Isoflavonoid formulations and methods of use

Abstract

Disclosed herein are pharmaceutical formulations of isoflavonoid and methods of use.

Description

Attorney Docket No.01309-0023-00PCT ISOFLAVONOID FORMULATIONS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of US Provisional Application No.63 / 709,273 filed on October 18, 2024, which is incorporated herein by reference herein in its entirety for any purpose. BACKGROUND OF THE INVENTION

[0002] Cancer is the leading cause of death worldwide. Isoflavonoid compounds may be useful in treating or preventing cancers. However, intravenous administration of an aqueous formulation of certain isoflavonoids may lead to an undesirable pharmacokinetic profile, characterized by sharp rises and falls in plasma levels of the drug. An object of the present invention is to improve the pharmacokinetic profile, and by extension the therapeutic benefit, of isoflavonoid compounds via the provision of new and advantageous compositions, formulations, and methods disclosed herein. INCORPORATION BY REFERENCE

[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. SUMMARY OF THE INVENTION

[0004] In one aspect, disclosed herein is a pharmaceutical composition comprising: about 5% to about 35% of ethanol by weight (w / w); about 55% (w / w) to about 90% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 1% (w / w) to about 15% (w / w) of benzyl alcohol; and d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound d-5):.

[0005] In some embodiments, the pharmaceutical composition further comprises about 5% (w / w) of ethanol. In some embodiments, the pharmaceutical composition furtherAttorney Docket No.01309-0023-00PCT comprises about 10% (w / w) of ethanol. In some embodiments, the pharmaceutical composition further comprises about 15% (w / w) of ethanol. In some embodiments, the pharmaceutical composition further comprises about 20% (w / w) of ethanol. In some embodiments, the pharmaceutical composition further comprises about 25% (w / w) of ethanol. In some embodiments, the pharmaceutical composition further comprises about 30% (w / w) of ethanol. In some embodiments, the pharmaceutical composition further comprises about 35% (w / w) of ethanol. In some embodiments, the pharmaceutical composition further comprises about 55% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition further comprises about 60% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition further comprises about 65% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition further comprises about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition further comprises about 75% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition further comprises about 80% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition further comprises about 85% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition further comprises about 90% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition further comprises about 1% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises about 2% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises about 3% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises about 4% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises about 5% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises about 15% (w / w) of benzyl alcohol.

[0006] In some embodiments, the pharmaceutical composition further comprises: about 10% (w / w) of ethanol; about 80% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzylAttorney Docket No.01309-0023-00PCT alcohol. In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises: about 30% (w / w) of ethanol; about 60% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises: about 10% (w / w) of ethanol; about 85% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 5% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 75% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 5% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises: about 30% (w / w) of ethanol; about 65% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 5% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition further comprises about 0.1% to about 1% of Povidone K30 by weight / volume (w / v). In some embodiments, the pharmaceutical composition further comprises about 0.1% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.2% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.3% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.4% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.5% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.6% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.7% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.8% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.9% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 1% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.2% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.3% (w / v) of Povidone K30. In some embodiments, the pharmaceutical compositionAttorney Docket No.01309-0023-00PCT comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.4% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.5% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 1 mg / ml to about 5 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 1 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 2 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 3 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 4 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 5 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 3 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the pharmaceutical composition is used for subcutaneous administration. In some embodiments, the pharmaceutical composition is used for intramuscular administration. In some embodiments, the pharmaceutical composition is used for intravenous administration. In some embodiments, the pharmaceutical composition is used for intradermal administration. In some embodiments, the pharmaceutical composition is used for intravenous transfusion. In some embodiments, the pharmaceutical composition further comprises about 10 mg / ml to about 350 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 10 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 20 mg / ml of d-cis-3- (4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 30 mg / ml of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 40 mg / ml of d-cis-3-(4-hydroxyphenyl)- 4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 50 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceuticalAttorney Docket No.01309-0023-00PCT composition further comprises about 55 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 60 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 65 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 70 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 75 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 80 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 85 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 90 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 95 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 100 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 150 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 200 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 250 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 300 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition further comprises about 350 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition passes freely through an 18 gauge needle without clog. In some embodiments, the pharmaceutical composition passes freely through a 21 gauge needle without clog. In some embodiments, the pharmaceutical composition passes freely through a 23 gauge needle without clog. In some embodiments, an amount of the pharmaceutical composition passesAttorney Docket No.01309-0023-00PCT through a 0.2 µm filter to produce a filtrate that is about 85% to about 100% of the amount before the filtration. In some embodiments, an amount of the pharmaceutical composition passes through a 0.2 µm filter to produce a filtrate that is about 90% to about 100% of the amount before the filtration. In some embodiments, an amount of the pharmaceutical composition passes through a 0.2 µm filter to produce a filtrate that is about 95% to about 100% of the amount before the filtration. In some embodiments, the pharmaceutical composition is stable for at least about 1 day when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 3 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 4 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 5 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 2℃ to about 8℃. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 10℃ to about 40℃. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 21℃ to about 22℃. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 40℃. In some embodiments, the pharmaceutical composition is considered stable when zero or an insignificant amount of precipitation is observed. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is zero or insignificant. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 2% of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 1% of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 0.5% of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 0.2% of the pharmaceutical composition.

[0007] In some embodiments, the impurity in the pharmaceutical composition isAttorney Docket No.01309-0023-00PCT measured by high performance liquid chromatography (HPLC) assay. In some embodiments, the pharmaceutical composition provides a steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol after administration into a subject. In some embodiments, the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 6 h to about 72 h after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 6 h after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 12 h after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 24 h after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 48 hr after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 72 hr after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1 day. In some embodiments, the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 2 days. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol continues for at least 3 days. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol continues for at least 4 days. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 5 days. In some embodiments, the steady plasma concentration of d-cis- 3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 6 days. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)- 4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1 week. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1-2 weeks. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol continues for at least 10 days. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol continues for at least 2 weeks. In some embodiments, the steady plasmaAttorney Docket No.01309-0023-00PCT concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 3 weeks. In some embodiments, the steady plasma concentration of d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 4 weeks. In some embodiments, the pharmaceutical composition is administered subcutaneously into the subject. In some embodiments, the pharmaceutical composition is administered intramuscularly into the subject. In some embodiments, the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4- (4-hydroxyphenyl)-8-methylchroman-7-ol at about 5 h to about 400 h (T1 / 2) after administration into the subject. In some embodiments, the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol at about 100 h to about 400 h (T1 / 2) after administration into the subject. In some embodiments, the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol at about 10 h (T1 / 2) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 2 h to about 10 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 4 h to about 8 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 4 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol at about 5 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 6 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 7 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol at about 8 h (Tmax) after administration into the subject. In some embodiments, the last quantifiable concentration of d-cis-3-(4-Attorney Docket No.01309-0023-00PCT hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is observed (TLAST) at a time that is about 50 h to about 500 h after administration of the pharmaceutical composition into the subject. In another aspect, disclosed herein is a method for treating a disease associated with mitochondrial oxidative phosphorylation (OXPHOS), comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition disclosed herein. In some embodiments, the disease comprises cancer. In another aspect, disclosed herein is a method for treating cancer comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition disclosed herein. In another aspect, disclosed herein is a method for treating cancer comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition disclosed herein, wherein the subject is refractory, non-responsive, or resistant to a prior cancer therapy, or intolerant of the prior cancer therapy. In some embodiments, the cancer comprises colon cancer, rectal cancer, colorectal cancer (CRC), metastatic colorectal cancer (mCRC), non-metastatic colorectal cancer, refractory CRC, refractory mCRC, relapsed CRC, relapsed mCRC, relapsed or refractory CRC, relapsed or refractory mCRC, recurrent CRC, recurrent mCRC, breast cancer, metastatic breast cancer, metastatic HER2-negative breast cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, lung cancer, squamous non- small cell lung cancer, non-squamous non-small cell lung cancer, bladder cancer, endometrial cancer, cervical cancer, uterine cancer, ovarian cancer, kidney cancer, liver cancer, leukemia, melanoma, Lewis lung carcinoma, non-Hodgkin lymphoma, pancreatic cancer, testicular cancer, prostate cancer, thyroid cancer, sarcoma (including osteosarcoma), esophageal cancer, gastric cancer, head and neck cancer, lung cancer melanoma, myeloma, neuroblastoma, glioblastoma, or a brain cancer. In some embodiments, the cancer comprises colon cancer. In some embodiments, the cancer comprises rectal cancer. In some embodiments, the cancer comprises CRC. In some embodiments, the cancer comprises mCRC. In some embodiments, the cancer comprises non-metastatic CRC. In some embodiments, the cancer comprises refractory CRC. In some embodiments, the cancer comprises refractory mCRC. In some embodiments, the cancer comprises recurrent CRC. In some embodiments, the cancer comprises recurrent mCRC. In some embodiments, the cancer comprises relapsed CRC. In some embodiments, the cancer comprises relapsed mCRC. In some embodiments, the cancer comprises relapsed or refractory CRC. In some embodiments, the cancer comprises relapsed or refractory mCRC. In some embodiments, the pharmaceutical composition is administered at least once a day. In some embodiments, the pharmaceutical composition is administered at least once every two days. In someAttorney Docket No.01309-0023-00PCT embodiments, the pharmaceutical composition is administered at least once every three days. In some embodiments, the pharmaceutical composition is administered at least once every four days. In some embodiments, the pharmaceutical composition is administered at least once every five days. In some embodiments, the pharmaceutical composition is administered at least once every six days. In some embodiments, the pharmaceutical composition is administered at least once every week. In some embodiments, the pharmaceutical composition is administered at least once every 10 days. In some embodiments, the pharmaceutical composition is administered at least once every two weeks. In some embodiments, the pharmaceutical composition is administered at least once every three weeks. In some embodiments, the pharmaceutical composition is administered at least once every four weeks. In some embodiments, the pharmaceutical composition is administered at least once every 45 days. In some embodiments, the pharmaceutical composition is administered at least once every two months. In some embodiments, the pharmaceutical composition is administered once a day. In some embodiments, the pharmaceutical composition is administered once every two days. In some embodiments, the pharmaceutical composition is administered once every three days. In some embodiments, the pharmaceutical composition is administered once every four days. In some embodiments, the pharmaceutical composition is administered once every five days. In some embodiments, the pharmaceutical composition is administered once every six days. In some embodiments, the pharmaceutical composition is administered once every week. In some embodiments, the pharmaceutical composition is administered once every 10 days. In some embodiments, the pharmaceutical composition is administered once every two weeks. In some embodiments, the pharmaceutical composition is administered once every three weeks. In some embodiments, the pharmaceutical composition is administered once every four weeks. In some embodiments, the pharmaceutical composition is administered once every 45 days. In some embodiments, the pharmaceutical composition is administered once every two months. In some embodiments, a second therapy is administered to the subject. In some embodiments, the second therapy comprises a glycolytic inhibitor. In some embodiments, the second therapy comprises an angiogenesis inhibitor. In some embodiments, the second therapy comprises a vascular endothelial growth factor (VEGF) inhibitor. In some embodiments, the second therapy comprises a VEGF receptor (VEGFR) inhibitor. In some embodiments, the second therapy comprises an anti-VEGF antibody. In some embodiments, the second therapy comprises an anti-VEGFR antibody. In some embodiments, the second therapy comprises bevacizumab, or a variant or biosimilar thereof. In some embodiments, the second therapyAttorney Docket No.01309-0023-00PCT comprises bevacizumab, bevacizumab-adcd, bevacizumab-awwb, bevacizumab-maly, or bevacizumab-bvzr, or combinations thereof. In some embodiments, the second therapy comprises nintedanib, everolimus, temsirolimus, pazopanib, axitinib, sorafenib, sunitinib, thalidomide, dovitinib, regorafenib, imatinib, or combinations thereof. In some embodiments, the subject is refractory, non-responsive, or resistant to a prior cancer therapy, or intolerant of the prior cancer therapy. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 1 to 2 weeks. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol that continues for at least 1 week. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 10 days. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 2 weeks. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Cmax of about 500 ng / ml to about 1000 ng / ml when the d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol provides a Cmax of about 500 ng / ml to about 2000 ng / ml when the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 140 mg / kg. In some embodiments, the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a Cmax of about 800 ng / ml to about 1600 ng / ml when the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 140 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a Cmax of at about 2h to about 4h after the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a Cmax of at about 4h to about 8h after the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 35 mg / kg to about 140 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol provides a Cmax of at about 2h to about 4h after the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-olAttorney Docket No.01309-0023-00PCT provides a Tlast of about 50 h to about 600 h after the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a T1 / 2 of about 50 h to about 400 h after the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a plasma concentration having a value of area under the concentration-time curve from time zero to time of last measurable concentration (AUClast) that is about 2000 hr*ng / ml to about 20000 hr*ng / ml, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a plasma concentration having a value of area under the concentration-time curve from time zero to time of last measurable concentration (AUClast) that is about 12000 hr*ng / ml to about 40000 hr*ng / ml, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7- ol is administered at a dose of about 140 mg / kg. In some embodiments, the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 5 mg / kg to about 200 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4- (4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 10 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol is administered at a dose of about 20 mg / kg. In some embodiments, the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 50 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol is administered at a dose of about 70 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 100 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 120 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol is administered at a dose of about 140 mg / kg. In some embodiments, the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 180 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 200 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol is administered at a dose of about 5 mg / kg to about 40 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at aAttorney Docket No.01309-0023-00PCT dose of about 10 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol comprises the d-cis isomer in at least 95% enantiomeric excess. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol comprises the d-cis isomer in at least 99% enantiomeric excess. In some embodiments, the pharmaceutical composition or second therapy is administered to the subject at least once, at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, or more than 10 times.

[0008] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. The features of each of the embodiments are combinable with those of any other embodiments described elsewhere herein to the extent that they are compatible. The present disclosure includes, but is not limited to, the following embodiments:

[0009] Embodiment 1. A pharmaceutical composition comprising: (a) about 5% to about 35% of ethanol by weight (w / w); (b) about 55% (w / w) to about 90% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; (c) about 1% (w / w) to about 15% (w / w) of benzyl alcohol; and (d) d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound d-5):.

[0010] Embodiment 2. The pharmaceutical composition of embodiment 1, comprising about 5% (w / w) of ethanol.

[0011] Embodiment 3. The pharmaceutical composition of embodiment 1, comprising about 10% (w / w) of ethanol.

[0012] Embodiment 4. The pharmaceutical composition of embodiment 1, comprising about 15% (w / w) of ethanol.

[0013] Embodiment 5. The pharmaceutical composition of embodiment 1, comprising about 20% (w / w) of ethanol.Attorney Docket No.01309-0023-00PCT

[0014] Embodiment 6. The pharmaceutical composition of embodiment 1, comprising about 25% (w / w) of ethanol.

[0015] Embodiment 7. The pharmaceutical composition of embodiment 1, comprising about 30% (w / w) of ethanol.

[0016] Embodiment 8. The pharmaceutical composition of embodiment 1, comprising about 35% (w / w) of ethanol.

[0017] Embodiment 9. The pharmaceutical composition of any one of the preceding embodiments, comprising about 55% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

[0018] Embodiment 10. The pharmaceutical composition of any one of the preceding embodiments, comprising about 60% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

[0019] Embodiment 11. The pharmaceutical composition of any one of the preceding embodiments, comprising about 65% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

[0020] Embodiment 12. The pharmaceutical composition of embodiments 1-7, comprising about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

[0021] Embodiment 13. The pharmaceutical composition of embodiments 1-6, comprising about 75% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

[0022] Embodiment 14. The pharmaceutical composition of embodiments 1-5, comprising about 80% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

[0023] Embodiment 15. The pharmaceutical composition of embodiments 1-4, comprising about 85% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

[0024] Embodiment 16. The pharmaceutical composition of embodiments 1-3, comprising about 90% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

[0025] Embodiment 17. The pharmaceutical composition of any one of the preceding embodiments, comprising about 1% (w / w) of benzyl alcohol.

[0026] Embodiment 18. The pharmaceutical composition of any one of the preceding embodiments, comprising about 2% (w / w) of benzyl alcohol.

[0027] Embodiment 19. The pharmaceutical composition of any one of the preceding embodiments, comprising about 3% (w / w) of benzyl alcohol.

[0028] Embodiment 20. The pharmaceutical composition of any one of the preceding embodiments, comprising about 4% (w / w) of benzyl alcohol.

[0029] Embodiment 21. The pharmaceutical composition of any one of the precedingAttorney Docket No.01309-0023-00PCT embodiments, comprising about 5% (w / w) of benzyl alcohol.

[0030] Embodiment 22. The pharmaceutical composition of embodiments 1-16, comprising about 10% (w / w) of benzyl alcohol.

[0031] Embodiment 23. The pharmaceutical composition of embodiments 1-15, comprising about 15% (w / w) of benzyl alcohol.

[0032] Embodiment 24. The pharmaceutical composition of embodiment 1, comprising: about 10% (w / w) of ethanol; about 80% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol.

[0033] Embodiment 25. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol.

[0034] Embodiment 26. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300; and about 10% (w / w) of benzyl alcohol.

[0035] Embodiment 27. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol.

[0036] Embodiment 28. The pharmaceutical composition of embodiment 1, comprising: about 30% (w / w) of ethanol; about 60% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol.

[0037] Embodiment 29. The pharmaceutical composition of embodiment 1, comprising: about 10% (w / w) of ethanol; about 85% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; andAttorney Docket No.01309-0023-00PCT about 5% (w / w) of benzyl alcohol.

[0038] Embodiment 30. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 75% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 5% (w / w) of benzyl alcohol.

[0039] Embodiment 31. The pharmaceutical composition of embodiment 1, comprising: about 30% (w / w) of ethanol; about 65% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 5% (w / w) of benzyl alcohol.

[0040] Embodiment 32. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.1% to about 1% of Povidone K30 by weight / volume (w / v).

[0041] Embodiment 33. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.1% (w / v) of Povidone K30.

[0042] Embodiment 34. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.2% (w / v) of Povidone K30.

[0043] Embodiment 35. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.3% (w / v) of Povidone K30.

[0044] Embodiment 36. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.4% (w / v) of Povidone K30.

[0045] Embodiment 37. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.5% (w / v) of Povidone K30.

[0046] Embodiment 38. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.6% (w / v) of Povidone K30.

[0047] Embodiment 39. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.7% (w / v) of Povidone K30.

[0048] Embodiment 40. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.8% (w / v) of Povidone K30.

[0049] Embodiment 41. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 0.9% (w / v) of Povidone K30.F

[0050] Embodiment 42. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 1% (w / v) of Povidone K30.Attorney Docket No.01309-0023-00PCT

[0051] Embodiment 43. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.2% (w / v) of Povidone K30.

[0052] Embodiment 44. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.3% (w / v) of Povidone K30.

[0053] Embodiment 45. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.4% (w / v) of Povidone K30.

[0054] Embodiment 46. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.5% (w / v) of Povidone K30.

[0055] Embodiment 47. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 1 mg / ml to about 5 mg / ml of sorbitan monolaurate.

[0056] Embodiment 48. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 1 mg / ml of sorbitan monolaurate.

[0057] Embodiment 49. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 2 mg / ml of sorbitan monolaurate.

[0058] Embodiment 50. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 3 mg / ml of sorbitan monolaurate.

[0059] Embodiment 51. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 4 mg / ml of sorbitan monolaurate.Attorney Docket No.01309-0023-00PCT

[0060] Embodiment 52. The pharmaceutical composition of any one of the preceding embodiments, further comprising about 5 mg / ml of sorbitan monolaurate.

[0061] Embodiment 53. The pharmaceutical composition of embodiment 1, comprising: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 3 mg / ml of sorbitan monolaurate.

[0062] Embodiment 54. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is a liquid formulation.

[0063] Embodiment 55. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is used for subcutaneous administration.

[0064] Embodiment 56. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is used for intramuscular administration.

[0065] Embodiment 57. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is used for intravenous administration.

[0066] Embodiment 58. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is used for intradermal administration.

[0067] Embodiment 59. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is used for intravenous transfusion.

[0068] Embodiment 60. The pharmaceutical composition of any one of the preceding embodiments, comprising about 10 mg / ml to about 350 mg / ml of d-cis-3-(4-hydroxyphenyl)- 4-(4-hydroxyphenyl)-8-methylchroman-7-ol.

[0069] Embodiment 61. The pharmaceutical composition of any one of the preceding embodiments, comprising about 10 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0070] Embodiment 62. The pharmaceutical composition of any one of the preceding embodiments, comprising about 20 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0071] Embodiment 63. The pharmaceutical composition of any one of the precedingAttorney Docket No.01309-0023-00PCT embodiments, comprising about 30 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0072] Embodiment 64. The pharmaceutical composition of any one of the preceding embodiments, comprising about 40 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0073] Embodiment 65. The pharmaceutical composition of any one of the preceding embodiments, comprising about 50 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0074] Embodiment 66. The pharmaceutical composition of any one of the preceding embodiments, comprising about 55 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0075] Embodiment 67. The pharmaceutical composition of any one of the preceding embodiments, comprising about 60 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0076] Embodiment 68. The pharmaceutical composition of any one of the preceding embodiments, comprising about 65 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0077] Embodiment 69. The pharmaceutical composition of any one of the preceding embodiments, comprising about 70 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0078] Embodiment 70. The pharmaceutical composition of any one of the preceding embodiments, comprising about 75 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0079] Embodiment 71. The pharmaceutical composition of any one of the preceding embodiments, comprising about 80 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0080] Embodiment 72. The pharmaceutical composition of any one of the preceding embodiments, comprising about 85 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0081] Embodiment 73. The pharmaceutical composition of any one of the preceding embodiments, comprising about 90 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0082] Embodiment 74. The pharmaceutical composition of any one of the preceding embodiments, comprising about 95 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-Attorney Docket No.01309-0023-00PCT hydroxyphenyl)-8-methylchroman-7-ol.

[0083] Embodiment 75. The pharmaceutical composition of any one of the preceding embodiments, comprising about 100 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0084] Embodiment 76. The pharmaceutical composition of any one of the preceding embodiments, comprising about 150 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0085] Embodiment 77. The pharmaceutical composition of any one of the preceding embodiments, comprising about 200 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0086] Embodiment 78. The pharmaceutical composition of any one of the preceding embodiments, comprising about 250 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0087] Embodiment 79. The pharmaceutical composition of any one of the preceding embodiments, comprising about 300 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0088] Embodiment 80. The pharmaceutical composition of any one of the preceding embodiments, comprising about 350 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0089] Embodiment 81. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition passes freely through an 18 gauge needle without clog.

[0090] Embodiment 82. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition passes freely through a 21 gauge needle without clog.

[0091] Embodiment 83. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition passes freely through a 23 gauge needle without clog.

[0092] Embodiment 84. The pharmaceutical composition of any one of the preceding embodiments, wherein an amount of the pharmaceutical composition passes through a 0.2 µm filter to produce a filtrate that is about 85% to about 100% of the amount before the filtration.

[0093] Embodiment 85. The pharmaceutical composition of any one of the preceding embodiments, wherein an amount of the pharmaceutical composition passes through a 0.2Attorney Docket No.01309-0023-00PCT µm filter to produce a filtrate that is about 90% to about 100% of the amount before the filtration.

[0094] Embodiment 86. The pharmaceutical composition of any one of the preceding embodiments, wherein an amount of the pharmaceutical composition passes through a 0.2 µm filter to produce a filtrate that is about 95% to about 100% of the amount before the filtration.

[0095] Embodiment 87. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 1 day when the pharmaceutical composition is stored at about 0℃ to about 50℃.

[0096] Embodiment 88. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 0℃ to about 50℃.

[0097] Embodiment 89. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 3 days when the pharmaceutical composition is stored at about 0℃ to about 50℃.

[0098] Embodiment 90. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 4 days when the pharmaceutical composition is stored at about 0℃ to about 50℃.

[0099] Embodiment 91. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 5 days when the pharmaceutical composition is stored at about 0℃ to about 50℃.

[0100] Embodiment 92. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 2℃ to about 8℃.

[0101] Embodiment 93. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 10℃ to about 40℃.

[0102] Embodiment 94. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 21℃ to about 22℃.

[0103] Embodiment 95. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 40℃.

[0104] Embodiment 96. The pharmaceutical composition of any one of the precedingAttorney Docket No.01309-0023-00PCT embodiments, wherein the pharmaceutical composition is considered stable when zero or an insignificant amount of precipitation is observed.

[0105] Embodiment 97. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is considered stable when an increase in an amount of an impurity is zero or insignificant.

[0106] Embodiment 98. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 2% of the pharmaceutical composition.

[0107] Embodiment 99. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 1% of the pharmaceutical composition.

[0108] Embodiment 100. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 0.5% of the pharmaceutical composition.

[0109] Embodiment 101. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 0.2% of the pharmaceutical composition.

[0110] Embodiment 102. The pharmaceutical composition of any one of the preceding embodiments, wherein the impurity in the pharmaceutical composition is measured by high performance liquid chromatography (HPLC) assay.

[0111] Embodiment 103. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol after administration into a subject.

[0112] Embodiment 104. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 6 h to about 72 h after administration into the subject.

[0113] Embodiment 105. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 6 h after administration into the subject.

[0114] Embodiment 106. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4-Attorney Docket No.01309-0023-00PCT hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 12 h after administration into the subject.

[0115] Embodiment 107. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 24 h after administration into the subject.

[0116] Embodiment 108. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 48 hr after administration into the subject.

[0117] Embodiment 109. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 72 hr after administration into the subject.

[0118] Embodiment 110. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1 day.

[0119] Embodiment 111. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 2 days.

[0120] Embodiment 112. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 3 days.

[0121] Embodiment 113. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 4 days.

[0122] Embodiment 114. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 5 days.

[0123] Embodiment 115. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 6 days.

[0124] Embodiment 116. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4-Attorney Docket No.01309-0023-00PCT hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1 week.

[0125] Embodiment 117. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1-2 weeks.

[0126] Embodiment 118. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 10 days.

[0127] Embodiment 119. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 2 weeks.

[0128] Embodiment 120. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 3 weeks.

[0129] Embodiment 121. The pharmaceutical composition of any one of the preceding embodiments, wherein the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 4 weeks.

[0130] Embodiment 122. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is administered subcutaneously into the subject.

[0131] Embodiment 123. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is administered intramuscularly into the subject.

[0132] Embodiment 124. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 5 h to about 400 h (T1 / 2) after administration into the subject.

[0133] Embodiment 125. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 100 h to about 400 h (T1 / 2) after administration into the subject.

[0134] Embodiment 126. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-Attorney Docket No.01309-0023-00PCT 7-ol at about 10 h (T1 / 2) after administration into the subject.

[0135] Embodiment 127. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 2 h to about 10 h (Tmax) after administration into the subject.

[0136] Embodiment 181. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 4 h to about 8 h (Tmax) after administration into the subject.

[0137] Embodiment 129. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 4 h (Tmax) after administration into the subject.

[0138] Embodiment 130. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 5 h (Tmax) after administration into the subject.

[0139] Embodiment 131. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 6 h (Tmax) after administration into the subject.

[0140] Embodiment 132. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 7 h (Tmax) after administration into the subject.

[0141] Embodiment 133. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 8 h (Tmax) after administration into the subject.

[0142] Embodiment 134. The pharmaceutical composition of any one of the preceding embodiments, wherein the last quantifiable concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is observed (TLAST) at a time that is about 50 h to about 500 h after administration of the pharmaceutical composition into the subject.Attorney Docket No.01309-0023-00PCT

[0143] Embodiment 135. A method for treating a disease associated with mitochondrial oxidative phosphorylation (OXPHOS), comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition of any one of the preceding embodiments.

[0144] Embodiment 136. The method of any one of the preceding embodiments, wherein the disease comprises cancer.

[0145] Embodiment 137. A method for treating cancer comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition of any one of the preceding embodiments.

[0146] Embodiment 138. A method for treating cancer comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of any one of the preceding embodiments, wherein the subject is refractory, non-responsive, or resistant to a prior cancer therapy, or intolerant of the prior cancer therapy.

[0147] Embodiment 139. The method of any one of the preceding embodiments, wherein the cancer comprises colon cancer, rectal cancer, colorectal cancer (CRC), metastatic colorectal cancer (mCRC), non-metastatic colorectal cancer, refractory CRC, refractory mCRC, relapsed CRC, relapsed mCRC, relapsed or refractory CRC, relapsed or refractory mCRC, recurrent CRC, recurrent mCRC, breast cancer, metastatic breast cancer, metastatic HER2-negative breast cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, lung cancer, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, bladder cancer, endometrial cancer, cervical cancer, uterine cancer, ovarian cancer, kidney cancer, liver cancer, leukemia, melanoma, Lewis lung carcinoma, non- Hodgkin lymphoma, pancreatic cancer, testicular cancer, prostate cancer, thyroid cancer, sarcoma (including osteosarcoma), esophageal cancer, gastric cancer, head and neck cancer, lung cancer melanoma, myeloma, neuroblastoma, glioblastoma, or a brain cancer.

[0148] Embodiment 140. The method of any one of the preceding embodiments, wherein the cancer comprises colon cancer.

[0149] Embodiment 141. The method of any one of the preceding embodiments, wherein the cancer comprises rectal cancer.

[0150] Embodiment 142. The method of any one of the preceding embodiments, wherein the cancer comprises CRC.

[0151] Embodiment 143. The method of any one of the preceding embodiments, wherein the cancer comprises mCRC.

[0152] Embodiment 144. The method of any one of the preceding embodiments,Attorney Docket No.01309-0023-00PCT wherein the cancer comprises non-metastatic CRC.

[0153] Embodiment 145. The method of any one of the preceding embodiments, wherein the cancer comprises refractory CRC.

[0154] Embodiment 146. The method of any one of the preceding embodiments, wherein the cancer comprises refractory mCRC.

[0155] Embodiment 147. The method of any one of the preceding embodiments, wherein the cancer comprises recurrent CRC.

[0156] Embodiment 148. The method of any one of the preceding embodiments, wherein the cancer comprises recurrent mCRC.

[0157] Embodiment 149. The method of any one of the preceding embodiments, wherein the cancer comprises relapsed CRC.

[0158] Embodiment 150. The method of any one of the preceding embodiments, wherein the cancer comprises relapsed mCRC.

[0159] Embodiment 151. The method of any one of the preceding embodiments, wherein the cancer comprises relapsed or refractory CRC.

[0160] Embodiment 152. The method of any one of the preceding embodiments, wherein the cancer comprises relapsed or refractory mCRC.

[0161] Embodiment 153. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once a day.

[0162] Embodiment 154. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every two days.

[0163] Embodiment 155. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every three days.

[0164] Embodiment 156. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every four days.

[0165] Embodiment 157. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every five days.

[0166] Embodiment 158. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every six days.

[0167] Embodiment 159. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every week.

[0168] Embodiment 160. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every 10 days.

[0169] Embodiment 161. The method of any one of the preceding embodiments,Attorney Docket No.01309-0023-00PCT wherein the pharmaceutical composition is administered at least once every two weeks.

[0170] Embodiment 162. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every three weeks.

[0171] Embodiment 163. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every four weeks.

[0172] Embodiment 164. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every 45 days.

[0173] Embodiment 165. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered at least once every two months.

[0174] Embodiment 166. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once a day.

[0175] Embodiment 167. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every two days.

[0176] Embodiment 168. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every three days.

[0177] Embodiment 169. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every four days.

[0178] Embodiment 170. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every five days.

[0179] Embodiment 171. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every six days.

[0180] Embodiment 172. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every week.

[0181] Embodiment 173. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every 10 days.

[0182] Embodiment 174. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every two weeks.

[0183] Embodiment 175. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every three weeks.

[0184] Embodiment 176. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every four weeks.

[0185] Embodiment 177. The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered once every 45 days.

[0186] Embodiment 178. The method of any one of the preceding embodiments,Attorney Docket No.01309-0023-00PCT wherein the pharmaceutical composition is administered once every two months.

[0187] Embodiment 179. The method of any one of the preceding embodiments, wherein a second therapy is administered to the subject.

[0188] Embodiment 180. The method of any one of the preceding embodiments, wherein the second therapy comprises a glycolytic inhibitor.

[0189] Embodiment 181. The method of any one of the preceding embodiments, wherein the second therapy comprises an angiogenesis inhibitor.

[0190] Embodiment 182. The method of any one of the preceding embodiments, wherein the second therapy comprises a vascular endothelial growth factor (VEGF) inhibitor.

[0191] Embodiment 183. The method of any one of the preceding embodiments, wherein the second therapy comprises a VEGF receptor (VEGFR) inhibitor.

[0192] Embodiment 184. The method of any one of the preceding embodiments, wherein the second therapy comprises an anti-VEGF antibody.

[0193] Embodiment 185. The method of any one of the preceding embodiments, wherein the second therapy comprises an anti-VEGFR antibody.

[0194] Embodiment 186. The method of any one of the preceding embodiments, wherein the second therapy comprises bevacizumab, or a variant or biosimilar thereof.

[0195] Embodiment 187. The method of any one of the preceding embodiments, wherein the second therapy comprises bevacizumab, bevacizumab-adcd, bevacizumab-awwb, bevacizumab-maly, or bevacizumab-bvzr, or combinations thereof.

[0196] Embodiment 188. The method of any one of the preceding embodiments, wherein the second therapy comprises nintedanib, everolimus, temsirolimus, pazopanib, axitinib, sorafenib, sunitinib, thalidomide, dovitinib, regorafenib, imatinib, or combinations thereof.

[0197] Embodiment 189. The method of any one of the preceding embodiments, wherein the subject is refractory, non-responsive, or resistant to a prior cancer therapy, or intolerant of the prior cancer therapy.

[0198] Embodiment 190. The method of any one of the preceding embodiments, wherein the administering results in a steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 1 to 2 weeks.

[0199] Embodiment 191. The method of any one of the preceding embodiments, wherein the administering results in a steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 1Attorney Docket No.01309-0023-00PCT week.

[0200] Embodiment 192. The method of any one of the preceding embodiments, wherein the administering results in a steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 10 days.

[0201] Embodiment 193. The method of any one of the preceding embodiments, wherein the administering results in a steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 2 weeks.

[0202] Embodiment 194. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Cmax of about 500 ng / ml to about 1000 ng / ml when the d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg.

[0203] Embodiment 195. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Cmax of about 500 ng / ml to about 2000 ng / ml when the d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 140 mg / kg.

[0204] Embodiment 196. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Cmax of about 800 ng / ml to about 1600 ng / ml when the d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 140 mg / kg.

[0205] Embodiment 197. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Cmax of at about 2h to about 4h after the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg.

[0206] Embodiment 198. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Cmax of at about 4h to about 8h after the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg to about 140 mg / kg.Attorney Docket No.01309-0023-00PCT

[0207] Embodiment 199. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Tlastof about 50 h to about 600 h after the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg.

[0208] Embodiment 200. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a T1 / 2 of about 50 h to about 400 h after the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg.

[0209] Embodiment 201. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a plasma concentration having a value of area under the concentration-time curve from time zero to time of last measurable concentration (AUClast) that is about 2000 hr*ng / ml to about 20000 hr*ng / ml, wherein the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg.

[0210] Embodiment 202. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a plasma concentration having a value of area under the concentration-time curve from time zero to time of last measurable concentration (AUClast) that is about 12000 hr*ng / ml to about 40000 hr*ng / ml, wherein the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 140 mg / kg.

[0211] Embodiment 203. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol comprises the d-cis isomer in at least 95% enantiomeric excess.

[0212] Embodiment 204. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol comprises the d-cis isomer in at least 99% enantiomeric excess.

[0213] Embodiment 205. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the pharmaceutical composition or second therapy is administered to the subject at least once, at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10Attorney Docket No.01309-0023-00PCT times, or more than 10 times.

[0214] Embodiment 206. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 5 mg / kg to about 200 mg / kg.

[0215] Embodiment 207. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 10 mg / kg.

[0216] Embodiment 208. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 20 mg / kg.

[0217] Embodiment 209. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 50 mg / kg.

[0218] Embodiment 210. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 70 mg / kg.

[0219] Embodiment 211. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 100 mg / kg.

[0220] Embodiment 212. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 120 mg / kg.

[0221] Embodiment 213. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 140 mg / kg.

[0222] Embodiment 214. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 180 mg / kg.

[0223] Embodiment 215. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 200 mg / kg.

[0224] Embodiment 216. The pharmaceutical composition or method of any one of the preceding embodiments, wherein the subject is human or animal.

[0225] Embodiment 217. The pharmaceutical composition or method of any one ofAttorney Docket No.01309-0023-00PCT the preceding embodiments, wherein the subject is mouse or rat. BRIEF DESCRIPTION OF THE DRAWINGS

[0226] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0227] FIG.1 illustrates the pharmacokinetic (PK) profile of Compound d-5 in humans following intravenous (IV) administration of an aqueous cyclodextrin solution (10% Captisol), dosed weekly.

[0228] FIG.2 illustrates the plasma concentrations of Compound d-5 in Male Sprague Dawley rats following intravenous dose administration of Compound d-5 formulations F31 (10% Captisol) and F32-F37 (liposomal IV formulations), in comparison to intramuscular formulation F38.

[0229] FIG.3 illustrates the plasma concentration of Compound d-5 in Male Sprague Dawley rats following dose administration of Compound d-5 formulations F31 (IV) and F40 – F45 (IM and SC), over a duration of 0-3 weeks post-dose.

[0230] FIG.4 illustrates the plasma concentration of Compound d-5 in Male Sprague Dawley rats following subcutaneous dose administration of Compound d-5 formulations F28 and F30 (140 mg / kg dose) of Example 10 and formulation F44 of Example 9 (35 mg / kg dose) DETAILED DESCRIPTION OF THE INVENTION

[0231] There is a continuing need to develop and provide effective therapies for the treatment of cancer. Described herein are compositions and formulations for the treatment of cancer. The compositions and therapies described herein comprise a benzopyran derivative of Formula (I). Specifically, provided herein are compositions and formulations of 3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound 5), or more specifically, d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound d-5). Also provided herein are methods to induce apoptosis in a cancer cell, methods to treat cancer in individuals in need of cancer therapy, and methods to increase sensitivity of a cancer cell to a chemotherapeutic agent and / or radiation therapy (or to sensitize an individual to a particular chemotherapy).

[0232] Compound d-5 is a synthetic small molecule mitochondrial inhibitor based onAttorney Docket No.01309-0023-00PCT the isoflavan ring structure. Preliminary screening studies have identified d-5 as a candidate for development as an anti-cancer product, given its broad anti-proliferative activity against a panel of human cancer cells representative of most major organ systems.

[0233] In vitro studies in a range of cancer cell lines showed that d-5 inhibits oxidative phosphorylation thereby causing energy starvation. Two forms of Compound d-5 induced cell death have been identified as a result of energy starvation; caspase-independent autophagy and apoptotic cell death induced by a Bax-mediated loss of mitochondrial membrane potential. Compound d-5 may be administered on a dosing regimen of 10 mg / kg, given by slow infusion once a week for 3 weeks in a 4-week cycle. Previous clinical studies indicate that 10 mg / kg weekly is the maximum tolerated dose for Compound d-5. In humans, Compound d-5 has a dose-proportional PK (when tested over a dose range of 1.25 mg / kg - 20 mg / kg). However, the compound is poorly soluble in aqueous media. One formulation of Compound d-5 is as a 35 mg / mL solution in 30% weight per volume (w / v) Captisol® (b- Cyclodextrin Sulfobutyl Ethers, Sodium salts) in water for injection, sterilized by filtration through a 0.22-micron filter. The mean half-life over several studies is ~ 6 hrs. Yet, because Compound d-5 is administered via IV, the Cmaxis reached soon after infusion. FIG.1 illustrates the PK profile of d-5 following IV administration (dosed weekly).

[0234] Provided herein are additional forms and formulations, and methods of use of Compound d-5. Some embodiments provided herein enable a smoother PK profile, characterized by less sharp peaks and drop-offs, relative to the IV formulation evaluated in FIG.1. Certain Definitions

[0235] Unless otherwise noted, terminology used herein should be given its normal meaning as understood by one of skill in the art.

[0236] As used herein, ranges and amounts can be expressed as “about” a particular value or range. In the present description, any concentration range, percentage range, temperature range, duration of time range, dose range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. “About” also includes the exact amount. Generally, the term “about” includes an amount that would be expected to be within experimental error, such as for example, ± 20%, ± 10%, ± 5%, or ± 1% of the indicated range or value, unless otherwise indicated.

[0237] The term “alkyl” as used herein, alone or in combination, refers to anAttorney Docket No.01309-0023-00PCT optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2- ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” or “C1-6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.

[0238] The terms “C1-C3-alkyl” and “C1-C6-alkyl” as used herein refer to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom. Examples of C1-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl. Examples of C1-C6-alkyl radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl.

[0239] The term “cycloalkyl” as used herein refers to a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound containing between three and twenty carbon atoms by removal of a single hydrogen atom.

[0240] The term “C3-C6cycloalkyl” denoted a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0241] The alkyl group or cycloalkyl group may optionally be substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, C1-4alkoxycarbonyl, C1-4alkylaminocarbonyl, di-(C1-4 alkyl)-aminocarbonyl, hydroxyl, C1-4 alkoxy, formyloxy, C1-4 alkylcarbonyloxy, C1-4 alkylthio, C3-6 cycloalkyl or phenyl.

[0242] The term “alkoxy” as used herein, alone or in combination, refers to an alkyl ether radical, -O-alkyl, including the groups -O-aliphatic and -O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined herein. Non-limiting examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.Attorney Docket No.01309-0023-00PCT

[0243] The terms “C1-C3-alkoxy”, “C1-C6-alkoxy” as used herein refers to the C1-C3- alkyl group and C1-C6-alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of C1-C6-alkoxy radicals include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n- hexoxy.

[0244] The term “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

[0245] The term “haloalkyl” includes “alkyl” wherein one or more such as 1, 2, 3, 4, or 5 of the hydrogens have been replaced by a halo atom. The haloalkyl may be straight chain or branched chain “alkyl” unit. Non-limiting examples include –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, –CF2CH2F, –CF2CHF2, –CF2CF3, –CH2Cl, –CHCl2, –CCl3, –CH2Br, –CHBr2, and –CBr3.

[0246] The term “fluoroalkyl” includes “alkyl” wherein one or more such as 1, 2, 3, 4, or 5 of the hydrogens have been replaced by fluoro. The fluoroalkyl may be straight chain or branched chain “alkyl” unit. Preferred fluoroalkyl groups include trifluoromethyl and pentafluoroethyl.

[0247] The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0248] The term “pharmaceutically acceptable”, as used herein, refers to a material, including but not limited, to a salt, carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0249] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference for this purpose. The salts are prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andAttorney Docket No.01309-0023-00PCT perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other documented methodologies such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0250] It should be understood that a reference to a salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0251] The term “cyclodextrin,” as used herein, refers to cyclic carbohydrates consisting of at least six to eight sugar molecules in a ring formation. The outer part of the ring contains water soluble groups; at the center of the ring is a relatively nonpolar cavity able to accommodate small molecules.

[0252] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are notAttorney Docket No.01309-0023-00PCT limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0253] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0254] The term “effective amount,” as used herein, refers to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

[0255] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0256] The term “patient”, “subject” or “individual” are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like, encompasses mammals and non-mammals. None of the terms require that the individual be under the care and / or supervision of a medical professional. Mammals are any member of the Mammalian class, including but not limited to humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, suchAttorney Docket No.01309-0023-00PCT as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In some embodiments of the methods and compositions provided herein, the individual is a mammal. In preferred embodiments, the individual is a human.

[0257] The terms “treat”, “treating” or “treatment”, as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include achieving a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0258] The terms “preventing” or “prevention” refer to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).

[0259] The term “carrier” as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

[0260] The term “biosimilar” as used herein, generally refers to a biological medical product (e.g., an antibody) that is a nearly identical copy of an original product. Alternate terms include “follow-on biologic” and “subsequent entry biologic.” A biosimilar generally has similar efficacy and side effects compared to the original product. By way of example, the anti-VEGF antibody bevacizumab (trade name: Avastin) has several biosimilar products including, but not limited to, bevacizumab-adcd (trade name: Vegzelma), bevacizumab-awwb (trade name: Mvasi), bevacizumab-maly (trade name: Alymsys), and bevacizumab-bvzr (trade name: Zirabev). As used herein, the term biosimilar includes any and all such variantsAttorney Docket No.01309-0023-00PCT as understood in the art as having a biosimilar relationship (e.g., similar structure and biological activity) to the reference product (e.g., bevacizumab).

[0261] A dosage of an oxidative phosphorylation inhibitor such as those compounds of formulas (I), (II), (III), or (IV), or a glycolytic inhibitor as disclosed herein may be expressed in absolute or relative terms. For example, a dosage of either a compound disclosed herein having the structure of formula (II), or a glycolytic inhibitor and / or angiogenesis inhibitor may be expressed as a certain number of milligrams (mg) of drug, or a pharmaceutically acceptable salt thereof, administered to a patient. In relative terms, a may be expressed as “mg / kg,” which expresses the number of milligrams the drug, or pharmaceutically acceptable salt thereof, administered to a patient per kg of the patient’s body weight. Dosage may also be expressed in terms of mg / m2, indicating the mass of active ingredient administered per square meter of the patient’s estimated surface area. Benzopyran Derivative Compounds

[0262] Some embodiments of the present invention describe benzopyran derivatives. In some embodiments, the benzopyran derivative is a substituted diaryl chroman derivative, super-benzopyrans, or a combination thereof.

[0263] In some embodiments, the benzopyran derivative has the structure of Formula (I):wherein R1is hydrogen, hydroxy, halo, NR14R15, C3-6cycloalkyl, C1-6alkoxy, C1-6haloalkyl, C2-6alkenyl, COOR12, COR13, (O)nC1-4alkyleneNR14R15 or C1-6alkyl optionally substituted by one or more hydroxy, chloro, bromo, iodo or NR14R15 groups; R2, R3, R4, R5, R6, R9, and R10are independently hydrogen, hydroxy, halo, NR14R15, C3-6cycloalkyl, C1-6alkoxy, C1-6haloalkyl, C2-6alkenyl, COOR12, COR13, or C1-6alkyl optionally substituted by one or more hydroxy, chloro, bromo, iodo or NR14R15groups;Attorney Docket No.01309-0023-00PCT R7 is hydrogen, hydroxy, halo, NR14R15, C3-6cycloalkyl, C1-6alkoxy, C2-6alkenyl, C1-6haloalkyl or C1-6alkyl optionally substituted by one or more hydroxy, chloro, bromo, iodo or NR14R15groups; the drawing and R2 together represent a double bond or the drawing represents a single bond and R11 is hydrogen, hydroxy, NR14R15, C1-3alkoxy, C1-3fluoroalkyl, halo or C1-3alkyl optionally substituted by one or more hydroxy, chloro, bromo, iodo or NR14R15groups; R11 and R12 are independently hydrogen, C1-6alkyl, C3-6cycloalkyl, or trialkyl silyl; R13is hydrogen, C1-6alkyl, C3-6cycloalkyl or NR14R15; n represents 0 or 1; and R14 and R15 independently represent hydrogen or C1-6alkyl or NR14R15 when taken together represents a 5 or 6 membered heteroaromatic or heterocyclic, or a pharmaceutically acceptable salt thereof.

[0264] Some embodiments of the present invention describe a benzopyran derivative having the structure of Formula (II):Formula (II) R1is hydroxy, alkoxy, haloalkyl, or halo; R2is hydroxy or alkoxy; R3, R4, R5, and R6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl and R7is alkyl or hydrogen; and R9 is hydroxy or alkoxy; or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, R1is hydroxy or alkoxy. In some embodiments, R1is hydroxy. In other embodiments, R1 is C1-C6alkoxy. In further or additional embodiments, R1 is C1-C3alkoxy. In other embodiments, R1 is C1-C2alkoxy. In specific embodiments, R1 is methoxy. In specific embodiments, R1is ethoxy. In specific embodiments, R1is propoxy. In specific embodiments, R1is iso-propoxy. In specific embodiments, R1is butoxy. In specificAttorney Docket No.01309-0023-00PCT embodiments, R1 is iso-butoxy. In specific embodiments, R1 is sec-butoxy. In specific embodiments, R1 is tert-butoxy. In specific embodiments, R1 is pentyloxy. In specific embodiments, R1is hexyloxy. In further or alternative embodiments, R1is fluoro. In other embodiments, R1 is chloro. In other embodiments, R1 is iodo. In other embodiments, R1 is bromo. In other embodiments, R1 is haloalkyl. In other embodiments, R1 is haloC1-6alkyl. In other embodiments, R1is haloC1-3alkyl. In other embodiments, R1is haloC1-2alkyl. In specific embodiments, R1is monofluoromethyl. In specific embodiments, R1is difluoromethyl. In specific embodiments, R1 is trifluoromethyl.

[0266] In some embodiments, R2is hydroxy. In some embodiments, R2is C1- C6alkoxy. In further or additional embodiments, R2is C1-C3alkoxy. In further or additional embodiments, R2 is C1-C2alkoxy. In specific embodiments, R2 is methoxy. In specific embodiments, R2 is ethoxy. In specific embodiments, R2 is propoxy. In specific embodiments, R2is iso-propoxy. In specific embodiments, R2is butoxy. In specific embodiments, R2 is iso-butoxy. In specific embodiments, R2 is sec-butoxy. In specific embodiments, R2 is tert-butoxy. In specific embodiments, R2 is pentyloxy. In specific embodiments, R2is hexyloxy.

[0267] In some embodiments, R3, R4, R5, and R6are independently hydrogen, alkoxy, or alkyl. In some embodiments, R3, R4, R5, and R6 are independently hydrogen or alkyl. In other embodiments, R3, R4, R5, and R6are independently hydrogen.

[0268] In some embodiments, R3is hydrogen. In some embodiments, R3is C1- C6alkyl. In other embodiments, R3 is C1-C3alkyl. In other embodiments, R3 is C1-C2alkyl. In specific embodiments, R3is methyl. In specific embodiments, R3is ethyl. In specific embodiments, R3is propyl. In specific embodiments, R3is iso-propyl. In specific embodiments, R3 is butyl. In specific embodiments, R3 is iso-butyl. In specific embodiments, R3 is sec-butyl. In specific embodiments, R3 is tert-butyl. In specific embodiments, R3 is pentyl. In specific embodiments, R3is hexyl. In some embodiments, R3is C1-C6alkoxy. In further or additional embodiments, R3 is C1-C3alkoxy. In further or additional embodiments, R3 is C1-C2alkoxy. In specific embodiments, R3 is methoxy. In specific embodiments, R3 is ethoxy. In specific embodiments, R3is propoxy. In further or alternative embodiments, R3is fluoro. In other embodiments, R3is chloro. In other embodiments, R3is iodo. In other embodiments, R3 is bromo. In other embodiments, R3 is haloalkyl. In other embodiments, R3 is haloC1-6alkyl. In other embodiments, R3is haloC1-3alkyl. In other embodiments, R3is haloC1-2alkyl. In specific embodiments, R3is monofluoromethyl. In specific embodiments, R3is difluoromethyl. In specific embodiments, R3 is trifluoromethyl.Attorney Docket No.01309-0023-00PCT

[0269] In some embodiments, R4 is hydrogen. In some embodiments, R4 is C1- C6alkyl. In other embodiments, R4 is C1-C3alkyl. In other embodiments, R4 is C1-C2alkyl. In specific embodiments, R4is methyl. In specific embodiments, R4is ethyl. In specific embodiments, R4 is propyl. In specific embodiments, R4 is iso-propyl. In specific embodiments, R4 is butyl. In specific embodiments, R4 is iso-butyl. In specific embodiments, R4is sec-butyl. In specific embodiments, R4is tert-butyl. In specific embodiments, R4is pentyl. In specific embodiments, R4is hexyl. In some embodiments, R4is C1-C6alkoxy. In further or additional embodiments, R4 is C1-C3alkoxy. In further or additional embodiments, R4is C1-C2alkoxy. In specific embodiments, R4is methoxy. In specific embodiments, R4is ethoxy. In specific embodiments, R4is propoxy. In further or alternative embodiments, R4is fluoro. In other embodiments, R4 is chloro. In other embodiments, R4 is iodo. In other embodiments, R4 is bromo. In other embodiments, R4 is haloalkyl. In other embodiments, R4 is haloC1-6alkyl. In other embodiments, R4is haloC1-3alkyl. In other embodiments, R4is haloC1-2alkyl. In specific embodiments, R4 is monofluoromethyl. In specific embodiments, R4 is difluoromethyl. In specific embodiments, R4 is trifluoromethyl.

[0270] In some embodiments, R5is hydrogen. In some embodiments, R5is C1- C6alkyl. In other embodiments, R5is C1-C3alkyl. In other embodiments, R5is C1-C2alkyl. In specific embodiments, R5 is methyl. In specific embodiments, R5 is ethyl. In specific embodiments, R5is propyl. In specific embodiments, R5is iso-propyl. In specific embodiments, R5is butyl. In specific embodiments, R5is iso-butyl. In specific embodiments, R5 is sec-butyl. In specific embodiments, R5 is tert-butyl. In specific embodiments, R5 is pentyl. In specific embodiments, R5is hexyl. In some embodiments, R5is C1-C6alkoxy. In further or additional embodiments, R5is C1-C3alkoxy. In further or additional embodiments, R5 is C1-C2alkoxy. In specific embodiments, R5 is methoxy. In specific embodiments, R5 is ethoxy. In specific embodiments, R5 is propoxy. In further or alternative embodiments, R5 is fluoro. In other embodiments, R5is chloro. In other embodiments, R5is iodo. In other embodiments, R5 is bromo. In other embodiments, R5 is haloalkyl. In other embodiments, R5 is haloC1-6alkyl. In other embodiments, R5 is haloC1-3alkyl. In other embodiments, R5 is haloC1-2alkyl. In specific embodiments, R5is monofluoromethyl. In specific embodiments, R5is difluoromethyl. In specific embodiments, R5is trifluoromethyl.

[0271] In some embodiments, R6 is hydrogen. In some embodiments, R6 is C1- C6alkyl. In other embodiments, R6is C1-C3alkyl. In other embodiments, R6is C1-C2alkyl. In specific embodiments, R6is methyl. In specific embodiments, R6is ethyl. In specific embodiments, R6 is propyl. In specific embodiments, R6 is iso-propyl. In specificAttorney Docket No.01309-0023-00PCT embodiments, R6 is butyl. In specific embodiments, R6 is iso-butyl. In specific embodiments, R6 is sec-butyl. In specific embodiments, R6 is tert-butyl. In specific embodiments, R6 is pentyl. In specific embodiments, R6is hexyl. In some embodiments, R6is C1-C6alkoxy. In further or additional embodiments, R6 is C1-C3alkoxy. In further or additional embodiments, R6 is C1-C2alkoxy. In specific embodiments, R6 is methoxy. In specific embodiments, R6 is ethoxy. In specific embodiments, R6is propoxy. In further or alternative embodiments, R6is fluoro. In other embodiments, R6is chloro. In other embodiments, R6is iodo. In other embodiments, R6 is bromo. In other embodiments, R6 is haloalkyl. In other embodiments, R6 is haloC1-6alkyl. In other embodiments, R6is haloC1-3alkyl. In other embodiments, R6is haloC1-2alkyl. In specific embodiments, R6is monofluoromethyl. In specific embodiments, R6is difluoromethyl. In specific embodiments, R6 is trifluoromethyl.

[0272] In some embodiments, R7 is C1-C6alkyl. In other embodiments, R7 is C1- C3alkyl. In other embodiments, R7is C1-C2alkyl. In specific embodiments, R7is methyl. In specific embodiments, R7 is ethyl. In specific embodiments, R7 is propyl. In specific embodiments, R7 is isopropyl. In alternative embodiments, R7 is hydrogen. In some embodiments, R7is methyl or hydrogen.

[0273] In some embodiments, R9is hydroxy. In some embodiments, R9is C1- C6alkoxy. In further or additional embodiments, R9 is C1-C3alkoxy. In further or additional embodiments, R9is C1-C2alkoxy. In specific embodiments, R9is methoxy. In specific embodiments, R9is ethoxy. In specific embodiments, R9is propoxy. In specific embodiments, R9 is iso-propoxy. In specific embodiments, R9 is butoxy. In specific embodiments, R9is iso-butoxy. In specific embodiments, R9is sec-butoxy. In specific embodiments, R9is tert-butoxy. In specific embodiments, R9is pentyloxy. In specific embodiments, R9 is hexyloxy.

[0274] In certain embodiments, R1 is hydroxy or alkoxy; R2 is hydroxy or alkoxy; R3, R4, R5, and R6are independently hydrogen, hydroxy, alkoxy, or alkyl; R7is alkyl or hydrogen; and R9 is hydroxy or alkoxy.

[0275] In certain embodiments, R1 is hydroxy or alkoxy; R2 is hydroxy or alkoxy; R3, R4, R5, and R6are independently hydrogen; R7is alkyl or hydrogen; and R9is hydroxy.

[0276] In some embodiments, R1is hydroxy or methoxy; R2is hydroxy or methoxy; R3, R4, R5, and R6 are independently hydrogen, hydroxy, methoxy, methyl; R7 is methyl or hydrogen; and R9is hydroxy or methoxy.

[0277] In some embodiments, R1is hydroxy or methoxy; R2is hydroxy or methoxy; R3, R4, R5, and R6 are independently hydrogen; R7 is methyl or hydrogen; and R9 is hydroxy.Attorney Docket No.01309-0023-00PCT

[0278] In some embodiments, compounds of the general Formula (II) have the substituents R1, R3, and R4 distributed as shown below:

[0279] In some embodiments, compounds of the general Formula (II) have the substituents R2, R5, and R6 distributed as shown below:

[0280] Some embodiments provided herein describe a compound of Formula (II) that has a structure of Formula (III-a) or (III-b):Formula (III-a) Formula (III-b).

[0281] Some embodiments provided herein describe a compound of Formula (II) that has a structure of Formula (IV):Formula (IV).

[0282] Some embodiments provided herein describe a compound of Formula (IV) that has a structure of Formula (IV-a) or (IV-b):Attorney Docket No.01309-0023-00PCT

[0283] In some embodiments, compounds of the general Formula (IV) have the substituents R3and R4distributed as shown below:

[0284] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives.

[0285] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0286] Exemplary compounds include the following compounds:Attorney Docket No.01309-0023-00PCTAttorney Docket No.01309-0023-00PCTor salts or a derivative thereof.

[0287] Exemplary compounds include the following compounds: 3-(4-hydroxyphenyl)-4-(4-methoxy-3-methylphenyl)chroman-7-ol (compound 1); 3-(4-hydroxyphenyl)-4-(4-hydroxy-3-methylphenyl)chroman-7-ol (compound 2); 3-(4-hydroxyphenyl)-4-(4-fluoro-3-methylphenyl)chroman-7-ol (compound 3); 3-(4-hydroxyphenyl)-4-(4-methoxy-3-fluorophenyl)chroman-7-ol (compound 4); 3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (compound 5); 3-(4-hydroxyphenyl)-4-(4-hydroxy-3-methylphenyl)-8-methylchroman-7-ol (compound 6);Attorney Docket No.01309-0023-00PCT 3-(4-hydroxyphenyl)-4-(4-methoxy-3-methylphenyl)-8-methylchroman-7-ol (compound 7); 3-(4-hydroxyphenyl)-4-(4-methoxy-3,5-dimethylphenyl)-8-methylchroman-7-ol (compound 8); 3-(4-hydroxyphenyl)-4-(4-fluoro-3-methylphenyl)-8-methylchroman-7-ol (compound 9); 3-(4-hydroxyphenyl)-4-(4-methoxy-3-fluorophenyl)-8-methylchroman-7-ol (compound 10); 3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)chroman-7-ol (compound 11); 3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)chroman-7-ol (compound 12); 3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-8-methylchroman-7-ol (compound 13); 3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-7-methoxy-8-methylchroman (compound 14); 3-(4-methoxyphenyl)-4-(4-methoxyphenyl)-7-methoxy-8-methylchroman-7-ol (compound 15); 3-(4-hydroxyphenyl)-4-phenylchroman-7-ol (compound 16); 3-(4-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (compound 17); 3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-8-methylchroman-7-ol (compound 18); 3-(4-hydroxyphenyl)-4-p-tolylchroman-7-ol (compound 19); 3-(4-methoxyphenyl)-4-(4-methoxyphenyl)-7-methoxychroman (compound 20); 4-(4-hydroxy-2,6-dimethoxyphenyl)-3-(4-hydroxyphenyl)chroman-7-ol (compound 21); 3-(4-hydroxyphenyl)-4-(2-hydroxyphenyl)chroman-7-ol (compound 22); 3-(4-hydroxyphenyl)-4-(3-acyl-2-hydroxy-4-methoxyphenyl)chroman-7-ol (compound 23); 3-(3-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (compound 24); 3-(4-bromophenyl)-4-(4-methoxyphenyl)chroman-7-ol (compound 25); 3-(4-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (compound 26); 4-(3-aminophenyl)-3-(4-hydroxyphenyl)chroman-7-ol (compound 27); and 3-(4-hydroxyphenyl)-4-(4-phenoxyphenyl)chroman-7-ol (compound 28).

[0288] It will be clear to persons skilled in the art that in the compounds according to certain embodiments of the invention, the aryl substituents on the heterocyclic ring can be cis or trans relative to each other. In certain embodiments of the invention, these substituents will be cis.

[0289] The compounds according to some embodiments of this invention include two chiral centers. The present invention includes all the enantiomers and diastereomers as well as mixtures thereof in any proportions. The invention also extends to isolated enantiomers or pairs of enantiomers. Some of the compounds herein (including, but not limited to benzopyran derivatives and reagents for producing the aforementioned compounds) have asymmetric carbon atoms and can therefore exist as enantiomers or diastereomers.Attorney Docket No.01309-0023-00PCT Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers, and mixtures thereof are considered as part of the compositions described herein.

[0290] The compounds according to some embodiments are racemic mixture. In other embodiments, any compound described herein is in the optically pure form (e.g., optically active (+) and (−), (R)- and (S)-,or (D)- and (L)-isomers). In certain preferred embodiments, a compound of Formulas (I), (II), (III), or (IV) is the d-isomer. Accordingly, provided herein, in some embodiments, is the optically active d-isomer having a structure of Formulas (I), (II), (III), or (IV) in enantiomeric excess. In some embodiments, the d-isomer of a compound of Formulas (I), (II), (III), or (IV) is provided in at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 95%, or 99.9% enantiomeric excess. In other embodiments, the d-isomer of a compound of Formulas (I), (II), (III), or (IV) is provided in greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% enantiomeric excess. In specific embodiments, of a compound of Formulas (I), (II), (III), or (IV) has greater than 95% enantiomeric excess.

[0291] Specific optically active compounds (i.e., enantiomers) of Formulas (I), (II), (III), or (IV) include: d-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3-methylphenyl)chroman-7-ol (d-1); d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxy-3-methylphenyl)chroman-7-ol (d-2); d-cis-3-(4-hydroxyphenyl)-4-(4-fluoro-3-methylphenyl)chroman-7-ol (d-3); d-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3-fluorophenyl)chroman-7-ol (d-4); d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (d-5); d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxy-3-methylphenyl)-8-methylchroman-7-ol (d-6); d-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3-methylphenyl)-8-methylchroman-7-ol (d-7); d-cis-3-(4-hydroxyphenyl)-4-(4-methoxy -3,5-dimethylphenyl)-8-methylchroman-7-ol (d-8); d-cis-3-(4-hydroxyphenyl)-4-(4-fluoro-3-methylphenyl)-8-methylchroman-7-ol (d-9); d-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3-fluorophenyl)-8-methylchroman-7-ol (d-10); d-cis-3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)chroman-7-ol (d-11);Attorney Docket No.01309-0023-00PCT d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)chroman-7-ol (d-12); d-cis-3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-8-methylchroman-7-ol (d-13); d-cis--(4-hydroxyphenyl)-4-(4-methoxyphenyl)-7-methoxy-8-methylchroman (d-14); d-cis--(4-methoxyphenyl)-4-(4-methoxyphenyl)-7-methoxy-8-methylchroman-7-ol (d-15); d-cis-3-(4-hydroxyphenyl)-4-phenylchroman-7-ol (d-16); d-cis-3-(4-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (d-17); d-cis-3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-8-methylchroman-7-ol (d-18); d-cis-3-(4-hydroxyphenyl)-4-p-tolylchroman-7-ol (d-19); d-cis-3-(4-methoxyphenyl)-4-(4-methoxyphenyl)-7-methoxychroman (d-20); d-cis-4-(4-hydroxy-2,6-dimethoxyphenyl)-3-(4-hydroxyphenyl)chroman-7-ol (d-21); d-cis-3-(4-hydroxyphenyl)-4-(2-hydroxyphenyl)chroman-7-ol (d-22); d-cis-3-(4-hydroxyphenyl)-4-(3-acyl-2-hydroxy-4-methoxyphenyl)chroman-7-ol (d-23); d-cis-3-(3-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (d-24); d-cis-3-(4-bromophenyl)-4-(4-methoxyphenyl)chroman-7-ol (d-25); d-cis-3-(4-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (d-26); d-cis-4-(3-aminophenyl)-3-(4-hydroxyphenyl)chroman-7-ol (d-27); d-cis-3-(4-hydroxyphenyl)-4-(4-phenoxyphenyl)chroman-7-ol (d-28); l-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3-methylphenyl)chroman-7-ol (l-1); l-cis-3-(4-hydroxyphenyl)-4-(4-hydroxy-3-methylphenyl)chroman-7-ol (l-2); l-cis-3-(4-hydroxyphenyl)-4-(4-fluoro-3-methylphenyl)chroman-7-ol (l-3); l-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3-fluorophenyl)chroman-7-ol (l-4); l-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (l-5); l-cis-3-(4-hydroxyphenyl)-4-(4-hydroxy-3-methylphenyl)-8-methylchroman-7-ol (l-6); l-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3-methylphenyl)-8-methylchroman-7-ol (l-7); l-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3,5-dimethylphenyl)-8-methylchroman-7-ol (l-8); l-cis-3-(4-hydroxyphenyl)-4-(4-fluoro-3-methylphenyl)-8-methylchroman-7-ol (l-9); l-cis-3-(4-hydroxyphenyl)-4-(4-methoxy-3-fluorophenyl)-8-methylchroman-7-ol (l-10); l-cis-3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)chroman-7-ol (l-11); l-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)chroman-7-ol (l-12); l-cis-3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-8-methylchroman-7-ol (l-13); l-cis--(4-hydroxyphenyl)-4-(4-methoxyphenyl)-7-methoxy-8-methylchroman (l-14); l-cis--(4-methoxyphenyl)-4-(4-methoxyphenyl)-7-methoxy-8-methylchroman-7-ol (l-15); l-cis-3-(4-hydroxyphenyl)-4-phenylchroman-7-ol (l-16); l-cis-3-(4-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (l-17);Attorney Docket No.01309-0023-00PCT l-cis-3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-8-methylchroman-7-ol (l-18); l-cis-3-(4-hydroxyphenyl)-4-p-tolylchroman-7-ol (l-19); l-cis-3-(4-methoxyphenyl)-4-(4-methoxyphenyl)-7-methoxychroman (l-20); l-cis-4-(4-hydroxy-2,6-dimethoxyphenyl)-3-(4-hydroxyphenyl)chroman-7-ol (l-21); l-cis-3-(4-hydroxyphenyl)-4-(2-hydroxyphenyl)chroman-7-ol (l-22); l-cis-3-(4-hydroxyphenyl)-4-(3-acyl-2-hydroxy-4-methoxyphenyl)chroman-7-ol (l-23); l-cis-3-(3-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (l-24); l-cis-3-(4-bromophenyl)-4-(4-methoxyphenyl)chroman-7-ol (l-25); l-cis-3-(4-hydroxyphenyl)-4-(3-methoxyphenyl)chroman-7-ol (l-26); l-cis-4-(3-aminophenyl)-3-(4-hydroxyphenyl)chroman-7-ol (l-27); and l-cis-3-(4-hydroxyphenyl)-4-(4-phenoxyphenyl)chroman-7-ol (l-28).

[0292] In specific embodiments, a compound of Formulas (I), (II), (III), or (IV) is d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)chroman-7-ol. In other embodiments, a compound of Formulas (I), (II), (III), or (IV) is d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol.

[0293] In certain embodiments, a compound of Formulas (I), (II), (III), or (IV) is the d-isomer. Accordingly, provided herein, in some embodiments, is the optically active d- isomer having a structure of Formulas (I), (II), (III), or (IV) in enantiomeric excess. In some embodiments, the d-isomer is provided in at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 95.5%, or 99.9% enantiomeric excess. In other embodiments, the d-isomer is provided in greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% enantiomeric excess. In specific embodiments, a compound of Formulas (I), (II), (III), or (IV) has greater than 95% enantiomeric excess. In specific embodiments, a compound of Formulas (I), (II), (III), or (IV) has greater than 98% enantiomeric excess. In specific embodiments, a compound of Formulas (I), (II), (III), or (IV) has greater than 99% enantiomeric excess. In specific embodiments, a compound of Formulas (I), (II), (III), or (IV) has greater than 99.9% enantiomeric excess.

[0294] In some embodiments, the benzopyran derivative is a super-benzopyran. In some embodiments, the benzopyran derivative is TrilexiumTM(TRXE-009), CantrixilTM(TRXE-002, Trx-1), or combinations thereof. In some embodiments, the benzopyran derivative is TrilexiumTM. In some embodiments, the benzopyran derivative is CantrixilTM.

[0295] In additional or further embodiments, the compounds described herein are used in the form of pro-drugs. In additional or further embodiments, the compoundsAttorney Docket No.01309-0023-00PCT described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0296] Any compound described herein may be synthesized according to the exemplary synthesis shown in Schemes 1 and 2. For example, compounds 6 and 7 are synthesized from 4’-bis-tert-butyldimethylsilyoxy-8-methyldihydrodaidzein.4’-bis-tert- butyldimethylsilyoxy-8-methyldihydrodaidzein is treated with 4-methoxy-3- methylphenylmagnesium bromide in anhydrous THF. The reaction mixture is treated with wet ether (50:50 H2O / Et2O). The resultant mixture is extracted with Et2O. The organic layer is washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue is treated with pTsOH and ethanol. The reaction mixture is heated to reflux for 3 hours. The reaction mixture is concentrated in vacuo then poured into water (0 °C). The mixture is extracted with EtOAc, then the organic layer is washed with water (3 x), brine, dried (MgSO4), filtered and concentrated in vacuo to provide the 3-alkene intermediate. The intermediate is treated with Pd catalyst and ethanol. The reaction mixture is hydrogenated at low pressure for 3 h. The reaction is filtered through Celite and the filtrate is concentrated to a volume of 15 mL. The resultant solution is added to water. The mixture is extracted with Et2O (3 x), the organic layers are combined and washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue is purified by recrystallization to provide compound 7. Scheme 1

[0297] Compound 7 is transferred to a flask purged with nitrogen. Hydrogen bromide in acetic acid (33 wt%) is added drop-wise to the reaction mixture. The mixture is heated to reflux at 130 °C for 7 h. The reaction mixture is placed in an ice bath and the pH is adjustedAttorney Docket No.01309-0023-00PCT 6. The reaction mixture is extracted with EtOAc and the organic layer is washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue is purified by column chromatography to yield compound 6. Scheme 2

[0298] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0299] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxylAttorney Docket No.01309-0023-00PCT group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.

[0300] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds are prodrugs for another derivative or active compound.

[0301] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0302] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Pharmaceutical Formulations

[0303] Disclosed herein are pharmaceutical formulations comprising a compound of Formula (II) disclosed herein, or a pharmaceutically acceptable salt thereof:Attorney Docket No.01309-0023-00PCTFormula (II), wherein R1is hydroxy, alkoxy, haloalkyl, or halo; R2is hydroxy or alkoxy; R3, R4, R5, and R6are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl; R7is alkyl or hydrogen; and R9 is hydroxy or alkoxy, wherein the subject is refractory, non-responsive, or resistant to a cancer therapy, or intolerant of the cancer therapy. In some embodiments, R1is hydroxy or alkoxy. In some embodiments, R2 is hydroxy. In some embodiments, R3, R4, R5, and R6 are independently hydrogen or alkyl. In some embodiments, R3, R4, R5, and R6 are independently hydrogen. In some embodiments, R7is methyl or hydrogen. In some embodiments, R1is hydroxy or alkoxy; R2is hydroxy or alkoxy; R3, R4, R5, and R6 are independently hydrogen, hydroxy, alkoxy, or alkyl; R7 is alkyl or hydrogen; and R9is hydroxy or alkoxy. In some embodiments, R1is hydroxy or alkoxy; R2is hydroxy or alkoxy; R3, R4, R5, and R6 are independently hydrogen; R7 is alkyl or hydrogen; and R9 is hydroxy. In some embodiments, R1is hydroxy or methoxy; R2is hydroxy or methoxy; R3, R4, R5, and R6 are independently hydrogen, hydroxy, methoxy, methyl; R7 is methyl or hydrogen; and R9 is hydroxy or methoxy. In some embodiments, R1 is hydroxy or methoxy; R2 is hydroxy or methoxy; R3, R4, R5, and R6are independently hydrogen; R7is methyl or hydrogen; and R9is hydroxy.

[0304] In some embodiments, the compound of Formula (II) is 3-(4-hydroxyphenyl)- 4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound 5):,Attorney Docket No.01309-0023-00PCT or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) is d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound d-5):, or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the pharmaceutical composition comprises about 5% to about 35% of ethanol by weight (w / w). In some embodiments, the pharmaceutical composition comprises about 55% (w / w) to about 90% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) to about 15% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound d-5):.

[0306] In some embodiments, disclosed herein is a pharmaceutical composition comprising: (a) about 5% to about 35% of ethanol by weight (w / w); (b) about 55% (w / w) to about 90% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; (c) about 1% (w / w) to about 15% (w / w) of benzyl alcohol; and (d) d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound d-5):Attorney Docket No.01309-0023-00PCT.

[0307] In some embodiments, the pharmaceutical composition comprises ethanol in an amount from about 5% (w / w) to about 35% (w / w). In some embodiments, the pharmaceutical composition comprises ethanol in an amount of about 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), 15% (w / w), 16% (w / w), 17% (w / w), 18% (w / w), 19% (w / w), 20% (w / w), 21% (w / w), 22% (w / w), 23% (w / w), 24% (w / w), 25% (w / w), 26% (w / w), 27% (w / w), 28% (w / w), 29% (w / w), 30% (w / w), 31% (w / w), 32% (w / w), 33% (w / w), 34% (w / w), or about 35% (w / w), or any amount therebetween. In some embodiments, the pharmaceutical composition comprises about 5% (w / w) of ethanol. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) of ethanol. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) of ethanol. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) of ethanol. In some embodiments, the pharmaceutical composition comprises about 25% (w / w) of ethanol. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) of ethanol. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) of ethanol.

[0308] In some embodiments, the pharmaceutical composition comprises polyethylene glycol 300 or polyethylene glycol 400 in amount from about 55% (w / w) to about 90% (w / w). In some embodiments, the pharmaceutical composition comprises polyethylene glycol 300 or polyethylene glycol 400 in an amount of about 55% (w / w), 56% (w / w), 57% (w / w), 58% (w / w), 59% (w / w), 60% (w / w), 61% (w / w), 62% (w / w), 63% (w / w), 64% (w / w), 65% (w / w), 66% (w / w), 67% (w / w), 68% (w / w), 69% (w / w), 70% (w / w), 71% (w / w), 72% (w / w), 73% (w / w), 74% (w / w), 75% (w / w), 76% (w / w), 77% (w / w), 78% (w / w), 79% (w / w), 80% (w / w), 81% (w / w), 82% (w / w), 83% (w / w), 84% (w / w), 85% (w / w), 86% (w / w), 87% (w / w), 88% (w / w), 89% (w / w), or about 90% (w / w), or any amount therebetween. In some embodiments, the pharmaceutical composition comprises about 55% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 60% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprisesAttorney Docket No.01309-0023-00PCT about 65% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 75% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 80% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 85% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 90% (w / w) of polyethylene glycol 300 or polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 55% (w / w) of polyethylene glycol 300. In some embodiments, the pharmaceutical composition comprises about 60% (w / w) of polyethylene glycol 300. In some embodiments, the pharmaceutical composition comprises about 65% (w / w) of polyethylene glycol 300. In some embodiments, the pharmaceutical composition comprises about 70% (w / w) of polyethylene glycol 300. In some embodiments, the pharmaceutical composition comprises about 75% (w / w) of polyethylene glycol 300. In some embodiments, the pharmaceutical composition comprises about 80% (w / w) of polyethylene glycol 300. In some embodiments, the pharmaceutical composition comprises about 85% (w / w) of polyethylene glycol 300. In some embodiments, the pharmaceutical composition comprises about 90% (w / w) of polyethylene glycol 300. In some embodiments, the pharmaceutical composition comprises about 55% (w / w) of polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 60% (w / w) of polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 65% (w / w) of polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 70% (w / w) of polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 75% (w / w) of polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 80% (w / w) of polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 85% (w / w) of polyethylene glycol 400. In some embodiments, the pharmaceutical composition comprises about 90% (w / w) of polyethylene glycol 400.

[0309] In some embodiments, the pharmaceutical composition comprises benzyl alcohol in amount from about 1% (w / w) to about 15% (w / w). In some embodiments, the pharmaceutical composition comprises benzyl alcohol in an amount of about 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), or about 15% (w / w), or any amountAttorney Docket No.01309-0023-00PCT therebetween. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises about 2% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises about 4% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises about 5% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) of benzyl alcohol.

[0310] In some embodiments, the pharmaceutical composition comprises: about 10% (w / w) of ethanol; about 80% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises: about 30% (w / w) of ethanol; about 60% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 10% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises: about 10% (w / w) of ethanol; about 85% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 5% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 75% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 5% (w / w) of benzyl alcohol. In some embodiments, the pharmaceutical composition comprises: about 30% (w / w) of ethanol; about 65% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and about 5% (w / w) of benzyl alcohol.

[0311] In some embodiments, the pharmaceutical composition comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol (Compound d-5):Attorney Docket No.01309-0023-00PCT.

[0312] In some embodiments, the pharmaceutical composition further comprises about 0.1% to about 1% of Povidone K30 by weight / volume (w / v), about 0.1% (w / v), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), or about 1% (w / w), or any amount therebetween. In some embodiments, the pharmaceutical composition further comprises about 0.1% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.2% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.3% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.4% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.5% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.6% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.7% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.8% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 0.9% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises about 1% (w / v) of Povidone K30.

[0313] In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.2% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.3% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 0.4% (w / v) of Povidone K30. In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; andAttorney Docket No.01309-0023-00PCT about 0.5% (w / v) of Povidone K30.

[0314] In some embodiments, the pharmaceutical composition further comprises about 1 mg / ml to about 5 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 1 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 2 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 3 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 4 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises about 5 mg / ml of sorbitan monolaurate. In some embodiments, the pharmaceutical composition further comprises: about 20% (w / w) of ethanol; about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; about 10% (w / w) of benzyl alcohol; and about 3 mg / ml of sorbitan monolaurate.

[0315] In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the pharmaceutical composition is used for subcutaneous administration. In some embodiments, the pharmaceutical composition is used for intramuscular administration. In some embodiments, the pharmaceutical composition is used for intravenous administration. In some embodiments, the pharmaceutical composition is used for intradermal administration. In some embodiments, the pharmaceutical composition is used for intravenous transfusion.

[0316] In some embodiments, the pharmaceutical composition comprises about 10 mg / ml to about 350 mg / ml of a compound of Formula (II) disclosed herein. In some embodiments, the pharmaceutical composition comprises about 10 mg / ml to about 350 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol, about 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, or about 350mg, or any amount therebetween.

[0317] In some embodiments, the pharmaceutical composition comprises about 10 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 20 mg / ml of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 30 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 40 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-Attorney Docket No.01309-0023-00PCT 8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 50 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 55 mg / ml of d-cis-3- (4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 60 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 65 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 70 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 75 mg / ml of d-cis-3- (4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 80 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 85 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 90 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 95 mg / ml of d-cis-3- (4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 100 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 150 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 200 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 250 mg / ml of d-cis- 3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 300 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol. In some embodiments, the pharmaceutical composition comprises about 350 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol.

[0318] In some embodiments, the pharmaceutical composition passes freely through an 18 gauge needle without clog. In some embodiments, the pharmaceutical composition passes freely through a 21 gauge needle without clog. In some embodiments, the pharmaceutical composition passes freely through a 23 gauge needle without clog. In some embodiments, an amount of the pharmaceutical composition passes through a 0.2 µm filter toAttorney Docket No.01309-0023-00PCT produce a filtrate that is about 85% to about 100% of the amount before the filtration, about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100%, or any percentage therebetween. In some embodiments, an amount of the pharmaceutical composition passes through a 0.2 µm filter to produce a filtrate that is about 90% to about 100% of the amount before the filtration, or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100%, or any percentage therebetween. In some embodiments, an amount of the pharmaceutical composition passes through a 0.2 µm filter to produce a filtrate that is about 95% to about 100% of the amount before the filtration, about 95%, 96%, 97%, 98%, 99%, or about 100%, or any percentage therebetween.

[0319] In some embodiments, the pharmaceutical composition is stable for at least about 1 day to at least about 7 days when the pharmaceutical composition is stored at about 0℃ to about 50℃, about 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, or about 50℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 1 day when the pharmaceutical composition is stored at about 0℃ to about 50℃, about 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, or about 50℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 0℃ to about 50℃, about 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, or about 50℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 3 days when the pharmaceutical composition is stored at about 0℃ to about 50℃, about 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, or about 50℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 4 days when the pharmaceutical composition is stored at about 0℃ to about 50℃,Attorney Docket No.01309-0023-00PCT about 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, or about 50℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 5 days when the pharmaceutical composition is stored at about 0℃ to about 50℃, about 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, or about 50℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 6 days when the pharmaceutical composition is stored at about 0℃ to about 50℃, about 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, or about 50℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 7 days when the pharmaceutical composition is stored at about 0℃ to about 50℃, about 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, or about 50℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 1 day when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 3 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 4 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 5 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 6 days when the pharmaceutical composition is stored at about 0℃ to about 50℃. In some embodiments, the pharmaceutical composition is stable for at least about 7 days when the pharmaceutical composition is stored at about 0℃ to about 50℃.Attorney Docket No.01309-0023-00PCT

[0320] In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 2℃ to about 8℃, or about 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, or about 8℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 10℃ to about 40℃, or about 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℃, or about 40℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 21℃ to about 22℃, or about 21℃, 21.1℃, 21.2℃, 21.3℃, 21.4℃, 21.5℃, 21.6℃, 21.7℃, 21.8℃, 21.9℃, or about 22℃, or any temperature therebetween. In some embodiments, the pharmaceutical composition is stable for at least about 1 day when the pharmaceutical composition is stored at about 40℃. In some embodiments, the pharmaceutical composition is stable for at least about 2 days when the pharmaceutical composition is stored at about 40℃. In some embodiments, the pharmaceutical composition is stable for at least about 3 days when the pharmaceutical composition is stored at about 40℃. In some embodiments, the pharmaceutical composition is stable for at least about 4 days when the pharmaceutical composition is stored at about 40℃. In some embodiments, the pharmaceutical composition is stable for at least about 5 days when the pharmaceutical composition is stored at about 40℃. In some embodiments, the pharmaceutical composition is stable for at least about 6 days when the pharmaceutical composition is stored at about 40℃. In some embodiments, the pharmaceutical composition is stable for at least about 7 days when the pharmaceutical composition is stored at about 40℃.

[0321] In some embodiments, the pharmaceutical composition is considered stable when zero or an insignificant amount of precipitation is observed. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is zero or insignificant. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 2% of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 1% of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 0.5% of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is considered stable when an increase in an amount of an impurity is less than 0.2% of theAttorney Docket No.01309-0023-00PCT pharmaceutical composition. In some embodiments, the impurity in the pharmaceutical composition is measured by high performance liquid chromatography (HPLC) assay.

[0322] In some embodiments, the pharmaceutical composition provides a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol after administration into a subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 6 h to about 72 h after administration into the subject, about 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 25h, 26h, 27h, 28h, 29h, 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h, 41h, 42h, 43h, 44h, 45h, 46h, 47h, 48h, 49h, 50h, 51h, 52h, 53h, 54h, 55h, 56h, 57h, 58h, 59h, 60h, 61h, 62h, 63h, 64h, 65h, 66h, 67h, 68h, 69h, 70h, 71h, or about 72h, or any time therebetween. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol starts about 6 h after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol starts about 12 h after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol starts about 24 h after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol starts about 48 hr after administration into the subject. In some embodiments, the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol starts about 72 hr after administration into the subject.

[0323] In some embodiments, the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1 day to at least 4 weeks, or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or at least about 30 days, or any time therebetween. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol continues for at least 1 day. In some embodiments, the steady plasma concentration of d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 2 days.

[0324] In some embodiments, the steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 3 days. InAttorney Docket No.01309-0023-00PCT some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol continues for at least 4 days. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol continues for at least 5 days. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 6 days. In some embodiments, the steady plasma concentration of d-cis- 3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1 week. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)- 4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 1-2 weeks. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol continues for at least 10 days. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol continues for at least 2 weeks. In some embodiments, the steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 3 weeks. In some embodiments, the steady plasma concentration of d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol continues for at least 4 weeks.

[0325] In some embodiments, the pharmaceutical composition is administered subcutaneously into the subject. In some embodiments, the pharmaceutical composition is administered intramuscularly into the subject. In some embodiments, the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4- (4-hydroxyphenyl)-8-methylchroman-7-ol at about 5 h to about 400 h (T1 / 2) after administration into the subject, or about 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 25h, 26h, 27h, 28h, 29h, 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h, 41h, 42h, 43h, 44h, 45h, 46h, 47h, 48h, 49h, 50h, 51h, 52h, 53h, 54h, 55h, 56h, 57h, 58h, 59h, 60h, 61h, 62h, 63h, 64h, 65h, 66h, 67h, 68h, 69h, 70h, 71h, 72h, 73h, 74h, 75h, 76h, 77h, 78h, 79h, 80h, 81h, 82h, 83h, 84h, 85h, 86h, 87h, 88h, 89h, 90h, 91h, 92h, 93h, 94h, 95h, 96h, 97h, 98h, 99h, 100h, 101h, 102h, 103h, 104h, 105h, 106h, 107h, 108h, 109h, 110h, 111h, 112h, 113h, 114h, 115h, 116h, 117h, 118h, 119h, 120h, 121h, 122h, 123h, 124h, 125h, 126h, 127h, 128h, 129h, 130h, 131h, 132h, 133h, 134h, 135h, 136h, 137h, 138h, 139h, 140h, 141h, 142h, 143h, 144h, 145h, 146h, 147h, 148h, 149h, 150h, 151h, 152h, 153h, 154h, 155h, 156h, 157h, 158h, 159h, 160h, 161h, 162h, 163h, 164h, 165h, 166h, 167h, 168h, 169h, 170h, 171h, 172h, 173h, 174h, 175h, 176h, 177h, 178h, 179h, 180h, 181h, 182h, 183h, 184h, 185h, 186h, 187h, 188h, 189h, 190h, 191h, 192h, 193h, 194h, 195h,Attorney Docket No.01309-0023-00PCT 196h, 197h, 198h, 199h, 200h, 201h, 202h, 203h, 204h, 205h, 206h, 207h, 208h, 209h, 210h, 211h, 212h, 213h, 214h, 215h, 216h, 217h, 218h, 219h, 220h, 221h, 222h, 223h, 224h, 225h, 226h, 227h, 228h, 229h, 230h, 231h, 232h, 233h, 234h, 235h, 236h, 237h, 238h, 239h, 240h, 241h, 242h, 243h, 244h, 245h, 246h, 247h, 248h, 249h, 250h, 251h, 252h, 253h, 254h, 255h, 256h, 257h, 258h, 259h, 260h, 261h, 262h, 263h, 264h, 265h, 266h, 267h, 268h, 269h, 270h, 271h, 272h, 273h, 274h, 275h, 276h, 277h, 278h, 279h, 280h, 281h, 282h, 283h, 284h, 285h, 286h, 287h, 288h, 289h, 290h, 291h, 292h, 293h, 294h, 295h, 296h, 297h, 298h, 299h, 300h, 301h, 302h, 303h, 304h, 305h, 306h, 307h, 308h, 309h, 310h, 311h, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 319h, 320h, 321h, 322h, 323h, 324h, 325h, 326h, 327h, 328h, 329h, 330h, 331h, 332h, 333h, 334h, 335h, 336h, 337h, 338h, 339h, 340h, 341h, 342h, 343h, 344h, 345h, 346h, 347h, 348h, 349h, 350h, 351h, 352h, 353h, 354h, 355h, 356h, 357h, 358h, 359h, 360h, 361h, 362h, 363h, 364h, 365h, 366h, 367h, 368h, 369h, 370h, 371h, 372h, 373h, 374h, 375h, 376h, 377h, 378h, 379h, 380h, 381h, 382h, 383h, 384h, 385h, 386h, 387h, 388h, 389h, 390h, 391h, 392h, 393h, 394h, 395h, 396h, 397h, 398h, 399h, or about 400h, or any time therebetween. In some embodiments, the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol at about 100 h to about 400 h (T1 / 2) after administration into the subject. In some embodiments, the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 10 h (T1 / 2) after administration into the subject.

[0326] In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol at about 2 h (Tmax) to about 10 h (Tmax) after administration into the subject, or about 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, or about 10h, or anytime therebetween. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol at about 4 h (Tmax) to about 8 h (Tmax) after administration into the subject, or about 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, or about 8h, or anytime therebetween. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol at about 4 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 5 h (Tmax) after administration into the subject. In some embodiments, the pharmaceuticalAttorney Docket No.01309-0023-00PCT composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)- 4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 6 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman- 7-ol at about 7 h (Tmax) after administration into the subject. In some embodiments, the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 8 h (Tmax) after administration into the subject.

[0327] In some embodiments, the last quantifiable concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is observed (TLAST) at a time that is about 50 h to about 500 h after administration of the pharmaceutical composition into the subject, or about 50h, 51h, 52h, 53h, 54h, 55h, 56h, 57h, 58h, 59h, 60h, 61h, 62h, 63h, 64h, 65h, 66h, 67h, 68h, 69h, 70h, 71h, 72h, 73h, 74h, 75h, 76h, 77h, 78h, 79h, 80h, 81h, 82h, 83h, 84h, 85h, 86h, 87h, 88h, 89h, 90h, 91h, 92h, 93h, 94h, 95h, 96h, 97h, 98h, 99h, 100h, 101h, 102h, 103h, 104h, 105h, 106h, 107h, 108h, 109h, 110h, 111h, 112h, 113h, 114h, 115h, 116h, 117h, 118h, 119h, 120h, 121h, 122h, 123h, 124h, 125h, 126h, 127h, 128h, 129h, 130h, 131h, 132h, 133h, 134h, 135h, 136h, 137h, 138h, 139h, 140h, 141h, 142h, 143h, 144h, 145h, 146h, 147h, 148h, 149h, 150h, 151h, 152h, 153h, 154h, 155h, 156h, 157h, 158h, 159h, 160h, 161h, 162h, 163h, 164h, 165h, 166h, 167h, 168h, 169h, 170h, 171h, 172h, 173h, 174h, 175h, 176h, 177h, 178h, 179h, 180h, 181h, 182h, 183h, 184h, 185h, 186h, 187h, 188h, 189h, 190h, 191h, 192h, 193h, 194h, 195h, 196h, 197h, 198h, 199h, 200h, 201h, 202h, 203h, 204h, 205h, 206h, 207h, 208h, 209h, 210h, 211h, 212h, 213h, 214h, 215h, 216h, 217h, 218h, 219h, 220h, 221h, 222h, 223h, 224h, 225h, 226h, 227h, 228h, 229h, 230h, 231h, 232h, 233h, 234h, 235h, 236h, 237h, 238h, 239h, 240h, 241h, 242h, 243h, 244h, 245h, 246h, 247h, 248h, 249h, 250h, 251h, 252h, 253h, 254h, 255h, 256h, 257h, 258h, 259h, 260h, 261h, 262h, 263h, 264h, 265h, 266h, 267h, 268h, 269h, 270h, 271h, 272h, 273h, 274h, 275h, 276h, 277h, 278h, 279h, 280h, 281h, 282h, 283h, 284h, 285h, 286h, 287h, 288h, 289h, 290h, 291h, 292h, 293h, 294h, 295h, 296h, 297h, 298h, 299h, 300h, 301h, 302h, 303h, 304h, 305h, 306h, 307h, 308h, 309h, 310h, 311h, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 319h, 320h, 321h, 322h, 323h, 324h, 325h, 326h, 327h, 328h, 329h, 330h, 331h, 332h, 333h, 334h, 335h, 336h, 337h, 338h, 339h, 340h, 341h, 342h, 343h, 344h, 345h, 346h, 347h, 348h, 349h, 350h, 351h, 352h, 353h, 354h, 355h, 356h, 357h, 358h, 359h, 360h, 361h, 362h, 363h, 364h, 365h, 366h, 367h, 368h, 369h, 370h, 371h, 372h, 373h, 374h, 375h, 376h, 377h, 378h, 379h, 380h, 381h, 382h, 383h, 384h, 385h, 386h, 387h, 388h, 389h, 390h, 391h, 392h, 393h, 394h, 395h, 396h, 397h, 398h, 399h,Attorney Docket No.01309-0023-00PCT 400h, 401h, 402h, 403h, 404h, 405h, 406h, 407h, 408h, 409h, 410h, 411h, 412h, 413h, 414h, 415h, 416h, 417h, 418h, 419h, 420h, 421h, 422h, 423h, 424h, 425h, 426h, 427h, 428h, 429h, 430h, 431h, 432h, 433h, 434h, 435h, 436h, 437h, 438h, 439h, 440h, 441h, 442h, 443h, 444h, 445h, 446h, 447h, 448h, 449h, 450h, 451h, 452h, 453h, 454h, 455h, 456h, 457h, 458h, 459h, 460h, 461h, 462h, 463h, 464h, 465h, 466h, 467h, 468h, 469h, 470h, 471h, 472h, 473h, 474h, 475h, 476h, 477h, 478h, 479h, 480h, 481h, 482h, 483h, 484h, 485h, 486h, 487h, 488h, 489h, 490h, 491h, 492h, 493h, 494h, 495h, 496h, 497h, 498h, 499h, or about 500h, or any time therebetween.

[0328] In another aspect, disclosed herein is a method for treating a disease associated with mitochondrial oxidative phosphorylation (OXPHOS), comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition disclosed herein. In some embodiments, the disease comprises cancer.

[0329] In another aspect, disclosed herein is a method for treating cancer comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition disclosed herein. In another aspect, disclosed herein is a method for treating cancer comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition disclosed herein, wherein the subject is refractory, non- responsive, or resistant to a prior cancer therapy, or intolerant of the prior cancer therapy. In some embodiments, the cancer comprises colon cancer, rectal cancer, colorectal cancer (CRC), metastatic colorectal cancer (mCRC), non-metastatic colorectal cancer, refractory CRC, refractory mCRC, relapsed CRC, relapsed mCRC, relapsed or refractory CRC, relapsed or refractory mCRC, recurrent CRC, recurrent mCRC, breast cancer, metastatic breast cancer, metastatic HER2-negative breast cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, lung cancer, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, bladder cancer, endometrial cancer, cervical cancer, uterine cancer, ovarian cancer, kidney cancer, liver cancer, leukemia, melanoma, Lewis lung carcinoma, non-Hodgkin lymphoma, pancreatic cancer, testicular cancer, prostate cancer, thyroid cancer, sarcoma (including osteosarcoma), esophageal cancer, gastric cancer, head and neck cancer, lung cancer melanoma, myeloma, neuroblastoma, glioblastoma, or a brain cancer. In some embodiments, the cancer comprises colon cancer. In some embodiments, the cancer comprises rectal cancer. In some embodiments, the cancer comprises CRC. In some embodiments, the cancer comprises mCRC. In some embodiments, the cancer comprises non- metastatic CRC. In some embodiments, the cancer comprises refractory CRC. In some embodiments, the cancer comprises refractory mCRC. In some embodiments, the cancerAttorney Docket No.01309-0023-00PCT comprises recurrent CRC. In some embodiments, the cancer comprises recurrent mCRC. In some embodiments, the cancer comprises relapsed CRC. In some embodiments, the cancer comprises relapsed mCRC. In some embodiments, the cancer comprises relapsed or refractory CRC. In some embodiments, the cancer comprises relapsed or refractory mCRC.

[0330] In some embodiments, the pharmaceutical composition is administered at least once a day. In some embodiments, the pharmaceutical composition is administered at least once every two days. In some embodiments, the pharmaceutical composition is administered at least once every three days. In some embodiments, the pharmaceutical composition is administered at least once every four days. In some embodiments, the pharmaceutical composition is administered at least once every five days. In some embodiments, the pharmaceutical composition is administered at least once every six days. In some embodiments, the pharmaceutical composition is administered at least once every week. In some embodiments, the pharmaceutical composition is administered at least once every 10 days. In some embodiments, the pharmaceutical composition is administered at least once every two weeks. In some embodiments, the pharmaceutical composition is administered at least once every three weeks. In some embodiments, the pharmaceutical composition is administered at least once every four weeks.

[0331] In some embodiments, the pharmaceutical composition is administered at least once every 45 days. In some embodiments, wherein the pharmaceutical composition is administered at least once every two months. In some embodiments, wherein the pharmaceutical composition is administered once a day. In some embodiments, wherein the pharmaceutical composition is administered once every two days. In some embodiments, wherein the pharmaceutical composition is administered once every three days. In some embodiments, wherein the pharmaceutical composition is administered once every four days. In some embodiments, the pharmaceutical composition is administered once every five days. In some embodiments, the pharmaceutical composition is administered once every six days. In some embodiments, the pharmaceutical composition is administered once every week. In some embodiments, the pharmaceutical composition is administered once every 10 days. In some embodiments, the pharmaceutical composition is administered once every two weeks. In some embodiments, the pharmaceutical composition is administered once every three weeks. In some embodiments, the pharmaceutical composition is administered once every four weeks.

[0332] In some embodiments, the pharmaceutical composition is administered once every 45 days. In some embodiments, the pharmaceutical composition is administered onceAttorney Docket No.01309-0023-00PCT every two months. In some embodiments, a second therapy is administered to the subject. In some embodiments, the second therapy comprises a glycolytic inhibitor. In some embodiments, the second therapy comprises an angiogenesis inhibitor. In some embodiments, the second therapy comprises a vascular endothelial growth factor (VEGF) inhibitor. In some embodiments, the second therapy comprises a VEGF receptor (VEGFR) inhibitor. In some embodiments, the second therapy comprises an anti-VEGF antibody. In some embodiments, the second therapy comprises an anti-VEGFR antibody. In some embodiments, the second therapy comprises bevacizumab, or a variant or biosimilar thereof. In some embodiments, the second therapy comprises bevacizumab, bevacizumab-adcd, bevacizumab-awwb, bevacizumab-maly, or bevacizumab-bvzr, or combinations thereof. In some embodiments, the second therapy comprises nintedanib, everolimus, temsirolimus, pazopanib, axitinib, sorafenib, sunitinib, thalidomide, dovitinib, regorafenib, imatinib, or combinations thereof. In some embodiments, the subject is refractory, non-responsive, or resistant to a prior cancer therapy, or intolerant of the prior cancer therapy.

[0333] In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for at least about 1 to about 30 days, or about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 28 days, 29 days, or at least about 30 days, or any time therebetween. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol that continues for at least 1 to 2 weeks, or at least about 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or at least about 14 days, or any time therebetween. In some embodiments, the administering results in a steady plasma concentration of d-cis-3- (4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for about 1 to about 2 weeks, or at least about 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or at least about 14 days, or any time therebetween. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol that continues for at least 1 week. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 10 days. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for 1 week. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-Attorney Docket No.01309-0023-00PCT hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for about 10 days. In some embodiments, the administering results in a steady plasma concentration of d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for at least 2 weeks. In some embodiments, the administering results in a steady plasma concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol that continues for about 2 weeks.

[0334] In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Cmax of about 500 ng / ml to about 1000 ng / ml when the d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol provides a Cmax of about 500 ng / ml to about 2000 ng / ml when the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 140 mg / kg. In some embodiments, the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a Cmax of about 800 ng / ml to about 1600 ng / ml when the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 140 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a Cmax of at about 2h to about 4h after the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 35 mg / kg. The pharmaceutical composition or method of any one of the preceding claims, wherein the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provides a Cmax of at about 4h to about 8h after the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg to about 140 mg / kg.

[0335] In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Cmax of at about 2h to about 4h after the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg, or about 2h, about 2.5h, about 3h, about 3.5h, or about 4h, or any time therebetween. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a Tlastof about 50 h to about 600 h after the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol provides a T1 / 2of about 50 h to about 400 h after the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-Attorney Docket No.01309-0023-00PCT 8-methylchroman-7-ol provides a plasma concentration having a value of area under the concentration-time curve from time zero to time of last measurable concentration (AUClast) that is about 2000 hr*ng / ml to about 20000 hr*ng / ml, wherein the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 35 mg / kg.

[0336] In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol provides a plasma concentration having a value of area under the concentration-time curve from time zero to time of last measurable concentration (AUClast) that is about 12000 hr*ng / ml to about 40000 hr*ng / ml, wherein the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 140 mg / kg.

[0337] In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 5 mg / kg to about 40 mg / kg, or about 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, or about 40 mg / kg, or any dose therebetween. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 10 mg / kg.

[0338] In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol comprises the d-cis isomer in at least 95% enantiomeric excess. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol comprises the d-cis isomer in at least 96% enantiomeric excess. In some embodiments, the d- cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol comprises the d-cis isomer in at least 97% enantiomeric excess. In some embodiments, the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol comprises the d-cis isomer in at least 98% enantiomeric excess. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol comprises the d-cis isomer in at least 99% enantiomeric excess. In some embodiments, the pharmaceutical composition or second therapy is administered to the subject at least once, at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, or more than 10 times. In some embodiments, the subject is human or animal. In some embodiments, the subject is mouse or rat. In some embodiments, the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose ofAttorney Docket No.01309-0023-00PCT about 140 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered to a rat at a dose of about 140 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 5 mg / kg to about 200 mg / kg, or about 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, 60 mg / kg, 61 mg / kg, 62 mg / kg, 63 mg / kg, 64 mg / kg, 65 mg / kg, 66 mg / kg, 67 mg / kg, 68 mg / kg, 69 mg / kg, 70 mg / kg, 71 mg / kg, 72 mg / kg, 73 mg / kg, 74 mg / kg, 75 mg / kg, 76 mg / kg, 77 mg / kg, 78 mg / kg, 79 mg / kg, 80 mg / kg, 81 mg / kg, 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, 100 mg / kg, 101 mg / kg, 102 mg / kg, 103 mg / kg, 104 mg / kg, 105 mg / kg, 106 mg / kg, 107 mg / kg, 108 mg / kg, 109 mg / kg, 110 mg / kg, 111 mg / kg, 112 mg / kg, 113 mg / kg, 114 mg / kg, 115 mg / kg, 116 mg / kg, 117 mg / kg, 118 mg / kg, 119 mg / kg, 120 mg / kg, 121 mg / kg, 122 mg / kg, 123 mg / kg, 124 mg / kg, 125 mg / kg, 126 mg / kg, 127 mg / kg, 128 mg / kg, 129 mg / kg, 130 mg / kg, 131 mg / kg, 132 mg / kg, 133 mg / kg, 134 mg / kg, 135 mg / kg, 136 mg / kg, 137 mg / kg, 138 mg / kg, 139 mg / kg, 140 mg / kg, 141 mg / kg, 142 mg / kg, 143 mg / kg, 144 mg / kg, 145 mg / kg, 146 mg / kg, 147 mg / kg, 148 mg / kg, 149 mg / kg, 150 mg / kg, 151 mg / kg, 152 mg / kg, 153 mg / kg, 154 mg / kg, 155 mg / kg, 156 mg / kg, 157 mg / kg, 158 mg / kg, 159 mg / kg, 160 mg / kg, 161 mg / kg, 162 mg / kg, 163 mg / kg, 164 mg / kg, 165 mg / kg, 166 mg / kg, 167 mg / kg, 168 mg / kg, 169 mg / kg, 170 mg / kg, 171 mg / kg, 172 mg / kg, 173 mg / kg, 174 mg / kg, 175 mg / kg, 176 mg / kg, 177 mg / kg, 178 mg / kg, 179 mg / kg, 180 mg / kg, 181 mg / kg, 182 mg / kg, 183 mg / kg, 184 mg / kg, 185 mg / kg, 186 mg / kg, 187 mg / kg, 188 mg / kg, 189 mg / kg, 190 mg / kg, 191 mg / kg, 192 mg / kg, 193 mg / kg, 194 mg / kg, 195 mg / kg, 196 mg / kg, 197 mg / kg, 198 mg / kg, 199 mg / kg, or about 200 mg / kg, or any dose therebetween. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 10 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 20 mg / kg. In some embodiments, the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 50 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-Attorney Docket No.01309-0023-00PCT 8-methylchroman-7-ol is administered at a dose of about 70 mg / kg. In some embodiments, the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 100 mg / kg. The pharmaceutical composition or method of any one of the preceding claims, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is administered at a dose of about 120 mg / kg. The pharmaceutical composition or method of any one of the preceding claims, wherein the d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 140 mg / kg. The pharmaceutical composition or method of any one of the preceding claims, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 180 mg / kg. The pharmaceutical composition or method of any one of the preceding claims, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 200 mg / kg.

[0339] Some embodiments provided herein describe a pharmaceutical composition, wherein the composition further comprises one or more pharmaceutical carriers, excipients, auxiliaries, binders and / or diluents. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.

[0340] Any composition described herein optionally comprises minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. In some embodiments, the composition further comprises one or more of lactose, dextrose, mannitol, pH buffering agents, antioxidant agents, preservative agents, tonicity adjusters or a combination thereof. Examples of pharmaceutically acceptable carriers that are optionally used include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents andAttorney Docket No.01309-0023-00PCT other pharmaceutically acceptable substances.

[0341] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0342] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0343] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ- hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1- napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate and xylenesulfonate.

[0344] Further, the compounds described herein, in some embodiments, are prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lacticAttorney Docket No.01309-0023-00PCT acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1 -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0345] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4alkyl)4, and the like.

[0346] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. The compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Base addition salts are be prepared by reacting the free acid form of the compounds described herein with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In addition, the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.Attorney Docket No.01309-0023-00PCT

[0347] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.

[0348] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0349] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. Tablets contain the active ingredient in admixture with non- toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate,Attorney Docket No.01309-0023-00PCT sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water-soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0350] All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0351] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water,Attorney Docket No.01309-0023-00PCT immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0352] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0353] Pharmaceutical compositions may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0354] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0355] Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0356] Pharmaceutical compositions may be administered topically, that is by non- systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0357] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site ofAttorney Docket No.01309-0023-00PCT inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for instance from 1% to 2% by weight of the formulation.

[0358] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0359] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0360] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. In some embodiments, the pharmaceutical composition contains additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid are employed together with various disintegrants such as starch, alginic acid and certain complex silicatesAttorney Docket No.01309-0023-00PCT and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. In other embodiments, solid compositions of a similar type are employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. In certain embodiments where aqueous suspensions or elixirs are desired for oral administration, the active compound therein is combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0361] In some embodiments, oily suspensions are formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. In certain embodiments, the oily suspensions contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. In further or additional embodiments, sweetening agents such as those set forth above, and flavoring agents are added to provide a palatable oral preparation. In other embodiments, these compositions are preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

[0362] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. In some embodiments, additional excipients, for example sweetening, flavoring and coloring agents, are also present. In further or additional embodiments, these compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

[0363] In some embodiments, pharmaceutical compositions are in the form of oil-in- water emulsions. In some embodiments, the oily phase is a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents include but are not limited to naturally-occurring phosphatides, for example soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. In further or additional embodiments, the emulsions contain sweetening agents, flavoring agents, preservatives and antioxidants.

[0364] In some embodiments, pharmaceutical compositions described herein are inAttorney Docket No.01309-0023-00PCT the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that are employed include but are not limited to water, Ringer’s solution, phosphate buffered saline solution, U.S.P. and isotonic sodium chloride solution, ethanol, and 1,3-butanediol.

[0365] In addition, sterile, fixed oils are optionally employed as a solvent or suspending medium. For this purpose any bland fixed oil is optionally employed including synthetic mono- or diglycerides. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes or other microparticulate systems may be used to target the agent to blood components or one or more organs. In some embodiments, the sterile injectable preparation is a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. In certain embodiments, the active ingredient is first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion. In further or additional embodiments, the injectable solutions or microemulsions are introduced into an individual’s blood-stream by local bolus injection. Alternatively, in some embodiments, it is advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device is utilized. An example of such a device is the Deltec CADD- PLUS™ model 5400 intravenous pump.

[0366] In other embodiments, the pharmaceutical composition is in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. In further or additional embodiments, this suspension is formulated using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. In some embodiments, the sterile injectable preparation is a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose in some embodiments, any bland fixed oil is optionally employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0367] In certain embodiments, pharmaceutical compositions are administered in the form of suppositories for rectal administration of the drug. These compositions are prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin,Attorney Docket No.01309-0023-00PCT hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

[0368] In some embodiments, the compounds or compositions described herein are delivered in a vesicle, such as a liposome. In further or alternative embodiments, the compounds and pharmaceutical compositions described herein are delivered in a controlled release system, or a controlled release system can be placed in proximity of the therapeutic target. In one embodiment, a pump is used.

[0369] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing an active agent is used. As used herein, topical application includes mouth washes and gargles.

[0370] In certain embodiments, pharmaceutical compositions are administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using transdermal skin patches. To be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage regimen.

[0371] Additional cyclodextrin derivatives suitable for use in intravenous compositions described herein are known in the art and are described in, e.g., U.S. Patent Nos.5,134,127and 5,376,645 each of which is incorporated by reference herein for such disclosure. In addition, examples of suitable cyclodextrin derivatives are described below.

[0372] Suitable cyclodextrins and derivatives useful in certain embodiments of the compositions, methods and kits described herein include, for example, those described in Challa et al., AAPS PharmSciTech 6(2): E329-E357 (2005), U.S. Patent Nos.5,134,127, 5,376,645, 5,874,418, each of which is incorporated by reference herein for such disclosure. In some embodiments, suitable cyclodextrins or cyclodextrin derivatives for use in certain embodiments of the compositions, methods and kits described herein include, but are not limited to, α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, SAE-CD derivatives (e.g., SBE- α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), and SBE-γ-CD) (Cydex, Inc. Lenexa, KS), hydroxyethyl, hydroxypropyl (including 2-and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methylhydroxyethyl, ethyl-hydroxyethyl and ethyl- hydroxypropyl ethers of α-, β- and γ-cyclodextrin; and the maltosyl, glucosyl and maltotriosyl derivatives of α-, β- and γ-cyclodextrin, which may contain one or more sugar residues, e. g. glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e. g. a mixture of maltosyl and dimaltosyl derivatives. Specific cyclodextrinAttorney Docket No.01309-0023-00PCT derivatives for use herein include hydroxypropyl-β-cyclodextrin, hydroxyethyl-β- cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl- β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β- cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, diethyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, tri-O-methyl-β- cyclodextrin, tri-O-ethyl-β-cyclodextrin, tri-O-butyryl-β-cyclodextrin, tri-O-valeryl-β- cyclodextrin, and di-O-hexanoyl-β-cyclodextrin, as well as methyl-β-cyclodextrin, and mixtures thereof such as maltosyl-β-cyclodextrin / dimaltosyl-β-cyclodextrin. Any suitable procedure may be utilized for preparing such cyclodextrins including, e.g., those procedures described in U.S. Patent No.5,024,998, which is incorporated by reference herein for such disclosure. Other cyclodextrins suitable for use in certain embodiments of the compositions, methods and kits described herein include the carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 by ORGANON (AKZO-NOBEL), hydroxybutenyl ether derivatives by EASTMAN, sulfoalkyl-hydroxyalkyl ether derivatives, sulfoalkyl-alkyl ether derivatives, and other derivatives, for example as described in U.S. Patent Application Nos. 2002 / 0128468, 2004 / 0106575, 2004 / 0109888, and 2004 / 0063663, or U.S. Patents Nos. 6,610,671, 6,479,467, 6,660,804, or 6,509,323, each of which is specifically incorporated by reference herein for such disclosure.

[0373] Hydroxypropyl-β-cyclodextrin can be obtained from Research Diagnostics Inc. (Flanders, NJ). Exemplary hydroxypropyl-β-cyclodextrin products include Encapsin® (degree of substitution ~4) and Molecusol® (degree of substitution ~8); however, embodiments including other degrees of substitution are also available and are within the scope of the present invention.

[0374] Dimethyl cyclodextrins are available from FLUKA Chemie (Buchs, CH) or Wacker (Iowa). Other derivatized cyclodextrins suitable for use in the invention include water soluble derivatized cyclodextrins. Exemplary water-soluble derivatized cyclodextrins include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy-β-cyclodextrins, e. g., succinyl-β- cyclodextrin (SCD). All of these materials can be made according to methods known in the art and / or are available commercially. Suitable derivatized cyclodextrins are disclosed in Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (Ed. Dominique Duchene, Editions deAttorney Docket No.01309-0023-00PCT Sante, Paris, France, 1991). Glycolytic Inhibitors

[0375] Some embodiments provided herein describe glycolytic inhibitors that are capable of inhibiting at least one step of the glycolytic pathway in a cell. In some embodiments, the glycolytic inhibitor is a hexokinase inhibitor. In some embodiments, the hexokinase inhibitor is 2-deoxyglucose, 6-fluoroglucose, 6-thioglucose, 2- fluorodeoxyglucose, 3-bromopyruvate, or a pharmaceutically acceptable salt thereof. In some embodiments, the hexokinase inhibitor is 2-deoxyglucose, 2-fluorodeoxyglucose, 3- bromopyruvate, or a pharmaceutically acceptable salt thereof. In certain embodiments, the glycolytic inhibitor is a homolog, analog and / or derivative of 2-deoxy-D-glucose. Non- limiting examples of 2-deoxyglucose derivatives include 2-deoxy-D-glucose, 2-deoxy-L- glucose; 2-bromo-D-glucose, 2-fluoro-D-glucose, 2-iodo-D-glucose, 6-fluoro-D-glucose, 6- thio-D-glucose, 7-glucosyl fluoride, 3-fluoro-D-glucose, 4-fluoro-D-glucose, 1-O-propyl ester of 2-deoxy-D-glucose, 1-O-tridecyl ester of 2-deoxy-D-glucose, 1-O-pentadecyl ester of 2-deoxy-D-glucose, 3-O-propyl ester of 2-deoxy-D-glucose, 3-O-tridecyl ester of 2-deoxy-D- glucose, 3-O-pentadecyl ester of 2-deoxy-D-glucose, 4-O-propyl ester of 2-deoxy-D-glucose, 4-O-tridecyl ester of 2-deoxy-D-glucose, 4-O-pentadecyl ester of 2-deoxy-D-glucose, 6-O- propyl ester of 2-deoxy-D-glucose, 6-O-tridecyl ester of 2-deoxy-D-glucose, 6-O- glycolytic inhibitor is a 3-halopyruvate. In certain embodiments, the 3-halopyruvate is 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate or 3-iodopyruvate.

[0376] In some embodiments, the glycolytic inhibitor is a lactic dehydrogenase inhibitor. In certain embodiments, the lactic dehydrogenase inhibitor is oxamate or a pharmaceutically acceptable salt thereof. In some embodiments, the glycolytic inhibitor is a glyceraldehyde 3-phosphate dehydrogenase (e.g., iodoacetate or a pharmaceutically acceptable salt thereof).

[0377] In some embodiments, the glycolytic inhibitor is a glucose-6-phosphate dehydrogenase inhibitor. In some instances, the glucose-6-phosphate dehydrogenase inhibitor is red algal bromophenols.

[0378] In some embodiments, the glycolytic inhibitor is an angiogenesis inhibitor. In some embodiments, the angiogenesis inhibitor is a multi-tyrosine kinase inhibitor. In some embodiments, angiogenesis inhibitors include agents targeting (e.g. inhibiting) endothelial- specific receptor tyrosine kinase (Tie-2), epidermal growth factor (receptor) (EGF(R)), insulin-like growth factor (receptor) (IGF-(R)), fibroblast growth factor (receptor) (FGF(R)),Attorney Docket No.01309-0023-00PCT platelet-derived growth factor (receptor) (PDGF(R)), hepatocyte growth factor (receptor) (HGF(R)), or vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR); as well as thrombospondin analogs, matrix metalloprotease (e.g. MMP-2 or MMP-9) inhibitors, thalidomide or thalidomide analogs, integrins, angiostatin, endostatin, vascular disrupting agents, protein kinase C(PKC) inhibitors, and the like.

[0379] In some embodiments, angiogenesis inhibitors are agents targeting (e.g. inhibiting) vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR). Agents targeting (e.g. inhibiting) VEGF / VEGFR relate to compounds which target (e.g. inhibit) one or more members of the VEGF or VEGFR family (VEGFR1, VEGFR2, VEGFR3) and include inhibitors of any vascular endothelial growth factor (VEGF) ligand (such as e.g. ligand antibodies or soluble receptors) as well as inhibitors of any VEGF receptor (VEGFR) (such as e.g. VEGFR tyrosin kinase inhibitors, VEGFR antagonists or receptor antibodies). Examples of small molecule VEGFR inhibitors include, without being limited to, sorafenib (Nexavar, also an inhibitor of Raf, PDGFR, Flt3, Kit and RETR), sunitinib (Sutent, also inhibitor of Kit, Flt3 and PDGFR), pazopanib (GW-786034, also inhibitor of Kit and PDGFR), cediranib (Recentin, AZD-2171), axitinib (AG-013736, also inhibitor of PDGFR and Kit), vandetanib (Zactima, ZD-6474, also inhibitor of EGFR and Ret), vatalanib (also inhibitor of PDGFR and Kit), motesanib (AMG-706, also inhibitor of PDGFR and Kit), brivanib (also FGFR inhibitor), linifanib (ABT-869, also inhibitor of PDGFR, Flt3 and Kit), tivozanib (KRN-951, also inhibitor of PDGFR, Kit, and MAP), BMS-690514 (also and inhibitor of EGFR and HER-2), E-7080 (also inhibitor of Kit and Kdr), regorafenib (BAY- 73-4506, also inhibitor of Tek), foretinib (XL-880, also inhibitor of Flt3, Kit and Met), telatinib (BAY-57-9352), MGCD-265 (also inhibitor of c-MET, Tie2 and Ron), dovitinib (also inhibitor of PDGFR, Flt3, Kit and FGFR), nintedanib (also inhibitor of FGFR and PDGFR), XL-184 (cabozantinib, also inhibitor of Met, Flt3, Ret, Tek and Kit). Examples of biological entities inhibiting VEGF(R) include, without being limited to, anti-VEGF ligand antibodies such as bevacizumab (Avastin); soluble receptors such as aflibercept (VEGF- Trap); anti-VEGF receptor antibodies such as ramucirumab (IMC-1121b) or IMC-18F1; VEGFR antagonists such as CT-322 or CDP-791.

[0380] Agents targeting (e.g. inhibiting) PDGFR relate to compounds which target (e.g. inhibit) one or more members of the PDGFR family and include inhibitors of a platelet- derived growth factor receptor (PDGFR) family tyrosin kinase (either as single kinase inhibitor or as multikinase inhibitor) as well as anti-PDGFR antibodies. Examples of small molecule PDGFR inhibitors include, without being limited to, nintedanib (also inhibitor ofAttorney Docket No.01309-0023-00PCT VEGFR and FGFR), axitinib (also inhibitor of VEGFR and Kit), dovitinib (also inhibitor of VEGFR, Flt3, Kit and FGFR), sunitinib (also inhibitor of VEGFR, Flt3 and Kit), motesanib (also inhibitor of VEGFR and Kit), pazopanib (also inhibitor of VEGFR and Kit), nilotinib (also inhibitor of Abl and Kit), tandutinib (also inhibitor of Flt3 and Kit), vatalanib (also inhibitor of VEGFR and Kit), tivozanib (KRN-951, also inhibitor of VEGFR, Kit, and MAP), AC-220 (also inhibitor of Flt3 and Kit), TSU-68 (also inhibitor of FGFR and VEGFR), KRN- 633 (also inhibitor of VEGFR, Kit and Flt3), linifinib (also inhibitor of Flt3, Kit and VEGFR), sorafenib (Nexavar, also an inhibitor of Raf, VEGFR, Flt3, Kit and RETR), imatinib (Gleevec, also inhibitor of Abl and Kit). Examples of anti-PDGFR antibodies include IMC-3G3.

[0381] Agents targeting FGFR relate to compounds which target one or more members of the FGFR family and include inhibitors of a fibroblast growth factor receptor family tyrosin kinase (either as single kinase inhibitor or as multikinase inhibitor). Examples of small molecule FGFR inhibitors include, without being limited to, nintedanib (also inhibitor of VEGFR and PDGFR), dovitinib (also inhibitor of VEGFR, Flt3, Kit and PDGFR), KW-2449 (also inhibitor of Flt3 and Abl), brivanib (also VEGFR inhibitor), TSU- 68 (also inhibitor of PDGFR and VEGFR).

[0382] Agents targeting (e.g. inhibiting) EGFR relate to compounds which target (e.g. inhibit) one or more members of the epidermal growth factor receptor family (erbB1, erbB2, erbB3, erbB4) and include inhibitors of one or more members of the epidermal growth factor receptor (EGFR) family kinases (either as single kinase inhibitor or as multikinase inhibitor) as well as antibodies binding to one or more members of the epidermal growth factor receptor (EGFR) family. Examples of small molecule epidermal growth factor receptor (EGFR) inhibitors include, without being limited to, erlotinib, gefitinib, afatinib, lapatinib, vandetanib (Zactima, also inhibitor of VEGFR and RETR), BMS-690514 (also an inhibitor of VEGFR), neratinib (HKI-272), varlitinib, AZD-8931, AC-480, AEE-788 (also inhibitor of VEGFR). Examples of antibodies against the epidermal growth factor receptor (EGFR) include the anti- ErbB1 antibodies cetuximab, panitumumab or nimotuzumab, the anti-ErbB2 antibodies trastuzumab, pertuzumab or ertumaxomab, and the anti-EGFR antibody zalutumumab.

[0383] IGF(R) inhibitors are agents that target one or more members of the insulin- like growth factor (IGF) family (e.g. IGF1 and / or IGF2), particularly of the IGFR family of tyrosine kinases, e.g. IGFR-1 (either as single kinase inhibitor or as multikinase inhibitor), and / or of insulin receptor pathways, and may include, without being limited to, the IGFR tyrosin kinase inhibitors OSI-906 (linsitinib) and 1-{4-[(5-cyclopropyl-1H-pyrazol-3-Attorney Docket No.01309-0023-00PCT yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}-N-(6-fluoro-3-pyridinyl)-2-methyl-L-prolinamide (BMS-754807), as well as the anti-IGF(R) antibodies figitumumab, cixutumumab, dalotuzumab, ganitumab and robatumumab.

[0384] HGF(R) inhibitors are agents that target one or more members of the hepatocyte growth factor (HGF) family, particularly of the HGFR family of tyrosine kinases (either as single kinase inhibitor or as multikinase inhibitor), and may include, without being limited to, the HGFR tyrosin kinase inhibitors cabozantinib (XL-184, also inhibitor of VEGFR, Flt3, Ret, Tek and Kit), crizotinib (also inhibitor of Alk), foretinib (also inhibitor of Flt3, Kit and VEGFR) and tivantinib, as well as the anti-HGF(R) antibodies ficlatuzumab and onartuzumab.

[0385] In some embodiments, vascular disrupting agents include, without being limited to, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, vadimezan), combretastatin A4 phosphate, or combretastatin A4 analogues, such as ombrabulin. In some instances, the angiogenesis inhibitor is nintedanib, bevacizumab, everolimus, temsirolimus, lenalidomide, pazopanib, ramucirumab, sorafenib, sunitinib, thalidomide, vandetanib, cediranib, axitinib, motesanib, vatalanib, dovitinib, brivanib, linifanib, tivozanib, lenvatinib, regorafenib, foretinib, telatinib, cabozantinib, nilotinib, tandutinib, imatinib, BMS-690514, quizartinib, orantinib, olaratumab, erlotinib, gefitinib, afatinib, lapatinib, varlitinib, AEE-788, trastuzumab, cetuximab, panitumumab, nimotuzumab, pertuzumab, ertumaxomab, or zalutumumab. In some embodiments, the angiogenesis inhibitor is nintedanib, everolimus, temsirolimus, pazopanib, axitinib, bevacizumab, sorafenib, sunitinib, thalidomide, dovitinib, regorafenib, or imatinib. In certain embodiments, the angiogenesis inhibitor is bevacizumab, dovitinib, regorafenib, or nintedanib. In certain embodiments, the angiogenesis inhibitor is bevacizumab. In certain embodiments, the angiogenesis inhibitor is dovitinib. In certain embodiments, the angiogenesis inhibitor is nintedanib. Methods

[0386] Some embodiments provided herein describe a method of inducing apoptosis in a cancer cell. Also described herein, in other embodiments, is a method of treating cancer in an individual in need of cancer therapy. In specific embodiments, the methods comprise contacting the cancer or cancer cell with an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor. In certain embodiments, the cancer or cancer cell is present in an individual. In specific embodiments, the individual is in need of cancer therapy.Attorney Docket No.01309-0023-00PCT

[0387] In other embodiments, provided herein is a method of treating a disease or disorder associated with dysregulation of cell proliferation. In some embodiments, the disease or disorder is cancer. In other embodiments, provided herein is a method of increasing, inducing, or restoring sensitivity to a cancer therapy in an individual. Some embodiments provided herein describe a method of treating a chemoresistant cancer. In specific embodiments, the methods comprise contacting the cancer or cancer cell with an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor. In certain embodiments, the cancer or cancer cell is present in an individual. In specific embodiments, the individual is in need of cancer therapy.

[0388] In some embodiments, disclosed herein is a method for treating cancer, comprising administering to a subject in need thereof an effective amount of (i) a glycolytic inhibitor; and (ii) a compound of formula (II), or a pharmaceutically acceptable salt thereof:wherein R1 is hydroxy, alkoxy, haloalkyl, or halo; R2is hydroxy or alkoxy; R3, R4, R5, and R6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl; R7 is alkyl or hydrogen; and R9is hydroxy or alkoxy. In some embodiments, the subject is refractory, non-responsive, or resistant to a cancer therapy, or intolerant of the cancer therapy. In some embodiments, the subject is refractory to the cancer therapy. In some embodiments, the subject is non- responsive to the cancer therapy. In some embodiments, the subject is resistant to the cancer therapy. In some embodiments, the subject is intolerant of the cancer therapy.

[0389] In some embodiments, R1 is hydroxy or alkoxy. In some embodiments, R2 is hydroxy. In some embodiments, R3, R4, R5, and R6are independently hydrogen or alkyl. In some embodiments, R3, R4, R5, and R6are independently hydrogen. In some embodiments, R7 is methyl or hydrogen. In some embodiments, R1 is hydroxy or alkoxy; R2 is hydroxy orAttorney Docket No.01309-0023-00PCT alkoxy; R3, R4, R5, and R6 are independently hydrogen, hydroxy, alkoxy, or alkyl; R7 is alkyl or hydrogen; and R9is hydroxy or alkoxy. In some embodiments, R1is hydroxy or alkoxy; R2is hydroxy or alkoxy; R3, R4, R5, and R6 are independently hydrogen; R7 is alkyl or hydrogen; and R9 is hydroxy.

[0390] In some embodiments, R1is hydroxy or methoxy; R2is hydroxy or methoxy; R3, R4, R5, and R6are independently hydrogen, hydroxy, methoxy, methyl; R7is methyl or hydrogen; and R9is hydroxy or methoxy.

[0391] In some embodiments, R1is hydroxy or methoxy; R2is hydroxy or methoxy; R3, R4, R5, and R6 are independently hydrogen; R7 is methyl or hydrogen; and R9 is hydroxy.

[0392] In some embodiments, the compound of Formula (II) is 3-(4-hydroxyphenyl)- 4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound 5):, or a pharmaceutically acceptable salt thereof.

[0393] In some embodiments, the compound of Formula (II) is d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound d-5):, or a pharmaceutically acceptable salt thereof.

[0394] In some embodiments, the glycolytic inhibitor comprises an angiogenesis inhibitor. In some embodiments, the glycolytic inhibitor comprises a vascular endothelial growth factor (VEGF) inhibitor. In some embodiments, the glycolytic inhibitor comprises a VEGF receptor (VEGFR) inhibitor. In some embodiments, the VEGF inhibitor comprises an anti-VEGF antibody. In some embodiments, the VEGFR inhibitor comprises an anti-VEGFR antibody. In some embodiments, the VEGFR inhibitor comprises a small molecule chemicalAttorney Docket No.01309-0023-00PCT compound. In some embodiments, the glycolytic inhibitor comprises a tyrosine kinase inhibitor (TKI). In some embodiments, the glycolytic inhibitor comprises a multi-tyrosine kinase inhibitor (MTKI). In some embodiments, the glycolytic inhibitor comprises a VEGFR TKI. In some embodiments, the glycolytic inhibitor comprises a VEGFR multi-tyrosine kinase inhibitor (MTKI). In some embodiments, the angiogenesis inhibitor comprises bevacizumab, or a variant or biosimilar thereof. In some embodiments, the angiogenesis inhibitor comprises bevacizumab, bevacizumab-adcd, bevacizumab-awwb, bevacizumab- maly, or bevacizumab-bvzr, or combinations thereof. In some embodiments, the angiogenesis inhibitor comprises bevacizumab. In some embodiments, the angiogenesis inhibitor comprises bevacizumab-adcd. In some embodiments, the angiogenesis inhibitor comprises bevacizumab-awwb. In some embodiments, the angiogenesis inhibitor comprises bevacizumab-maly. In some embodiments, the angiogenesis inhibitor comprises bevacizumab-bvzr.

[0395] In some embodiments, the angiogenesis inhibitor comprises nintedanib, everolimus, temsirolimus, pazopanib, axitinib, sorafenib, sunitinib, thalidomide, dovitinib, regorafenib, imatinib, or combinations thereof. In some embodiments, the angiogenesis inhibitor comprises nintedanib. In some embodiments, the angiogenesis inhibitor comprises regorafenib.

[0396] In some embodiments, the glycolytic inhibitor and the compound of Formula (II) are administered simultaneously or sequentially. In some embodiments, the glycolytic inhibitor and the compound of Formula (II) are administered sequentially. In some embodiments, the glycolytic inhibitor and the compound of Formula (II) are administered simultaneously.

[0397] In some embodiments, the cancer therapy is a prior cancer therapy. In some embodiments, the subject exhibits progression of disease after the prior cancer therapy. In some embodiments, the subject exhibits worsening of disease after the prior cancer therapy. In some embodiments, the prior cancer therapy comprises a chemotherapy drug. In some embodiments, the chemotherapy drug comprises fluoropyrimidine, oxaliplatin, or irinotecan. In some embodiments, the prior cancer therapy further comprises a VEGF inhibitor or VEGFR inhibitor. In some embodiments, the prior cancer therapy comprises sorafenib, sunitinib, pazopanib, cediranib, axitinib, vandetanib, vatalanib, motesanib, brivanib, linifanib, tivozanib, BMS-690514, E-7080, regorafenib, foretinib, telatinib, MGCD-265, dovitinib, nintedanib, cabozantinib, bevacizumab, aflibercept, ramucirumab, IMC-18F1, CT-322, or CDP-791. In some embodiments, the prior cancer therapy further comprises an epidermalAttorney Docket No.01309-0023-00PCT growth factor receptor (EGFR) inhibitor. In some embodiments, the EGFR inhibitor comprises cetuximab, panitumumab, nimotuzumab, or necitumumab. In some embodiments, the prior cancer therapy further comprises a BRAF (B-Raf Proto-Oncogene, Serine / Threonine Kinase) inhibitor. In some embodiments, the BRAF inhibitor comprises vemurafenib, dabrafenib, or encorafenib. In some embodiments, the prior cancer therapy further comprises an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor comprises a programmed death-1 (PD-1) inhibitor, a programmed death ligand-1 (PD-L1) inhibitor, a cytotoxic T-lymphocyte antigen 4 (CTLA-4, or CD152) inhibitor, or a lymphocyte activation gene-3 (LAG-3) inhibitor. In some embodiments, the PD-1 inhibitor comprises pembrolizumab, nivolumab, or cemiplimab. In some embodiments, the PD-L1 inhibitor comprises atezolizumab, avelumab, or durvalumab. In some embodiments, the CTLA-4 inhibitor comprises ipilimumab. In some embodiments, the LAG- 3 inhibitor comprises relatlimab. In some embodiments, the prior cancer therapy further comprises an investigational treatment or an experimental treatment.

[0398] In some embodiments, the cancer comprises colon cancer, rectal cancer, colorectal cancer (CRC), metastatic colorectal cancer (mCRC), non-metastatic colorectal cancer, refractory CRC, refractory mCRC, relapsed CRC, relapsed mCRC, relapsed / refractory CRC, relapsed / refractory mCRC, recurrent CRC, recurrent mCRC, breast cancer, metastatic breast cancer, metastatic HER2-negative breast cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, lung cancer, squamous non- small cell lung cancer, non-squamous non-small cell lung cancer, bladder cancer, endometrial cancer, cervical cancer, uterine cancer, ovarian cancer, kidney cancer, liver cancer, leukemia, melanoma, Lewis lung carcinoma, non-Hodgkin lymphoma, pancreatic cancer, testicular cancer, prostate cancer, thyroid cancer, sarcoma (including osteosarcoma), esophageal cancer, gastric cancer, head and neck cancer, lung cancer melanoma, myeloma, neuroblastoma, glioblastoma, or a brain cancer. In some embodiments, the cancer comprises colon cancer. In some embodiments, the cancer comprises rectal cancer. In some embodiments, the cancer comprises CRC.

[0399] In some embodiments, the cancer comprises mCRC. In some embodiments, the cancer comprises non-metastatic CRC. In some embodiments, the cancer comprises refractory CRC. In some embodiments, the cancer comprises refractory mCRC. In some embodiments, the cancer comprises recurrent CRC. In some embodiments, the cancer comprises recurrent mCRC. In some embodiments, the cancer comprises relapsed CRC. In some embodiments, the cancer comprises relapsed mCRC. In some embodiments, the cancerAttorney Docket No.01309-0023-00PCT comprises relapsed / refractory CRC. In some embodiments, the cancer comprises relapsed / refractory mCRC.

[0400] In some embodiments, the cancer comprises cells that express a wildtype form of a rat sarcoma virus (RAS) gene. In some embodiments, the cancer comprises cells that express a mutant form of a RAS gene. In some embodiments, the cancer comprises cells that express the phenotype of microsatellite instability-high / deficient mismatch repair (MSI- H / dMMR). In some embodiments, the cancer comprises cells that express a mutant form of BRAF, wherein the mutant form of BRAF comprises a V600E mutation.

[0401] In some embodiments, the cancer or cancer cell has lost sensitivity to a chemotherapeutic agent, anti-cancer agent or radiation therapy. In some embodiments, the combination of an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor has an enhanced effect. In other embodiments, the combination of an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative), a glycolytic inhibitor, and an additional anti-cancer agent has an enhanced effect. In some embodiments, the combination therapies and / or compositions described herein chemosensitize cancer cells, wherein the combination therapies and / or compositions lower the amount of anti-cancer agent that is required to kill the cancer cell. In other embodiments, the combination therapies and / or compositions described herein chemosensitize cancer cells, wherein the combination therapies and / or compositions convert cancer cells from a state of chemo-resistant to chemo- sensitive. In further or additional embodiments, the combination therapies and / or compositions described herein radiosensitize cancer cells, wherein the combination therapies and / or compositions lower the amount of gamma-irradiation that is required to kill the cancer cell. In other embodiments, the combination therapies and / or compositions described herein radiosensitize cancer cells, wherein the combination therapies and / or compositions convert cancer cells from a state of radio-resistant to radio-sensitive.

[0402] In some embodiments, the cancer is drug-resistant or chemoresistant. In some embodiments, the cancer is multi-drug resistant. As used herein, a “drug-resistant cancer” is a cancer that is resistant to conventional commonly known cancer therapies. Examples of conventional cancer therapies include treatment of the cancer with agents such as methotrexate, doxorubicin, 5-fluorouracil, vincristine, vinblastine, pamidronate disodium, anastrozole, exemestane, cyclophosphamide, epirubicin, toremifene, letrozole, trastuzumab, megestrol, tamoxifen, paclitaxel, docetaxel, capecitabine, goserelin acetate, etc. In some embodiments, the cancer is resistant to bevacizumab. A “multi-drug resistant cancer” is a cancer that resists more than one type or class of cancer agents, i.e., the cancer is able to resistAttorney Docket No.01309-0023-00PCT a first drug having a first mechanism of action, and a second drug having a second mechanism of action.

[0403] Provided herein in some embodiments, is a method to treat cancer in an individual, the method comprising administering to the individual an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor, wherein the side-effects associated with chemotherapy, radiotherapy, or cancer therapy are reduced or minimized. In some instances, the combination therapies and / or compositions described herein provide chemo-protective and / or radio-protective properties to non-cancerous cells. In further or additional embodiments, the lower amount of oxidative phosphorylation inhibitor (e.g., a benzopyran derivative), a glycolytic inhibitor, or additional anti-cancer agent reduces or minimizes any undesired side-effects associated with chemotherapy. Non-limiting examples of side-effects associated with chemotherapy, radiotherapy or cancer therapy include fatigue, anemia, appetite changes, bleeding problems, diarrhea, constipation, hair loss, nausea, vomiting, pain, peripheral neuropathy, swelling, skin and nail changes, urinary and bladder changes, and trouble swallowing.

[0404] Also described herein, in some embodiments, is a method of killing cancer cells in an individual, wherein the cancer cells include cancer cells that create ATP for energy anaerobically and cancer cells that aerobically generate ATP, the method comprising administering to an individual an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor.

[0405] In some instances, cancer cells, e.g., at the inner core of a tumor, are poorly oxygenated and consequently rely on anaerobic metabolism for survival. In some instances, cancer cells use steps of the glycolytic pathway to create ATP for energy anaerobically. In some instances, these tumor cells divide more slowly than outer growing aerobic cells and consequently are more resistant to standard chemotherapeutic agents which target rapidly dividing cells. In some instances, the anaerobic tumor cells are resistant to chemotherapeutic agents that target aerobic metabolism (e.g., oxidative phosphorylation). In some instances, cells growing anaerobically exhibit a form of multidrug resistance (MDR).

[0406] In some instances, cancer cells metabolize glucose at high rates to synthesize high levels of ATP, exhibiting increased glycolysis. In some instances where the glycolytic pathway is inhibited, cancer cells develop an escape mechanism and switch to mitochondrial oxidative phosphorylation to synthesize ATP. In some instances, the cancer cells shift to reliance on mitochondrial metabolism as the primary energy source.

[0407] In some embodiments, the combination therapies and / or compositions are usedAttorney Docket No.01309-0023-00PCT to treat anaerobic tumor cells and aerobic tumor cells (with inhibitors of oxidative phosphorylation). In some embodiments, the combination therapies and / or compositions provide synergistic antitumor activity. In some instances, inhibiting oxidative phosphorylation to convert aerobic tumor cells to anaerobic cells, hypersensitizes the cancer cells to glycolytic inhibitors. In some instances, inhibiting glycolysis to convert anaerobic tumor cells to aerobic cells, hypersensitizes the cancer cells to oxidative phosphorylation inhibitors (e.g., benzopyran derivatives).

[0408] The administration time of the oxidative phosphorylation inhibitors (e.g., benzopyran derivatives) and the glycolytic inhibitors is not restricted. In some embodiments, the oxidative phosphorylation inhibitors (e.g., benzopyran derivatives) and the glycolytic inhibitors are administered to an individual simultaneously. In other embodiments, the oxidative phosphorylation inhibitors (e.g., benzopyran derivatives) and the glycolytic inhibitors are administered at staggered times. In certain embodiments, the individual is first treated with a glycolytic inhibitor, followed by an oxidative phosphorylation inhibitor. In certain embodiments, the individual is first treated with an oxidative phosphorylation inhibitor, followed by a glycolytic inhibitor.

[0409] Some embodiments provided herein describe a method of treating cancer or a tumor in a subject, the method comprising i) treating the subject with a glycolytic inhibitor; ii) administering to the subject a positron emission tomography (PET) scan (or other imaging procedure suitable to assess efficacy of anti-cancer or anti-tumor treatment with the glycolytic inhibitor); and iii) if the result of the PET scan (or other imaging) testing procedure in step ii is positive (i.e., if the cancer or tumor is responsive), treating the subject with the glycolytic inhibitor and an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative). In some instances, if the result of the PET scan (or other imaging procedure) in step ii is negative (i.e., the tumor or cancer is unresponsive to the glycolytic inhibitor), treatment with the glycolytic inhibitor is continued and the PET scan (or other imaging procedure) in step ii is re-administered in 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, at which point, if the result of the PET scan (or other imaging) testing procedure in step ii is positive (i.e., if the cancer or tumor is responsive), treating the subject with the glycolytic inhibitor and an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative).

[0410] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, metastatic breast cancer, metastatic HER2-negative breast cancer, colon cancer, rectal cancer, metastatic colorectal cancer, endometrial cancer, cervicalAttorney Docket No.01309-0023-00PCT cancer, uterine cancer, ovarian cancer, kidney cancer, liver cancer, leukemia, lung cancer (both small cell and non-small cell), squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, melanoma, Lewis lung carcinoma, non-Hodgkin lymphoma, pancreatic cancer, testicular cancer, prostate cancer, thyroid cancer, sarcoma (including osteosarcoma), esophageal cancer, gastric cancer, head and neck cancer, lung cancer melanoma, myeloma, neuroblastoma, glioblastoma, and cancers of the brain. In some embodiments, the cancer is selected from, by way of non-limiting example, human breast, prostate, ovarian, pancreatic, or cervical cancer. In certain specific embodiments, the cancer is human breast cancer or ovarian cancer.

[0411] A tumor cell in a subject or individual may be part of any type of cancer. Some examples of cancer include, but are not limited to, biliary tract cancer; bladder cancer; brain cancer including glioblastomas and medulloblastomas; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric cancer; hematological neoplasms including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS-associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms including Bowen's disease and Paget's disease; liver cancer; lung cancer; lymphomas including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer including squamous cell carcinoma; ovarian cancer including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; rectal cancer; sarcomas including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma; skin cancer including melanoma, Kaposi's sarcoma, basocellular cancer, and squamous cell cancer; testicular cancer including germinal tumors such as seminoma, non-seminoma, teratomas, choriocarcinomas; stromal tumors and germ cell tumors; thyroid cancer including thyroid adenocarcinoma and medullar carcinoma; and renal cancer including adenocarcinoma and Wilms' tumor.

[0412] In some embodiments, the methods described herein are useful in treating various cancers including but not limited to bone cancers including Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain and CNS tumours including acoustic neuroma, neuroblastomas, glioma and other brain tumours, spinal cord tumours, breast cancers including ductal adenocarcinoma, metastatic ductal breast carcinoma, colorectal cancers, advanced colorectal adenocarcinomas, colon cancers, endocrine cancers including adenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine neoplasma, gastrointestinal cancers including stomach cancer, esophageal cancer, small intestine cancer, liver cancer, extra hepatic bileAttorney Docket No.01309-0023-00PCT duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers including testicular cancer, penile cancer, prostate cancer, gynaecological cancers including cervical cancer, ovarian cancer, vaginal cancer, uterus / endometrium cancer, vulva cancer, gestational trophoblastic cancer, fallopian tube cancer, uterine sarcoma, head and neck cancers including oral cavity cancer, lip cancer, salivary gland cancer, larynx cancer, hypopharynx cancer, orthopharynx cancer, nasal cancer, paranasal cancer, nasopharynx cancer, leukemias including childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia, erythroleukemia, myelomas, haematological disorders including myelodysplasia syndromes, myeloproliferative disorders, aplastic anemia, Fanconi anemia, Waldenstroms Macroglobulinemia, lung cancers including small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, Lewis lung carcinoma, mesothelioma, lymphomas including Hodgkin's disease, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS related Lymphoma, B-cell lymphoma, Burkitt's lymphoma, eye cancers including retinoblastoma, intraocular melanoma, skin cancers including melanoma, non-melanoma skin cancer, squamous cell carcinoma, merkel cell cancer, soft tissue sarcomas such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers including kidney cancer, Wilms tumour, bladder cancer, urethral cancer, and transitional cell cancer.

[0413] In some embodiments, the cancer is a hematological malignancy. In some embodiments, wherein the hematological malignancy is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, thrombolytic leukemia, a myelodysplasia syndrome (MDS), a myeloproliferative disorder, refractory anemia, a preleukemia syndrome, a lymphoid leukemia, lymphoma, non-Hodgkin's lymphoma, or an undifferentiated leukemia. In some specific embodiments, the cancer is myelodysplasia syndrome (MDS) or acute myeloid leukemia (AML). Non-limiting examples of non-Hodgkin's lymphoma include diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL).

[0414] Other exemplary cancers that may be treated by the methods described herein include but are not limited to leukemias such as erythroleukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute lymophocytic leukemia, acute T-cell leukemia and lymphoma such as B-cell lymphoma (e.g. Burkitt's lymphoma), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma.Attorney Docket No.01309-0023-00PCT Additional Agents

[0415] Any of the methods described herein, in some embodiments, further comprise administering cancer therapy to the individual or patient. In certain embodiments, the cancer therapy is, by way of non-limiting example, at least one anti-cancer agent (e.g., chemotherapeutic agent), radiation therapy, or surgery. In some embodiments, a combination of (1) administration of an effective amount of a compound described herein and (2) 1 to 3 therapies selected from the group consisting of (i) administration of an effective amount of an additional anticancer agents, (ii) administration of an effective amount of hormonal therapeutic agents and (iii) non-drug therapy prevents and / or treats cancer more effectively.

[0416] The administration time of the combination therapy / composition and a concomitant anti-cancer agent is not restricted. In some embodiments, the combination therapy / composition and a concomitant anti-cancer agent are administered to an individual simultaneously. In other embodiments, the combination therapy / composition and a concomitant anti-cancer agent are administered at staggered times.

[0417] An anti-cancer agent includes but is not limited to a chemotherapeutic agent, immunotherapeutic agent, a pharmaceutical agent that inhibits the action of cell growth factor and a receptor thereof and the like. Among the chemotherapeutic agents that are optionally employed, by way of non-limiting example, are cisplatin, carboplatin, paclitaxel, gemcitabine or doxorubicin. Further, non-limiting examples of chemotherapeutic agents include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.

[0418] Alkylating agents include but are not limited to nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin, and the like.

[0419] Antimetabolites include but are not limited to mercaptopurine, 6- mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, and the like), aminopterine, leucovorin calcium, tabloid, butocine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine,Attorney Docket No.01309-0023-00PCT mitoguazone, thiazophrine, ambamustine and the like.

[0420] Anticancer antibiotics include but are not limited to actinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and the like.

[0421] Plant-derived anticancer agents include but are not limited to etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and the like.

[0422] Immunotherapeutic agents include but are not limited to picibanil, krestin, sizofuran, lentinan, ubenimex, interferons, interleukins, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, and the like.

[0423] Non-limiting examples of a cell growth factor in pharmaceutical agents that inhibit the action of cell growth factors or cell growth factor receptors include any substances that promote cell proliferation, which are normally peptides having a molecular weight of not more than 20,000 that are capable of exhibiting their activity at low concentrations by binding to a receptor, including (1) EGF (epidermal growth factor) or substances possessing substantially the same activity as it [e.g., EGF, heregulin, and the like], (2) insulin or substances possessing substantially the same activity as it [e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2, and the like], (3) FGF (fibroblast growth factor) or substances possessing substantially the same activity as it [e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10, and the like], (4) other cell growth factors [e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), and the like], and the like.

[0424] Cell growth factor receptors include but are not limited to any receptors capable of binding to the aforementioned cell growth factors, including EGF receptor, heregulin receptor (HER2), insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2, and the like.

[0425] Pharmaceutical agents that inhibit the action of cell growth factor include but are not limited to HER2 antibody (e.g., trastuzumab), imatinib mesylate, ZD1839 or EGFRAttorney Docket No.01309-0023-00PCT antibody (e.g., cetuximab), antibody to VEGF (e.g., bevacizumab), VEGFR antibody, VEGFR inhibitor, and EGFR inhibitor (e.g., erlotinib).

[0426] In addition to the aforementioned drugs, other anti-cancer agents include but are not limited to L-asparaginase, aceglatone, procarbazine hydrochloride, protoporphyrin- cobalt complex salt, mercuric hematoporphyrin-sodium, topoisomerase I inhibitors (e.g., irinotecan, topotecan, and the like), topoisomerase II inhibitors (e.g., sobuzoxane, and the like), differentiation inducers (e.g., retinoid, vitamin D, and the like), α-blockers (e.g., tamsulosin hydrochloride, naftopidil, urapidil, alfuzosin, terazosin, prazosin, silodosin, and the like) serine / threonine kinase inhibitor, endothelin receptor antagonist (e.g., atrasentan, and the like), proteasome inhibitor (e.g., bortezomib, and the like), Hsp 90 inhibitor (e.g., 17- AAG, and the like), spironolactone, minoxidil, 11α-hydroxyprogesterone, bone resorption inhibiting / metastasis suppressing agent (e.g., zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid) and the like.

[0427] Non-limiting examples of hormonal therapeutic agents include fosfestrol, diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, gestrinone, nomegestrol, Tadenan, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti-estrogens (e.g., tamoxifen citrate, toremifene citrate, and the like), ER down-regulator (e.g., fulvestrant and the like), human menopausal gonadotrophin, follicle stimulating hormone, pill preparations, mepitiostane, testrolactone, aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin, and the like), droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, retrozole, exemestane, vorozole, formestane, and the like), anti-androgens (e.g., flutamide, bicartamide, nilutamide, and the like), 5α-reductase inhibitors (e.g., finasteride, dutasteride, epristeride, and the like), adrenocorticohormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, and the like), androgen synthesis inhibitors (e.g., abiraterone, and the like), and retinoid and drugs that retard retinoid metabolism (e.g., liarozole, and the like), etc. and LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin).

[0428] The non-drug therapy is exemplified by surgery, radiotherapy, gene therapy, thermotherapy, cryotherapy, laser cauterization, and the like, and any combinations thereof. Dosing and Treatment Regiments

[0429] In one embodiment, the inhibitors and agents described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for theAttorney Docket No.01309-0023-00PCT treatment of diseases or conditions. Methods for treating any of the diseases or conditions described herein in an individual in need of such treatment, involve administration of pharmaceutical compositions described herein to said individual.

[0430] In certain embodiments, the compositions described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0431] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0432] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds is administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. EXAMPLES

[0433] The following example is provided for illustrative purposes only and not to limit the scope of the claims provided herein. AbbreviationsAttorney Docket No.01309-0023-00PCT

[0434] Unless otherwise specified, abbreviations shall be understood to have the common meaning in the fields of medicine, medicinal chemistry, and pharmacology. Scientific units and elements may be abbreviated in the following examples according to standard convention in art without being explicitly defined herein. Other abbreviations used throughout the working examples generally have the meanings provided below, unless otherwise specified (i.e., by subscript or by context). API = active pharmaceutical ingredient AUC = area under the curve BA = benzyl alcohol (or BnOH) BB = benzyl benzoate Cmax = maximum concentration achieved d-5 = d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol HPLC = high pressure liquid chromatography IM = intramuscular IV = intravenous EDTA = ethylenediaminetetraacetic acid LC = liquid chromatography LIPO = liposomal formulation MS = mass spectrometry PEG = polyethylene glycol PBS = phosphate buffered saline PK = pharmacokinetics rpm = revolutions per minute RT = room temperature SC = subcutaneous T(0) = initial time Compounding Procedures Preparation of Vehicles

[0435] Vehicle 01 - 2 / 7 / 1 (w / w / w) EtOH / PEG-300 / BA

[0436] Approximately 40 g of ethanol is weighed into a suitable container with a cap and the weight is recorded. Approximately 140 g of PEG-300 is weighed into the same container and the weight recorded. Approximately 20 g of benzyl alcohol is weighed into the same container, and the weight is recorded. The bottle is mixed by shaking.Attorney Docket No.01309-0023-00PCT

[0437] Vehicle 02 - 0.5% (w / v) povidone K30 in 2 / 7 / 1

[0438] Approximately 100 mg of Povidone K30 is weighted into a suitable container. A graduated cylinder is used to transfer 20 mL of 2 / 7 / 1 (w / w / w) Ethanol / PEG-300 / Benzyl Alcohol into the same container. The mixture is vortexed for 30 seconds, or until all solids have completely dissolved.

[0439] Vehicle 03 - 3 mg / mL sorbitan monolaurate in 2 / 7 / 1

[0440] Approximately 60 mg of sorbitan monolaurate is weighed into a suitable container. A graduated cylinder is used to transfer 20 mL of 2 / 7 / 1 (w / w / w) Ethanol / PEG- 300 / Benzyl Alcohol into the same container. The mixture is vortexed for 30 seconds, or until all solids have completely dissolved. Preparation of Formulations of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol (“d-5”)

[0441] General Compounding Procedure: Approximately 350 mg of Compound d-5 is weighed and transferred into a 5 mL volumetric flask, and approximately 1 mL (or 20% of the total volume) of vehicle (e.g., Vehicle 01, 02, or 03) is added and gently swirled to pre- wet solids. The solvent-mixture is diluted to volume with remaining vehicle. A stir-bar is added to the flask and stirred until Compound d-5 is dissolved (~1 hr). The flask is inverted several times before filtering through a Pall Acrosdisc 25 mm Nylon Syringe Filter, 0.2 µm, (or similar) prior to dosing. Solubility Studies Example 1: Solubility of Compound d-5 in Formulations F01 – F10.

[0442] Equilibrium solubility (via concentration analysis by HPLC) of compound d-5 (d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol) in ten (10) vehicles (24-hours, 25°C, 200 rpm) is presented in Table 1. Visual observations of supernatant of formulations after 24-hours at 2-8°C and room temperature, are presented in Table 2. Samples were prepared by adding vehicle / mixtures to d-5 at saturated conditions. Samples were monitored after initial mixing to maintain an excess of d-5 in the sample solution (i.e., additional drug substance was added if solids completely dissolved at the first targeted concentration). The solubility of d-5 in ten vehicles / mixtures was determined after shaking at 200 rpm for twenty-four hours at 25°C. After thirty minutes of temperature-controlled centrifugation, the supernatant was collected. A portion of the supernatant was diluted for analysis by HPLC, and another portion of the supernatant was transferred into an autosampler vial for visual solubility assessment after twenty-four hours at 2 – 8 °C.Attorney Docket No.01309-0023-00PCT Table 1. Vehicle Compositions and Solubilities for Formulations F01 – F10Table 2. Visual Observations – 24 Hours Stability of Supernatants F01 - F10Attorney Docket No.01309-0023-00PCTExample 2: Solubility of Compound d-5 in Formulations F11 – F25.

[0443] Formulations F11 – F25 were prepared by dissolving d-5 in the vehicle with the composition as specified in Table 3. The solubility of d-5 was determined as above.

[0444] Equilibrium solubility (via concentration analysis by HPLC) of compound d-5 in fifteen (15) vehicles (24-hours, 25°C, 200 rpm) is presented in Table 3. Visual observations of supernatant of formulations after 24-hours at 2-8°C and room temperature, is presented in Table 4. Samples were prepared by adding vehicle / mixtures to d-5 at saturated conditions, as described previously. Samples were monitored after initial mixing to maintain an excess of d-5 in the sample solution (i.e., additional drug substance was added if solids completely dissolved at the first targeted concentration). The solubility of d-5 was determined after shaking at 200 rpm for twenty-four hours at 25°C. After thirty minutes of temperature- controlled centrifugation, the supernatant was collected. A portion of the supernatant was diluted for analysis by HPLC, and another portion of the supernatant was transferred into an autosampler vial for visual solubility assessment after twenty-four hours at 2 – 8 °C. Table 3. Vehicle Compositions and Solubilities for Formulations F11 – F25Attorney Docket No.01309-0023-00PCTTable 4. Visual Observations – 24 Hours Stability of Supernatants F11 – F25Example 3: Syringeability Analysis.

[0445] Qualitative analysis of Compound d-5 intramuscular (IM) formulations and subcutaneous (SC) suspensions, syringe-loading and dispensing (“syringeability”) is presented in Table 5. Table 5. Qualitative assessment of IM and SC needles (“syringeability”)Attorney Docket No.01309-0023-00PCTExample 4: Preparation and Filter Interference Testing of Formulations F26 – F29.

[0446] F26 - F29 are prepared by dissolving 70 mg d-5 per 1 mL of vehicle listed in Table 6. Table 6. Vehicle Composition and Dose Concentration of Formulations F26 – F29Filter Interference

[0447] Data from a filter interference assay for formulations F26 – F28 are presented in Table 7. Table 7. Percent difference between filtrate (Pall® / Acrosidisc 25 mm Nylon Syringe Filter, 0.2 µm) and centrifuged sample [70 mg / mL]Attorney Docket No.01309-0023-00PCT

[0448] Samples were prepared for analysis by diluting 10 μL of filtrate / supernatant in 990 μL of ethanol diluent to achieve a target concentration of 0.7 mg / mL as d-5. Stability Studies Example 5: Stability Testing of Compound d-5 Formulations F26 – F29.

[0449] Assay and impurities analysis by HPLC of four (4) formulations stored in centrifuge tubes at room temperature, 40°C, and 2-8°C, was performed. Assay values for the first 3 formulations did not significantly change and individual impurities changed by not more than 0.2% from T(0) up to 48 hours at all storage conditions. Assay values for the formulation in sesame oil were not reproducible; no stability trend was observed. Results are presented in Tables 8 - 14. Table 8. Concentration Analysis of Formulation F26Table 9. Impurities (%AUC) – Formulation F26Attorney Docket No.01309-0023-00PCT Table 10. Concentration Analysis of Formulation F27Table 11. Impurities (%AUC) – Formulation F27Table 12. Concentration Analysis of Formulation F28Table 13. Impurities (%AUC) - Formula F28Attorney Docket No.01309-0023-00PCTTable 14. Concentration Analysis of Formulation F29Pharmacokinetics Studies of Compound d-5 in Mice and Rats Example 6: Preparation of Dosing Formulations F28 and F30 for Subcutaneous Administration to Sprague Dawley Rats.

[0450] Compound d-5 is formulated into Formulation F28 and F30 based on the amounts and compositions set forth in Table 15. Table 15. Vehicle Composition and Dose Concentration of Formulations F28 and F30Attorney Docket No.01309-0023-00PCTPreparation of Formulation F28

[0451] An amount of 200 g of Vehicle 01 (2 / 7 / 1 (w / w / w) Ethanol / PEG-300 / Benzyl Alcohol) is prepared by combining 40g of ethanol, 140 g of PEG-300, and 20 g of benzyl alcohol into a container and mixing by shaking. To prepare Formulation F28 at a dosage concentration of 70 mg Compound d-5 per 1 mL vehicle, 750 mg of Compound d-5 is weighed into a suitable container. Approximately 20% of the total volume of Vehicle 01 is added to pre-wet solids, and the mixture is swirled. The remaining volume is added, and the mixture is stirred with magnetic stirring for 1 hr. The solution is inverted to ensure mixing and filtered through a Pall Acrodisc 25 mm Nylon Syringe Filter, 0.2 µm, before dosing. Preparation of Formulation F30

[0452] An amount of 350 mg of d-5 is weighed in a suitable container and diluted in approximately 20% of the total volume of Vehicle 01 (i.e., 1 mL). After swirling gently to pre-wet, the remaining volume (i.e., 4 mL) is added and the mixture stirred for ~1 hour. The 70 mg / mL solution is inverted to ensure mixing then filtered. Example 7: Assessment of Pharmacokinetics of Compound d-5 Following Subcutaneous Dose Administration of Formulation F28 and F30 to Male C56BL / 6 Mice.

[0453] Male C57BL / 6 mice, ~25-30g, are received from an approved vendor and allowed to acclimate to the Test Facility for at least 2 days prior to the start of the study. Fasting is not required for this study. Body weights are recorded prior to dose administration and weekly. The volume of each dose delivered (mL / kg) is based on each individual animal’s body weight. Doses (as assigned above) will be administered in accordance with test facility standard operating procedures. Doses are administered on Day 0.

[0454] Test article is administered subcutaneously using a polypropylene syringe with a 23G needle. All dose syringes are weighed prior to and following dosing to gravimetrically determine the amount of formulation administered. All animals are observed at dosing and each scheduled collection. All abnormalities are recorded. If the animal is observed to be moribund, a terminal blood is collected following Study Director or Test FacilityAttorney Docket No.01309-0023-00PCT Veterinarian approval. The sponsor is notified as soon as possible of any observations or actions.

[0455] 12 subjects are enrolled in the study, into 3 groups. Group 1 (4 mice) is subcutaneously administered Compound d-5 Formulation F30 at a dose level of 750 mg / kg (5 mL); Group 2 (4 mice) is administered Compound d-5 Formulation F28 at a dose level of 750 mg / kg of d-5 (10.71 mL of Formulation 28); and Group 3 (4 mice) is subcutaneously administered Compound d-5 Formulation F28 at a dose level of 375 mg / kg of d-5 (5.357 mL of Formulation 28). Table 16. Study Design for Assessing PK of Compound d-5 following SC Dosing in C56BL / 6 Mice

[0456] Blood samples are collected via tail vein snip. Serial blood sample collection (vol.250 μL) is performed at the following intervals: 1h, 4h, 8h, 24h, 48h, 72h, 96h, 168h, 240h, 336h, 408h, 504h, 600h, and 672h. All blood collection sites are documented. Blood samples are collected into tubes with anticoagulant. Tubes are stored on wet ice until processed to plasma by centrifugation (3500 rpm at 5 °C for 10 minutes) within 30 minutes of collection. Plasma is transferred into individual uniquely labeled matrix tubes and stored at nominal -80 °C until transferred to analytical chemistry for analysis. Week One plasma is analyzed following the Day 7 collection prior to study completion. Remaining plasma samples are stored at nominal -80 °C until analysis until transferred to analytical chemistry for analysis. Example 8: Assessment of Pharmacokinetics of Compound d-5 Following Intravenous and Intramuscular Dose Administration of Formulations F31 – F38 to Male Sprague Dawley Rats.

[0457] Formulations F31 – F38 of Compound d-5 were prepared and administered intravenously or intramuscularly to eight groups of Sprague Dawley rats (4 animals perAttorney Docket No.01309-0023-00PCT group). Formulation F31 is a liquid formulation of Compound d-5 in 10% Captisol, while F32 – F37 represent 6 different liposomal formulations of d-5 (MP37, MP39, MP43, MP44, MP46, and MP47 respectively). Formulation F38 is an intramuscular formulation of d-5 in 4.5 / 4.5 / 1 (w / w / w) PEG300 / EtOH / BnOH. The compositions of formulations F31-F38 are provided in Table 17. Table 17. Composition of Formulations F31 – F38

[0458] Serial blood samples were collected from each animal at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after dosing for Groups 1-8 and an additional 48 hour post dose sample was collected from each animal of Groups 2-8. Group 9 terminal blood was collected as a pre- dose sample. Blood samples were collected into tubes containing K2EDTA and then processed for plasma. Plasma from Group 9 was aliquoted into 3 separate 500 µL samples and spiked with 5,12.5 or 50 µL of the MP39 formulation F33. Plasma samples from Groups 1-8 were analyzed for d-5 using a LC-MS / MS method and spiked plasma from Group 9 was used for method development only. Non-compartmental pharmacokinetic parameter estimates were calculated from the plasma concentration-time data for each animal in Groups 1-8.Attorney Docket No.01309-0023-00PCT

[0459] Animals were observed for any clinically relevant abnormalities during dosing and at each sample collection period. Edema was observed at the intramuscular dose site of the Group 8 animals at 24 hours post dose, but subsided by 48 hours.

[0460] Formulation F38 (4.5 / 4.5 / 1(w / w / w)PEG300 / EtOH / BnOH) administered at 35 mg / kg intramuscularly had a plasma exposure of 9980 h*ng / mL 0-48 H (AUC0-48). Cmax was 640 ng / mL, 3h post dose with the terminal half-life occurring after 10.5 hours. Dose Formulation

[0461] Group 1: The dose formulation was prepared at a target concentration of 10 mg / mL.3.227 g of 35 mg / mL stock solution of d-5 in 30% w / v Captisol was diluted with 7.171 g of 0.9% saline. The vehicle for Goup 8 was prepared by slowly adding PEG-300 to Ethanol in a glass bottle. Benzyl alcohol was slowly added and mixed. The dose formulation was prepared at a target concentration of 70 mg / mL. The formulation was sterile filtered through 0.22 µm nylon membrane. The final formulation was a clear pale yellow liquid and stored refrigerated at 2-8 °C. Dose Administration

[0462] Prior to dosing, the body weight of each animal was recorded. Compound d-5 was administered at a target dose level of 35 mg / kg for Group 1, and at a target dose level of 3.5 mg / kg for Groups 2-7. Formulation F38 was administered at a target dose level of 35 mg / kg for Group 8 by intramuscular injection. Doses (rounded to the nearest 0.01 mL) were calculated based on the pretreatment body weight (kg). Dosing syringes were weighed immediately prior to and immediately after dosing each animal, and the quantity of formulation administered to each animal was determined from the difference in syringe weights.

[0463] Intravenous doses for Groups 1-7 were administered once as a bolus injection through an indwelling jugular vein cannula. Catheters were flushed with 0.5 mL of saline immediately after dosing and tied off to prevent re-access.

[0464] Intramuscular dose for Group 8 was administered using an appropriately sized polypropylene syringe with a 23 G sized needle into the quadricep after anesthetizing the animals using isoflurane. The actual amount of formulation administered was determined by weighing syringes immediately prior to and immediately after use for each animal. Sample Collection

[0465] Serial blood samples (~0.25 mL per sample) were collected from each animal at 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose for Groups 1-8 and an additional 48 hour post dose sample was collected from each animal of Groups 2-8. Samples were collected, viaAttorney Docket No.01309-0023-00PCT jugular vein cannula, into tubes containing K2EDTA. Blood samples were stored on wet ice until processed to plasma by centrifugation (3500 rpm at 5 °C for 10 minutes) within 30 minutes of collection. Plasma samples aliquots were transferred into individual uniquely labeled matrix tubes and then stored in a -70 °C freezer until transferred for analysis. Pharmacokinetic Analysis

[0466] Male Sprague Dawley rat plasma samples were analyzed for d-5 using a LC- MS / MS method. Pharmacokinetic parameter estimates were calculated from the individual animal d-5plasma concentration-time data using the actual dose based on the analysis of the dosing formulations, nominal sampling times, and non-compartmental methods. The concentration-time data were analyzed to fit either an intravenous – bolus plasma analysis model or extravascular dosing plasma analysis model using the software Phoenix WinNonlin (Pharsight). The single-dose pharmacokinetic parameters assessed include, as appropriate: Cmax(observed peak or maximum concentration); Tmax(observed time of peak concentration); T½ (terminal half-life); Vz (volume of distribution based on the terminal phase); Vss (volume of distribution at steady state); AUCinf (area under the concentration-time curve computed from time zero to infinity); AUClast(area under the concentration-time curve computed from time zero to the time of the last quantifiable concentration); C0(back-extrapolated concentration at time zero); Cl (total body clearance); Vz / F (volume of distribution for extravascular administration based on the terminal phase); Cl / F (total body clearance for extravascular administration); F (bioavailability); and MRTlast (mean residence time).

[0467] Areas-under-the-plasma concentration-time curves (AUC) were estimated using the linear-log trapezoidal rule. The area through the time (Tlast) of the last observable concentration (Clast) is reported as AUClast. AUC extrapolated to infinity, (AUCinf) was estimated by adding AUClast and the ratio of Clast / λz, where λ z is the terminal rate constant. Apparent terminal half-life (T1 / 2) was calculated as ln(2) / λz and determined using the slope of the log-linear terminal phase of the concentration-time curve, defined by a minimum of three plasma concentration-time points. Half-lives are reported if the correlation for the regression line, as measured by r squared, is ≥ 0.9 when rounded. After IV administration, volume of distribution (Vz) was calculated as Dose / λz* AUCinf, clearance (Cl) was calculated as Dose / AUCinf and volume of distribution at steady state (Vss) was estimated as MRTinf*Cl. Mean residence time (MRT) from the time of dosing to the time of the last measurable concentration was calculated as AUClast / AUClast. For the extravascular model, the bioavailability (i.e. fraction of total dose that reaches the systemic circulation) cannot be calculated. Consequently, volume and clearance for this model is Vz / F or Cl / F, respectively;Attorney Docket No.01309-0023-00PCT where F is defined as bioavailability (i.e. fraction of total dose that reaches the systemic circulation; (Average AUClast-po / Average AUClast-iv)*[DoseIV / DosePO]*100). Pharmacokinetics Data for Formulations F31 – F38

[0468] Formulation F31, administered at 35mg / kg intravenously, had a mean plasma exposure of 1280 h*ng / mL from 0-8 h (AUC0-8) and 13500 h*ng / mL from 0-24 h (AUC0-24). The Cmaxfor d-5 averaged 13600 ng / mL at 0.25h post dose with the terminal half-life occurring after 3.55 hours. The mean clearance rate was 43.7 ml / min / kg and the volume of distribution was 3.12 L / kg.

[0469] A total of 6 different liposome formulations were administered IV at a 10-fold decrease of the API at 3.5 mg / kg (relative to F31 at 35 mg / kg). Tmaxaveraged 0.25h for all IV liposome formulations of Compound d-5, and Tlast ranged from 8-24h. Groups 2 and 3 had a Tlast of 24h and Groups 4-7 had a Tlast of 8h. Mean Cmax ranged from 357-920 ng / mL for the IV liposome formulations, and all were under-proportional to dose compared to the API, Compound d-5 (30% Captisol) dosed intravenously at 35 mg / kg. Half-life for IV d-5 liposome formulations ranged from 1.5h - 6.75 h.

[0470] Plasma exposure AUC0-8ranged from 517-1150 h*ng / mL for the liposome formulations. AUC0-24for groups 2 and 3 were 1240 and 1180 h*ng / mL, respectively.

[0471] AUC0-24 values for groups 2 and 3 as well as AUC0-8 values for Groups 2, 3 and 5 were all proportional to dose compared to Group 1 (F31) and Groups 4, 6 and 7 were all under-proportional to dose compared to Group 1. d-5liposome clearance ranged from 47.7-111 ml / min / kg and volume of distribution ranged from 3.93-10.2 L / kg.

[0472] Intramuscular formulation F38, dosed at 35 mg / kg, provided a plasma exposure of 9980h*ng / mL 0-48h (AUC0-48). Cmaxwas 640 ng / mL, 3h post-dose with the terminal half-life occurring after 10.5 hours.

[0473] d-5 formulated in 10% Captisol and administered intravenously at 35 mg / kg had a mean exposure of 13500 h*ng / mL over 24 h and 12800 h*ng / mL over 8 h. When dose normalized, comparable exposure was seen in 3 / 6 liposome formulations: F32, F33, F35. Formulation F34 and F36 had a 2-fold lower exposure when compared to d-5 formulated in 10% Captisol, and F38 was about 1.5-fold lower.

[0474] Formulation F38 administered at 35 mg / kg intramuscularly had a plasma exposure of 9980 h*ng / mL over the duration of 48 h. Cmax was 640 ng / mL, 3 h post-dose with the termial half-life occurring after 10.5 h.

[0475] The plasma concentrations of Compound d-5 are illustrated in FIG.2. The liposomal formulations F32-F37 achieve plasma concentrations lower than that of the 10%Attorney Docket No.01309-0023-00PCT Captisol formulation, F31. Notably, the intramuscular formulation F38 plasma concentrations remained above 100 ng / mL after 24 h, whereas formulations F31-F37 resulted in plasma concentrations of 10% or less after 24 h. Example 9: Assessment of the Pharmacokinetics of Compound d-5 Following Intramuscular and Subcutaneous Dose Administration of Formulations F40 – F45 to Male Sprague Dawley Rats.

[0476] Formulations F40-F45 were prepared and administered intramuscularly or subcutaneously to six groups of Sprague Dawley rats (4 animals per group). Formulations F40-F43 are intramuscular formulations, while F44 and F45 are subcutaneous formulations. The compositions of formulations F40-F45 are provided in Table 18. Table 18. Composition of Formulations F40 – F45

[0477] Serial blood samples were collected from each animal at 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 96, 168, 240, 336, 408, and 504 hours after dosing. Samples were collected, via jugular vein cannula, into tubes containing K2EDTA and then processed for plasma. Plasma samples were analyzed for Compound d-5 using an LC-MS / MS method. Non-compartmental pharmacokinetic parameter estimates were calculated from the plasma concentration-time data for each animal.

[0478] Animals were observed for any clinically relevant abnormalities during dosing and at each sample collection period. A total of 3 animals were euthanized due to a body weight loss exceeding 20%. One animal from group 4 was found deceased 20 days post-dose.Attorney Docket No.01309-0023-00PCT Dose Formulation

[0479] Group 1: The dose formulation was prepared at a target concentration of 70 mg / mL by combining d-5 (350 mg) and 20% vehicle (1.028 g). The formulation was vortex mixed. Additional 80% vehicle (4.130 g) was added for a total volume of 5 mL. A magnetic stir bar was added to the container and sterile filtered through 0.22µm nylon membrane. The formulation was a clear liquid.

[0480] The vehicle, 2 / 7 / 1 (w / w / w) Ethanol / PEG-300 / Benzyl Alcohol, was prepared by slowly adding Ethanol (20.013 g) to PEG-300 (70.030 g) in a glass bottle. Benzyl alcohol (10.005 g) was slowly added to the solution mixture. The mixture was stirred by inversion and vortexed for homogeneity.

[0481] Group 2: The dose formulation was prepared at a target concentration of 70 mg / mL by combining d-5 (350 mg) and 20% vehicle (1.037 g). The formulation was vortex mixed. Additional 80% vehicle (4.080 g) was added for a total volume of 5 mL. A magnetic stir bar was added to the container and sterile filtered through 0.22µm nylon membrane. The formulation was a clear liquid.

[0482] The vehicle, Povidone K30 (0.5% w / v) in 2 / 7 / 1 (w / w / w) Ethanol / PEG- 300 / Benzyl Alcohol, was prepared by slowly adding Povidone K30 (0.100 g) to 2 / 7 / 1 (w / w / w) Ethanol / PEG-300 / Benzyl Alcohol (20.684 g) in a container. The mixture was stirred by inversion and vortexed for homogeneity.

[0483] Group 3: The dose formulation was prepared at a target concentration of 70 mg / mL by combining d-5 (350 mg) and 20% vehicle (1.031 g). The formulation was vortex mixed. Additional 80% vehicle (4.086 g) was added for a total volume of 5 mL. A magnetic stir bar was added to the container and sterile filtered through 0.22µm nylon membrane. The formulation was a clear liquid.

[0484] The vehicle, Sorbitan monolaurate (3 mg / mL) in 2 / 7 / 1 (w / w / w) Ethanol / PEG- 300 / Benzyl Alcohol, was prepared by adding Sorbitan monolaurate (0.060 g) to 2 / 7 / 1 (w / w / w) Ethanol / PEG- 300 / Benzyl Alcohol (20.670g) in a container. The mixture was stirred by inversion and vortexed for homogeneity.

[0485] Group 4: The dose formulation was prepared at a target concentration of 70 mg / mL by combining d-5 (350 mg) and 20% vehicle (0.924 g). The formulation was vortex mixed. Additional 80% vehicle (3.757 g) was added for a total volume of 5 mL and sterile filtered through 0.22µm nylon membrane. The formulation was a clear liquid.

[0486] The vehicle, 4.5 / 4.5 / 1 (w / w / w) Ethanol / PEG-300 / Benzyl Alcohol, was prepared by slowly adding Ethanol (9.002 g) to PEG-300 (9.000 g) in a glass bottle. BenzylAttorney Docket No.01309-0023-00PCT alcohol (1.999 g) was slowly added to the solution mixture. The mixture was stirred by inversion for homogeneity.

[0487] Group 5: The dose formulation was prepared at a target concentration of 70 mg / mL by combining d-5 (350 mg) and 20% vehicle (1.034 g). The formulation was hand mixed and vortexed. Additional 80% vehicle (4.127 g) was added for a total volume of 5 mL. A magnetic stir bar was added to the container and sterile filtered through 0.22µm nylon membrane. The formulation was a clear liquid.

[0488] The vehicle, 2 / 7 / 1 (w / w / w) Ethanol / PEG-300 / Benzyl Alcohol, was prepared by slowly adding Ethanol (20.013 g) to PEG-300 (70.030 g) in a glass bottle. Benzyl alcohol (10.005 g) was slowly added to the solution mixture. The mixture was stirred by inversion and vortexed for homogeneity.

[0489] Group 6: The dose formulation was prepared at a target concentration of 20 mg / mL by combining d-5 (100 mg) and 20% vehicle, deionized water (0.995 g). The formulation was hand mixed and vortexed. Additional 80% vehicle (3.981 g) was added for a total volume of 5 mL. A magnetic stir bar was added to the container and was stirred during treatments. The final formulation was a hazy white uniform suspension. Dose Administration

[0490] Animal fasting was not required. Water was provided ad libitum. Prior to dosing, the body weight of each animal was recorded. Compound d-5 was administered at a target dose level of 35 mg / kg. Doses (rounded to the nearest 0.01 mL) were calculated based on the pretreatment body weight (kg). Intramuscular dose for Groups 1-4 was administered using an appropriately sized polypropylene syringe with a 23 G sized needle into the quadricep after anesthetizing the animals using isoflurane. Subcutaneous dose for Groups 5 and 6 was administered using an appropriately sized polypropylene syringe with a 23 G (Group 5) or 21G (Group 6) sized needle to the subcutaneous space in the shaved interscapular region. The actual amount of formulation administered was determined by weighing syringes immediately prior to and immediately after use for each animal. Pharmacokinetic Analysis

[0491] Male Sprague Dawley rat plasma samples were analyzed for Compound d-5 using a LC-MS / MS method. Non-compartmental pharmacokinetic parameter estimates were calculated from the individual animal d-5 concentration-time data using Phoenix WinNonlin (Pharsight) using nominal times. The single-dose pharmacokinetic parameters assessed include, as appropriate: maximum concentration (Cmax); time of maximum observed concentration (Tmax); terminal half-life (T½); area under the concentration-time curve fromAttorney Docket No.01309-0023-00PCT time zero to the last quantifiable concentration (AUClast); and area under a concentration-time curve from time zero extrapolated to infinity (AUCinf).

[0492] Areas-under-the-plasma concentration-time curves (AUC) were estimated using the linear trapezoidal rule. The area through the time (Tlast) of the last observable concentration (Clast) is reported as AUClast. Area under the curve extrapolated to infinity, (AUCinf) was estimated by adding AUClastand the ratio of Clast / λz, where λ z is the terminal rate constant. Apparent terminal half-life (T1 / 2) was calculated using the slope of the log- linear terminal phase of the concentration-time curve, defined by a minimum of three plasma concentration-time points. Half-lives were reported if the correlation for the regression line, as measured by r squared, was ≥ 0.9, when rounded. Pharmacokinetics Data for Formulations F40 – F45

[0493] Mean plasma concentration of Compound d-5 following intramuscular and subcutaneous administration of Formulations F40 – F45 to male Sprague Dawley rats are reported in FIG.3. Mean pharmacokinetic parameter estimates for Compound d-5 in plasma following intramuscular and subcutaneous administration of Formulations F40 – F45 to male Sprague Dawley Rats are reported in Table 19. Table 19. Estimated pharmacokinetic parameters of Compound d-5 following intramuscular and subcutaneous administration of Compound d-5 Formulations F40 – F45Attorney Docket No.01309-0023-00PCT

[0494] Four intramuscular and two subcutaneous formulations of Compound d-5 were administered into male Sprague Dawley rats at a dose level of 35mg / kg. Compound d-5 formulated in 2:7:1 EtOH / PEG 300 / Benzyl Alcohol and administered intramuscularly at 35mg / kg (Group 1) resulted in a mean Cmax of 630±175 ng / mL after 3.0 hours (Tmax), a Tlast of 504 hours ranging from 336-504 hours post dose, and a half-life (T1 / 2) of 197±114 hours. Exposure levels of d-5 averaged 12200±1040 hr*ng / ml for AUC0-∞.

[0495] Compound d-5 formulated in 0.5% Povidone K30 and 2:7:1 EtOH / PEG 300 / Benzyl Alcohol and administered intramuscularly at 35 mg / kg (Group 2) resulted in a mean Cmaxof 594±81.5 ng / mL after 2.0 hours (Tmax), a Tlastof 288 hours ranging from 168-504 hours post dose, and a half-life (T1 / 2) of 126±105 hours. Exposure levels of Compound d-5 averaged 10200±979 hr*ng / ml for AUC0-∞. Compound d-5 formulated in 3mg / mL Sorbitan Monolaurate and 2:7:1 EtOH / PEG 300 / Benzyl Alcohol and administered intramuscularly at 35mg / kg (Group 3) resulted in a mean Cmaxof 825±128 ng / mL after 4.0 hours (Tmax), a Tlastof 132 hours ranging from 72-504 hours post dose, and a half-life (T1 / 2) of 117±194 hours. Exposure levels of d-5 averaged 12600±2320 hr*ng / ml for AUC0-∞.

[0496] Compound d-5 formulated in 4.5:4.5:1 EtOH / PEG 300 / Benzyl Alcohol and administered intramuscularly at 35mg / kg (Group 4) resulted in a mean Cmax of 478±97.1 ng / mL after 4.0 hours (Tmax), a Tlastof 504 hours ranging from 408-504 hours post dose, and a half-life (T1 / 2) of 277±64.1 hours. Exposure levels of d-5 averaged 11000±822 hr*ng / ml for AUC0-∞.

[0497] Compound d-5 formulated in 2:7:1 EtOH / PEG 300 / Benzyl Alcohol and administered subcutaneously at 35mg / kg (Group 5) resulted in a mean Cmaxof 845±136 ng / mL after 4.0 hours (Tmax), and a Tlast of 336 hours ranging from 72-336 hours post dose. A half-life could not be calculated due to the steady state behavior of the compound after 48H for animals 17, 18, 19 and 20. Mean exposure level of d-5 was 28100±13600 hr*ng / ml for AUClastand 15600±957 hr*ng / ml for AUC0-72. Compound d-5 formulated in water and administered subcutaneously at 35mg / kg (Group 6) resulted in a mean Cmax of 85.5±26.1 ng / mL after 2.0 hours (Tmax), and a Tlastof 408 hours ranging from 408-504 hours post dose. Half-life (T1 / 2) could only be determined for animals 21 and 22 and averaged 91.9±58.2 hours. Mean exposure levels of d-5 for animals 21 and 22 were 5020±1020 hr*ng / ml for AUC0-∞. Mean exposure level of d-5 for the entire group was 3950±1220 hr*ng / ml forAttorney Docket No.01309-0023-00PCT AUClast.

[0498] All four intramuscular formulations of Compound d-5 that were administered into male Sprague Dawley rats at a dose level of 35mg / kg had comparable exposure levels with mean AUC0-∞ ranging from 10200-12600 h*ng / mL. Mean Cmax ranged from 478-825 ng / mL, Tmax ranged from 2-4 hours and Tlast ranged from 132-504 hours. Half-life for the intramuscular administrations ranged from 117 hours with the 3mg / mL in Sorbitan Monolaurate, 2:7:1 EtOH / PEG 300 / Benzyl Alcohol formulation to 277 hours with the 4.5:4.5:1 EtOH / PEG 300 / Benzyl Alcohol formulation.

[0499] Compound d-5 formulated in 2:7:1 EtOH / PEG 300 / Benzyl Alcohol and administered subcutaneously at 35mg / kg resulted in a mean Cmax of 845±136 ng / mL after 4.0 hours (Tmax), and a Tlast of 336 hours ranging from 72-336 hours post dose. Mean exposure level of d-5 was 28100±13600 hr*ng / ml for AUClast. Compound d-5 formulated in water and administered subcutaneously at 35mg / kg resulted in a much lower Cmaxaverage of 85.5±26.1 ng / mL after 2.0 hours (Tmax), and a Tlast of 408 hours ranging from 408-504 hours post dose. Mean exposure levels of d-5 for animals 21 and 22 were 5020±1020 hr*ng / ml for AUC0-∞. Mean exposure level of d-5 for the entire Group 6 was 3950±1220 hr*ng / ml for AUClast.

[0500] Although Half-life (T1 / 2) could be determined for animals 21 and 22 in Group 6 and averaged 91.9±58.2 hours, an overall half-life could not be calculated for the subcutaneous administrations due to the steady state behavior of the compound after 48h. Concentration in Plasma of Compound...

Claims

Attorney Docket No.01309-0023-00PCT CLAIMS WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising: (a) about 5% to about 35% of ethanol by weight (w / w); (b) about 55% (w / w) to about 90% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; (c) about 1% (w / w) to about 15% (w / w) of benzyl alcohol; and (d) d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol (Compound d-5):.

2. The pharmaceutical composition of claim 1, comprising about 20% (w / w) of ethanol.

3. The pharmaceutical composition of claim 1 or 2, comprising about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400.

4. The pharmaceutical composition of any one of claim 1-3, comprising about 10% (w / w) of benzyl alcohol.

5. The pharmaceutical composition of claim 1, comprising: (a) about 20% (w / w) of ethanol; (b) about 70% (w / w) of polyethylene glycol 300 or polyethylene glycol 400; and (c) about 10% (w / w) of benzyl alcohol.

6. The pharmaceutical composition of any one of claims 1-5, further comprising about 0.1% to about 1% of Povidone K30 by weight / volume (w / v).

7. The pharmaceutical composition of any one of claims 1-6, further comprising about 1 mg / ml to about 5 mg / ml of sorbitan monolaurate.

8. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition is a liquid formulation.Attorney Docket No.01309-0023-00PCT 9. The pharmaceutical composition of any one of claims 1-8, comprising about 10 mg / ml to about 350 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol.

10. The pharmaceutical composition of any one of claims 1-9, comprising about 70 mg / ml of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol.

11. The pharmaceutical composition of any one of claims 1-10, wherein the pharmaceutical composition passes freely through an 18 gauge needle without clog.

12. The pharmaceutical composition of any one of claims 1-11, wherein the pharmaceutical composition is stable for at least about 1 day when the pharmaceutical composition is stored at about 0℃ to about 50℃, optionally wherein the pharmaceutical composition is considered stable when zero or an insignificant amount of precipitation is observed, and / or when an increase in an amount of an impurity is zero or insignificant.

13. The pharmaceutical composition of any one of claims 1-12, wherein the pharmaceutical composition provides a steady plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol after administration into a subject.

14. The pharmaceutical composition of any one of claims 1-13, wherein the pharmaceutical composition is administered subcutaneously or intramuscularly into a subject.

15. The pharmaceutical composition of any one of claims 1-14, wherein the pharmaceutical composition provides a half maximal plasma concentration of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 5 h to about 400 h (T1 / 2) after administration into a subject.

16. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical composition provides a maximal plasma concentration (Cmax) of d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol at about 2 h to about 10 h (Tmax) after administration into a subject.

17. The pharmaceutical composition of any one of claims 1-16, wherein the last quantifiable concentration of d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol is observed (TLAST) at a time that is about 50 h to about 500 h after administration of the pharmaceutical composition into the subject.Attorney Docket No.01309-0023-00PCT 18. A method for treating a disease associated with mitochondrial oxidative phosphorylation (OXPHOS), comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition of any one of claims 1-17.

19. A method for treating cancer comprising administering to a subject in need thereof an effective dose of the pharmaceutical composition of any one of claims 1-17.

20. The method of claim 19, wherein the cancer comprises colon cancer, rectal cancer, colorectal cancer (CRC), metastatic colorectal cancer (mCRC), non-metastatic colorectal cancer, refractory CRC, refractory mCRC, relapsed CRC, relapsed mCRC, relapsed or refractory CRC, relapsed or refractory mCRC, recurrent CRC, recurrent mCRC, breast cancer, metastatic breast cancer, metastatic HER2-negative breast cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung cancer, lung cancer, squamous non- small cell lung cancer, non-squamous non-small cell lung cancer, bladder cancer, endometrial cancer, cervical cancer, uterine cancer, ovarian cancer, kidney cancer, liver cancer, leukemia, melanoma, Lewis lung carcinoma, non-Hodgkin lymphoma, pancreatic cancer, testicular cancer, prostate cancer, thyroid cancer, sarcoma (including osteosarcoma), esophageal cancer, gastric cancer, head and neck cancer, lung cancer melanoma, myeloma, neuroblastoma, glioblastoma, or a brain cancer.

21. The method of any one of claims 18-20, wherein a second therapy is administered to the subject.

22. The method of any one of claims 18-21, wherein the subject is refractory, non- responsive, or resistant to a prior cancer therapy, or intolerant of the prior cancer therapy.

23. The pharmaceutical composition of any one of claims 1-17, or the method of any one of claims 18-22, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol comprises the d-cis isomer in at least 95% enantiomeric excess.

24. The method of any one of claims 18-23, wherein the d-cis-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol is administered at a dose of about 5 mg / kg to about 200 mg / kg.

25. The method of any one of claims 18-24, wherein the subject is human.

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