing based on the pharmacokinetic profile of the subject. In some embodiments of the method, a reduction in dosage of compound (1), the analog thereof, or the pharmaceutically acceptable salt thereof is indicated to reduce risk of toxicity based on one or more pharmacokinetic parameters. In some embodiments of the method, the reduction in dosage of the compound or salt thereof is indicated based on time above threshold, wherein the threshold is the drug concentration above which toxicity occurs, or one or more of AUC, AUCmf, mean residence time (MRT), exponentials defining the pharmacokinetic profile, volume of distribution at steady state (Vss), volume of distribution during the terminal phase (Vz) or combination of a group of pharmacokinetic variable to adequately describe the pharmacokinetic profile. In some embodiments of the method, a dose adjustment of the compound or salt thereof is indicated to increase efficacy based on one or more pharmacokinetic parameters. In some embodiments of the method, an increase in dosage of the compound or salt thereof is indicated based on one or more of AUC, AUCmf, MRT, exponentials defining the pharmacokinetic profile, steady state volume (Vss) of distribution, volume of distribution during the terminal phase (Vz) or combination of a group of pharmacokinetic variables to adequately describe the pharmacokinetic profile. In some embodiments of the method, the dose of the compound or salt thereof is adjusted to within 5% to 25% of a desired target value. In some embodiments of the method, each of the samples is applied to the point-of-care device or the point of use device for determining the concentration of the compound or a metabolite thereof, wherein the point-of-care device or the point of use device comprises a lateral flow strip having a construction and composition such that an application of one or more of the samples to the lateral flow strip causes a fraction of the drug in the sample to bind to with a component of the lateral flow strip such that a detectable signal proportional to the concentration of the drug in the applied sample is produced . In some embodiments of the method, the samples are applied to matrices suitable for storage of the samples prior to quantitation by a laboratory. In some embodiments of the method, the samples are stored as dried blood spots. In some embodiments of the method, drug concentrations are measured by ELISA, LC MS MS, LC UV or LCMS. In some embodiments of the method, the pharmacokinetic parameters include at least one of steady state concentration, absorption, and terminal Ti/2. In some embodiments of the method, at least one of the samples is whole blood. IX. MULTIMODAL THERAPEUTIC METHODS
[00230] In one aspect, provided herein are multimodal therapeutic methods in which administration of a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment is supplemented by administration of other therapeutic modalities. In one embodiment, the multimodal therapeutic method comprises administering to a subject a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a
pharmaceutically acceptable salt thereof in conj unction with radiation therapy or after radiation is determined to not have been efficacious. In one embodiment, the multimodal therapeutic method comprises administering to a subject a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof in conjunction with radiation therapy, wherein the pharmaceutical composition comprising the compound of formula (1 ) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof and the radiation therapy are administered concurrently or sequentially in any order, in one embodiment, the multimodal therapeutic method comprises administering to a subject a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof in conjunction with radiation therapy in a sequential arrangement. In one embodiment, the multimodal therapeutic method comprises administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of formula (!) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof thereof concurrently with radiation therapy. In one embodiment, the multimodal therapeutic method is used for the treatment of cancer. In one embodiment, the multimodal therapeutic method includes administering to a cancer subject in need of such treatment a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof and irradiating cancer cells with a radiation beam. In one embodiment, the multimodal therapeutic method uses the technique of conformal radiotherapy (CRT) to deliver a dose volume histogram (DVH) prescribed to a cancer subject. In one embodiment, the multimodal therapeutic method uses the technique of intensity modulated radiation therapy (IMRT) to deliver radiation to cancer ceils. In one embodiment, the multimodal therapeutic method uses techniques that compensate for motion of tumors in the subject during treatment (e.g., where doses of radiation must be administered to a thoracic tumor which moves as the patient breathes). For example, the multimodal therapeutic method use Four Dimensional Computed Tomography (4D CT) scanning techniques to adjust the delivered radiation field to compensate for tumor motion over the breathing cycle.
[00231] Any suitable type of radiation, including gamma radiation which is given fractionated, IMRT (intensity modulated radiation therapy), gamma knife, proton therapy and brachytherapy can be used with the multimodal therapeutic method. Radiation therapy and administering a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof can be used to treat brain tumors such as glioblastoma or disease that has metastasized to the brain from lung cancer. The multimodal therapeutic method can be used to treat lung cancer, pancreatic cancer, rectal cancer, breast cancer, sarcoma, prostate cancer, gynecological malignancies, and lymphoma. The gamma knife is used frequently to treat brain metastases. In one embodiment, the multimodal therapeutic method includes use of proton therapy to treat cancer, including brain tumors, prostate cancer and any tumor proximate vital organs where it is very important to minimize toxicity to nearby normal tissue.
[00232] In one embodiment, the multimodal therapeutic method includes administering to a cancer subject in need of such treatment a pharmaceutical composition comprising a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof in combination with adoptive cell therapy (e.g., CAR-T (JCAR 14, 15, 16, 17, KTE-C19, or CTL019); other T Cell (ATM 13); or NK (CDNO-109 orNK-92)) either simultaneously or in combination.
[00233] In one embodiment, the multimodal therapeutic method eliminates minimal residual disease without adding to toxicity resu lting from treatment by a compound of formula (1) or of formula (10), an analog thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the multimodal therapeutic method improves prognosis and/or reduces adverse side-effects associated with a disease state or condition in a subject undergoing treatment.
X. ADDITIONAL DERIVATIVES AND ANALOGS OF AND SALTS OF
COMPOUND (1) AND RELATED COMPOUNDS
[00234] In one aspect, pro vided herein are analogs and related salts of compound (1) and processes of making the same. Persons skilled in the art will understand that the same general principles and concepts described above in conjunction with compounds (1), (10) and salts thereof, including principles and concepts related to methods and pharmaceutical
compositions, apply with equal force to derivatives and analogs of and salts of compound (1) and salts thereof. [00235] In one embodiment, the analogs have the structure of compound (25):
Figure imgf000093_0001
00236 mi , wherein Y represents NR4 or O, and wherein R-. , R2, R3, and
R4 independently represent hydrogen, alkyl, cycloalkyl, cycioalkylalkyl, carboxyi, haioalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, araikyl, hydroxyalky], alkoxy, aryloxy, alkoxyalkyl, aikoxycarbonyi, araikoxy, aralkylthio, aikanoyi, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaiyi, acyl, and heterocycie radicals. In some embodiments, Ri , R2, R3, and R4 are optionally substituted In some embodiments, some or all hydrogens in Ri , R2, R3, and R4 may be substituted by deuterium. Irs other embodiments, the analogs have the structure of compound (25), wherein Rj , R2, R3, and R4 are independently selected from the group consisting of H,
Figure imgf000093_0002
C1.4alkylph.enyl,
C1-4benzyl-piperazine, and in Ci_4alkyl, Ci-4alkylphenyl,
C1-4alkylphenylketone, and
Figure imgf000093_0003
are optionally substituted with C1-4alkyl, hydroxy!, or halo. In still other embodiments, the analogs have the structure of compound (25), wherein Ri, R2, R3, and R4 are independently selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.
[00237] In one embodiment, the analogs have the structure of compound (26):
Figure imgf000093_0004
, wherein Rj and R2 independently represent hydrogen, alkyl, cycloalkyl, cycioalkylalkyl, carboxyi, haioalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, araikyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, aikoxycarbonyi, araikoxy, aralkylthio, aikanoyi, mercapto, alkylthio, arylthio, alkylsulfinyi, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaiyi, acyl, and heterocycie radicals. In some embodiments, Rj and R2 are independently selected from the group consisting of H, Chalk 1, Ci-4alkylphenyl, Ci-4alkylphenylketone,
Ci-4benzyl-piperazine, and Ci.4alkylthienyl, wherein Ci-4alkyl,
Figure imgf000093_0005
Cj-4alkylphenylketone, and Ci_4benzy3~piperazine are optionally substituted with Ci-4alkyl,
Ci-4alkoxyl, hydroxyi, perhalogenated or halo. In some embodiments, Ri is selected from the group consisting of H, CH3) CH2Ph, CH2-((2-Cl)-Ph)s CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-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-benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.
[00238] In some embodiments, Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, -NG2, -OCH3s -CXH2) --CX2H, -CX3, -CH2(CX3), ·( '! Si CX : } ·. -C(CX3)3, -CpX -i, -OCX3, or -OCpX -i, where p is an integer from 2 to 20 and where X represents a halogen including a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. In some embodiments, R2 is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, - 02, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p+i, ~OCX3, or -OCpX2p+i, where p is an integer from 2 to 20 and where X represents a halogen.
[00239] In some embodiments, Rj is a hydrogen. In some embodiments, R; is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, the arylalkyl is
Figure imgf000094_0001
Ci_4alkoxyl, hydroxy!, perhalogenated C] -4alkyl, or halo.
[00240] In some embodiments, R2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, the arylalkyl is substituted with
Figure imgf000094_0002
Ci-4alkoxyl, hydroxy!, perhalogenated C j ^alkyl, or halo. In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In some embodiments, R2 is a substituted or an unsubstituted
heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or an unsubstituted heteroarylalkyl, such as an
isoxazolidinylmethvl or pyridylmethyl group. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with
Figure imgf000094_0003
hydroxyl, perhalogenated Ci-4alkyl, or halo. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. [00241] In one embodiment, the analogs have the structure of compound (27):
Figure imgf000095_0001
, wherein R; represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haioalkyl, alkenyl, cycloalkeiiyl, alkynyl, ar l, aralkyl,
hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkyltliio, aiyltliio, alkylsulfinvl, arylsulfinyl, alkylsuifonyl, arylsulfonyl, heteroaryl, acyl, and heterocycle radicals. In some embodiments, Ri is selected from the group consisting of H, Ci-4alkyl,
Figure imgf000095_0002
Ci.4benzyl-piperazine, and
Ci-4alkylthienyi, wherein
Figure imgf000095_0003
Cj-4alkylphenyl, Cj_4alkyiphenyiketone, and
Ci-4benzyl-piperazine are optionally substituted with Chalky 1, Ci_4a3koxyl, hydroxy!, perhaiogenated Ci..4aikyl, or halo. In some embodiments, Ri is selected from the group consisting of H, CH , CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl)s CH2CH2Ph,
CH2CH2(4-N-benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph.
[00242] In some embodiments, Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meia, and/or para positions of the benzyl ring: -CH3, -N02, -OC'l . -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p; i, -OCXs, or -OCpX2p; 1, where p is an integer from 2 to 20 and where X represents a halogen including a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. In some embodiments, j is a hydrogen. In some embodiments, Ri is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, the arylalkyl is substituted with Chalk 1,
Ci_4alkoxyl, hydroxyl, perhaiogenated
Figure imgf000095_0004
or halo.
[00243] In one embodiment, the analogs have the structure of compound (28):
Figure imgf000095_0005
wherein Ri and R2 independently represent hydrogen, alkyl, cycloalkyl, cvcloalkylalkvl, carboxyl, haioalkyl, alkenyl, cycloalkeiiyl, alkynyl, aryl, aralkyl, hydroxvalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arvlthio, alkylsu!finy!, arylsuliinyl, alkylsuifonyl, arylsulfonyl, heteroaxyi, acyl, and heterocycle radicals. In some embodiments, Ri and R2 are independently selected from the group consisting of H,
Figure imgf000096_0001
Chalk lphenyl, Ci-4alkylphenylketone,
Ci -ibexizyl-piperazine, and
Figure imgf000096_0002
Figure imgf000096_0003
are optionally substituted with Chalky], Ci-4alkoxyl, hydroxy!, perhalogenated Q^alkyl, or halo. In some embodiments, Rj is selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2- 2»thienyI), CH2CH2Ph, CH2-(2,4-di I- -Ph ). CH2-((2-CH3)-Ph), CH2CHOHPh, CH2CH2(4-N-benzyi-piperazine), and (CH2)3CO-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-benzy1-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph. In some embodiments, when Ri represents CH2Ph, R2 does not represent CH2-((2-CH3)-Ph.
[00244] In some embodiments, Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, -N02, -OC 'l . -CXH2, -CX2H, -CX3> -C1¾(CX3), -CH(CX3)2, -C(CX3)3> -CpX2p; -i, -OCXs, or -OCpX2p; !, where p is an integer from 2 to 20 and where X represents a halogen including a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. In some embodiments, R is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, -NQ2, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p+!, -OCX3, or -QCpX2p+i, where p is an integer from 2 to 20 and where X represents a halogen.
[00245] In some embodiments, Ri is a hydrogen. In some embodiments, R i is a substituted or an unsubstituted arylalkyl, suc as a benzyl or phenylethyl group. In some embodiments, the arylalkyl is substituted with
Figure imgf000096_0004
or halo.
[00246] In some embodiments, R2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, the arylalkyl is substituted with Ci-4alkyl, Ci-4alkoxyl, hydroxy!, perhalogenated Cj ^alkyl, or halo. In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of ha!o, -CH3, -CF3, and -OCH3. In some embodiments, R2 is a substituted or an unsubstituted
heterocycloaikylalkyi, such as a morpholinoalkyl or piperazinyla!ky! group. In some embodiments, R2 is a substituted or an unsubstituted heteroarylalkyl, such as an
isoxazolidinylmethyl or pyridylmethyl group. In some embodiments, the heterocycloaikylalkyi or heteroarylalkyl is substituted with C1-4alkoxyl, hydroxy!, perhalogenated Ci_4alkyl, or halo. In some embodiments, the heterocycioalkylaikyl or heteroarylalkyi is substituted with one or more substituents selected from the group consisting of halo, -C!¾, -CF3, and -OCH3-
|00247] In one embodiment, the analogs have the structure of compound (29):
Figure imgf000097_0001
, wherein Ri and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl,
hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfiiiyi, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaiyl, acyl, and heterocycle radicals. In some embodiments, Ri and R2 are independently selected from the group consisting of H,
Figure imgf000097_0002
Ci-4benzyl-piperazine, and
Figure imgf000097_0003
C1.4alkylph.enyl,
Chalk Iphenylketone, and C1-4benzyl-piperazine are optionally substituted with C1.4alk.yl, hydroxyl, perhalogenated Ci_4alkyi, or halo. In some embodiments, Rj is selected from the group consisting of H, CH3, C i l -Ph. CH2-((2-Cl)-Ph), Ci ] -{ 2-ihien i ). CH2CH2Ph, CH2CH2(4- -benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CQ-4F--Ph, In some embodiments, R2 is selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cf)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph. In some embodiments, when Ri represents CH2Ph, R2 does not represent CH2-((2-CH3)-Ph.
[00248] In some embodiments, Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, -N02, -OCH3, -CXH2, -CX2H, -CX , -CH2(CX3), -CH(CX3)2, -C(CX3) , ~CpX2pH , -OCX3, or -OCpX2p-; -1, where p is an integer from 2 to 20 and where X represents a halogen including refers to a fluorine, chlorine, bromine, or iodine atom, preferably , fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. In some embodiments, R2 is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, -N02, -OCH3, -CXH2, -CX2H, -CX3, -C1¾(CX3), -CH(CX3)2, -C(CX3)3, -CpX pH , -OCX3, or ( Κ ' ΓΧ -Γ . where p is an integer from 2 to 20 and where X represents a halogen. [00249] In some embodiments, Rj is a hydrogen. In some embodiments, R; is a substituted, or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, the arvialkyl is substituted with Chalk 1, Ci.4alkoxyl, hydroxyl, perhalogenated
Figure imgf000098_0001
or halo. |00250] In some embodiments, R2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, the arylalkyl is substituted with Ci-4alkyi, Ci-4alkoxyl, hydroxyl, perhalogenated
Figure imgf000098_0002
or halo. In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In some embodiments, R2 is a substituted or an unsubstituted
heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or an unsubstituted heteroaryialkyl, such as an
isoxazolidinylmethvl or pyridy Imethyl group. In some embodiments, the heterocycloalkylalkyl or heteroaryialkyl is substituted with
Figure imgf000098_0003
hydroxyl, perhalogenated Ci-4alky], or halo. In some embodiments, the heterocycloalkylalkyl or heteroaryialkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -(.'! ' :. ami ·( )(.'! I ;.
[00251 ] In one embodiment, the analogs have the structure of compound (30):
Figure imgf000098_0004
, wherein Ri and R2 independently represent hydrogen, aikyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkyithio, alkanoyl, mercapto, alkylthio, aiylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryi, acyl, and heterocycle radicals. In some embodiments, Rj and R2 are independently selected from the group consisting of H, Chalky 1, Cj ^alkylphenyl, Cj ^alkyiphenyiketone,
Ci-4benzyl-piperazine, and
C1_4alkylphenylketone, and
Figure imgf000098_0005
Ci-4alkoxyl, hydroxyl, perhalogenated
Figure imgf000098_0006
is selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4- -benzy]-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-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-benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph. In some embodiments, when Ri represents CH2Ph, R2 does not represent CH2-((2-CH3)-Ph. [00252] In some embodiments, Ri is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, -N02, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, "CpX pt-i, -OCX3, or OCpX v. · . where p is an integer from 2 to 20 and where X represents a halogen including refers to a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. In some embodiments, R2 is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH , -N02, -OCH3, -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CPX2P-H , -OCX3, or ( Κ ΓΧ -Γ . where p is an integer from 2 to 20 and where X represents a halogen.
|00253] In some embodiments, Ri is a hydrogen. In some embodiments, Ri is a substituted or an unsubstituted ar lalkyl, such as a benzyl or phenylethyl group. In some embodiments, the ar lalkyl is substituted with Ci.4alkyl, Ci-4alkoxyl, hydroxy], perhalogenated
Figure imgf000099_0001
or halo.
[00254] In some embodiments, R2 is a substituted or an unsubstituted arylalkyl, such as a benzyl or phenylethyl group. In some embodiments, the arylalkyl is substituted with
Figure imgf000099_0002
Ci-4alkoxyl, hydroxy!, perhalogenated Ci_4alkyl, or halo. In some embodiments, the arylalkyl is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -OCH3. In some embodiments, R2 is a substituted or an unsubstituted
heterocycloalkyialkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or an unsubstituted heteroarylalkyi, such as an
isoxazolidinylmethyl or pyridylmethvl group. In some embodiments, the heterocycloalkyialkyl or heteroarylalkyi is substituted with
Figure imgf000099_0003
hydroxyl, perhalogenated Ci-4alkyl, or halo. In some embodiments, the heterocycloalkyialkyl or heteroarylalkyi is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -QU I
[00255] In one embodiment, the analogs have the structure of compound (31):
Figure imgf000099_0004
, wherein Ri and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyi, haloalkyl, alkenyl, cycloalkenyl, alkynyl, ar l, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, aikylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaiyl, acyl, and heterocycle radicals. In some embodiments, Rj and R? are independently selected from the group consisting of H, Cj
Figure imgf000100_0001
Ci-4benzyl-piperazine, and d.-jalkylthienyl, wherein C^alkyl, Chalk Iphenyl,
Ci-4alkylphenylketone, and
Figure imgf000100_0002
are optionally substituted with
O -ialkoxyi, hydroxy 1, perhalogenated
Figure imgf000100_0003
or halo. In some embodiments, Ri is selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzyl-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-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-benzyI-piperazine), CH2-(2,4-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph. In some embodiments, when Rj represents CH Ph, R2 does not represent CH2-((2-CH3)-Ph.
[00256] In some embodiments, Rj is a benzyl optionally substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, -N02, -OCH3s -CXH2, -CX2H, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p+; , -OCX3, or -OCpX2p+; , where p is an integer from 2 to 20 and where X represents a halogen including refers to a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. In some embodiments, R2 is a benzyl substituted with one or more of the following substituents alone or in combination in the ortho, meta, and/or para positions of the benzyl ring: -CH3, -NO?, -OCH3, -CXH2, -CX2H, -CX , -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX2p÷i, -OCX3, or -OCpX2p-H, where p is an integer from 2 to 20 and where X represents a halogen.
[00257] In some embodiments, Rj is a hydrogen. In some embodiments, R; is a substituted or an unsubsiituted arylalkyi, such as a benzyl or phenylethyl group. In some embodiments, the arvlalkyl is substituted with
Figure imgf000100_0004
hydroxyl, perhalogenated or halo.
[00258] In some embodiments, R2 is a substituted or an unsubsiituted arylalkyi, such as a benzyl or phenylethyl group. In some embodiments, the arylalkyi is substituted with Cj ^aikyi, Ci-4alkoxyl, hydroxyl, perhalogenated C^alkyl, or halo. In some embodiments, the arylalkyi is substituted with one or more substituents selected from the group consisting of halo, -CH3, -CF3, and -GCH3. In some embodiments, R2 is a substituted or an unsubsiituted
heterocycloalkylalkyl, such as a morpholinoalkyl or piperazinylalkyl group. In some embodiments, R2 is a substituted or an unsubsiituted heteroarylalkyl, such as an
isoxazolidinylmethyl or pyridylmethyl group. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with
Figure imgf000100_0005
hydroxyl, perhalogenated Ci-4alkyl, or halo. In some embodiments, the heterocycloalkylalkyl or heteroarylalkyl is substituted with one or more substituents selected from the group consisting of halo, -C3¾, -CF3, and -OCH3.
XI. EXAMPLES
[00259] It should be understood that the description and specific examples provided below are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure. The following examples are intended to illustrate the embodiments disclosed and are not to be construed as being limitations thereto. Additional compounds, other than those described below, may be prepared using the following reaction schemes described above or appropriate variations or modifications thereof.
Example 1. Synthesis of 2-Chlorobenzylammo-2-imidazoline faydriodide
[002601 To a stirred solution of 2-methylthio-2-imidazoline hydriodide (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 for 90 min at 70 C. under an atmosphere of argon. The solution was cooled to room temperature, filtered on a sintered funnel, washed with cold dioxane (2 mL) and dried under vacuum. The white solid compound 4·! 11 (R2=2-chlorobenzyl) was obtained (242 mg, 72%) and used without further purification.
Example 2. Synthesis of 2-Chlorobenzylamino-2 -imidazoline
[00261] To a stirred solution of 2-chlorobenzylamino-2-imidazoline hydriodide (242 mg, 0.72 mMol) in water (3 mL), was added 1.0 N sodium hydroxide (2 mL) at 7 °C. The reaction mixture was stirred for 30 min at 7 °C under argon. After that methylene chloride (5 mL) was added and the mixture stirred for another 5 min. The reaction mixture was extracted with methylene chloride (2* 2.5 mL), The organic layer was dried over anhydrous a2S04, filtered and evaporated. The resulting free base (150 mg, 100%) was obtained as a viscous liquid and was used for the next reaction without any further purification. MS(ESI) 210(M+H).
Example 3. Synthesis of Methyl- 1 -benzyl 4-oxo-3-piperidine carboxylate (Compound (6)).
[00262] To a stirred methyl- 1 -benzyl 4-oxo-3-piperidine carboxylate hydrochloride (5.7 g, 20 mMol) in ethyl acetate (50 mL), was added triethylamine (6 mL) at 7 °C. The reaction mixture was stirred for 30 min at 7 °C under atmosphere of argon. The reaction mixture was extracted with ethyl acetate (2x 50 mL) washed with water (50 mL), The organic layer was dried over anhydrous Na2S04, filtered and evaporated. The resulting free base residue (5, Ri=benzyl) as a viscous oil was used in the next reaction without any further purification MS(ESI) 248(M+H) Example 4. Synthesis of ONC902 (Compound (14))
[002631 To a solution of 2-ehlorobenzylamino-2- imidazoline (150 mg, 0.72 mMol), methyl 1 -benzyl 4- oxo-3-piperidine earboxylate (5,
Figure imgf000102_0001
(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. After that the reaction mixture was refiuxed at 125 °C to 130 °C for 2h. The solvents were removed under vacuum, extracted with ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (2x 10 mL) and water (10 mL). The organic layer was dried over anhydrous Na2S04, filtered and evaporated. The crude free base was purified by RP HPLC (10%-40%
aeetonitriie/water) to give ONC902 TFA salt as a white solid (228 mg, 50% yield) MS(ESI) 407 (M+H).
[00264] The same process was used starting with different benzylamines to prepare various analogs, e.g. , QNC903, 904, 905, 906, 912, 210, 21 1, 212, 213, 214, 217, 218, 219, 220, 221 , 222, 223, 224, 225, and 226.
Example 5. Synthesis of ONC907 (Compound (19))
[00265] 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 in 0.5 h at room temperature under an atmosphere of nitrogen. After addition of a tew drops of methanol, a solution of l -tert-butoxycarbonyl-4-piperidone (4.8 g, 24 mMol) dissolved in dry toluene (20 mL) was added dropwise to the reaction mixture while stirring at 80 °C over I h. The reaction mixture was stirred for 3 h at the same temperature and then cooled to 0 °C (ice bath) and adjusted to pH 6-6.5 with acetic acid. The resulting cold mixture was diluted with water (lOmL) 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 layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure The compound was dried in vacuum to give methyl-l-tert-butoxycarbonyl- 4-oxo-3-piperidine earboxylate (5.0 g, 80%). The compound obtained was carried to next reaction without any further purification.
[00266] 2 -methybenzylamino-2 -imidazoline (190 mg, 1 mMol), methyl
1-tert-butoxycarbonyl- 4-oxo-3-piperidine earboxylate (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. After that the reaction mixture was refiuxed at 125 CC to 130 °C for 2h. The solvents were removed under vacuum, extracted with ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (2x 10 mL) and water (10 mL). The organic layer was dried over anhydrous Na2S0 , filtered and evaporated. The crude free base was cleaved with 10% trifluoroacetic acid in dichloromethane, purified by RP HPLC (10%-40% acetonitrile/water) to give ONC907 (262 mg, 50%) TFA salt as a white solid MS(ESI) 297 (M+H).
Example 6. Synthesis of ONC909 (Compound (21))
[00267] A mixture of O C907 (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 solvents were removed under vacuum, extracted with ethyl acetate (10 mL), washed with water (5 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and evaporated. The erode free base was purified by RP HPLC (10%-40% acetonitrile/water) to give ONC909 (62 mg, 50%) TFA salt as a white solid MS(ESI) 401 (M+H).
[00268] The same process was used starting with different halides to give ONC910 and 214. Compounds 227, 228, 229, 230, 231 , 232, 233, 234, 235, and 236 were prepared using the analogous process from Examples 1 and 5 starting with a different benzylamine. Then treating the intermediate compound where Ri is H with different halides as above.
[00269] Compound ONC91 1 was prepared from ONC910 by treatment with TFA.
[00270] Compound (72) was prepared by reacting the precursor NH compound prepared in analogy to Example 5 and treating it with styrene oxide.
Example 7. Synthesis of QNC908 (Compound (20))
[00271] To a solution of 2-methylbenzylamino-2 -imidazoline (190.0 mg, 1.0 mmol), methyl 1 -methyl 4-oxo-3-piperidine carboxylate (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. After that the reaction mixture was refluxed at 125 °C to 130 °C for 2h. The solvents were removed under vacuum, extracted with ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (2* 10 mL) and water (10 mL). The organic layer was dried over anhydrous Na?SC , filtered and evaporated. The crude free base was purified by HPLC 10%-40% acetonitrile and water to give ONC908 (270.0 mg., 50%) TFA salt as a white solid MS(ESI) 31 1 (M+H).
Example 8. Synthesis of ONC201 (Compound (1))
[00272] To a stirred 800 mL saturated NaHCOs in a 2 L round bottom flask, compound (3) (239.7 g, 0.845 mol, 1.6 equiv) was added in portions. n-Butanol (500 mL) was added to the resulting mixture and the mixture was stirred for 30 min and then transferred to a separating funnel. The organic phase, containing compound (4), was separated and transferred to a 2 L three-neck round bottom flask equipped with mechanical stirring, "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 gm 0.026 mol, 5 mol%) were added to the contents of the flask. The resulting mixture was heated to reflux for 6 hours. Water in the reaction mixture was separated into the Dean-Stark trap as necessary. Refluxing temperature increased from 93 C to 1 8 C. Reaction progress was monitored by HPLC. When the peak area of compound (!) on HPLC remained constant with the reaction time, the reaction was stopped.
Example 9. Synthesis of Pi-Salt of ONC201 (Compound (l>2HCi)
[00273] Without isolation of the 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-neck round bottom flask equipped with mechanical stirring, N2 inlet, a thermocouple, a condenser and a Dean-Stark trap. While agitating the reaction mixture, 1 N HC1 in dioxane-MTBE solution was added dropwise (4 N HCi in dioxane: 300 mL, 1.2 mol, 2.27 equiv; MTBE: 1200 mL) until no more solid precipitated out of the reaction mixture upon addition of HCI. The reaction mixture was heated to reflux at 60-65 °C for 2 hours. Water was separated into the Dean-Stark trap as necessary. 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 in the vacuum oven at 65°C overnight (16 hours) to afford 200 g yellow solid.
[00274] To a 2 L three-neck round bottom flask equipped with mechanical stirring, N2 inlet, a thermocouple and a condenser, the above solid (200 g) was added, 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 χ 3). The wet solid was dried in the vacuum oven at 85°C for 3 days until the residual solvent met specification. 120 g of compound (2) was obtained as a white solid in a yield of 49%, with HPLC purity 99.7%.
Example 10. Activity of analogs of Compound (1)
[00275] A number of exemplary analogs of compound (1) were prepared based on the syntheses described here. For each of these compounds, the viability of human cancer cells at 72 hours post- treatment with the compound was measured. The change in potency (relative to ONC201) was determined and is presented in the table below. RELATIVE POTENCY OF ANALOGS OF COMPOUND (1)
Figure imgf000105_0001
* Relative to the potency of ONC201; A Indicates a potency increase of >2-fold of ONC201 ; B Indicates potency that is within 2-fold of ONC201; and C Indicates a potency decrease of 2- i id of C3NC20L
[00276] Irs addition, a single dose of compound (52) by oral or intraperitoneal administration to human colon cancer xenograft-bearing mice resulted in a significant reduction of tumor volume compared to vehicle-treated control cohorts. Compound (52) has a wide therapeutic window, as it is well tolerated at doses at least up to 225 mg/kg in mice. Example 11. Dosing Regimens
[002771 Compound (1) is administerd to tumor-bearing mice, according to one of the following dosing regimens using a 7 day recurring cycle.
1) Day 1 : 200 mg/kg orally;
2) Day 1 / Day 4: 100 mg/kg orally per dose:
3) Day 1 / Day 2: 100 mg/kg orally per dose; or
4) Day 1 : 2 doses split 6 hours apart at lOOmg/kg orally per dose,
[002781 The efficacy of the dosing regimens are assessed and compared.
Example 12. Preliminary Determination of Interactions with Compound (1)
[002791 The preliminar spectrum of compound (1) in the human colon carcinoma cell line HCT1 16 was determined.
|00280] Briefly, compound (33) (ONC911) was immobilized at different immobilization densities to sepharose beads. For analysis by quantitative mass spectrometry, HCTl 16 human colon carcinoma cells were grown in media with different forms of isotopicallv labeled amino acids (SILAC = stable isotope labeling by amino acids in cell culture). The corresponding proteomes can be distinguished by the introduced mass difference. Binding experiments were performed in duplicate with a partial switch of labels to exclude labeling artifacts. Bound proteins were completely eluted from the affinity matrices, separated by SDS-PAGE and subjected to tryptic digestion. Recovered peptides were analyzed by LC-MS/MS on an LTQ Orbitrap Velos mass spectrometer (Thermo Fisher). Raw data generated by LC-MS/MS were processed by MaxQuant to obtain quantitative protein abundance data.
[00281] Quantified proteins were analyzed for enrichment of proteins compared to the control matrix and competition of bound protein by incubation with compound (1). Such a binding and displacement pattern would be expected of a specific target protein.
Results
[00282] First, HCTl 16 cells were cultivated and metabolically labeled by SILAC. Efficient SILAC encoding with incorporation rates of the isotopic variants of arginine and lysine exceeding 95% was achieved. Sufficient cells were prepared for subsequent experiments. Cell extracts were generated by detergent mediated cell lysis. In addition, remaining cell nuclei were extracted by lysis in the presence of 400 mM NaCl in order to include nuclear proteins. The cytosolic and nuclear extracts were combined.
[00283] The linker compound (33) (ONC.911) was immobilized via its amino group to sepharose beads. Bead with four different immobilization densities of 6 mM, 3 mM, 1 mM and 0,3 mM were prepared. These matrices wrere used to enrich proteins from HCT116 extracts and to investigate displacement of bound proteins by 50 μΜ of compound (1).
[00284] In total, -3600 proteins were identified. Specific enrichment of proteins by immobilized compound (33) (ONC911) was observed for all coupling densities and replicates. 100285] The number of candidates increased with the immobilisation density. Table 3 summarizes the target candidates of compound (1). At the highest coupling density (6 mM) enrichment by the affinity matrix and consistent displacement over two replicates by compound (1) was observed for 14 proteins. At a coupling density of 3 mM two potential target candidates were identified, both of which were shared with the high coupling density . At the lower coupling densities (1 and 0.3 mM) two and one protein behaved consistently as targets, respectively,
|00286] In addition, several proteins showed enrichment by the affinity matrix and displacement by compound (1), but displacement was observed in only one of the two replicates per coupling density. Such proteins are designated as "OK (with outlier)" in Table 3.
[00287] In summary, immobilized compound (33) (ONC911) appears to be functional and is able to specifically enrich proteins from a cell lysate. Additionally, distinct competition with 50 μΜ of compound (1) was observed.
Figure imgf000108_0001
Figure imgf000109_0001
outlier)
Uniprot ID: Best Uniprot identifier; Protein name: Protein name according to Uniprot. [00288] Target classification: Evaluation of the respective protein at the indicated coupling density of compound ONC216. "OK" indicates that the respective protein was consistently enriched and competed over 2 independent replicate experiments. "OK (with outlier)" indicates enrichment by the affinity matrix and displacement by Compound (1), but displacement was observed in only one of the two replicates.
Example 13. GPCR Antagonism of Compound (1)
[00289] ONC201 was evaluated in a whole cell, functional assay of a β-Arrestin G protein- coupled receptor (GPCR) activity that directly measure dopamine receptor activity by detecting the interaction of β-Arrestin with the activated GPCR that can serve as a reporter. For each dopamine receptor (DRD1 , DRD2S, DRD2L, DRD3, DRD4, and DRD5), cell lines overexpressing the reporter constructs were expanded from freezer stocks. Cells were seeded in a total volume of 20 μΐ, into white walled, 38 -well microplates and incubated at 37°C prior to testing, with antagonist followed by agonist challenge at the ECso concentration.
Intermediate dilution of sample stocks was performed to generate 5* sample in assay buffer. 3,5 p,L of 5X sample was added to cells and incubated at 37°C or room temperature for 30 minutes. Vehicle concentration was 1%. 5 μΕ of 6x ECgo agonist in assay buffer was added to the cells and incubated at 37°C or room temperature for 90 or 180 minutes prior to assay readout. % Antagonism was calculated using the following formula % Antagonism =100% x (1— (mean RLU of test sample— mean RLU of vehicle control) / (mean RLU of ECso control — mean RLU of vehicle control).
Example 14. Assessing Compound (1 ) interactions with Efflux and transporter proteins
[00290] The ability of ONC201 to interfere with transporter protein activity is evaluated to determine the dosing regimens for ONC201 in combination with substrates on transporter proteins. The timing or dose level of ONC201 in combination with another therapeutic agent may be modified based on these assay results. Transporter proteins include OATP1B1 , OATP1B3, OAT1, OAT3, OCT! , OCT2, MATE1 and MATE2-f solute earners (SLC).
[00291] The ability of ONC20! to interfere with the efflux proteins was evaluated to determine if ONC201 could inhibit the ability of these proteins to efflux small molecule substrates. Inhibiting these efflux proteins could increase the efficacy of efflux protein substrates by combining with ONC201 to increase its intracellular concentrations or to alter its biodistribution. Efflux proteins include MDR1 and BCRP.
[00292] The interaction of ONC201 with the human MD 1 and BCRP transporter was investigated in vitro using MDR1 and BCRP over-expressing Madin-Darby canine kidney (MDCKll-MDRl and MDCKIl-BCRP) and the parental cells (MDCKII). The bidirectional permeability of respective probe substrates in MDCKII-MDRl and -BCRP and MDCKII monolayers was performed to investigate if ONC20.1 is an inhibitor for MDR1 and BCRP, Digoxin and prazosin were used as the probe substrates for MDRl and BCRP, respectively,
[00293] The inhibition assay results are summarized in Table 4 below. ONC201 is an inhibitor of MDR 1 and BCRP at 200 micrornolar. The combination of ONC201 with substrates of MDR l or BCRP may increase the efficacy of the substrate by increasing intracellular concentrations of the substrate or altering its biodistribution.
Table 4:
Figure imgf000111_0001
A-B: apical-to-basolateral; B-A: basolateral-to-apical; PC: positive control
Example 15. Assessing inhibitory potential of Compound (1) for P450 Enzymes
[00294] The potential of ONC201 to induce human cytochrome P450 (CYP) enzymes with attention to the three major inducible drug-metabolizing enzymes, i.e. CYP 1A2, 2B6, and 3A4, using eryopreserved plateable human hepatocytes was evaluated.
[00295] The experimental CYP induction results of ONC201 are summarized in Table 5 below. ONC201 did not induce P450 to an effect that was >20% of positive controls in this assay. Therefore can be used in combination of other drugs with out changing the activity of CYP enzymes.
Table 5: Induction of CYP mR A in Cyropreserved H man Hepatocytes with
Treatments
Figure imgf000112_0001
* CYP mRNA induction fold values were calculated using a standard AACj method with ί 8S gene as the reference gene and target (C YP) gene expression of hepatocytes treated with vehicle control as the baseline.
0 NC: Negative control - flumazenil (25 μΜ) was used as the negative control treatment
0 PC: Positive control - omeprazole (50 μΜ), phenobarbital (750 μΜ) and rifampin (25 μΜ) were used as the positive control treatment for CYP 1 A2, 2B6 and 3A4, respectively.
Data is calculated from triplicate measurements.
[00296] The inhibitory potentials of ONC201 against seven (7) human cytochrome P450s
(CYP), i.e. CYP1A2, 2B6, 2C8, 2C9, 2C 19, 2D6, and 3A4, were investigated in vitro in pooled human liver microsomes (HLM) using eight (8) CYP isoform specific marker substrate reactions. They were CYP1 A2 -mediated phenacetin O deethylation, CYP2B6-mediated bupropion hydroxylation, CYP2C8-mediated amodiaquine N deethylation ,
CYP2C9-mediated diclofenac 4' hydroxylation, CYP2C 19 mediated S mephenytoin 4' hydroxylation, CYP2D6-mediated bufuralol Γ hydroxylation, CYP3A4 mediated midazolam
1 ' hydroxylation, and testosterone 6β hydroxylation.
[002971 ONC201 inhibited CYP isozymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) with ICso values ranging from 34.9 to 428.6 μΜ (4 to 48-fold above Cmax of 9uM; 40-480-fold above average plasma concentration at 24-hours of 0.9uM) 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 related to drug-drug interactions. Table 6:
Figure imgf000113_0001
"ICso values for Error! Reference source not found, were determined by fitting normalized data to sigmoidal inhibitory non-linear regression model using GRAPHPAD PRISM*.
b>500 - no inhibition > 50% within the concentration range tested (1.5 - 500 μΜ).
Example 16 Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors. |00298] ONC201 induces apoptosis in tumor, but not normal, cells at doses that trigger high levels of cell death in human cancer cells. The safely profile of ONC201 in GLP safety studies in rats and dogs was consistent with the preferential cytotoxicity of ONC201 in tumor over normal cells in vitro. Thus the in vitro and in vivo profiles of ONC201 indicate a wide therapeutic window that is highly desirable for cancer therapeutics. A schedule of every 21 days was selected for the clinical studies based on preclinical results that indicate sustained PD in tumors and after initial preliminary experiments suggesting that more frequent dosing did not appear to substantially increase the in vivo efficacy.
[00299] Based on the compelling efficacy and safety profile of O C201, as well as the novel engagement of signaling pathways that are important for many cancers, the clinical introduction of ONC201 in patients with advanced cancers was undertaken. The primary objective of this first-in-human, phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of ONC201 administered orally in patients with advanced cancers, as well as to evaluate the safety and tolerability of the drug. Secondary objectives included assessments of pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ONC201.
[00300] Briefly, this phase I, open-label study treated 10 patients during dose escalation with histologically-confirmed advanced solid tumors. An additional 10 patients have been accrued in an ongoing expansion phase to increase the safety experience. Patients received GNC2Q1 orally every 3 weeks at closes from 125 to 625 mg using an accelerated titration design.
[00301] The RP2D was defined as 625 mg that achieved a Cmax of 1 .5 - 7.5 rng/mL (-3.9-19.4 DiM). Plasma concentrations saturated at 375 mg, suggesting dose escalation above 625 mg was not warranted. No Grade >1 drag-related adverse events occurred. During the dose escalation phase, the mean number of cycles (21 days) was 3.1 , The expansion phase with 10 patients confirmed the safety of ONC201 at the RP2D. PK analysis revealed a half-life of 9.6 hours and an AUC of 25 h^g/L. Prolonged induction of serum caspase-cleaved keratin 18 and induction of TRAIL was observed. Eight of 10 patients had stable disease and one patient with prostate adenocarcinoma experienced prolonged stable disease, remaining on study for 27 weeks. One additional patient with endometrial cancer underwent a mixed response.
|00302] QNC2Q1 is extremely well tolerated, possesses a favorable PK profile with saturable absorption of micromolar plasma concentrations, and exhibits signs of clinical activity when orally administered at 625 mg every 3 weeks.
PATIENTS AND METHODS
Ethics
[00303] The study was carried at the Robert Wood Johnson University Hospital / Rutgers Cancer Institute of New Jersey (CINJ) in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines and was approved by relevant regulatory committees and the Institutional Review Board of CINJ. Patients provided written, informed consent for their study participation.
Patient Population
[00304] Patients of 18 years of age or o lder with ad vanced solid tumors who had no standard treatment or were resistant to standard treatments, ECOG performance status of >1, and assessable disease by RECIST 1.1 criteria were eligible. If patients had received radiation therapy, they had to have one measurable lesion outside the irradiated area. Patients had to have finished all prior cytotoxic chemotherapy at least 4 weeks, alkylating agents at least 6 weeks, molecularly targeted agents at least 28 days, and radiotherapy at least 14 days prior to the first dose. All prior treatment related adverse events Grade < 2 except alopecia and neuropathy had to have been resolved. Patients had to have exhibited normal maxrow and organ function as defined by the following parameters: absolute neutrophil count > 1,500/mcL; platelets > 100,000/mcL; hemoglobin > 9.0 mg/dL without transfusion in 2 prior weeks; total bilirubin within 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 measured or estimated creatinine clearance > 40 mL/min/1.73 m2 for patients with creatinine levels above normal. Exclusion criteria included symptomatic brain metastases or asymptomatic brain metastases treated with steroids, prior bevacizumab treatment, prior allergic reactions to compounds similar to ONC201, uncontrolled intercurrent illnesses, combination retroviral therapy for HIV, active cardiac disease/history of cardiac dysfunction, stroke or seizures in the last 3 months, impairment of GI function that may alter absorption of ONC201 , pregnancy and treatment with hematopoietic colony-stimulating growth factor < 2 weeks prior to beginning treatment. Study Design, and Toxicity Assessment
[00305] The design was an open-label, dose- escalation phase I trial of monoagent ONC201 in patients with advanced, refractory tumors who had exhausted or refused standard treatment options for their respective indications. Capsules (125 mg) of ONC201 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 no-observed-adverse-event-level in rats and dogs). The study was conducted with a single patient accelerated dose escalation design that was designed to stop if any patient experienced a Grade > 2 adverse event that was at least possibly related to ONC201. In this case a traditional 3+3 dose escalation design would have been used. Dose escalation could proceed after the previously dosed cohort completed one treatment cycle and met the criteria to proceed with the next dose level. Enrollment at each subsequent dose level required that all patients enrolled at the prior dose level completed Cycle 1 dosing and were evaluated 21 days later to assess safety. Dose levels proceeded from 125 mg to 250 mg, 375 mg, 500 mg and finally to 625 mg.
[00306] Following determination of the RP2D, an expansion phase of up to 22 patients was initiated to enroll additional patients at the RP2D to increase the robustness of the safety data generated by the trial
[00307] All toxicities were evaluated based on the Common Terminology Criteria for Adverse Events version 4. DLT was defined as a drug-related adverse event or abnormal laboratory result that occurred in the first cycle of treatment that met any of the following criteria: > Grade 3 non-hematological toxicity; > Grade 3 nausea, vomiting, or diarrhea that has persisted for > 72 hours despite optimal antiemetic or antidiarrheal therapy; Grade 3-4 AST/ALT in combination with a Grade 2 elevation in bilirubin; Grade 4 neutropenia lasting = 7 days; Grade 4 neutropenia and fever of > 38.5°C; Grade 3 neutropenia with > Grade 3 infection; thrombocytopenia of any grade if associated with clinically significant bleeding; Grade 4 thrombocytopenia; or Grade 4 anemia and was assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications; and is determined by the investigator to be "possibly related", "probably related" or "definitely related" to the administration of ONC201. Safety Assessments
[003081 Safety assessments including complete blood count, serum chemistry, and toxicity were evaluated at baseline, followed by weekly during the first 2 cycles, and then ever}' 3 weeks afterward. Electrocardiograph monitoring was carried out just before ONC201 administration, followed by 15 minutes, 1 hour and 2 hours, after drug administration. Adverse events were graded using the CTCAE version 4.0, Tumor responses were assessed using RECIST every 2 cycles.
Pharmacokinetic Analyses
[00309] Plasma samples for PK were collected at baseline, 30 minutes, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, and 168 hours following the first dose of ONC201 and before doses prior to treatment in cycles 2-6. PK was analyzed 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).
Statistical Analysis
[00310] Descriptive statistics were used for the analysis of safety and tumor response data. Pharmacodynamic Analyses
[00311] Blood samples for PD were collected at 6 hours, days 2, 3, 8, and 15 after ONC201 treatment for cycle 1 , and pre-dose on the day of drug administration for cycle 2 and 3. Serum levels of cleaved cytokeratin 18 (cCK18) were assessed using the M30 assay and serum levels of total cytokeratin 18 (CK18) were assessed using the M65 assay (Perviva A.B., Sweden). Assessments of other tumor-specific markers were also evaluated per standard of care.
Tumor Type In Vitro Sensitivity
[00312] The in vitro activity of ONC201 was evaluated in 1020 genetically annotated cell lines that from the Genomic of Dr g Sensitivity in Cancer (http://www.cancerrxgene.org) collection. IC50 values were determined by cell viability assays at 72 hours post-treatment as reported previously. The estimated IC50 values were averaged across multiple cell lines for each tumor type. Tumor types were categorized into three different groups that represented tertiles of average IC50 values. These groups are referred to as "high", "low" and "medium" in Table 11 based on their textile classification within the ONC201 sensitivity spectrum.
RESULTS
Patient Characteristics
[00313] During the dose escalation phase, 10 evaluable patients were enrolled in this study. Patient characteristics are listed in Table 7. Following the completion of the dose escalation phase, an additional 10 patients were enrolled in an ongoing expansion phase (Table 8). Table 7, Patient demographics ar id safety€ xperience with ON< C201 administei•ed every three we eks in dose esca ilation phs ise.
Age Weight ONC201 Adverse Events
Pat # Tumor Type Sex
Grade
(years) (Kg) (mg) Grade 1
2-4
Fever
1 NSCLC 80 F 47.3 125 0
(Possibly-reiated)
Appendiceal
2 77.8 250 0 0 adenocarcinoma 47 M
3 Uterine cancer 72 F 48 375 0 0
4 Renal cancer 62 M 123 500 0 0
5 Breast cancer 55 F 87 625 0 0
Prostate
6 69 M 92.4 625 0 0 adenocarcinoma
Small cell lung
7 70 M 55 625 0 0 cancer
Colon
8 71 M 73,5 625 0 0 adenocarcinoma
Spindle cell
9 74 F 95.2 625 0 0 sarcoma
10 Ovarian 68 F 61 625 0 0
Median 69.5 75.7
Table 8. Patient demo graphics and safet y experie ace in th e expansion ph ase with
ONC201 RP2D (625mg every t rs ;e weeks).
No. of
Age Weight l>oses Adverse Events
Pai # Tumor Tvpe Sex
(years) (Kg) Grade 1 Grade 2-4 1 1 Uterine cancer 67 F 72.7 5* o 0
12 Uterine cancer 56 F 47.7 5* 0
2 Vomiting
13 Ovarian cancer 64 F 49.3 (possibly 0 related)
Gall bladder 4*
14 75 F 60.6 0 0 cancer
2
Desmopiastic
15 small round cell 26 M 49.3 0 0 tumor (DSRCT)
16 Colon cancer 48 M 84.5 2 0 0
3*
Prostate
17 69 M 82.2 0 0 adenocarcinoma
18 Ovarian cancer 56 F 62.7 0 0 3 *
Prostate
19 67 M 1 18.2 0 0 adenocarc inoma
2 *
20 Uterine Cancer 60 F 82.7 0 0
Median 62 67.7 3
indicates patient remains on study.
Dose Escalation Method, Determination of RP2D and Safety
[00314] Dose cohorts are listed in Table 9. 625 mg was the highest dose reached and was determined to be the P2D. The only adverse event during the dose escalation phase that was possibly attributed to ONC201 was a low grade fever in one patient. One patient enrolled in the top dose cohort was replaced due to rapid disease progression in cycle 1.
[00315] The only adverse event among the 10 patients enrolled in the expansion phase that was possibly attributed to ONC20.1 was vomiting in one patient. Both of these adverse events were Grade 1 and reversed rapidly. Laboratory studies and physical exams did not reveal any drug-related abnormalities. Similarly, cardiovascular assessments revealed no drag-related effects.
Table 9: Dose-escalation and expansion cohorts with ONC201 dosed every 3 weeks.
Figure imgf000118_0001
[00316] Pharmacokinetics
[00317] Plasma collected at serial time points was used to analyze the systemic exposure levels of ONC201 in patients (Figure 5). PK parameters were determined for all patients and summarized for the top-dose cohort (Table 10). While dose escalation involved single patient cohorts, systemic exposure to ONC201 , as determined by AUC and Cmax, appeared to saturate at a dose of 375 mg (Figure 6). For the top dose cohort, the mean Cmax was 3312 (SD 2133) ng/niL, which occurred on average 1.8 hours following administration. The mean Vz was 381 (SD 164) L, consistent with a large distributive volume. Mean AUC was 26.3 (SD 10.8) h.,Lig/mL, and mean CL/F was 27.19 (SD 10.95) L/h. The mean tj/? was 9.62 (SD 1.76) hours. Table 10. Mean OS C201 pharmacokinetic parameters determined in patients receiving
625 mg ONC201 every three weeks.
C ^ mas T * mas Tiag AUCiast t'i/2 AUC Vz/'F CI . F
(iig/mL) (h) (h) (h.ng/L) (h-1) (h) (h.ng/'m) (L) (L/h)
N 6 6 6 6 6 6 6 6 6
Mean 33Ϊ2 1.79 0.05 25515 0.074 9.62 26344 381 27.19
SD 2133 1.30 0.12 10677 0.013 1.76 10763 164 10.95
Min 1530 0.37 0.00 13490 0.055 7.71 13868 156 14.03
Median 2725 1.91 0.00 24265 0.072 9.60 25620 404 24.83
Max 7470 3.95 0.30 43830 0.090 12.55 44555 616 45.07
CV% 64.4 72.4 244.9 41.8 17.4 18.3 40.9 42.9 40.3
Geo. Mean 2894 1.34 23777 0.073 9.49 24601 348 25.41
Geo. CV% 58.0 113.5 42,9 18.0 18.0 42.4 52.9 42.4
[00318] Generally, CL/F was observed to be variable but consistent across all the dose groups. There were no apparent relationships between drug CL/F and patient sex and age. Noticeable, shallow trends were observed with patient weight and BSA. An overall increase in CL/F was observed as weight and BSA increased. Although a slight upward trend was observed, there was no strong correlation between CL/F and CLCR.
[00319] Stronger correlations were observed with the distributive volume estimate (Vz) and patient weight and BSA. A pronounced increase in Vz was observed with increasing patient weight, A greater than 2-fold increase in Vz is predicted from this trend with an increase in weight from 50 to 100 kg. A similar trend was observed between V and BSA. The effect of patient weight was farther explored on dose-normalized exposure parameters. Trends of decreasing exposure with increasing weight were observed in plots of Cmax/Dose and AUC/Dose versus patient weight. Weight normalized CL/F was plotted versus Dose, showing a similar trend to un-normalized CL/F, but with significantly less variability across patients in the 625 mg dose group.
Patient Responses
[00320] Table 11 lists patient outcomes for the 10 evaluable patients enrolled in the dose escalation phase. Out of 10 evaluable patients completed at least 2 cycles, 4 patients completed at least 4 cycles, and 1 patient received 8 cycles and remains on therapy. On average, patients received 3, 1 doses of ONC201. Among the 10 patients enrolled in the expansion phase, 6 patients remain on therapy.
Table 11. Clinical responses and pharmacodynamic in the dose escalation phase.
Figure imgf000120_0001
*MR-mixed response, SD - stable disease, PD - Progressive disease. Tumor type in vitro sensitivity categorization is described in the methods section.
[00321] Clinical and laboratory results indicated that the drug possessed biological activity in the treated patients. Patient #3, a 72 year old patient with advanced clear cell endometrial cancer had a mixed response with multiple nodes decreasing by >30% along with the development of new nodes. Patient #4, a 62 -year-old male with renal cancer and bone metastasis with debilitating pain in the clavicle experienced relief from his clavicular pain. Patient #6, a 69-year-old patient with prostate adenocarcinoma experienced prolonged stable disease and was on study for 27 weeks. Patient #8, a 71-year old colon cancer patient had stable disease for 12 weeks with 4 doses of ONC201.
Pharmacodynamics
[00322] Given the heterogeneity of the tumor types in the enrolled patients, no widely used biomarker was available to uniformly assay ail patient samples. In particular, the serum M30 assay is able to detect a caspase-cleaved form of cytokeratin- 18 that occurs during apoptosis, which is useful in a heterogeneous study of solid tumors because most solid tumors express cytokeratin- 18. The M30 sandwich ELISA has been used extensively in clinical trials as biomarkers of cell death induced by a variety of different cancer chemotherapeutic agents in a spectrum of different solid tumors. In addition to the serum M30 assay, the M65 sandwich ELISA assay, which has also been used in clinical studies to detect increases in total cytokeratin 18 that can occur with tumor necrosis and disease progression, was used to differentiate tumor apoptosis from necrosis.
[00323] As expected, the patient with rapid clinical progression who was on study for one cycle exhibited increases in the M65, but not in the M30 assay. In contrast, the patient who has remained on study through 8 cycles exhibited increases in the M30, but not in the M65, assay. Four of the patients enrolled in the dose escalation phase of the study had an induction in the M30 assay after a single dose of ONC201, most often on day 21 post- treatment (Figure 7). To attempt to further understand the relevance of the observed the heterogeneous M30 induction, the in vitro sensitivity of the tumor types determined in a large collection of cell lines from the Genomic of Drug Sensitivity in Cancer program (GDSC) was compared with those of the study patients (Figure 8). Interestingly these patients who experienced induction in M30 were also the 3 patients with tumor types that exhibited high in vitro sensitivity to ONC201 (Table 1 1).
[00324] Given the downstream induction of TRAIL by ONC201 in preclinical models, serarn TRAIL levels were also quantified using ELISA assays. Half of the patients exhibited a modest (-20%) increase in serum TRAIL that mostly peaked within the first 24 hours of drug administration.
DISCUSSION
[00325] This Example is the first study of ONC201 , an investigational cancer therapy, in humans. The primary objective of the study was to determine the RP2D of oral O C201 administered every 3 weeks to patients with solid tumors who have exhausted all treatment options. As anticipated by the benign preclinical safety profile of ONC201 , no drug-related > grade 1 toxicities were observed at micromolar plasma concentrations that are effective in preclinical models in any patient. Due to the excellent safety profile of the drug, the study allowed progression to the next dose levels without requiring additional patient enrollments and was completed without digressing from the accelerated titration design. This study determined 625 mg administered once every 3 wreeks as the RP2D on the absence of toxicity and the fact that this dose achieves therapeutic plasma concentration. This RP2D exceeds the saturation threshold observed at 375mg and thus does not require adjustment for body-surface-area to consistently achievable target blood levels. The RP2D has been confirmed in an expansion phase with an additional 10 patients evaiuable for safety.
[00326] The pharmacokinetic profile of ONC201 indicates significant absorption of the drug with oral administration that was rapid, as indicated by the 1.8 hour mean. Importantly, the PK parameters such as Cmax and AUC in the top dose cohort treated at the RP2D exceeded those associated with the NOAEL in GLP toxicology studies. The observation that systemic exposure to ONC201 saturated at 2 dose levels below the RP2D is suggestive of saturation of absorption. Since saturation of absorption occurs at a dose that yields therapeutic plasma concentrations that are apparently well tolerated, this may function as a safety feature. These observations support the decision to discontinue further dose escalation of ONC20.1 beyond the RP2D while providing a safety margin around the target dose.
[00327] Given that the primary endpoint of the study was based on clinical safety in a group of highly heterogeneous patients with aggressive cancers, it is noteworthy that some patients showed some evidence of clinical benefit. These included a patient with treatment-resistant clear cell endometrial cancer who had a mixed response, 2 patients who had alleviation of symptoms associated with sites of tumor manifestation, and 2 patients (adenocarcinomas of prostate and colon) with stable disease for > 2 months. In this clinical trial, treatment was terminated following disease progression using RECIST criteria, which stipulates a 20% increase in tumor size. The signs of anti -tumor activity and absence of any meaningful side effects in this trial indicate that ONC201 may offer clinical benefit without imposing the typical toxicities that anticancer therapies impose on patients.
[00328] Similar to preclinical findings, PD measurements with the M30 assay revealed that the effects of ONC201 were sustained over time in several patients. Seram TRAIL induction was noted in 2 patients; however, this assay was limited to the detection of serum soluble TRAIL as biopsies were not available. The ONC201 PK profile together with its sustained PD effects yields an opportunity for combination regimens with staggered administration that minimizes drag-drug interaction risks while maintaining synergistic biological activity. Synergistic interactions between O C201 and approved cancer therapies have been identified with taxanes, bevacizumab, bortezomib, and sorafenib.
[00329] In conclusion, wre have shown that ONC201 is very well tolerated at the RP2D of 625 mg and exhibits signs of biological activity in patients with advanced solid tumors.
[00330] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the exemplary embodiments shown and described, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the claims. For example, specific features of the exemplary embodiments may or may not be part of the claimed invention and features of the disclosed embodiments may be combined. Unless specifically set forth herein, the terms "a", "an" and "the" are not limited to one element but instead should be read as meaning "at least one".
[00331] It is to be understood that at least some of the figures and descriptions of the invention have been simplified to focus on elements that are relevant for a clear understanding of the in vention, while eliminating, for purposes of clarity , other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the invention. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the invention, a description of such elements is not provided herein.
[00332] Further, to the extent that the method does not rely on the particular order of steps set forth herein, the particular order of the steps should not be construed as limitation on the claims. The claims directed to the method of the present in vention sh ould not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the steps may be varied and still remain within the spirit and scope of the present invention.
[00333] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

Claims

CLA: I
What is claimed is:
1. A compound having formula (10)
Figure imgf000124_0001
or a pharmaceutically acceptable salt thereof; wherein Ri and R2 are independently selected from the group consisting of H, C1.4alk.yl, Ci.4alkylphenyl, Ci-4alkylphenylketone,
Ci-4benzyl-piperazine,
Figure imgf000124_0002
Figure imgf000124_0003
Ci.4alkylpheny3,
Figure imgf000124_0004
Chalk lthienyl,
Ci-4alkylpyridinyl, Ci-4alkylisoxazolidinyl,
Figure imgf000124_0005
Ci-4alkylthiazolyl, and Cj
Figure imgf000124_0006
hydroxy!, perhalogenated Chalky!, or halogen, and wherein when R; represents CH2Ph, R2 does not represent CH2-((2-CH3)-Ph.
2. The compound of claim 1 , wherein Ri and/or R2 is a benzyl optionally substituted with one or more of the following substituents on the benzyl ring; X, -CH3, -N02, -OCH3, -CN, •CX i · ί/Χ>! 1. CVC4 alkyl, »CX3, -CH2(CX3), -CH(CX3)2, ~C(CX3)3, · ΓΓΧ.ν. · . -OCX3, -OCpH2pH, -OCpX2p+i, ORm, SRm, NRmRn, NRmC(0)Rn, SORm, S02Rm, C(0)Rm, and C(0)ORm;
where Rm and Rn are independently selected from hydrogen or a C1-C4 a J;kyl;
where p is an integer from 2 to 20; and
X represents a halogen.
3 The compound of claim 1 , wherein Ri is a hydrogen or an unsubstitued benzyl.
4. The compound of claim 1 , wherein R2 is a substituted or an un substituted, heterocy cloalkylalky 1 ,
5. The compound of claim 4, wherein the substituted heterocycloalkylalkyi is a morpholinoalkyl or piperazinylaikyl group.
6. The compound of claim 1, wherein R2 is a substituted or an unsubstituted
heteroarylalkyl.
7. The compound of claim 5, wherein the substituted heteroary lalkyl is a pyridylalkyl or isoxazolidinylalkyl or group.
6. The compound of claim 1 , wherein the compound is represented by formula (40)
Figure imgf000125_0001
or a pharmaceutically acceptable salt thereof; wherein
wherein Rai, Ra2, Ra3, Ra4, and Ras are each independently selected from the group consisting of hydrogen, X, -CH3> -N02, -OCH3) -CN, -CXH2, -( X I L C2-C4 alkyl, -CX3> -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CpX^H, -OCX3, -OCpH2p+i, -OCpX^i, ORm, SRm, RmR", RmC(0)R'\ SORrn, S02R"', C(0)R"', and C(0)ORm;
where Rm and Rn are independently selected from hydrogen or a Cj -C4 alkyl;
p is an integer from 2 to 20; and
X represents a halogen.
9. The compound of claim 8, wherein is a hydrogen.
The compound of claim 8, wherein the compound is represented by formula (45)
Figure imgf000125_0002
or a pharmaceutically acceptable salt thereof.
1 1. The compound of claim 8, wherein Ra3 is fluorine.
12. The compound of claim 8, wherein Ra2 and Ra4 are fluorine.
13. The compound of claim 1 having formula (50)
Figure imgf000126_0001
or a pharmaceutically acceptable salt thereof; wherein
Rb is selected from the group consisting of X, -CH3, -NO2, -OCH3, -C , -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), -CH(CX3)2, -C(CX3)3, -CPX2p+! , -OCX3, -OCpH2p-H, -GCPX2pH, GRm, SRra, NR ' R . NRinC(0)Rn, SORm, Si ) >R:r. C(0)Rm, and C(0)ORin;
Rai , Ra?., a4, and Ra5 are each independently selected from the group consisting of hydrogen, X, -CH3, -N02, -OCH , -CN, -CXH2, -CX2H, C2-C4 alkyl, -CX3, -CH2(CX3), --CH(CX3)2, "C(CX3)3, -CpX2p+i, -OCX3, ·( )(:,.! ] ·,, . -OCpX2p+i , OR™, SRm, NRmR",
NRmC(0)Rn, SORm, S02Rm, C(0)Rm, and C(0)QRm;
where Rm and Rn are independently selected from hydrogen or a C1-C4 alkyl;
p is an integer from 2 to 20;
and X represents a halogen.
14. The compound of claim 13, wherein Rj is a hydrogen.
15. The compound of claim 13 , wherein the compound is represented by formula (55)
Figure imgf000126_0002
a pharmaceutically acceptable salt thereof.
16. The compound of claim 13, wherein Rb is a fluorine and R.ai is a methyl.
17. The compound of claim 13, wherein _b and Ra2 are each selected from fluorine or chlorine.
18. The compound of claim 13 having formula (60)
Figure imgf000127_0001
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 13, wherein ¾ is a CH3 or a OCH substituent.
20. The compound of claim 13, wherein Rb is CI, and Ral is CI.
21. A composition comprising a salt of a compound of any one of claims 1 - 20.
22. The composition according to claim 21, wherein the salt comprises a counterion selected from the group consisting of: hydrochloride, hydrobromide, hydrogensulphate, sulfate, phosphate, fumarats, succinate, oxalates and lactates, bisulfate, hydroxy!, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, acetate, and carboxylate, p-toluene-sulfonate, benzenesultonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate, glucuronate, ascorbate and maleate, ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, methylamino, dimethylamino, diethylamino and triethylamino.
23. The composition according to claim 21, wherein the salt is a di-salt.
24. The composition according to claim 23, wherein the di-salt is a hydrochloride di-salt.
25. The composition according to claim 23, wherein the di-salt is a hydrobromide di-salt,
26. A pharmaceutical composition comprising a compound according to any one of claims 1 - 20 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
27. A method of treatment, comprising administering to a subject in need of such treatment a pharmaceutically acceptable amount of a compound according to any one of claims 1 - 20 or a pharmaceutically acceptable salt thereof,
28. The method of claim 27, wherein the treatment is for a Non-Hodgkin's lymphoma or an acute leukemia.
29. The method of claim 27, wherein the treatment is a salvage therapy.
30. The method of claim 27, wherein the pharmaceutically acceptable amount of the compound is administered according to an infrequent dosing regimen.
31. The method of claim 27, wherein the pharmaceutically acceptable amount of the compound or the pharmaceutically acceptable salt thereof is a dose ranging from about 100 mg to about 200 mg.
32. A method of treating a condition in a subject, comprising:
(i) administering to the subject the first therapeutic agent including a compound according to any one of claims 1 - 20 or a pharmaceutically acceptable salt thereof; and
(ii) monitoring level of the compound or a pharmaceutically acceptable salt thereof or a metabolite thereof in the subject using pharmacokinetic profiling
33. The method of claim 32, wherein dosing of the compound or a pharmaceutically acceptable salt thereof is selected to maintain a maximum concentration of the compound or a pharmaceutically acceptable salt thereof in blood (whole blood, plasma, or serum) of the subject between about 85 ng/niL and 1500 ng/mL for a therapeutic time period.
34. The method of claim 32, wherein dosing of the compound or a pharmaceutically acceptable salt thereof is selected to maintain an exposure of the compound or a
pharmaceutically acceptable salt thereof over time as measured in blood (whole blood, plasma, or semm) of the subject between about 150 ng hr/ml, and about 8000 ng hr/ml, for a therapeutic time period.
35. The method according to claim 32, further comprising administering the second therapeutic agent conditional on the level of the first therapeutic agent in the subject.
36. A method of treatment, comprising administering to a subject in need of such treatment: (i) a first therapeutic agent including a compound according to any one of claims 1 - 20 or a pharmaceutically acceptable salt thereof in combination with (ii) a second therapeutic agent, wherein the first therapeutic agent and the second therapeutic agent are administered either simultaneously or sequentially.
37. A method of treating a condition in a subject, comprising:
(i) over a first time interval, administering a plurality of doses of a therapeutic agent including compound (1 ):
Figure imgf000129_0001
, an analog thereof, or a pharmaceutically acceptable salt of compound (1) or an analog thereof, wherein the plurality of doses is administered over a second time interval within the first time interval; and
(ii) repeating step (i) one or more additional times.
38. The method of claim 37, wherein the condition is cancer.
39. The method of claim 37, wherein the subject is a human.
40. The method of claim 37, wherein the subject is a domesticated pet.
41. The method of claim 37, wherein the therapeutic agent is compound (1) or a pharmaceutically acceptable salt thereof.
42. The method of claim 37, wherein the therapeutic agent is an analog of compound (1) a pharmaceutically acceptable salt thereof.
43. The method of claim 42, wherein the analog of compound (1) has the structure of compound (10).
44. The method of claim 43, wherein the analog is a compound according to any one of claims 1 - 20 or a pharmaceutically acceptable salt thereof.
45. The method of claim 37, further comprising the step of waiting for a predetermined waiting time between one or more repetitions of step (i).
46. The method of claim 45, wherein the predetermined waiting time is the same length the first time interval.
47. The method of claim 46, wherein the pharmaceutically acceptable salt is a di-salt.
48. The method of claim 47, wherein the di-salt is a hydrochloride di-salt.
49. The method of claim 37, wherein the therapeutic agent is administered orally. The method of claim 49, wherein each oral dose ranges from about 1 mg to about 1000 mg.
51. The method of claim 37, wherein the therapeutic agent is administered intravenously.
52. The method of claim 37, wherein the therapeutic agent is administered topically.
53. The method of claim 37, wherein the subject has received at least one prior therapy.
54. The method of claim 37, wherein the first time interval is 7 days.
55. The method of claim 54, wherein the second time interval is from two to five consecutive days.
56. The method of claim 55, wherein the second time interval is two consecutive days.
57. The method of claim 55, wherein the second time interval is three consecutive days.
58. The method of claim 54, wherein the therapeutic agent is administered once daily within the second time interval.
59. The method of claim 54, wherein the therapeutic agent is administered twice daily within the second time interval
60. A method of treating or preventing a disease or condition comprising; administering to a human or animal subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of compound (1 ):
Figure imgf000130_0001
or a pharmaceutically acceptable salt thereof.
61. The method of claim 60, wherein the disease is a B-ceil cancer.
62. The method of claim 61, wherein the B-ceil cancer is a multiple myeloma, B-cell lymphoma or a B-cell leukemia.
63. The method of claim 60, wherein the disease is a pediatric cancer.
64. The method of claim 63, wherein the subject is younger than 18, wherein is younger than 13 years old, or is younger than 5 years old.
65. The method of claim 60, wherein the pediatric cancer is selected from the group consisting of pediatric solid tumors, pediatric sarcomas, pediatric Ewing's sarcomas, pediatric gliomas, pediatric central nervous system cancers, pediatric leukemia and pediatric lymphoma.
66. The method of claim 60, where the disease or condition prevented or treated is metastases.
67. The method of claim 60, wherein the condition is pain.
68. The method of claim 60, wherein the condition is edema.
69. The method of claim 60, wherein the condition is hemiplegia.
70. The method of claim 60, wherein the disease is a lymphadenopathy.
71. The method of claim 60, wherein the disease is a cancer and the treatment does not cause severe or serious adverse events.
72. The method of claim 60, wherein the disease is a cancer and the treatment does not cause peripheral neuropathy.
73. The method of claim 60, wherein the disease is a cancer and the treatment does not cause cardiotoxicity.
74. A method of treating or preventing a disease or condition comprising: administering to a human or animal subject in need of such treatment a pharmaceutical composition comprising an effective amount of compound (1):
Figure imgf000131_0001
or a pharmaceutically acceptable salt thereof, wherein the effective amount of compound (1) or the pharmaceutically acceptable salt thereof is a dose ranging from about 125 mg to about 625 mg.
75. The method of claim 74, wherein the dose of compound (1) or the pharmaceutically acceptable salt thereof ranges from about 250 mg to about 625 mg.
76. The method of claim 75, wherein the dose of compound (1) or the pharmaceutically acceptable salt thereof ranges from about 375 mg to about 625 mg.
77. The method of claim 76, wherem the dose of compound (1) or the pharmaceutically acceptable salt thereof ranges from about 500 mg to about 625 mg
78. The method of claim 77, wherein the dose of compound (1) or the pharmaceutically acceptable salt thereof is about 625 mg.
79. The method of claim 74, where the dosage is based on compound (1) in its free base form.
80. The method of claim 74, wherein the pharmaceutical composition is administered twice a day.
8 . The method of claim 74, wherein the pharmaceutical composition is administered daily, continuously or without intermittent periods of withholding drug administration.
82. The method of claim 74, wherein the pharmaceutical composition is administered twice per week or once per week.
83. The method of claim 74, wherein the pharmaceutical composition is administered once every two weeks, once every three weeks, or once every four weeks.
84. The method according to any one of claims 74-83, further comprising the step of administering a second therapeutic agent, wherein compound (1) or the pharmaceutically acceptable salt thereof is administered before, simultaneously, or after the second therapeutic agent.
85. A method of treating a disease or condition in a human or animal subj ect in need of such treatment, the method comprising:
(i) administering to the subject a pharmaceutical composition comprising a
therapeutically effective amount of compound (1):
Figure imgf000132_0001
or a pharmaceutically acceptable salt thereof; and (ii) monitoring levels of compound (1), the pharmaceutically acceptable salt thereof!, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of compound (1) or a pharmaceutically acceptable salt thereof is selected to maintain a concentration of compound (1), the pharmaceutically acceptable salt thereof, or the metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject is at least about 400 ng/niL for a therapeutic time period within 4 hours post-treatment.
86. The method of claim 85, wherein the concentration is at least about 1 ,500 ng/mL.
87. The method of claim 85, wherein the concentration is between about 400 to 8,000 ng/mL
88. The method of claim 85, wherein the concentration is between about 1 ,500 to 8,000 ng/mL.
89. A method of treating a disease or condition in a human or animal subject in need of such treatment, the method comprising:
(i) administering to the subject a pharmaceutical composition comprising a
therapeutically effective amount of compound (1):
Figure imgf000133_0001
or a pharmaceutically acceptable salt thereof; and
(ii) monitoring levels of compound (1 ), the pharmaceutically acceptable salt
thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of compound (1) or a pharmaceutically acceptable salt thereof is selected to obtain an AUC of compound (1), the pharmaceutically acceptable salt thereof, or the metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject is at least about 3,500 hr-ng/mL with a time period of 24 or 48 hours post-treatment or extrapolated to infinity.
The method of claim 89, wherein the AUC is at least about 15,000 hr-ng/mL.
91. The method of claim 89, wherein the AUC is between about 3,500 and 65,000
hr-ng/mL. The method of claim 89, wherein the AUC is between about 15,000 and 65,000 hr-ng/mL.
93. A method of treating a disease or condition in a human or animal subject in need of such treatment, the method comprising;
(i) administering to the subject a pharmaceutical composition comprising a
therapeutically effective amount of compound (1):
Figure imgf000134_0001
, or a pharmaceutically acceptable salt thereof; and
(ii) monitoring levels of compound (1), the pharmaceutically acceptable salt
thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of compound (1) or a pharmaceutically acceptable salt thereof is selected to result in undetectable concentrations of compound (1), the pharmaceutically acceptable salt thereof, or the metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject at 3 days, 4 days, 5 days, 6 days, or 7 days post-treatment.
The method according to any one of claims 85-93, wherein the metabolite is selected from monohydroxylated or dihydroxylated compound (1).
A method of treating or preventing a disease, disorder, or condition comprising:
administering to a human or animal subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of compound (1):
Figure imgf000134_0002
or a pharmaceutically acceptable salt thereof.
96. The method of claim 95, wherein the disease is prostate cancer or endometrial cancer.
97. The method of claim 95, wherein the disorder is psychosis.
98. The method of claim 95, wherein the disorder is a CNS disorder.
99. The method of claim 95, wherein the disorder or disease is associated with dysregulated dopamine signaling.
100. The method of claim 95, wherein the disorder Tourette syndrome.
101. The method of claim 100, wherein the subject suffers from nausea or emesis.
102. The method of claim 95, wherein the disorder is schizophrenia or bipolar disorder.
103. The method of claim 95, wherein the disorder is anxiety.
104. The method of claim 95, wherein the disorder is hypotension,
105. The method of claim 95, wherein the disease is a virus.
106. The method of claim 105, wherein the virus is an RNA virus, D A virus, or
retroviruses.
107. The method of claim 105, wherein the virus is selected from the group consisting of influenza A virus including subtype ΗΓΝ1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS eoronavirus, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51 , 52, 56, 58, 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, noro virus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever vims, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, ebola virus, marburg virus, herpes simplex virus-! (HSV-1 ), herpes simplex virus-2 (HSV-2), varicella zoster vims (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, Kaposi's sarcoma-associated herpesvirus, hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), hepatitis E (HEV), humanimmunodeficiency virus (HIV), The Human T-lymphotropic virus Type I (HTLV-1), Friend spleen focus-forming virus (SFFV) or Xenorropic MuLV-Related Virus (XMRV).
108. The method according to any one of claims 95-107, further comprising the step of administering a second therapeutic agent, wherein compound (1) or salt thereof is administered before, simultaneously, or after the second therapeutic agent.
109. The method of claim 108, wherein the administration of compound (1) or salt thereof and the administration of the second therapeutic agent are separated by a time interval of at least one day, at least two days, or at least three days.
110. The method according to any one of claims 95-107, further comprising assaying
cleaved cytokeratin-18 in a sample obtained from the subject.
11 1. The method of claim 110, wherein the cleaved cytokeratin- 18 is measured from blood from the subject using a M30 ELISA assay.
1 12. The method of either claim 48 or claim 49, determining whether cleaved cytokeratin- 18 has increased upon treatment with compound (1) or salt thereof.
113. The method according to any one of claims 95-107, further comprising assaying total c tokeratin-18 in a sample obtained from the subject.
114. The method of claim 113, wherein the cleaved cytokeratin -18 is measured from blood from the subject using a M65 ELISA assay,
115. The method according to any one of claims 95-107, comprising assaying both cleaved and total cytokeratin- 18 in the sample obtained from the subject.
1 16. The method of claim 115, where is the sample is obtained on days 1-21, 2-21 , 7-21 , 14-21 , or 21 after administering compound (1) or salt thereof.
1 17. The method of claim 115, continuing the treatment of the subject with compound (1) or salt thereof, if there is a disproportionate increase in the amount of cleaved cytokeratin 18 relative to total cytokeratin 18.
118. A method of identifying whether a subject having cancer is likely to be responsive to administration of compound (1), comprising:
(i) obtaining a biological sample from the subject;
(ii) measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, or DR5 in the sample;
(iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and (iv) determining whether the subject is likely to be responsive to administration of compound (1), based on the levels measured and/or mutations found in the sampie to those for the pre-determined standard.
119. A method of assessing the effectiveness of or monitoring a subject having cancer and undergoing administration of compound (1), comprising:
(i) obtaining a biological sample from the subject;
(ii) measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, DR5, or cleaved or total cytokeratm 18 in the sample;
(iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and
(iv) determining whether the subject is responsive to administration of compound (1), based on the levels measured and/or mutations found in the sampie to those for the pre-determined standard,
120. A method of identifying whether a subject having cancer is likely to be responsive to administration of compound (1), comprising:
(i) obtaining a biological sample from the subject;
(ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample;
(iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and
(iv) determining whether the subject is likely to be responsive to administration of compound (1), based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
121. The method of claim 120, wherein the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRDS.
122. The method of claim 120, wherein the dopamine receptor is from the D2-like family of dopamine receptors.
123. The method of of claim 120, further comprising the step of administering an effective amount of compound (1) to the subject.
124. A method of assessing the effectiveness of or monitoring a subject having cancer and undergoing administration of compound (1), comprising:
(i) obtaining a biological sample from the subject;
(ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample;
(iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and.
(iv) determining whether the subject is responsive to administration of compound (1 ), based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.
125. The method of claim 124, wherein the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3.
126. The method of claim 124, wherein the dopamine receptor is from the D2-3ike family of dopamine receptors.
127. A method for screening a potential cancer therapeutic, comprising:
(i) contacting at least one G protein-coupled receptor (GPCR) with a test
compound suspected of being a cancer therapeutic;
(ii) measuring the binding affinity, interaction or GPCR signalling of the test compound to the GPCR; and
(iii) comparing the binding affinity or interaction of test compound to a
pre-determined threshold, wherein GPCR antagonism or GPCR signaling antagonism of the test compound comparable to or greater than the threshold is indicative of a cancer therapeutic.
128. A method for screening a potential cancer therapeutic, comprising:
(i) contacting at least one dopamine receptor with a test compound suspected of being a cancer therapeutic;
(ii) measuring the binding affinity or interaction of the test compound to the at least one dopamine receptor; and
(iii) comparing the binding affinity or interaction of the test compound to a
pre-determined threshold, wherein inhibition of the at least one dopamine receptor by the test compound comparable to or greater than the threshold is indicative of a cancer therapeutic.
129. The method of claim 128, wherein the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3.
130. The method of claim 128, wherein inhibition of the D2-3ike family of dopamine
receptors is indicative of a cancer therapeutic.
131. The method of claim 128, wherein inhibition of both DRD2 and DRD3 dopamine receptors is indicative of a cancer therapeutic.
132. The method according to any one of claims 128-131, wherein the pre-determined
threshold is the inhibition of the at least one dopamine receptor by compound (1).
133. A method for screening a potential cancer therapeutic using a processor, comprising:
(i) using a computational docking method to model binding or interaction, if any, of one or more 3 -dimensional structures of a test molecule suspected of being a cancer therapeutic to a 3 -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 structure to the structure of the at least one dopamine receptor; and
(iii) using the computational method to compare the binding affinity or interaction of the test molecule to a pre-determined threshold, wherein inhibition of the at least one dopamine receptor by the test compound comparable to or greater than the threshold is indicative of a cancer therapeutic.
134. The method of claim 133, wherein the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3.
135. The method of claim 133, wherein inhibition of the D2-like family of dopamine
receptors is indicative of a cancer therapeutic.
136. The method of claim 133, wherein inhibition of both DRD2 and DRD3 dopamine receptors is indicative of a cancer therapeutic.
137. The method according to any one of claims 133-136, wherein the pre-determined
threshold is the inhibition of the at least one dopamine receptor by compound (1).
138. A method of identifying whether a subject having cancer is likely to be responsive to administration of compound (1), comprising:
(i) obtaining a biological sample from the subject;
(ii) measuring prolactin levels;
(iii) determining whether the subject is likely to be responsive to administration of compound (1 ), based on the levels measured relative to those for a pre-determined standard,
139. A method of assessing the effectiveness of or monitoring a subject having cancer and undergoing administration of compound (1), comprising:
(i) obtaining a biological sample from the subject;
(ii) measuring prolactin levels;
(iii) determining whether the subject is likely to be responsive to administration of compound (I), based on the levels measured relative to those for a pre-determined standard,
140. A method for screening a potential cancer therapeutic that induces prolactin in pituitary cells or causes prolactin secretion into the peripheral blood.
141. A method of treatment comprising administering a compound that induces prolactin in pituitary cells or causes prolactin secretion into the peripheral blood.
PCT/US2016/015817 2015-01-30 2016-01-29 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 in therapy WO2016123571A1 (en)

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CA2975476A CA2975476C (en) 2015-01-30 2016-01-29 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo [1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one, analogs thereof, and salts thereof and methods for their use in therapy
LTEP16744237.5T LT3250208T (en) 2015-01-30 2016-01-29 7-benzyl-4-(4-(trifluoromethyl)benzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4h)-one and salts thereof and their use in therapy
RS20201566A RS61243B1 (en) 2015-01-30 2016-01-29 7-benzyl-4-(4-(trifluoromethyl)benzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4h)-one and salts thereof and their use in therapy
PL16744237T PL3250208T3 (en) 2015-01-30 2016-01-29 7-benzyl-4-(4-(trifluoromethyl)benzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4h)-one and salts thereof and their use in therapy
MDE20170317T MD3250208T2 (en) 2015-01-30 2016-01-29 7-benzyl-4-(4-(trifluoromethyl)benzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4h)-one and salts thereof and their use in therapy
MX2017009841A MX2017009841A (en) 2015-01-30 2016-01-29 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 in therapy.
SI201631003T SI3250208T1 (en) 2015-01-30 2016-01-29 7-benzyl-4-(4-(trifluoromethyl)benzyl)-1,2,6,7,8,9-hexahydroimidazo(1,2-a)pyrido(3,4-e)pyrimidin-5(4h)-one and salts thereof and their use in therapy
JP2017540230A JP6802172B2 (en) 2015-01-30 2016-01-29 7-Benzyl-4- (2-methylbenzyl) -2,4,6,7,8,9-hexahydroimidazole [1,2-A] pyrido [3,4-E] pyrimidine-5 (1H)- On, its analogs, and their salts and their use in treatment
IL288525A IL288525B (en) 2015-01-30 2016-01-29 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo [1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one, analogs thereof, and salts thereof and methods for their use in therapy
DK16744237.5T DK3250208T3 (en) 2015-01-30 2016-01-29 7-BENZYL-4- (4- (TRIFLUOROMETHYL) BENZYL) -1,2,6,7,8,9-HEXAHYDROIMIDAZO [1,2-A] PYRIDO [3,4-E] PYRIMIDIN-5 (4H) - ON AND SALTS THEREOF AND ITS USE IN THERAPY
KR1020237044537A KR20240005186A (en) 2015-01-30 2016-01-29 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 in therapy
MX2021001096A MX2021001096A (en) 2015-01-30 2016-01-29 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 in therapy.
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MA41434A MA41434B1 (en) 2015-01-30 2016-01-29 7-Benzyl-4- (4- (trifluoromethyl) benzyl) -1,2,6,7,8,9-hexahydroimidazo [1,2-a] pyrido [3,4-e] pyrimidin-5 (4h) - one, its salts and their use in therapy
EP16744237.5A EP3250208B1 (en) 2015-01-30 2016-01-29 7-benzyl-4-(4-(trifluoromethyl)benzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4h)-one and salts thereof and their use in therapy
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AU2016211243A AU2016211243B2 (en) 2015-01-30 2016-01-29 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 in therapy
BR112017016487-6A BR112017016487B1 (en) 2015-01-30 2016-01-29 COMPOUND, ITS SALTS AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
SG11201706062TA SG11201706062TA (en) 2015-01-30 2016-01-29 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 in therapy
ES16744237T ES2839401T3 (en) 2015-01-30 2016-01-29 7-Benzyl-4- (4-trifluoromethyl) benzyl) -1,2,4,6,7,8,9-hexahydroimidazo [1,2-A] pyrido [3,4-E] pyrimidin-5 (4H) -one and salts thereof and its use in therapy
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US15/049,613 US9845324B2 (en) 2015-01-30 2016-02-22 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo [1,2-A]pyrido[3,4-E]pyrimidin-5(1H)-one, analogs thereof, and salts thereof and methods for their use in therapy
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SG11201806401YA SG11201806401YA (en) 2016-01-29 2017-01-30 G protein-coupled receptor (gpcr) modulation by imipridones
EP17745078.0A EP3408298A4 (en) 2016-01-29 2017-01-30 G protein-coupled receptor (gpcr) modulation by imipridones
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KR1020187024948A KR20180125460A (en) 2016-01-29 2017-01-30 Already regulated G protein-coupled receptor (GPCR) by prion
AU2017211423A AU2017211423B2 (en) 2016-01-29 2017-01-30 G protein-coupled receptor (GPCR) modulation by imipridones
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US16/073,228 US11116771B2 (en) 2016-01-29 2017-01-30 G protein-coupled receptor (GPCR) modulation by imipridones
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