[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

US20190374550A1 - Quinolone analogs and their salts, compositions, and method for their use - Google Patents

Quinolone analogs and their salts, compositions, and method for their use Download PDF

Info

Publication number
US20190374550A1
US20190374550A1 US16/277,089 US201916277089A US2019374550A1 US 20190374550 A1 US20190374550 A1 US 20190374550A1 US 201916277089 A US201916277089 A US 201916277089A US 2019374550 A1 US2019374550 A1 US 2019374550A1
Authority
US
United States
Prior art keywords
compound
composition
pharmaceutically acceptable
months
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US16/277,089
Other languages
English (en)
Inventor
Hshiou-Ting Liu
John Soong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Senhwa Biosciences Inc
Original Assignee
Senhwa Biosciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Senhwa Biosciences Inc filed Critical Senhwa Biosciences Inc
Priority to US16/277,089 priority Critical patent/US20190374550A1/en
Assigned to SENHWA BIOSCIENCES, INC. reassignment SENHWA BIOSCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SOONG, JOHN, LIU, HSHIOU-TING
Publication of US20190374550A1 publication Critical patent/US20190374550A1/en
Priority to US17/394,541 priority patent/US11524012B1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

  • the present invention generally relates to fused naphthyridinone or quinolone analogs, pharmaceutical composition containing them, and methods of using them and a solid lyophilized composition of tetracyclic quinolone compounds or the salts and/or solvates of the tetracyclic quinolone compounds, pharmaceutical composition containing them, and methods of using them.
  • tetracyclic quinolone compounds or napththyridinone fused tetracyclic compounds have been suggested to function by interacting with quadruplex-forming regions of nucleic acids and modulating ribosomal RNA transcription. See, for example, U.S. Pat. Nos. 7,928,100 and 8,853,234.
  • the tetracyclic quinolone compounds can stabilize the DNA G-quadruplexes (G4s) in cancer cells and thereby induce synthetic lethality in cancer cells.
  • DSB formation induced by G4-stabilizing ligand/agent such as the tetracyclic quinolones
  • G4-stabilizing ligand/agent such as the tetracyclic quinolones
  • the tetracyclic quinolone compounds selectively inhibit rRNA synthesis by RNA polymerase I (Pol I) in the nucleolus, but do not inhibit mRNA synthesis by RNA polymerase II (Pol II) and do not inhibit DNA replication or protein synthesis.
  • RNA polymerase I RNA polymerase I
  • the p53 protein normally functions as a tumor suppressor by causing cancer cells to self-destruct.
  • Activating p53 to kill cancer cells is a well validated anticancer strategy and many approaches are being employed to exploit this pathway.
  • Selective activation of p53 in tumor cells would be an attractive method of treating, controlling, ameliorating tumor cells while not affecting normal healthy cells.
  • the aforementioned tetracyclic quinolones are disclosed in U.S. Pat. Nos. 7,928,100 and 8,853,234, and the contents of this publication are herein incorporated by reference in their entirety for all intended purposes.
  • a solid form an active pharmaceutical ingredient offers the best method for controlling important physiochemical qualities, such as stability, solubility, bioavailability, particle size, bulk density, flow properties, polymorphic content, and other properties.
  • important physiochemical qualities such as stability, solubility, bioavailability, particle size, bulk density, flow properties, polymorphic content, and other properties.
  • composition comprises less than about 1% impurities.
  • the pharmaceutical composition is a solid composition comprising a lyophilized Compound I or a pharmaceutically acceptable salt and/or solvate thereof.
  • the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for at least 28 days. In another embodiment, the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 28 days. In one embodiment, the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at room temperature for 28 days.
  • the pharmaceutical composition comprises less than 0.5% impurities after the composition is stored at room temperature for 42 days. In one embodiment, the pharmaceutical composition comprises less than about 0.4% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 28 days. In one embodiment, the pharmaceutical composition comprises less than 0.1% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 28 days; wherein the oxidation of Compound I is at one or more hydrocarbons.
  • the pharmaceutical composition comprises less than 0.1% of Compound 10 after the composition is stored at room temperature for 28 days.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 14 days; wherein the oxidation of Compound I is an N-oxide of Compound I. In one embodiment, the pharmaceutical composition comprises less than 0.2% of Compound 9 after the composition is stored at room temperature for 14 days.
  • the pharmaceutical composition comprises less than 0.1% impurities resulting from oxidation of Compound I after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for at least 28 days; wherein the oxidation of Compound I is at one or more hydrocarbons. In one embodiment, the pharmaceutical composition comprises less than 0.1% of Compound 10 after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for at least 28 days.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 14 days; wherein the oxidation of Compound I is an N-oxide of Compound I. In one embodiment, the pharmaceutical composition comprises less than 0.2% of Compound 9 after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 14 days.
  • the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for at least 1 month. In another embodiment, the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month. In one embodiment, the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at room temperature for 1 month.
  • the pharmaceutical composition comprises less than 0.5% impurities after the composition is stored at room temperature for 1 month. In one embodiment, the pharmaceutical composition comprises less than about 0.4% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 1 month. In one embodiment, the pharmaceutical composition comprises less than 0.1% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 1 month; wherein the oxidation of Compound I is at one or more hydrocarbons.
  • the pharmaceutical composition comprises less than 0.1% of Compound 10 after the composition is stored at room temperature for 1 month.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 1 month; wherein the oxidation of Compound I is an N-oxide of Compound I. In one embodiment, the pharmaceutical composition comprises less than 0.2% of Compound 9 after the composition is stored at room temperature for 1 month.
  • the pharmaceutical composition comprises less than 0.1% impurities resulting from oxidation of Compound I after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month; wherein the oxidation of Compound I is at one or more hydrocarbons. In one embodiment, the pharmaceutical composition comprises less than 0.1% of Compound 10 after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month; wherein the oxidation of Compound I is an N-oxide of Compound I.
  • the pharmaceutical composition comprises less than 0.2% of Compound 9 after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month.
  • the pharmaceutical composition comprises comprises less than about 1.0% impurities after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for about 36 months. In one embodiment, the pharmaceutical composition comprises less than 0.3% of Compound 10 after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for about 36 months. In one embodiment, the pharmaceutical composition comprises less than 0.2% of Compound 9 after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for about 36 months.
  • the pharmaceutical composition comprises less than about 1.2% impurities after the composition is stored at room temperature for about 36 months. In one embodiment, the pharmaceutical composition comprises less than 0.6% of Compound 10 after the composition is stored at room temperature for about 36 months. In one embodiment, the pharmaceutical composition comprises less than 0.3% of Compound 9 after the composition is stored at room temperature for about 36 months.
  • the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for about 24 months. In one embodiment, the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for about 12 months. In one embodiment, the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for about 6 months. In one embodiment, the pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for about 3 months.
  • the pharmaceutical composition is substantially free of an N-oxide impurity of Compound I.
  • the solution for lyophilizing composition comprises Compound I at a concentration greater than 15 mg/ml. In one embodiment, the solution for lyophilizing composition comprises Compound I at a concentration greater than 25 mg/ml.
  • the pharmaceutical composition is substantially free of an antioxidant. In one embodiment, the pharmaceutical composition is substantially free of ascorbic acid.
  • the composition upon reconstitution with a pharmaceutically acceptable diluent provides a pH ranging from about 4 to about 6. In one embodiment of the pharmaceutical composition, the composition upon reconstitution with a pharmaceutically acceptable diluent, provides a pH ranging from about 4 to about 5.5.
  • the pharmaceutical composition exhibits a differential scanning calorimetry (DSC) thermogram having exotherm peaks at about ⁇ 18.23 ⁇ 2.0° C. and about ⁇ 27.26 ⁇ 2.0° C.
  • DSC differential scanning calorimetry
  • the pharmaceutical composition has a water content of less than 1%.
  • the pharmaceutical composition comprises about 150 mg of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the pharmaceutical composition comprises less than 0.5% impurities. In one embodiment, the pharmaceutical composition comprises less than 0.3% impurities.
  • the pharmaceutical composition less than 0.7% impurities after the composition is stored at room temperature for 6 months. In one embodiment, the pharmaceutical composition less than about 0.5% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 6 months. In one embodiment, the pharmaceutical composition comprises less than 0.5% impurities after the composition is stored at room temperature for 3 months.
  • the pharmaceutical composition comprises less than 0.1% of Compound 10.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I, wherein the oxidation of Compound I is a N-oxide of Compound I. In one embodiment, the pharmaceutical composition comprises less than 0.2% of Compound 9.
  • the pharmaceutical composition comprises less than 1.2% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 36 months. In one embodiment, the pharmaceutical composition comprises less than 1.0% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 24 months. In one embodiment, the pharmaceutical composition comprises less than 1.0% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 6 months. In one embodiment, the pharmaceutical composition comprises less than 0.7% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 3 months. In one embodiment, the pharmaceutical composition comprises less than about 0.5% impurities resulting from oxidation of Compound I after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 2 months.
  • the pharmaceutical composition comprises less than 0.1% of Compound 10.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I, wherein the oxidation of Compound I is a N-oxide of Compound I. In one embodiment, the pharmaceutical composition comprises less than 0.2% of Compound 9.
  • the testing of said impurities is performed using parameters as in Example 5 at room temperature or at 50° C., 14 days after lyophilization, 28 days after lyophilization, 42 days after lyophilization, 96 days after lyophilization, 6 months after lyophilization, 12 months after lyophilization, 24 months after lyophilization, and/or 36 months after lyophilization.
  • the testing of said impurities is performed using parameters as in Example 5 or Example 10 at about ⁇ 20° C., at a range of about 2° C.
  • the pharmaceutical composition comprises less than about 0.5% of Compound 7 after the composition is stored at room temperature for 3 months or less. In another embodiment, the pharmaceutical composition comprises less than about 0.35% of Compound 7 after the composition is stored at room temperature for 3 months or less.
  • the pharmaceutical composition comprises a bulking agent.
  • the bulking agent selected from one or more of the group consisting of sucrose, mannitol, and trehalose.
  • the bulking agent is sucrose. In other embodiments, the bulking agent is mannitol.
  • the pharmaceutical composition is a liquid composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, the pharmaceutical composition is an aqueous composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof.
  • the liquid or the aqueous pharmaceutical composition comprises less than or equal to 1 ppm of dissolved oxygen. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than 1 ppm of dissolved oxygen.
  • the liquid or the aqueous pharmaceutical composition comprises a bulking agent.
  • the bulking agent selected from one or more of the group consisting of sucrose, mannitol, and trehalose.
  • the bulking agent is sucrose. In other embodiments, the bulking agent is mannitol.
  • the liquid or the aqueous pharmaceutical composition has a pH of 4.5 ⁇ 1. In one embodiment, the liquid or the aqueous pharmaceutical composition has a pH of 4.5 ⁇ 0.5. In one embodiment, the liquid or the aqueous pharmaceutical composition has a pH of 4.5 ⁇ 0.1. In one embodiment, the liquid or the aqueous pharmaceutical composition has a pH of 4.0 ⁇ 0.5.
  • the liquid or the aqueous pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for at least 28 days. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 0.7% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 28 days. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for at least 2 months. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 3 months.
  • the liquid or the aqueous pharmaceutical composition comprises less than about 0.1% of Compound 10 after the composition is stored at temperature in the range of about 25° C./60% RH for 28 days. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 0.2% of Compound 10 after the composition is stored at temperature in the range of about 25° C./60% RH for 2 months.
  • the liquid or the aqueous pharmaceutical composition at the time of preparation comprises less than 1 ppm of dissolved oxygen.
  • the liquid or the aqueous pharmaceutical composition comprises less than about 0.5% of Compound 7 after the composition is stored for 3 months or less. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 0.5% of Compound 7 after the composition is stored for 3 months or less at a storage temperature of about 5° C., 25° C., 30° C. or 40° C.
  • the liquid or the aqueous pharmaceutical composition comprises less than about 0.4% of Compound 7 after the composition is stored for 3 months or less. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 0.4% of Compound 7 after the composition is stored for 3 months or less at a storage temperature is about 5° C., 25° C., 30° C. or 40° C.
  • the liquid or the aqueous pharmaceutical composition comprises less than about 0.5% of Compound 10 after the composition is stored for 3 months or less. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 0.2% of Compound 10 after the composition is stored for 3 months or less at room temperature. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 0.25% of Compound 10 after the composition is stored for 3 months or less at about 30° C. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 0.25% of Compound 10 after the composition is stored for 1 month or less at about 40° C. In one embodiment, the liquid or the aqueous pharmaceutical composition comprises less than about 0.35% of Compound 10 after the composition is stored for 2 months or less at about 40° C.
  • the liquid or the aqueous pharmaceutical composition is in a vial.
  • the liquid or the aqueous pharmaceutical composition is further diluted in an I.V. solution/fluid bag or I.V. solution line.
  • the pharmaceutical composition is a liquid composition which is a reconstituted solution from a solid lyophilized Compound I or a pharmaceutically acceptable salt and/or solvate thereof.
  • the liquid reconstituted pharmaceutical composition comprises less than about 1% impurities. In one embodiment, the liquid reconstituted pharmaceutical composition comprises less than about 0.5% impurities. In one embodiment, the liquid reconstituted pharmaceutical composition comprises less than 0.5% impurities after the solid lyophilized composition is stored at room temperature for 42 days. In one embodiment, the liquid reconstituted pharmaceutical composition comprises less than about 0.4% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for 28 days.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for 28 days; wherein the oxidation of Compound I is at one or more hydrocarbons. In one embodiment, the liquid reconstituted pharmaceutical composition comprises less than 0.1% of Compound 10 after the solid lyophilized composition is stored at room temperature for 28 days.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 14 days; wherein the oxidation of Compound I is a N-oxide of Compound I.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.2% of the Compound 9 after the solid lyophilized composition is stored at room temperature for 14 days.
  • the liquid reconstituted pharmaceutical composition comprises less than about 0.4% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for at least 28 days. In one embodiment, the liquid reconstituted pharmaceutical composition comprises less than about 0.4% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 28 days.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.5% impurities after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 42 days.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 28 days; wherein the oxidation of Compound I is at one or more hydrocarbons. In one embodiment, the liquid reconstituted pharmaceutical composition comprises less than 0.1% of Compound 10 after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 28 days.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 14 days; wherein the oxidation of Compound I is a N-oxide of Compound I.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.2% of the Compound 9 after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 14 days.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.3% impurities.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.1% of Compound 10.
  • the liquid reconstituted pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I, wherein the oxidation of Compound I is a N-oxide of Compound I. In one embodiment, the liquid reconstituted pharmaceutical composition comprises less than 0.2% of Compound 9.
  • the liquid reconstituted pharmaceutical composition comprises Compound I at a concentration of about ⁇ 15 mg/ml. In one embodiment, the liquid reconstituted pharmaceutical composition comprises Compound I at a concentration of about ⁇ 25 mg/ml.
  • the liquid reconstituted pharmaceutical composition comprises a bulking agent.
  • the bulking agent selected from one or more of the group consisting of sucrose, mannitol, and trehalose.
  • the bulking agent is sucrose. In other embodiments, the bulking agent is mannitol.
  • the liquid reconstituted pharmaceutical composition is substantially free of an N-oxide degradant of Compound I. In one embodiment, the liquid reconstituted pharmaceutical composition is substantially free of an antioxidant.
  • the liquid reconstituted pharmaceutical composition provides a pH ranging from about 4 to about 6. In one embodiment, the liquid reconstituted pharmaceutical composition provides a pH ranging from about 4 to about 5.5.
  • the liquid reconstituted pharmaceutical composition comprises about 150 mg of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the liquid reconstituted pharmaceutical composition is in a vial.
  • the liquid reconstituted pharmaceutical composition is further diluted in an I.V. solution/fluid bag or I.V. solution line.
  • the liquid reconstituted pharmaceutical composition has any of the above-described characteristics after the solid lyophilized composition is stored for 1 month at about 2° C. to about 30° C.
  • the pharmaceutical composition is a liquid composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof.
  • the pharmaceutical composition comprises less than about 1% impurities. In one embodiment, the pharmaceutical composition comprises less than about 0.5% impurities. In one embodiment, the pharmaceutical composition comprises less than 0.5% impurities after the solid lyophilized composition is stored at room temperature for 1 month. In one embodiment, the pharmaceutical composition comprises less than about 0.4% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for 1 month.
  • the pharmaceutical composition comprises less than 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for 1 month; wherein the oxidation of Compound I is at one or more hydrocarbons. In one embodiment, the pharmaceutical composition comprises less than 0.1% of Compound 10 after the solid lyophilized composition is stored at room temperature for 1 month.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 1 month; wherein the oxidation of Compound I is a N-oxide of Compound I.
  • the pharmaceutical composition comprises less than 0.2% of the Compound 9 after the solid lyophilized composition is stored at room temperature for 1 month.
  • the pharmaceutical composition comprises less than about 0.4% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month. In one embodiment, the pharmaceutical composition comprises less than about 0.4% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month.
  • the pharmaceutical composition comprises less than 0.5% impurities after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month.
  • the pharmaceutical composition comprises less than 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month; wherein the oxidation of Compound I is at one or more hydrocarbons. In one embodiment, the pharmaceutical composition comprises less than 0.1% of Compound 10 after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month; wherein the oxidation of Compound I is a N-oxide of Compound I.
  • the pharmaceutical composition comprises less than 0.2% of the Compound 9 after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C. for 1 month.
  • the pharmaceutical composition comprises less than 0.3% impurities.
  • the pharmaceutical composition comprises less than 0.1% of Compound 10.
  • the pharmaceutical composition comprises less than 0.2% impurities resulting from oxidation of Compound I, wherein the oxidation of Compound I is a N-oxide of Compound I. In one embodiment, the pharmaceutical composition comprises less than 0.2% of Compound 9.
  • the pharmaceutical composition comprises Compound I at a concentration of about ⁇ 15 mg/ml. In one embodiment, the pharmaceutical composition comprises Compound I at a concentration of about ⁇ 25 mg/ml.
  • pharmaceutical composition comprises a bulking agent.
  • the bulking agent selected from one or more of the group consisting of sucrose, mannitol, and trehalose.
  • the bulking agent is sucrose. In other embodiments, the bulking agent is mannitol.
  • the pharmaceutical composition is substantially free of an N-oxide degradant of Compound I. In one embodiment, the pharmaceutical composition is substantially free of an antioxidant.
  • the pharmaceutical composition provides a pH ranging from about 4 to about 6. In one embodiment, the pharmaceutical composition provides a pH ranging from about 4 to about 5.5.
  • the pharmaceutical composition comprises about 150 mg of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the pharmaceutical composition is in a vial.
  • the pharmaceutical composition is further diluted in an I.V. solution/fluid bag or I.V. solution line.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises one or more compound selected from the group consisting of Compound 1, Compound 7, Compound 8, Compound 9 and Compound 10.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 1.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 7.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 8.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 9.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 10.
  • the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt and/or solvate thereof, and Compound 9 and Compound 10.
  • the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt and/or solvate thereof, Compound 1, Compound 7, Compound 8, Compound 9 and Compound 10.
  • the pharmaceutical composition further comprises one or more compounds selected from the group consisting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 11, and Compound 12.
  • the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt and/or solvate thereof, and Compound 1-12.
  • the present disclosure relates to Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof.
  • Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof are isolated.
  • Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof are purified.
  • the compound is
  • the present disclosure relates to at least one of Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof which is substantially pure.
  • the at least one of Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof is at least about 95% pure.
  • Compound 7 or a pharmaceutically acceptable salt thereof is at least 95% pure.
  • the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one of Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one of Compounds 1 and 8-10, or a pharmaceutically acceptable salt thereof.
  • the Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof in any one of the pharmaceutical composition as disclosed herein is substantially pure. In some embodiments, the Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof in any one of the pharmaceutical composition as disclosed herein is at least about 95% pure. In other embodiments, the Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof in any one of the pharmaceutical composition as disclosed herein is at least about 97% pure. In some embodiments, the Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof in any one of the pharmaceutical composition as disclosed herein is at least 95% pure. In other embodiments, the Compounds 1-6 and 8-12, or a pharmaceutically acceptable salt thereof in any one of the pharmaceutical composition as disclosed herein is at least 97% pure.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and substantially pure Compound 7, or a pharmaceutically acceptable salt thereof.
  • Compound 7, or a pharmaceutically acceptable salt thereof in any one of the pharmaceutical composition as disclosed herein is about 95% pure.
  • Compound 7, or a pharmaceutically acceptable salt thereof in any one of the pharmaceutical composition as disclosed herein is 95% pure.
  • the Compounds 1-12, or a pharmaceutically acceptable salt thereof, in any one of the pharmaceutical composition as disclosed herein demonstrates sensitivity to a BRCA2 null cell line relative to the parental cell line wherein BRCA2 is wild type.
  • the sensitivity is at least two fold higher. In other embodiments, the sensitivity is at least twenty fold higher. In some embodiments, the sensitivity is at least 200 fold higher.
  • the pharmaceutical composition as disclosed herein further comprises at least one pharmaceutically active agent.
  • the at least one pharmaceutically active agent is a PARP inhibitor or a CDK inhibitor.
  • the pharmaceutical composition as disclosed herein further comprises at least one PARP inhibitor selected from 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1 (2H)-one (olaparib, AZD2281, Ku-0059436), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (veliparib, ABT-888), (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (talazoparib, BMN 673), 4-iodo-3-nitrobenzamide (iniparib, BSI-201), 8-fluoro-5-(4-((methylamino)
  • the pharmaceutical composition as disclosed herein further comprises at least one CDK inhibitor selected from AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC202, R-roscovitine), ZK-304709 AT7519M, P276-00, SCH 727965, AG-024322, LEE011, LY2835219, P1446A-05, BAY 1000394, SNS-032, or 5-((3-chlorophenyl)amino)benzo[c][2,6]naphthyridine-8-carboxylic acid.
  • CDK inhibitor selected from AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509
  • the present invention provides a method for treating or ameliorating cell proliferation disorder in a subject, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of any one of the pharmaceutical composition comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as described herein.
  • the pharmaceutical composition is injected directly into the subject.
  • the pharmaceutical composition is diluted in an I.V. solution/fluid bag or I.V. line that is then administration to the subject.
  • the cell proliferation disorder is cancer in methods as described herein.
  • cancer is selected from the group consisting of heme cancer, colorectum cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing's sarcoma, pancreatic cancer, cancer of the lymph nodes, colon cancer, prostate cancer, brain cancer, cancer of the head and neck, skin cancer, kidney cancer, osteosarcoma, cancer of the heart, uterine cancer, gastrointestinal malignancies, and carcinomas of the larynx and oral cavity.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, Ewing's sarcoma, head and neck cancer, and cervical cancer.
  • the heme cancer is selected from the group consisting of: leukemia, lymphoma, myeloma, and multiple myeloma.
  • cancer treated or ameliorated by the method as described herein is homologous recombination (HR) dependent double strand break (DSB) repair deficient cancer or non-homologous end joining (NHEJ) DSB repair deficient cancer.
  • the present disclosure relates to a method for treating or ameliorating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as described herein, wherein the cancer is a BRCA mutant or BRCA-like mutant cancer.
  • the BRCA mutant cancer is a BRCA2-mutated cancer.
  • the BRCA mutant or BRCA-like mutant cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • the BRCA mutant or BRCA-like mutant cancer is breast cancer or prostate cancer.
  • the present disclosure relates to a method for treating or ameliorating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as described herein, wherein the cancer is BRCA2 deficient or BRCA1 deficient cancer. In some embodiments, the cancer is BRCA2 deficient cancer.
  • the present disclosure relates to a method for treating or ameliorating cell proliferation disorder in a human subject, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as described herein.
  • the human subject carries a BRCA mutation. In other embodiments, the human subject carries t a BRCA2 mutation.
  • the methods provided herein further comprise administering one or more additional therapeutic agents.
  • the one or more additional therapeutic agent is an anticancer agent or immunotherapeutic agent.
  • the one or more therapeutically active agent is an immunotherapeutic agent.
  • one or more immunotherapeutic agents includes, but is not limited to, a monoclonal antibody, an immune effector cell, adoptive cell transfer, an immunotoxin, a vaccine, or a cytokine.
  • the methods provided herein further comprise administering radiotherapy to the patient before, during, or after the administration of a pharmaceutical composition comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as described herein.
  • the therapeutically effective amount of any one of the pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as described herein is administered intravenously.
  • the pharmaceutical composition comprises about 25 mg to about 850 mg of the Compound I or a pharmaceutically acceptable salt and/or solvate thereof, per body surface area of the subject (m 2 ).
  • the pharmaceutical composition comprises about 150 mg to about 750 mg of the Compound I or a pharmaceutically acceptable salt and/or solvate thereof, per body surface area of the subject (m 2 ).
  • the pharmaceutical composition comprises about 375 mg to about 750 mg of the Compound I or a pharmaceutically acceptable salt and/or solvate thereof, per body surface area of the subject (m 2 ). In one embodiment, the pharmaceutical composition comprises about 550 mg to about 750 mg of the Compound I or a pharmaceutically acceptable salt and/or solvate thereof, per body surface area of the subject (m 2 ). In one embodiment, the pharmaceutical composition comprises about 25 mg to about 250 mg of the Compound I or a pharmaceutically acceptable salt and/or solvate thereof, per body surface area of the subject (m 2 ).
  • the pharmaceutical composition comprises about 50 mg to about 170 mg of the Compound I or a pharmaceutically acceptable salt and/or solvate thereof, per body surface area of the subject (m 2 ). In another embodiment, the pharmaceutical composition comprises about 150 mg of the Compound I or a pharmaceutically acceptable salt and/or solvate thereof.
  • the method further comprises co-administering one or more additional therapeutic agents and/or radio therapy.
  • the one or more additional therapeutic agent is an anticancer agent or immunotherapeutic agent.
  • the present invention provides a method of inhibiting Pol I transcription in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of any one of the pharmaceutical composition comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as described herein.
  • the inhibiting Pol I transcription is in peripheral blood mononuclear cells. In other embodiments, an average level of about 15% or greater inhibition is observable 1 hour after administering therapeutically effective amount of the pharmaceutical composition.
  • the therapeutically effective amount of the pharmaceutical composition comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as described herein is administered intravenously.
  • the pharmaceutical composition is injected directly into the subject.
  • the pharmaceutical composition is diluted in an I.V. solution/fluid bag or I.V. line that is then administration to the subject.
  • the present disclosure relates to a method for treating or ameliorating cell proliferation disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the pharmaceutical composition disclosed herein comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt thereof.
  • the cell proliferation disorder is cancer.
  • the present disclosure relates to a method for treating or ameliorating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the pharmaceutical composition disclosed herein comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of heme cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, cancer of the lymph nodes, colon cancer, prostate cancer, brain cancer, cancer of the head and neck, bone cancer, Ewing's sarcoma, skin cancer, kidney cancer, osteosarcoma, and cancer of the heart.
  • the cancer is selected from the group consisting of heme cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, cancer of the lymph nodes, colon cancer, prostate cancer, brain cancer, cancer of the head and neck, bone cancer, Ewing's sarcoma, skin cancer, kidney cancer,
  • the cancer is selected from the group consisting of wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, Ewing's sarcoma, head and neck cancer, and cervical cancer.
  • the heme cancer is selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma.
  • the present disclosure relates to a method for treating or ameliorating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the pharmaceutical composition disclosed herein comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt thereof, wherein the cancer is a BRCA mutant cancer.
  • the BRCA mutant cancer is a BRCA2-mutated cancer.
  • the BRCA mutant cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • the BRCA mutant cancer is breast cancer or prostate cancer.
  • the present disclosure relates to a method for treating or ameliorating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the pharmaceutical composition disclosed herein comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt thereof, wherein the cancer is BRCA2 deficient or BRCA1 deficient cancer. In some embodiments, the cancer is BRCA2 deficient cancer.
  • the present disclosure relates to a method for treating or ameliorating cell proliferation disorder in a human subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the pharmaceutical composition disclosed herein comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt thereof.
  • the human subject carries a BRCA mutation. In other embodiments, the human subject carries t a BRCA2 mutation.
  • FIG. 1 is a differential scanning calorimetry (DSC) thermogram of Run 1 as described in Example 4.
  • FIG. 2 is a magnification of the differential scanning calorimetry (DSC) thermogram of Run 1 as described in Example 4.
  • FIG. 3 is a magnification of the differential scanning calorimetry (DSC) thermogram of Run 1 as described in Example 4.
  • FIG. 4 is a differential scanning calorimetry (DSC) thermogram of Run 2 as described in Example 4.
  • FIG. 5 is a magnification of the differential scanning calorimetry (DSC) thermogram of Run 2 as described in Example 4.
  • FIG. 6 is a magnification of the differential scanning calorimetry (DSC) thermogram of Run 2 as described in Example 4.
  • FIG. 7 is a magnification of the differential scanning calorimetry (DSC) thermogram of Run 2 as described in Example 4.
  • FIG. 8 is a differential scanning calorimetry (DSC) thermogram of Run 3 as described in Example 4.
  • FIG. 9 is a magnification of the differential scanning calorimetry (DSC) thermogram of Run 3 as described in Example 4.
  • FIG. 10 is a differential scanning calorimetry (DSC) thermogram of Run 4 as described in Example 4.
  • FIG. 11 is a magnification of the differential scanning calorimetry (DSC) thermogram of Run 4 as described in Example 4.
  • FIG. 12A is a DSC thermogram of warming curve of solution containing Compound I (no bulking agent or other excipients).
  • FIG. 12B is a DSC thermogram of warming curve for lyophilization solution of Compound I (solution of Table 19).
  • FIG. 13 shows cell proliferation assay results for Compound I in DLD1 and isogenic BRCA2 ⁇ / ⁇ cell lines.
  • FIG. 14A shows the change in tumor volume in a mice (BRCA WT) receiving Compound I over the 28 day course of treatment.
  • FIG. 14B shows the change in tumor volume in a mice (BRCA1 Mut) receiving Compound I over the 28 day course of treatment.
  • FIG. 14C shows the change in tumor volume in a mice (BRCA2 Mut) receiving Compound I over the 28 day course of treatment.
  • FIG. 15A shows composite display of the Compound I concentration-time data in mouse across dose regimen for IV administration in Study 1-4 of Example 16.
  • FIG. 15B shows composite display of the mouse Compound I concentration-time data across dose regimen for or administration in Study 1, 2, and 4 of Example 16.
  • FIG. 16A shows observed time course of tumor volume following Compound I dosing to athymic nude mice further stratified by patient-derived xenograft model CTG-0012.
  • FIG. 16B shows observed time course of tumor volume following Compound I dosing to athymic nude mice further stratified by patient-derived xenograft model CTG-0888.
  • FIG. 16C shows observed time course of tumor volume following Compound I dosing to athymic nude mice further stratified by patient-derived xenograft model HBCx-10.
  • FIG. 16D shows observed time course of tumor volume following Compound I dosing to athymic nude mice further stratified by patient-derived xenograft model HBCx-14.
  • FIG. 16E shows observed time course of tumor volume following Compound I dosing to athymic nude mice further stratified by patient-derived xenograft model HBCx-15.
  • FIG. 17A shows visual predictive check evaluation of Compound I concentration-time in mouse after IV administration discussed in Example 16.
  • FIG. 17B shows visual predictive check evaluation of Compound I concentration-time in mouse after oral administration discussed in Example 16.
  • FIG. 19A shows dose response curve for Compound I in a cell proliferation assay.
  • FIG. 19B shows dose response curve for Compound 1 in a cell proliferation assay.
  • FIG. 19C shows dose response curve for Compound 7 in a cell proliferation assay.
  • FIG. 19D shows dose response curve for Compound 8 in a cell proliferation assay.
  • FIG. 19E shows dose response curve for Compound 9 in a cell proliferation assay.
  • FIG. 19F shows dose response curve for Compound 10 in a cell proliferation assay.
  • the present invention relates to a solid lyophilized form of tetracyclic quinolone compounds, which stabilize G-quadruplexes (G4s) and/or inhibit Pol I, as well as a solid lyophilized form of the salts and/or solvates of the tetracyclic quinolone compounds.
  • G4s G-quadruplexes
  • Pol I Pol I-quadruplexes
  • These solid materials can be formulated into pharmaceutical compositions and used for treating disorders characterized by proliferation of cells.
  • compound(s) of the present invention refers to 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (Compound I) or isomers, salts, N-oxides, sulfoxides, sulfones, or solvates thereof, or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof.
  • the solid lyophilized forms of Compound I described throughout the application includes a solid lyophilized form of any single isomer of Compound I, or a mixture of any number of isomers of Compound I.
  • degradant of a compound as used herein, means a chemical change of the compound over time.
  • Common degradants of a compound are often the product of, but are not limited to, hydrolysis, oxidation, decarboxylation and isomerization of the compound.
  • oxidation product refers to oxygenated derivatives (addition of an oxygen to the structure) of said product, including but are not limited to alcohol, aldehyde, ketone, N-oxide, sulfoxide, and sulfone derivatives.
  • oxidation can take place on a hydrocarbon to form a new alcohol, aldehyde, or ketone moiety.
  • oxidation can take place a nitrogen to form an N-oxide moiety.
  • oxidation can take place on a sulfur to form a sulfoxide or a sulfone moiety.
  • oxidation products may be identified by mass spectrometry where addition of 16 atomic mass units (e.g., N-oxide and hydroxyl like oxidation) or addition of 14 atomic mass units (e.g., oxidation of a methylene to a keto group) are observed.
  • 16 atomic mass units e.g., N-oxide and hydroxyl like oxidation
  • 14 atomic mass units e.g., oxidation of a methylene to a keto group
  • impurity of a compound means chemicals other than the compound, including, derivatives of the compound, or degradants of the compound that remain with the compound due to incomplete purification, or that develop over time, such as during stability testing, formulation development of the compound or storage of the compound.
  • co-administration refers to administration of a formulation or a composition reconstituted from (a) a solid lyophilized form of Compound I, or a solid lyophilized form of pharmaceutically acceptable salt, solvate and/or prodrug of Compound I; and (b) one or more additional therapeutic agent and/or radio therapy, in combination, i.e., together in a coordinated fashion.
  • isomers refers to compounds having the same chemical formula but may have different stereochemical formula, structural formula, or special arrangements of atoms.
  • isomers include stereoisomers, diastereomers, enantiomers, conformational isomers, rotamers, geometric isomers, and atropisomers.
  • N-oxide also known as amine oxide or amine-N-oxide, means a compound that derives from a compound of the present invention via oxidation of an amine group of the compound of the present invention.
  • An N-oxide typically contains the functional group R 3 N + —O (sometimes written as R 3 N ⁇ O or R 3 N ⁇ O).
  • esters refers to any ester of a compound of the present invention in which any of the —COOH functions of the molecule is replaced by a —COOR function, in which the R moiety of the ester is any carbon-containing group which forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl and substituted derivatives thereof.
  • esteer includes but is not limited to pharmaceutically acceptable esters thereof.
  • esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids.
  • “Sulfoxide” refers to a compound that derived from a compound of the present invention via oxidation of a sulfur (S) atom. Sulfoxides are commonly written as —S( ⁇ O)—, —S(O)—, or —(S ⁇ O)—. “Sulfone” refers to a compound that derived from a compound of the present invention via further oxidation of a sulfur atom. Sulfones are commonly written as —S( ⁇ O) 2 —, —S(O) 2 —, or —(S( ⁇ O) 2 )—.
  • Ketone impurity refers to a byproduct of a compound where a methylene group (—CH 2 —) is oxidized to a keto group (—C( ⁇ O)—).
  • room temperature means from 21 degrees Celsius to 27 degrees Celsius.
  • composition denotes one or more substance in a physical form, such as solid, liquid, gas, or a mixture thereof.
  • a pharmaceutical composition i.e., a composition related to, prepared for, or used in medical treatment.
  • formulation is also used to indicate one or more substance in a physical form, such as solid, liquid, gas, or a mixture thereof.
  • carboxylic acid refers to an organic acid characterized by one or more carboxyl groups, such as acetic acid and oxalic acid.
  • Sulfonic acid refers to an organic acid with the general formula of R—(S(O) 2 —OH) n , wherein R is an organic moiety and n is an integer above zero, such as 1, 2, and 3.
  • polyhydroxy acid refers to a carboxylic acid containing two or more hydroxyl groups. Examples of polyhydroxy acid include, but are not limited to, lactobionic acid, gluconic acid, and galactose.
  • “pharmaceutically acceptable” means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use within the scope of sound medical judgment.
  • Salts include derivatives of an active agent, wherein the active agent is modified by making acid or base addition salts thereof.
  • the salts are pharmaceutically acceptable salts.
  • Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphate
  • Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e.g., lysine and arginine dicyclohexylamine and the like.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Standard methods for the preparation of pharmaceutically acceptable salts and their formulations are well known in the art, and are disclosed in various references, including for example, “Remington: The Science and Practice of Pharmacy”, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.
  • solvate means a complex formed by solvation (the combination of solvent molecules with molecules or ions of the compounds of the present invention), or an aggregate that consists of a solute ion or molecule (the compounds of the present invention) with one or more solvent molecules.
  • the preferred solvate is hydrate. Examples of hydrate include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc. It should be understood by one of ordinary skill in the art that the pharmaceutically acceptable salt of the present compound may also exist in a solvate form.
  • the solvate is typically formed via hydration which is either part of the preparation of the present compound or through natural absorption of moisture by the anhydrous compound of the present invention.
  • Solvates including hydrates may be consisting in stoichiometric ratios, for example, with two, three, four salt molecules per solvate or per hydrate molecule. Another possibility, for example, that two salt molecules are stoichiometric related to three, five, seven solvent or hydrate molecules.
  • Solvents used for crystallization such as alcohols, especially methanol and ethanol; aldehydes; ketones, especially acetone; esters, e.g. ethyl acetate; may be embedded in the crystal grating.
  • Preferred are pharmaceutically acceptable solvents.
  • substantially similar as used herein with regards to bioavailability of pharmacokinetics means that the two or more therapeutically active agents or drugs provide the same therapeutic effects in a subject.
  • substantially free of means free from therapeutically effective amounts of compounds when administered in suggested doses, but may include trace amounts of compounds in non-therapeutically effective amounts.
  • excipient “carrier”, and “vehicle” are used interchangeably throughout this application and denote a substance with which a compound of the present invention is administered.
  • “Therapeutically effective amount” means the amount of a solid lyophilized form that is further formulated or reconstituted in a composition, when administered to a patient for treating a disease or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease or condition.
  • the therapeutically effective amount will vary depending on the solid lyophilized form, the disease or condition and its severity, and the age, weight, etc. of the patient to be treated. Determining the therapeutically effective amount of a given solid lyophilized form is within the ordinary skill of the art and requires no more than routine experimentation.
  • additional pharmaceutical agent or “additional therapeutic agent” or “additional therapeutically active agent” with respect to the compounds described herein refers to an active agent other than the Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, which is administered to elicit a therapeutic effect.
  • the pharmaceutical agent(s) may be directed to a therapeutic effect related to the condition that the compounds of the present disclosure is intended to treat or ameliorate (e.g., cancer) or, the pharmaceutical agent may be intended to treat or ameliorate a symptom of the underlying condition (e.g., tumor growth, hemorrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastic phenomena, thrombosis, etc.) or to further reduce the appearance or severity of side effects of the compounds of the present disclosure.
  • a symptom of the underlying condition e.g., tumor growth, hemorrhage, ulceration, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastic phenomena, thrombosis, etc.
  • a disorder characterized by cell proliferation or “a condition characterized by cell proliferation” include, but are not limited to, cancer, benign and malignant tumors.
  • cancer and tumors include, but are not limited to, cancers or tumor growth of the colorectum, breast (including inflammatory breast cancer), lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, kidney, osteosarcoma, blood and heart (e.g., leukemia, lymphoma, and carcinoma).
  • treating means one or more of relieving, alleviating, delaying, reducing, improving, or managing at least one symptom of a condition in a subject.
  • the term “treating” may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
  • patient or “subject” as used herein, includes humans and animals, preferably mammals.
  • the terms “inhibiting” or “reducing” cell proliferation is meant to slow down, to decrease, or, for example, to stop the amount of cell proliferation, as measured using methods known to those of ordinary skill in the art, by, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, when compared to proliferating cells that are not subjected to the methods and compositions of the present application.
  • apoptosis refers to an intrinsic cell self-destruction or suicide program.
  • cells undergo a cascade of events including cell shrinkage, blebbing of cell membranes and chromatic condensation and fragmentation. These events culminate in cell conversion to clusters of membrane-bound particles (apoptotic bodies), which are thereafter engulfed by macrophages.
  • Compound I is a synthetically derived small molecule, which can selectively binds and stabilizes DNA G-quadruplex (G4) structures.
  • Key attributes of Compound I include induction of DNA damage through G4 stabilization which is dependent on intact BRCA1/2 and other homologous recombination mediated pathways for resolution. Cumulative mutations affecting BRCA1/2 and homologous recombination (HR) deficient tumor cells result in synthetic lethality.
  • Compound I showed specific toxicity against BRCA1/2 deficient cells in a number of cell lines of different genetic backgrounds (colon, breast and ovary) and different specifies origin (mouse and human). Compound I exhibited a wide therapeutic index of activity in BRCA2 knockout tumor cells in a xenograft model, when compared with isogenic wild type control cells. Without bound to any theory, the data to date attribute the anti-tumor activity of Compound I to bind and stabilize G4 DNA structure and impede the progression of DNA replication complexes and induces single stranded DNA gaps or breaks. The BRCA pathway is required for the repair of Compound I induced DNA damage, and that compromised DNA damage repair in the absence of BRCA genes will lead to lethality.
  • BRCA deficient cells can be killed by Compound I at low drug concentration which are not effective at inhibiting rDNA transcription which suggests, without bound to any theory, that the dose used to treat BRCA deficient cancers is lower than that required to inhibit RNA Polymerase I and disrupt nucleons function.
  • the present invention provides a solid lyophilized form of Compound I (free base). In another embodiment, the present invention provides a solid lyophilized form of a pharmaceutically acceptable salt and/or solvate of Compound I.
  • the present invention provides a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition, upon reconstitution with diluent, has a pH from about 4 to about 6.
  • the reconstituted solution of a solid lyophilized form of compound I, or a pharmaceutically acceptable salt and/or solvate thereof has a pH from about 4 to about 5.5.
  • the diluent utilized for reconstitution is 5% dextrose in water or 5% glucose in water.
  • a non-lyophilized Compound I formulated as ready-to-use solution (25 mg/mL in 50 mM monobasic sodium phosphate, pH 6.0) has shown to have limited stability and as a result, required frequent (e.g., every 6 months) and repeated manufacturing to maintain supplies. See Example 1.
  • the ready-to-use solution stored at 25° C./60% RH for 3 months and 6 months showed more than 1% impurities by HPLC.
  • the ready-to-use solution stored at 40° C./75% RH for 3 months showed more than 2% impurities by HPLC and more than 3% impurities when stored at 40° C./75% RH for 6 months (Tables 1 and 2).
  • the present invention provides a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the solid lyophilized form has a superior shelf life when compared to a conventional ready-to-use formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the present invention provides a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the solid lyophilized form is more stable during storage when compared to a conventional ready-to-use formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • maintaining soluble oxygen content ⁇ 1.0 ppm during the process of preparing the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is critical in improving stability.
  • the solid lyophilized composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition comprises less than 0.5% impurities. In another embodiment, the composition comprises less than 0.3% impurities.
  • the solid lyophilized composition comprises less than 0.7% impurities after the composition is stored at room temperature for 6 months. In another embodiment, the solid lyophilized composition comprises less than 0.5% impurities after the composition is stored at room temperature for 3 months. In some embodiments, the solid lyophilized composition comprises less than about 0.5% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 6 months.
  • the present disclosure provides a composition comprising a solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition comprises less than about 3% impurities. In one embodiment, the present disclosure provides a composition comprising a solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition comprises less than about 2% impurities. In one embodiment, the present disclosure provides a composition comprising a solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition comprises less than about 1% impurities.
  • the present disclosure provides a composition comprising a solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition comprises less than about 0.5% impurities.
  • the purity and impurities of Compound I are measured as area % by high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • the HPLC is reverse-phase HPLC.
  • the determination of the impurities of Compound I is by running the reconstituted composition over reverse-phase HPLC using the following parameters:
  • the purity and impurity of any one of the compounds and composition as disclosed herein is determined using the above described RP-HPLC Chromatography conditions with acid mobile phase. In one embodiment, the purity and impurity of any one of the compounds and composition as disclosed herein is determined in accordance to Example 5.
  • the purity and impurity of any one of the compounds and composition as disclosed herein is determined using the above described RP-HPLC Chromatography conditions with base mobile phase. In one embodiment, the purity and impurity of any one of the compounds and composition as disclosed herein is determined in accordance to Example 10.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at room temperature for 28 days. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 2% impurities after the composition is stored at room temperature for 28 days. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the composition is stored at room temperature for 28 days. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.5% impurities after the composition is stored at room temperature for 28 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at room temperature for 1 month. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 2% impurities after the composition is stored at room temperature for 1 month. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the composition is stored at room temperature for 1 month. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.5% impurities after the composition is stored at room temperature for 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at room temperature for less than or equal to 28 days. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 2% impurities after the composition is stored at room temperature for less than or equal to 28 days. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the composition is stored at room temperature for less than or equal to 28 days. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.5% impurities after the composition is stored at room temperature for less than or equal to 28 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3%, less than about 2%, less than about 1% impuritie, or less than about 0.5% after the composition is stored at room temperature for at least 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at room temperature for up to 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 2% impurities after the composition is stored at room temperature for up to 24 months and any subranges therebetween. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the composition is stored at room temperature for up to 24 months and any subranges therebetween. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.5% impurities after the composition is stored at room temperature for up to 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at room temperature for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the composition is stored at room temperature for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at room temperature for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, or at least about 15 weeks.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at room temperature for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, or at least about 24 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at room temperature for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% impurities after the composition is stored at about ⁇ 20° C. for up to 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% impurities after the composition is stored at about ⁇ 20° C. for up to 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% impurities after the composition is stored at about ⁇ 20° C.
  • the composition is stored for about 1 month, about 2 months, or about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months, or any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% impurities after the composition is stored at about 5° C. for up to 24 months and any subranges therebetween. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% impurities after the composition is stored at about 5° C. for up to 24 months and any subranges therebetween. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% impurities after the composition is stored at about 5° C.
  • the composition is stored for about 1 month, about 2 months, or about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months, or any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at a temperature in the range of about 2 to about 8° C. for at least 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at a temperature in the range of about 2 to about 8° C. for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 2% impurities after the composition is stored at a temperature in the range of about 2 to about 8° C. for up to 36 months and any subranges therebetween. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1.5% impurities after the composition is stored at a temperature in the range of about 2 to about 8° C. for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2 to about 8° C. for up to 36 months and any subranges therebetween.
  • the composition is stored for about 1 month, about 2 months, or about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, or about 33 months, about 34 months, about 35 months, or about 36 months.
  • the composition when the composition is stored at about 2 to about 8° C., it is under ambient relative humidity.
  • the composition is stored at about 2° C., at about 3° C., at about 4° C., at about 5° C., at about 6° C., at about 7° C., or at about 8° C. under ambient relative humidity. In one embodiment, the composition is stored at about 5° C. under ambient relative humidity.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at about 25° C./60% relative humidity (RH) for at least 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at about 25° C./60% relative humidity (RH) for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 2% impurities after the composition is stored at about 25° C./60% RH for up to 36 months and any subranges therebetween. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1.5% impurities after the composition is stored at about 25° C./60% RH for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at about 25° C./60% RH for up to 36 months and any subranges therebetween. In some embodiments, the composition is stored at about 25° C./60% RH for up to 24 months.
  • the composition is stored for about 1 month, about 2 months, or about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, or about 33 months, about 34 months, about 35 months, or about 36 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at about 30° C./65% RH for at least 3 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at about 30° C./65% RH for up to 3 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 2% impurities after the composition is stored at about 30° C./65% RH for up to 3 months and any subranges therebetween. In another embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1.5% impurities after the composition is stored at about 30° C./65% RH for up to 3 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at about 30° C./65% RH for up to 3 months and any subranges therebetween. In one embodiment, the composition is stored for about 1 month, about 2 months, or about 3 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at about 40° C./75% RH for at least 3 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the composition is stored at about 40° C./75% RH for up to 3 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 2% impurities after the composition is stored at about 40° C./75% RH for up to 3 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1.5% impurities after the composition is stored at about 40° C./75% RH for up to 3 months and any subranges therebetween.
  • the composition is stored for about 1 month, about 2 months, or about 3 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at 50° C. for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the composition is stored at 50° C. for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at 50° C. for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at 50° C.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at 5° C. for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the composition is stored at 5° C. for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at 5° C. for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the composition is stored at 5° C.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 28 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 28 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for less than or equal to 28 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for less than or equal to 28 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is substantially free of an oxidization product of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • maintaining soluble oxygen ⁇ 1.0 ppm during the process of preparing the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is critical in providing the composition that is substantially free of an oxidization product of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • maintaining soluble oxygen ⁇ 1 ppm during the process of preparing the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is critical in providing the composition that is substantially free of an oxidization product of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the oxidation product of Compound I is selected from:
  • the oxidation product is a ketone product. In some embodiments, the oxidation product is an N-oxide product. In one embodiment, the ketone product is Compound 10. In one embodiment, the N-oxide product is Compound 9.
  • the solid lyophilized composition comprises less than 0.1% of
  • the solid lyophilized composition comprises less than 0.2% impurities resulting from oxidation of Compound I, wherein the oxidation of Compound I is a N-oxide of Compound I. In other embodiments, the solid lyophilized composition comprises less than 0.2% of
  • composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at room temperature for 1 month. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at room temperature for 28 days or for 1 month. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 10, after the composition is stored at room temperature for 28 days or for 1 month. In some embodiments, the composition is stored at room temperature for at least 28 days or for 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for 28 days or 1 month. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at 25° C./60% RH for 28 days or 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at 25° C./60% RH for 28 days or 1 month. In some embodiments, the composition is stored at room temperature for at least 28 days or 1 month. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% of Compound 10, after the composition is stored at 25° C./60% RH for 28 days or 1 month. In some embodiments, the composition is stored at room temperature for at least 28 days or 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal 3 months. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 3 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 3 months. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 3 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 12 months. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 12 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 12 months. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 24 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 24 months. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 24 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.6% of Compound 10, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.6% of Compound 10, after the composition is stored at 25° C./60% RH for up to 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.6% of Compound 10, after the composition is stored at 25° C./60% RH for up to 12 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% of Compound 10, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.4% of Compound 10, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.5% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 12 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at about 5° C. for up to 3 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% of Compound 10, after the composition is stored at about 5° C. for up to 3 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the composition is stored at room temperature for 14 days.
  • the composition comprising solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the composition is stored at room temperature for 14 days. In some embodiments, the composition is stored at room temperature for at least 14 days.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% N-oxides of the Compound I after the composition is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% N-oxides of the Compound I after the composition is stored at a temperature in the range of 2° C.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% N-oxides of the Compound I after the composition is stored at a temperature in the range of 2° C.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% impurities resulting from oxidation of Compound I after the composition is stored at room temperature, at about 5° C., or at 25° C./60% RH for up to 3 months, or any subranges therebetween. In one embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% impurities resulting from oxidation of Compound I after the composition is stored at room temperature, at about 5° C., or at 25° C./60% RH for up to 3 months, or any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% N-oxides of the Compound I after the composition is stored at room temperature, at about 5° C., or at 25° C./60% RH for up to 3 months, or any subranges therebetween. In one embodiment, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% N-oxides of the Compound I after the composition is stored at room temperature, at about 5° C., or at 25° C./60% RH for up to 3 months, or any subranges therebetween.
  • composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, is substantially free of an N-oxide of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 9, after the composition is stored at room temperature for 28 days or 1 month. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 9, after the composition is stored at room temperature for 28 days or 1 month. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 9, after the composition is stored at room temperature for less than or equal to 28 days or 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at room temperature for less than or equal to 28 days or 1 month. In some embodiments, the composition is stored at room temperature for at least 28 days or at least 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 9, after the composition is stored at 25° C./60% RH for 28 days or 1 month. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 9, after the composition is stored at 25° C./60% RH for 28 days or 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 9, after the composition is stored at 25° C./60% RH for less than or equal to 28 days or 1 month. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 9, after the composition is stored at 25° C./60% RH for less than or equal to 28 days or 1 month. In some embodiments, the composition is stored at room temperature for at least 28 days or at least 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% of Compound 9, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.5% of Compound 9, after the composition is stored at 25° C./60% RH for up to 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% of Compound 9, after the composition is stored at 25° C./60% RH for up to 12 months and any subranges therebetween. In some embodiments, the composition is stored at room temperature for at least 12 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4% of Compound 9, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 9, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 9, after the composition is stored at 25° C./60% RH for less than or equal to 24 months. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 9, after the composition is stored at 25° C./60% RH for less than or equal to 24 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.15% of Compound 9, after the composition is stored at 25° C./60% RH for less than or equal to 24 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.5% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 24 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 12 months and any subranges therebetween. In some embodiments, the composition is stored at room temperature for at least 12 months.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to 36 months and any subranges therebetween.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 30° C., and at any subranges therebetween, for less than or equal to 28 days or 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 30° C., and at any subranges therebetween, for less than or equal to 28 days or 1 month.
  • the composition is stored at room temperature for at least 28 days or at least 1 month.
  • the composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is substantially free of an antioxidant.
  • composition comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, is substantially free of ascorbic acid.
  • the present invention provides a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the pharmacokinetic properties and bioavailability do not significantly differ from Compound I, or a pharmaceutically acceptable salt and/or solvate thereof produced by different pathways.
  • the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, when reconstituted as an IV infusion or solution have substantially similar or identical bioavailability compared to a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof produced by different pathways.
  • the present invention provides a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the solid lyophilized form comprises a bulking agent.
  • the bulking agent can be sucrose, mannitol, or trehalose.
  • the bulking agent is mannitol.
  • the bulking agent is sucrose.
  • the composition comprises a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof and a bulking agent in about 6:1, about 3:1, about 3:2, about 1:1, about 3:4, about 3:5, about 1:2, about 3:7, about 3:8, about 1:3, about 3:10, about 3:11, or about 1:4 ratio by weight, or any other value or range of values therein.
  • the composition comprises a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof and a bulking agent in about 3:2.
  • the composition comprises a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof and a bulking agent in about 3:10.
  • the present invention provides a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the water content of the solid lyophilized form is less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%. In one embodiment, the present invention provides a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the water content of the solid lyophilized form is less than 1%. In some embodiments, the water content of the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, is less than about 0.2% or less than about 0.1%.
  • the water content of the solid lyophilized form of the present disclosure is less than about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, or about 0.01%, or any other value or range of values therein.
  • the Compound I sample used to prepare the solid lyophilized form of Compound I comprises Compound I Polymorphs A and/or E or non-polymorphic form of Compound I.
  • thee Compound I sample used to prepare the solid lyophilized form of Compound I comprises Compound I Polymorphs A and E. See WO 2017/105382, the contents of which are hereby incorporated in its entirety for all intended purposes.
  • the solid lyophilized forms are characterized by Differential Scanning Calorimetry (DSC).
  • DSC thermogram is typically expressed by a diagram plotting the normalized heat flow in units of Watts/gram (“W/g”) versus the measured sample temperature in degree C.
  • W/g Watts/gram
  • the DSC thermogram is usually evaluated for extrapolated onset and end (outset) temperatures, peak temperature, and heat of fusion.
  • a peak characteristic value of a DSC thermogram is often used as the characteristic peak to distinguish one form of a structure from others.
  • the measurements of the DSC thermogram for a given solid form of the same compound will vary within a margin of error.
  • the values of a single peak characteristic value, expressed in degree C. allow appropriate error margins.
  • the error margins are represented by “ ⁇ ”.
  • the single peak characteristic value of about “53.09 ⁇ 2.0” denotes a range from about 53.09 ⁇ 2, i.e., about 55.09, to about 53.09-2, i.e., about 51.09.
  • the appropriate error of margins for a single peak characteristic value can be ⁇ 2.5; ⁇ 2.0; ⁇ 1.5; ⁇ 1.0; ⁇ 0.5; or less.
  • the storage of the solid lyophilized Compound I samples can take place at about ⁇ 20° C., at a range of about 2° C. to about 8° C., at about 5° C., room temperature, at about 25° C., at about 30° C., at about 40° C., or at about 50° C.
  • the storage of the solid lyophilized Compound I samples can be for a duration of at least about 14 days after lyophilization, at least about 28 days after lyophilization, at least about 42 days after lyophilization, at least about 96 days after lyophilization, at least about 6 months after lyophilization, at least about 12 months after lyophilization, at least about 24 months after lyophilization, and/or at least about 36 months
  • the storage of the solid lyophilized Compound I samples can be for a duration of at least about 1 month after lyophilization, at least about 2 months after lyophilization, or at least about 3 months after lyophilization.
  • the storage of the solid lyophilized Compound I samples can be for a duration of about 14 days after lyophilization, about 28 days after lyophilization, about 42 days after lyophilization, about 96 days after lyophilization, about 6 months after lyophilization, about 12 months after lyophilization, about 24 months after lyophilization, and/or about 36 months. In one embodiment, the storage of the solid lyophilized Compound I samples can be for a duration of about 1 month after lyophilization, about 2 months after lyophilization, or about 3 months after lyophilization.
  • the present invention provides a process of producing a solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the present invention provides a process of producing a solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof where the solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is sparged with nitrogen prior to lyophilization.
  • all reagents and solutions used to prepare the solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is sparged with nitrogen.
  • all reagents and solutions used to prepare the solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is sparged with nitrogen at every step of the process of preparation of a lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, up to the lyophilization step.
  • soluble oxygen (dissolved oxygen content) in all reagents and solutions used to prepare the solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in less than or equal to 1.0 ppm ( ⁇ 1.0 ppm).
  • soluble oxygen in a solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof prior to lyophilization in less than or equal to 1.0 ppm. In one embodiment, soluble oxygen is not higher than 1 ppm during the process of preparing a lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, soluble oxygen is measured using a dissolved oxygen meter equipped with a dissolved oxygen probe (e.g., Mettler Toledo M400; Mettler Toledo InPro6860i).
  • a dissolved oxygen probe e.g., Mettler Toledo M400; Mettler Toledo InPro6860i
  • a process of producing a solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises the following steps:
  • water used in a preparation of solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is degassed or sparged with nitrogen. In some embodiment, degassing or sparging with nitrogen takes place with stirring.
  • soluble oxygen in water used in a preparation of solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is ⁇ 1.0 ppm. In one embodiment, soluble oxygen in water used in a preparation of solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is ⁇ 1 ppm. In one embodiment, water is water for injection (WFI).
  • about 5% to about 15% bulking agent solution is prepared using water which is degassed or sparged with nitrogen. In some embodiment, degassing or sparging with nitrogen takes place with stirring.
  • soluble oxygen in about 5% to about 15% bulking agent solution is ⁇ 1.0 ppm. In one embodiment, soluble oxygen in about 5% to about 15% bulking agent solution is ⁇ 1 ppm.
  • an aqueous acid, an aqueous base, and/or a buffer salt or solution used in a preparation of solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is prepared using water which is degassed or sparged with nitrogen.
  • an aqueous acid, an aqueous base, and/or a buffer salt or solution used in a preparation of solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is degassed or sparged with nitrogen. In some embodiment, degassing or sparging with nitrogen takes place with stirring.
  • soluble oxygen in an aqueous acid, an aqueous base, and/or a buffer salt or solution used in a preparation of solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is ⁇ 1.0 ppm. In one embodiment, soluble oxygen in an aqueous acid, an aqueous base, and/or a buffer salt or solution used in a preparation of solid lyophilized form of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is ⁇ 1 ppm.
  • about 5% to about 15% bulking agent solution comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof is degassed or sparged with nitrogen. In some embodiment, degassing or sparging with nitrogen takes place with stirring. In some embodiment, degassing or sparging with nitrogen takes place after Compound I or a pharmaceutically acceptable salt and/or solvate thereof is dissolved in solution.
  • soluble oxygen in about 5% to about 15% bulking agent solution comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof is ⁇ 1.0 ppm. In one embodiment, soluble oxygen in about 5% to about 15% bulking agent solution comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof is ⁇ 1 ppm.
  • the aqueous acid added to step a) and/or to adjust pH of the solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is HCl.
  • the concentration of HCl used to adjust pH is about 0.1 M to about 5 M. In other embodiments, the concentration of HCl used to adjust pH is about 0.1 M to about 2 M.
  • the aqueous base used to adjust pH of the solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is NaOH.
  • the concentration of NaOH used to adjust pH is about 0.1 M to about 5 M. In other embodiments, the concentration of NaOH used to adjust H is about 0.1 M to about 2 M.
  • buffer solutions are used to adjust pH of the solution. Buffer solutions commonly known in the art can be used.
  • the solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is degassed or sparged with nitrogen after the pH of the solution is adjusted. In some embodiment, degassing or sparging with nitrogen takes place with stirring.
  • soluble oxygen in pH adjusted solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is ⁇ 1.0 ppm. In one embodiment, soluble oxygen in pH adjusted solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is ⁇ 1 ppm.
  • the pH adjusted solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is transferred into lyophilization vials.
  • the pH adjusted solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is filled in 30 mL lyophilization vial at a fill volume of about 1 mL to about 20 mL (or in a different size lyophilization vial at a volume proportional as noted here).
  • the pH adjusted solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is filled in 30 mL lyophilization vial at a fill volume of about 5 mL or about 10 mL.
  • the pH adjusted solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is filled in 30 mL lyophilization vial at a fill volume of about 5 mL. In one embodiment, the pH adjusted solution comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof has soluble oxygen content ⁇ 1.0 ppm or ⁇ 1 ppm.
  • fill volume of the lyophilization vials reduced the incident of vial breakage during lyophilization. For example, fill volume of about 5 mL can reduce vial breakage during lyophilization compared to fill volume of about 10 mL when using 30 mL lyophilization vials.
  • freezing step c) is carried out in at least two stages.
  • a first freezing temperature is at between ⁇ 20 to about ⁇ 40° C.
  • the first freezing temperature is at between ⁇ 25 to about ⁇ 35° C.
  • the first freezing temperature is at ⁇ 30° C.
  • the ramp rate to the first freezing temperature in one embodiment, is between about 0.1 and 0.5° C./min.
  • the hold time at the first freezing temperature in some embodiments, is between about 30 minutes and about 500 minutes. In one embodiment, the hold time at the first freezing temperature is between about 90 minutes and about 240 minutes.
  • freezing is carried out at a second temperature.
  • the second freezing temperature is at between ⁇ 30 to about ⁇ 55° C.
  • the second freezing temperature is at between ⁇ 35 to about ⁇ 50° C.
  • the second freezing temperature is at ⁇ 45° C.
  • the ramp rate to the second freezing temperature in one embodiment, is between about 0.1 and 0.5° C./min.
  • the hold time at the second freezing temperature in some embodiments, is between about 30 minutes and about 500 minutes. In one embodiment, the hold time at the second freezing temperature is between about 90 minutes and about 240 minutes.
  • the an annealing process takes place subsequent to freezing the solution comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, the an annealing process takes place subsequent to freezing the solution comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof and baking agent.
  • the annealing temperature is at between about ⁇ 5° C. to about ⁇ 50° C. That is, in some embodiments, the annealing temperature is at about ⁇ 5, ⁇ 10, ⁇ 15, ⁇ 20, ⁇ 25, ⁇ 30, ⁇ 35, ⁇ 40, ⁇ 45, or ⁇ 50° C.
  • the annealing temperature is at between about ⁇ 5° C. to about ⁇ 25° C. In one embodiment, the annealing temperature is at about ⁇ 10° C.
  • the ramp rate to the annealing temperature in one embodiment, is between about 0.1 and 0.5° C./min.
  • the hold time at the annealing temperature in some embodiments, is between about 30 minutes and about 500 minutes. In one embodiment, the hold time at the annealing temperature is between about 90 minutes and about 240 minutes.
  • the bulking agent is used in about 600 mg, about 500 mg, about 400 mg, about 300 mg, about 200 mg, or about 100 mg per 150 mg of Compound I. In another embodiment, the bulking agent is used in about 150 mg, about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, or about 50 mg per 150 mg of Compound I. In one embodiment, the bulking agent is used in about 100 mg per 150 mg of Compound I, or any other value or range of values therein.
  • about 200 mg, about 225 mg, about 150 mg, about 125 mg, or about 100 mg of Compound I, or any other value or range of values therein, is in every lyophilization vial. In one embodiment, about 150 mg of Compound I is in every lyophilization vial.
  • the bulking agent is sucrose.
  • the bulking agent is mannitol.
  • the annealing process subsequent to freezing the solution comprising a Compound I and mannitol is advantageous in promoting better crystallization of mannitol.
  • lack of annealing subsequent to freezing the solution comprising a Compound I and mannitol leads to partial crystallization of mannitol.
  • annealing subsequent to freezing the solution comprising a Compound I and mannitol at temperature between ⁇ 15° C. to ⁇ 20° C. leads to partial crystallization of mannitol.
  • a drying process of the frozen solution comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; or Compound I or a pharmaceutically acceptable salt and/or solvate thereof and a bulking agent requires two separate temperatures.
  • the first drying temperature is between about ⁇ 10° C. to about ⁇ 40° C. That is, the first drying temperature is about ⁇ 10, ⁇ 15, ⁇ 20, ⁇ 25, ⁇ 30, ⁇ 35, or ⁇ 40° C. In one embodiment, the first drying temperature is between about ⁇ 10° C. to about ⁇ 20° C.
  • the ramp rate to the first drying temperature in one embodiment, is between about 0.1 and 0.5° C./min.
  • the first drying process requires about 1 hour to about 1 week. In some embodiments, the first drying process requires about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 36, about 60, about 84, about 108, about 132, or about 156 hours. In some embodiments, the first drying process requires about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days. In one embodiment, the first drying process requires about 2 to about 4 days.
  • the first drying process requires a pressure between about 300 mTorr to about 500 mTorr. That is, the first drying pressure is about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, or about 500 mTorr. In one embodiment, the first drying process requires a pressure between about 300 mTorr to about 400 mTorr.
  • the first drying process between about ⁇ 10° C. to about ⁇ 40° C. can be repeated at same or different temperatures prior to the second drying process.
  • a process of producing a solid lyophilized form of Compound I or a pharmaceutically acceptable salt and/or solvate thereof requires a second drying step after the first drying step.
  • the second drying temperature is between about 0° C. to about 30° C. That is, the second drying temperature is about 0, 5, 10, 15, 20, 25, or 30° C. In one embodiment, the second drying temperature is between about 20° C. to about 30° C.
  • the ramp rate to the second drying temperature in one embodiment, is between about 0.1 and 0.5° C./min.
  • the second drying process requires about 1 hour to about 1 week. In some embodiments, the second drying process requires about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 36, about 60, about 84, about 108, about 132, or about 156 hours. In some embodiments, the second drying process requires about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days. In one embodiment, the second drying process requires about 3 to about 24 hours.
  • the second drying process requires a pressure between about 25 mTorr to about 100 mTorr. That is, the second drying pressure is about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 mTorr. In one embodiment, the first drying process requires a pressure between about 300 mTorr to about 400 mTorr.
  • the second drying process between about 0° C. to about 30° C. can be repeated at same or different temperatures.
  • the solid content (i.e., Compound I and bulking agent) in the lyophilization solution is less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5% by weight of a lyophilization solution.
  • the “lyophilization solution” refers to a solution containing Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, prior to the solution being subjected to under the lyophilization conditions.
  • the solid content is about 6.5% by weight of the lyophilization solution. In another embodiment, the solid content is about 5% by weight of the lyophilization solution.
  • lyophilization solution can comprise 150 mg Compound I and 100 mg sucrose for total of 250 mg solid content with a 5 mL water for injection (5000 mg), which provides 6.5% solid content by weight of the lyophilization solution.
  • lyophilization solution can comprise 150 mg Compound I and 500 mg mannitol for total of 650 mg solid content with a 10 mL water for injection (10,000 mg), which provides 6.1% solid content by weight of the lyophilization solution.
  • the lyophilization solution comprises Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, at a concentration greater than about 10 mg/mL, greater than about 11 mg/mL, greater than about 12 mg/mL, greater than about 13 mg/mL, greater than about 14 mg/mL, greater than about 15 mg/mL, greater than about 16 mg/mL, greater than about 17 mg/mL, greater than about 18 mg/mL, greater than about 19 mg/mL, greater than about 20 mg/mL, greater than about 21 mg/mL, greater than about 22 mg/mL, greater than about 23 mg/mL, greater than about 24 mg/mL, or greater than about 25 mg/mL, or any other value or range of values therein.
  • the lyophilization solution comprises Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, at a concentration greater than about 15 mg/mL. In other embodiments, the lyophilization solution comprises Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, at a concentration greater than about 25 mg/mL.
  • the lyophilization is conducted in vial having a volume of about 50 cc, about 40 cc, about 30 cc, about 25 cc, about 20 cc or about 15 cc. In some embodiments, the lyophilization is conducted in a 20 cc vial. In one embodiment, the vial is de-pyrogenated glass vials.
  • the lyophilization solution or the solid lyophilization composition does not comprise excipients that may facilitate oxidation or degradation of Compound I. In other embodiments, the lyophilization solution or the solid lyophilization composition is substantially free of excipients that may facilitate oxidation or degradation of Compound I.
  • the present invention provides a composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate.
  • the composition is in a solid form or a liquid form.
  • the present invention provides a composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition comprises less than about 1% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for at least 28 days or at least 1 month.
  • the present invention provides a liquid composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate.
  • the liquid composition is an aqueous solution.
  • the liquid composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate includes the composition just before lyophilization, as disclosed herein.
  • the present invention provides a pharmaceutical formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation comprises less than about 3% impurities and wherein the formulation is a reconstituted solution from a solid lyophilized composition. In one embodiment, the present invention provides a pharmaceutical formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation comprises less than about 2% impurities and wherein the formulation is a reconstituted solution from a solid lyophilized composition.
  • the present invention provides a pharmaceutical formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation comprises less than about 1% impurities and wherein the formulation is a reconstituted solution from a solid lyophilized composition. In one embodiment, the present invention provides a pharmaceutical formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation comprises less than about 0.5% impurities and wherein the formulation is a reconstituted solution from a solid lyophilized composition.
  • the formulation as described herein can be prepared by reconstituting the solid lyophilized composition of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, with any sterile diluent appropriate for human administration known in the art.
  • sterile diluent includes, water, glucose solution, dextrose solution, sucrose solution, and saline.
  • the purity and impurities of the formulation comprising Compound I are measured as area % by high-performance liquid chromatography (HPLC).
  • the present disclosure relates to a pharmaceutical formulation comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation comprises less than about 1% impurities; and wherein the formulation is a reconstituted solution from a solid lyophilized composition.
  • the pharmaceutical formulation comprises less than 0.5% impurities.
  • the pharmaceutical formulation comprises less than about 0.4% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for 28 days.
  • the pharmaceutical formulation comprises less than 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for 28 days, wherein the oxidation of Compound I is at one or more hydrocarbons. In another embodiment, the pharmaceutical formulation comprises less than about 0.4% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for less than or equal to 28 days or 1 month. In one embodiment, the pharmaceutical formulation comprises less than 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for less than or equal to 28 days or 1 month, wherein the oxidation of Compound I is at one or more hydrocarbons. In some embodiments, the composition is stored at room temperature for at least 28 days or 1 month.
  • the pharmaceutical formulation comprises less than 0.1% of
  • the pharmaceutical formulation comprises less than 0.1% of Compound 10 after the solid lyophilized composition is stored at room temperature for less than or equal to 28 days or 1 month. In some embodiments, the composition is stored at room temperature for at least 28 days or 1 month. In one embodiment, the pharmaceutical formulation comprises less than 0.2% impurities resulting from oxidation of Compound I after the composition is stored at room temperature for 14 days, wherein the oxidation of Compound I is a N-oxide of Compound I. In other embodiments, the pharmaceutical formulation comprises less than 0.2% of
  • the pharmaceutical formulation comprises less than 0.2% of Compound 9 after the solid lyophilized composition is stored at room temperature for 1 month. In some embodiments, the pharmaceutical formulation comprises less than 0.3% impurities. In some embodiments, the composition is stored at room temperature for at least 14 days, at least 28 days, or at least 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% impurities resulting from oxidation of Compound I after the composition is stored at room temperature, at about 5° C., or at 25° C./60% RH for up to 3 months, or any subranges therebetween. In one embodiment, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% impurities resulting from oxidation of Compound I after the composition is stored at room temperature, at about 5° C., or at 25° C./60% RH for up to 3 months, or any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% N-oxides of the Compound I after the composition is stored at room temperature, at about 5° C., or at 25° C./60% RH for up to 3 months, or any subranges therebetween. In one embodiment, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% N-oxides of the Compound I after the composition is stored at room temperature, at about 5° C., or at 25° C./60% RH for up to 3 months, or any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 10, after the composition is stored at room temperature for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 10, after the composition is stored at room temperature for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at room temperature for 28 days or 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% or less than about 0.1% of Compound 10, after the composition is stored at room temperature for less than or equal to 28 days or 1 month.
  • the composition is an aqueous solution.
  • the composition is stored at room temperature for at least 28 days or at least 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at room temperature for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 10, after the composition is stored at room temperature for up to about 2 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 3 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% or less than about 0.05% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 2 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 2 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for at least about 1 month and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 1 month and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 1 month and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 1 month and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% of Compound 10, after the composition is stored at 25° C./60% RH for up to about 1 month and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 24 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 24 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 10, after the composition is stored at 25° C./60% RH for less than or equal to 24 months.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.6% of Compound 10, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.6% of Compound 10, after the composition is stored at 25° C./60% RH for up to 24 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.6% of Compound 10, after the composition is stored at 25° C./60% RH for up to 12 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to about 3 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% of Compound 10, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to about 3 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at about 5° C. for up to 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% of Compound 10, after the composition is stored at about 5° C. for up to 3 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 10, after the composition is stored at 30° C./65% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 10, after the composition is stored at 30° C./65% RH for up to about 2 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the composition is stored at 30° C./65% RH for up to about 1 month and any subranges therebetween. In some embodiments, the composition is stored at room temperature for at least 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% of Compound 10, after the composition is stored at 40° C./75% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.4% of Compound 10, after the composition is stored at 40° C./75% RH for up to about 2 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 10, after the composition is stored at 40° C./75% RH for up to about 1 month and any subranges therebetween. In some embodiments, the composition is stored at room temperature for at least 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at room temperature for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 9, after the composition is stored at room temperature for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% of Compound 9, after the composition is stored at room temperature for 28 days or 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at room temperature for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% or less than about 0.1% of Compound 9, after the composition is stored at room temperature for less than or equal to 28 days or 1 month. In one embodiment, the composition is an aqueous solution. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.05% of Compound 9, after the composition is stored at room temperature for less than or equal to 28 days or 1 month. In one embodiment, the composition is an aqueous solution. In some embodiments, the composition is stored at room temperature for at least 28 days or 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 9, after the composition is stored at room temperature for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.0.5% of Compound 9, after the composition is stored at room temperature for up to about 3 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at 25° C./60% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 9, after the composition is stored at 25° C./60% RH for up to about 3 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.05% of Compound 9, after the composition is stored at 25° C./60% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition is stored up to about 2 months or up to about 1 month. In some embodiments, the composition is stored at room temperature for at least 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3% of Compound 9, after the composition is stored at 25° C./60% RH for less than or equal to 24 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 9, after the composition is stored at 25° C./60% RH for less than or equal to 24 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.15% of Compound 9, after the composition is stored at 25° C./60% RH for less than or equal to 24 months.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.6% of Compound 9, after the composition is stored at 25° C./60% RH for up to 36 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.6% of Compound 9, after the composition is stored at 25° C./60% RH for up to 24 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.6% of Compound 9, after the composition is stored at 25° C./60% RH for up to 12 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to about 3 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.05% of Compound 9, after the composition is stored at a temperature in the range of about 2° C. to about 8° C. for up to about 3 months and any subranges therebetween. In some embodiments, the composition is stored up to about 2 months or up to about 1 month. In some embodiments, the composition is stored at room temperature for at least 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at 30° C./65% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 9, after the composition is stored at 30° C./65% RH for up to about 3 months and any subranges therebetween.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.05% of Compound 9, after the composition is stored at 30° C./65% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition is stored up to about 2 months or up to about 1 month. In some embodiments, the composition is stored at room temperature for at least 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the composition is stored at 40° C./75% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 9, after the composition is stored at 40° C./75% RH for up to about 3 months and any subranges therebetween. In some embodiments, the composition is stored up to about 2 months or up to about 1 month. In some embodiments, the composition is stored at room temperature for at least 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 0.15% of Compound 9, after the composition is stored at 5° C. for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.15% of Compound 9, after the composition is stored at 5° C. in ambient relative humidity for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.15% of Compound 9, after the composition is stored at 5° C. for 3 months.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 0.15% of Compound 9, after the composition is stored at 5° C. in ambient relative humidity for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.13% of Compound 9, after the composition is stored at 5° C. in ambient relative humidity for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.05% of Compound 10, after the composition is stored at 5° C. for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.05% of Compound 10, after the composition is stored at 5° C. in ambient relative humidity for 3 months.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 1% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 5° C. in ambient relative humidity for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.5% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 5° C. in ambient relative humidity for 28 days or 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 0.25% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 5° C. in ambient relative humidity for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.1% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 5° C. in ambient relative humidity for 28 days or 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 1% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 5° C. in ambient relative humidity for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.5% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 5° C. in ambient relative humidity for 3 months.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 0.25% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 5° C. in ambient relative humidity for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.1% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 5° C. in ambient relative humidity for 3 months.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 0.15% of Compound 9, after the composition is stored at 25° C./60% RH for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.13% of Compound 9, after the composition is stored at 25° C./60% RH for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.05% of Compound 10, after the composition is stored at 25° C./60% RH for 3 months.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 1% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 25° C./60% RH for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.5% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 25° C./60% RH for 28 days or 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 0.25% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 25° C./60% RH for 28 days or 1 month. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.1% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 25° C./60% RH for 28 days or 1 month.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 1% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 25° C./60% RH for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.5% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 25° C./60% RH for 3 months.
  • the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than 0.25% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 25° C./60% RH for 3 months. In some embodiments, the composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than 0.15% of water content as measured by USP ⁇ 921 Method 1c> after the composition is stored at 25° C./60% RH for 3 months.
  • the present invention provides a composition or a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition further comprises at least one of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
  • the present invention provides a composition or a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition further comprises at least one of Compounds 1, 7, 8, 9, and 10.
  • the present invention provides a composition or a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition further comprises at least one of Compounds 9 and 10.
  • the present invention provides a composition or a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition further comprises Compounds 9 and 10.
  • the present disclosure provides a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 1.
  • the present disclosure provides a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 7.
  • the present disclosure provides a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 8.
  • the present disclosure provides a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 9.
  • the present disclosure provides a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises Compound 10.
  • the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt and/or solvate thereof, and Compound 9 and Compound 10.
  • the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt and/or solvate thereof, Compound 1, Compound 7, Compound 8, Compound 9 and Compound 10.
  • the pharmaceutical composition further comprises one or more compounds selected from the group consisting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 11, and Compound 12.
  • the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt and/or solvate thereof, and Compound 1-12.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the solid lyophilized composition is stored at room temperature for 28 days. In another embodiment, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 2% impurities after the solid lyophilized composition is stored at room temperature for 28 days. In another embodiment, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the solid lyophilized composition is stored at room temperature for 28 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% impurities after the solid lyophilized composition is stored at room temperature for 28 days. In some embodiments, the composition is stored at room temperature for at least 28 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the is stored at room temperature for less than or equal to 28 days or 1 month. In another embodiment, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 2% impurities after the solid lyophilized composition is stored at room temperature for less than or equal to 28 days or 1 month. In another embodiment, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the solid lyophilized composition is stored at room temperature for 28 days or 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% impurities after the solid lyophilized composition is stored at room temperature for less than or equal to 28 days or 1 month. In some embodiments, the composition is stored at room temperature for at least 28 days or 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the formulation is stored at room temperature for less than or equal to 28 days or 1 month. In another embodiment, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 2% impurities after the formulation is stored at room temperature for less than or equal to 28 days or 1 month. In another embodiment, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the formulation is stored at room temperature for 28 days or 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.5% impurities after the formulation is stored at room temperature for less than or equal to 28 days or 1 month. In some embodiments, the composition is stored at room temperature for at least 28 days or at least 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at room temperature for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the solid lyophilized composition is stored at room temperature for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at room temperature for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at room temperature for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the formulation is stored at room temperature for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at room temperature for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 2% impurities after the formulation is stored at room temperature for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days, or any subranges therebetween. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 2% impurities after the formulation is stored at room temperature for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at a temperature in the range of about 2° C. to about 30° C. for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 2% impurities after the formulation is stored at a temperature in the range of about 2° C. to about 30° C. for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 2% impurities after the formulation is stored at a temperature in the range of about 2° C. to about 30° C.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at a temperature in the range of about 2° C. to about 30° C. for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at 50° C. for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the solid lyophilized composition is stored at 50° C. for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at 50° C. for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at 50° C.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at 5° C. for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 1% impurities after the solid lyophilized composition is stored at 5° C. for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at 5° C. for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the solid lyophilized composition is stored at 5° C.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the formulation is stored at 40° C./75% RH for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days, or any subranges therebetween. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 3% impurities after the formulation is stored at 40° C./75% RH for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at 5° C. for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at 40° C./75% RH for about 1 month, about 2 months, or about 3 months, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 3% impurities after the formulation is stored at 40° C./75% RH for at least about 7 days, at least about 14 days, at least about 28 days, at least about 42 days, or at least about 96 days, or any subranges therebetween. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 3% impurities after the formulation is stored at 40° C./75% RH for about 7 days, about 14 days, about 28 days, about 42 days, or about 96 days, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at 5° C. for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1% impurities after the formulation is stored at 40° C./75% RH for about 1 month, about 2 months, or about 3 months, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for 28 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for 28 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for less than or equal to 28 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for less than or equal to 28 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for less than or equal to 28 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for less than or equal to 28 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the solid lyophilized composition is stored at a temperature in the range of about 2° C. to about 30° C.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the formulation is stored at a temperature in the range of about 2° C. to about 30° C.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for up to about 3 months.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for up to about 3 months.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for up to about 24 months.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for up to about 24 months.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for up to about 36 months.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities resulting from oxidation of Compound I after the formulation is stored at room temperature for up to about 36 months.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is substantially free of an oxidization product of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • maintaining soluble oxygen ⁇ 1.0 ppm during the process of preparing the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is critical in providing the formulation that is substantially free of an oxidization product of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • maintaining soluble oxygen ⁇ 1.0 ppm during the process of preparing the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is critical in providing the formulation that is substantially free of an oxidization product of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • maintaining soluble oxygen ⁇ 1.0 ppm at the time of preparing a liquid formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is critical in providing the formulation that is substantially free of an oxidization product of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • maintaining soluble oxygen ⁇ 1.0 ppm during the process of preparing a liquid formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is critical in providing the formulation that is substantially free of an oxidization product of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the oxidation product of Compound I is selected from: Compounds 2, 3, 4, 9, or 10. In one embodiment, the oxidation product is a ketone product. In some embodiments, the oxidation product is an N-oxide product.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.1% of Compound 10, after the solid lyophilized composition is stored at room temperature for 28 days. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 10, after the solid lyophilized composition is stored at room temperature for 1 month. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.1% of Compound 10 after the formulation is stored at room temperature for 28 days or 1 month. In one embodiment, the formulation is an aqueous liquid formulation.
  • the formulation comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the solid lyophilized composition is stored at room temperature for 14 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the solid lyophilized composition is stored at room temperature for 14 days.
  • the formulation comprising the solid lyophilized Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the solid lyophilized composition is stored at room temperature for 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the solid lyophilized composition is stored at room temperature for 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the formulation is stored at room temperature for 14 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the formulation is stored at room temperature for 14 days.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the formulation is stored at room temperature for 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.3%, less than about 0.2%, or less than about 0.1% of N-oxides of Compound I after the formulation is stored at room temperature for 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% N-oxides of the Compound I after the solid lyophilized composition is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% N-oxides of the Compound I after the formulation is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% N-oxides of the Compound I after the solid lyophilized composition is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 6 months, about 9 months, about 12 months, about 18 months, about 24 months, and about 36 months, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% N-oxides of the Compound I after the formulation is stored at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks, about 6 months, about 9 months, about 12 months, about 18 months, about 24 months, and about 36 months, or any subranges therebetween.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is substantially free of an N-oxide of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof comprises less than about 0.2% of Compound 9, after the solid lyophilized composition is stored at room temperature for 14 days. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 9, after the solid lyophilized composition is stored at room temperature for 1 month. In some embodiments, the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, comprises less than about 0.2% of Compound 9 after the formulation is stored at room temperature for 14 days or for 1 month.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is substantially free of an antioxidant.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is substantially free of ascorbic acid.
  • purity or impurity of the compounds of the present invention or any of the compositions or formulations thereof is determined by HPLC.
  • the HPLC method is any one of the methods disclosed herein.
  • the HPLC parameters are any one of the parameters as disclosed herein.
  • the HPLC condition is the basic method as described herein.
  • the HPLC condition is the acidic method as described herein
  • the storage of the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof can take place at about ⁇ 20° C., at a range of about 2° C. to about 8° C., at about 5° C., room temperature, at about 25° C., at about 30° C., at about 40° C., or at about 50° C.
  • the storage of the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof can be for a duration of at least about 14 days after lyophilization, at least about 28 days after lyophilization, at least about 42 days after lyophilization, at least about 96 days after lyophilization, at least about 6 months after lyophilization, at least about 12 months after lyophilization, at least about 24 months after lyophilization, and/or at least about 36 months
  • the storage of the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof can be for a duration of about 14 days after lyophilization, about 28 days after lyophilization, about 42 days after lyophilization, about 96 days after lyophilization, about 6 months after lyophilization, about 12 months after lyophilization, about 24 months after lyophilization, and/or about 36 months.
  • the storage of the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof can be for a duration of at least about 1 month after lyophilization, at least about 2 months after lyophilization, or at least about 3 months after lyophilization.
  • the formulation comprises Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, at a concentration greater than about 10 mg/mL, greater than about 11 mg/mL, greater than about 12 mg/mL, greater than about 13 mg/mL, greater than about 14 mg/mL, greater than about 15 mg/mL, greater than about 16 mg/mL, greater than about 17 mg/mL, greater than about 18 mg/mL, greater than about 19 mg/mL, greater than about 20 mg/mL, greater than about 21 mg/mL, greater than about 22 mg/mL, greater than about 23 mg/mL, greater than about 24 mg/mL, or greater than about 25 mg/mL, or any other value or range of values therein.
  • the formulation comprises Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, at a concentration greater than about 15 mg/mL. In other embodiments, the formulation comprises Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, at a concentration greater than about 25 mg/mL.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation is a reconstituted solution from a solid lyophilized composition comprises a bulking agent.
  • the bulking agent can be sucrose, mannitol, or trehalose.
  • the bulking agent is mannitol.
  • the bulking agent is sucrose.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation comprises a bulking agent.
  • the bulking agent can be sucrose, mannitol, or trehalose. In one embodiment, the bulking agent is mannitol. In one embodiment, the bulking agent is sucrose.
  • the present invention provides a liquid composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition, has a pH from about 4 to about 6. In some embodiments, the liquid composition has a pH from about 4 to about 5. In some embodiments, the liquid composition has a pH of about 4.5. In some embodiments, the liquid composition has a pH of 4.5 ⁇ 0.1.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation is a reconstituted solution from a solid lyophilized composition has a pH from about 4 to about 6. In some embodiments, the formulation has a pH from about 4 to about 5.5. In some embodiments, the solution utilized for reconstitution is 5% dextrose in water or 5% glucose in water.
  • the formulation comprises about 200 mg, about 225 mg, about 150 mg, about 125 mg, or about 100 mg of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation is a reconstituted solution from a solid lyophilized composition of Compound I. In one embodiment, the formulation comprises about 150 mg of Compound I.
  • the formulation comprises about 200 mg, about 225 mg, about 150 mg, about 125 mg, or about 100 mg of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, the formulation comprises about 150 mg of Compound I.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation is a reconstituted solution from a solid lyophilized composition of Compound I is in a vial.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation is in a vial.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation is a reconstituted solution from a solid lyophilized composition of Compound I is further diluted in an I.V. (intravenous) solution or an I.V. fluid bag or in an I.V. solution line.
  • I.V. intravenous
  • I.V. fluid bag or in an I.V. solution line.
  • the formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the formulation is further diluted in an I.V. (intravenous) solution or an I.V. fluid bag or in an I.V. solution line.
  • I.V. intravenous
  • I.V. fluid bag or in an I.V. solution line.
  • the following numbered embodiments are provided for reconstituted solution prepared from a solid lyophilized Compound I or a pharmaceutically acceptable salt and/or solvate thereof.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein, as the active ingredient, combined with a pharmaceutically acceptable excipient or carrier.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein, as the active ingredient, combined with a pharmaceutically acceptable excipient or carrier.
  • the excipients are added to the formulation for a variety of purposes.
  • the present disclosure relates to an aqueous composition
  • an aqueous composition comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the composition comprises less than or equal to 1 ppm of dissolved oxygen. In one embodiment, the aqueous composition comprises less than 1 ppm of dissolved oxygen.
  • the aqueous composition comprises a bulking agent.
  • the bulking agent is selected from one or more of the group consisting of sucrose, mannitol, and trehalose.
  • the bulking agent is mannitol.
  • the bulking agent is sucrose.
  • the aqueous composition has a pH of 4.5 ⁇ 1. In another embodiment, the aqueous composition has a pH of 4.5 ⁇ 0.5. In some embodiments, the aqueous composition has a pH of 4.5 ⁇ 0.1.
  • the aqueous composition is the composition prior to lyophilization to prepare the lyophilized composition as disclosed herein.
  • diluents may be added to the formulation of the present invention (any formulation comprising a compound of the present invention).
  • diluents include, but are not limited to, water, aqueous solutions of saccharides and/or sugar alcohols (e.g., glucose solution, dextrose solution, lactose solution, maltose solution, fructose solution), saline solution, and other aqueous medium.
  • Bulking agent may be added to the formulations of the present invention.
  • Bulking agents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Bulking agents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, sucrose, trehalose, polymethacrylates (e.g., EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., AVICEL
  • microfine cellulose lactose
  • starch prege
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
  • carbomer e.g., carbopol
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.
  • a disintegrant include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g.,
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention (any composition comprising a compound of the present invention) include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • a liquid pharmaceutical compositions may be prepared using Compound I or a pharmaceutically acceptable salt and/or solvate thereof, and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid pharmaceutical compositions may be prepared using the solid lyophilized forms of the present invention (one or more of compounds of the present invention in lyophilized form) and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Preservatives, chelating agents, and antioxidants such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • antioxidants include, ascorbic acid, monothioglycerol, L-cysteine, thioglycolic acid, sodium metabisulfite, sodium EDTA, di-sodium EDTA, monoethanolamine gentisate, sodium formaldehyde sulfoxylate and sodium bisulfite.
  • preservatives, chelating agents, and/or antioxidants are added to achieve improved storage stability of at least about 18 months or at least about 24 months. In one embodiment, preservatives, chelating agents, and/or antioxidants are added to achieve improved storage stability of at least about 36 months. In one embodiment, preservatives, chelating agents, and/or antioxidants are added to achieve improved storage stability of at about 12 months, about 18 months, about 24 months, or about 36 months.
  • a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, one preferred route of administering the compounds of the present invention is by oral administration.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • the present invention provides a lyophilized solid composition of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein, to be used for intravenous administration upon reconstitution with an appropriate injection solution.
  • the present invention provides a kit comprising a lyophilized solid composition of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein, and an injection solution.
  • the present invention provides a liquid formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein, to be used for intravenous administration.
  • the present invention provides a kit comprising a liquid formulation of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein, and an injection solution.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions, aerosols and elixirs.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • a composition for tableting or capsule filling may be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting; however, they are not subjected to a final tableting step.
  • compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
  • a dosage form may be provided as a kit comprising a solid lyophilized form of Compound I and pharmaceutically acceptable excipients and carriers as separate components.
  • the dosage form kit allow physicians and patients to formulate an oral solution or injection solution prior to use by dissolving, suspending, or mixing the solid lyophilized form of Compound I with pharmaceutically acceptable excipients and carriers.
  • a dosage form kit which provides solid lyophilized form of Compound I has improved stability of Compound I compared to pre-formulated liquid formulations of Compound I.
  • the solid lyophilized form of Compound I or a pharmaceutically acceptable salt and/or solvate thereof is placed in a sterile glass vials at about 5 mg/mL to 50 mg/mL, which is readily used to reconstituted a liquid formulation by addition of a pharmaceutically acceptable diluent to the vial.
  • a sterile vial contains about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/mL.
  • a sterile 10 mL vial contains about 10, 15, 20, or 25 mg of Compound I or a pharmaceutically acceptable salt and/or solvate thereof.
  • a liquid formulation comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof can be placed in a sterile glass vials at about 5 mg/mL to 50 mg/mL, which can be readily used via intravenous administration.
  • a sterile vial contains about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/mL.
  • a sterile 10 mL vial contains about 10, 15, 20, or 25 mg of Compound I or a pharmaceutically acceptable salt and/or solvate thereof.
  • the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is reconstituted prior to administration in pharmaceutically acceptable carrier or solvent.
  • the reconstituted solution formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is administered by an IV.
  • the liquid formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is diluted prior to administration. In one embodiment, the diluted liquid formulation comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, is administered by an IV.
  • solid lyophilized forms of the present invention may be used in pharmaceutical formulations or compositions as single components or mixtures together with other forms of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • pharmaceutical formulations or compositions of the present invention contain 25-100% or 50-100% by weight, of at least one of the solid lyophilized form of Compound I as described herein, in the formulation or composition.
  • compositions of the present invention can comprise about 25-100% or 50-100% by weight, of Compound I or a pharmaceutically acceptable salt and/or solvate thereof, as described herein.
  • the present invention also provides Compounds 1-12, or pharmaceutically acceptable salt or ester thereof.
  • the present invention relates to isolated Compounds 1-12, or pharmaceutically acceptable salt or ester thereof.
  • the present invention relates to purified Compounds 1-12, or pharmaceutically acceptable salt or ester thereof.
  • the present invention relates to isolated and purified Compounds 1-12, or pharmaceutically acceptable salt or ester thereof.
  • the present invention relates to substantially pure Compounds 1-12, or pharmaceutically acceptable salt or ester thereof.
  • the term “purified” refers to a compound that has been separated from other components of a reaction mixture and measures at least 90% (by area) by HPLC.
  • the compound of the present disclosure can be purified by any known purification techniques, including but not limited to, chromatography and recrystallization.
  • purified Compound 1 is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 95% (by area) when analyzed by HPLC.
  • Compounds 1-12, or pharmaceutically acceptable salt or ester thereof can be purified.
  • the Compounds 1-12, or pharmaceutically acceptable salt or ester thereof can be isolated and purified.
  • substantially pure refers to a compound that is at least about 95% pure (by area) as determined by HPLC.
  • substantially pure Compound 1 is at least about 95%, at least about 95.5%, at least about 96%, at least about 96.5%, at least about 97%, at least about 97.5%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, or at least about 99.5%, pure (by area) as determined by HPLC.
  • Compounds 1-12, or pharmaceutically acceptable salt or ester thereof can be substantially pure.
  • Compounds 1, 7, 8, 9, and 10 has the following relative retention times in using the reverse-phase HPLC methods as disclosed herein.
  • RRT (RP-HPLC RRT (RP-HPLC Compound basic mobile phase) acidic mobile phase) 1 0.62 0.88 7 0.75 1.00 10 1.12 1.07 9 0.35 1.05 8 1.24 1.05
  • the present invention relates to Compounds 1-12, or pharmaceutically acceptable salt or ester thereof, which is substantially free of Compound I.
  • Compounds 1-12, or pharmaceutically acceptable salt or ester thereof comprises less than about 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of Compound I.
  • the present disclosure relates to Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, which demonstrates sensitivity to a BRCA2 null cell line relative to the parental cell line.
  • the sensitivity of the BRCA2 null cell line is at least two hundred fold greater than the BRCA2 wild type cell line.
  • the sensitivity is at least twenty fold higher. In some embodiments, the sensitivity is at least 200 fold higher. In other embodiment, the sensitivity is at least 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200 or 400 fold higher.
  • the sensitivity to BRCA2 null cell lines can be determined through proliferation assay on DLD-1 Parental and BRCA2 ⁇ / ⁇ isogenic cell lines as discussed in Example 24.
  • Compounds 1-12, or pharmaceutically acceptable salt or ester thereof can be formed from Compound I via degradation or as impurities during the synthesis of Compound I.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as disclosed herein as the active ingredient, with a pharmaceutically acceptable excipient or carrier.
  • the excipients are added to the formulation for a variety of purposes.
  • Diluents may be added to any formulations described herein. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., AVICEL
  • microfine cellulose lactose
  • starch pregelatinized starch
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
  • carbomer e.g., carbopol
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.
  • a disintegrant include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g.,
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention (any composition comprising a compound of the present invention) include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions may be prepared using the crystalline forms of the present invention (any crystalline form of a compound of the present invention) and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in any liquid compositions described herein, including, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Bulking agents can be included in a pharmaceutical composition.
  • Non-limiting examples include mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hydroxyethylstarch (hetastarch), cellulose, cyclodextrins, glycine, or mixtures thereof.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, one of the preferred route of administration of the compound of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions, aerosols and elixirs.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • a composition for tableting or capsule filling may be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting; however, they are not subjected to a final tableting step.
  • compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
  • a dosage form may be provided as a kit comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, and pharmaceutically acceptable excipients and carriers as separate components.
  • the dosage form kit allow physicians and patients to formulate an oral solution or injection solution prior to use by dissolving, suspending, reconstituting, or mixing the crystalline form of at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, with pharmaceutically acceptable excipients and carriers.
  • formulations of the present invention contain only one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof.
  • Two or more compounds selected from Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof may be used in pharmaceutical formulations or compositions as single components or mixtures.
  • pharmaceutical formulations or compositions of the present invention contain 25-100% or 50-100% by weight, at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as described herein, in the formulation or composition.
  • the pharmaceutical composition of the present disclosure comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, further comprises one or more pharmaceutically active agent.
  • the one or more therapeutically active agent is an anticancer agent.
  • the one or more therapeutically active anticancer agents include, but are not limited to, paclitaxel, vinblastine, vincristine, etoposide, doxorubicin, herceptin, lapatinib, gefitinib, erlotinib, tamoxifen, fulvestrant, anastrazole, lectrozole, exemestane, fadrozole, cyclophosphamide, taxotere, melphalan, chlorambucil, mechlorethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, carboplatin, dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin,
  • Suitable PARP inhibitors include, but are not limited to, 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1 (2H)-one (olaparib, AZD2281, Ku-0059436), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (veliparib, ABT-888), (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (talazoparib, BMN 673), 4-iodo-3-nitrobenzamide (iniparib, BSI-201), 8-fluoro-5-(4-((methylamino)methyl)phenyl)
  • the one or more therapeutically active agent is an immunotherapeutic agent.
  • the one or more immunotherapeutic agents includes, but are not limited to, a monoclonal antibody, an immune effector cell, adoptive cell transfer, an immunotoxin, a vaccine, a cytokine, and the like.
  • Suitable CDK inhibitors include, but are not limited to, AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC202, R-roscovitine), ZK-304709 AT7519M, P276-00, SCH 727965, AG-024322, LEEO11, LY2835219, P1446A-05, BAY 1000394, SNS-032, 5-((3-chlorophenyl)amino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), and the like.
  • the present invention also provides treatment of disorders related to proliferation of cells.
  • a method for selectively activating p53 protein comprising contacting a cell afflicted by disorder related to cell proliferation with Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the method comprises contacting cancer and/or tumor cells with the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein.
  • the method of contacting cancer and/or tumor cells with the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein may induce cell apoptosis or alleviate or delay the progression of the disorder.
  • a method for selectively activating p53 protein comprising contacting a cell afflicted by disorder related to cell proliferation with at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as disclosed herein.
  • a method for stabilizing G-quadruplex (G4) comprising contacting a cell afflicted by disorder related to cell proliferation with at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as disclosed herein.
  • the method comprises contacting cancer and/or tumor cells with at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as disclosed herein.
  • the method of contacting cancer and/or tumor cells with at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as disclosed herein may induce cell apoptosis or alleviate or delay the progression of the disorder.
  • Non limiting examples of cancer that may be treated by the methods of this disclosure include cancer or cancer cells of: colorectum, breast, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, ovary, cervical, thyroid, bladder, kidney, osteosarcoma, blood and heart (e.g., leukemia, lymphoma, and carcinoma), uterine, gastrointestinal malignancies, and carcinomas of the larynx and oral cavity.
  • Non limiting examples of tumors that may be treated by the methods of this disclosure include tumors and tumor cells of: colorectum, breast, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, kidney, osteosarcoma, blood and heart (e.g., leukemia, lymphoma, and carcinoma), uterine, gastrointestine, larynx, and oral cavity.
  • tumors and tumor cells of: colorectum, breast, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, kidney, osteosarcoma, blood and heart (e.g., leukemia, lymphoma, and carcinoma), uterine, gastrointestine, larynx, and oral cavity.
  • the present invention also provides methods of treating, delaying, ameliorating and/or alleviating the progression of disorders or conditions characterized by cell proliferation in a subject. More particularly, the methods of the present invention, as described herein, can involve administration of an effective amount of the solid lyophilized form of the quinolone compounds described herein, in a subject to treat a disorder or a condition characterized by cell proliferation. In one embodiment, the methods of the present invention, as described herein, can involve administration of an effective amount of any one of the compounds of the present invention, in a subject to treat a disorder or a condition characterized by cell proliferation.
  • a formulation or a composition reconstituted from the solid lyophilized form can be administered in an amount effective selectively activate p53 proteins in cancer and/or tumor cells, which may lead to cell death or apoptosis.
  • the terms “subject” and “patient” are used interchangeably throughout the present application.
  • Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as disclosed herein, can be administered in an amount effective to stabilize G4 in cancer and/or tumor cells, which may lead to cell death or apoptosis.
  • disorders or conditions characterized by cell proliferation is cancer.
  • the present invention provides methods of treating or ameliorating cancer, comprising administering a therapeutically effective amount of the formulation which is a reconstituted solution from a solid lyophilized Compound I, or a pharmaceutically acceptable salt or ester thereof as disclosed herein, to a subject in need thereof.
  • the present invention provides methods of treating or ameliorating cancer, comprising administering a therapeutically effective amount of at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, to a subject in need thereof.
  • the method disclosed herein comprises injecting the formulation which is a reconstituted solution from a solid lyophilized Compound I, or a pharmaceutically acceptable salt or ester thereof, directly into a subject.
  • the formulation which is a reconstituted solution from a solid lyophilized Compound I, or a pharmaceutically acceptable salt or ester thereof is further diluted in an I.V. solution/fluid bag or I.V. line then administration to the subject.
  • cancer treated or ameliorated by the method as disclosed herein may be selected from one or more of the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extrahepatic Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma),
  • cancer treated or ameliorated by any one of the methods as disclosed herein may be selected from the group consisting of: heme cancer, colorectum cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing's sarcoma, pancreatic cancer, cancer of the lymph nodes, colon cancer, prostate cancer, brain cancer, cancer of the head and neck, skin cancer, kidney cancer, cancer of the heart, uterine cancer, gastrointestinal malignancies, and carcinomas of the larynx and oral cavity.
  • the cancer treated or ameliorated by the said method is selected from the group consisting of uterine cancer, gastrointestinal malignancies, and carcinomas of the larynx and oral cavity.
  • cancer treated or ameliorated by the said method is heme cancer which is selected from the group consisting of: leukemia, lymphoma, myeloma, and multiple myeloma.
  • cancer treated or ameliorated by any one of the methods as disclosed herein may be selected from the group consisting of: heme cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing's sarcoma, pancreatic cancer, cancer of the lymph nodes, colon cancer, prostate cancer, brain cancer, cancer of the head and neck, skin cancer, kidney cancer, osteosarcoma, and cancer of the heart.
  • cancer treated or ameliorated by the said method is heme cancer which is selected from the group consisting of: leukemia, lymphoma, myeloma, and multiple myeloma.
  • cancer treated or ameliorated by any one of the methods as disclosed herein can be wherein the subject has a mutation in a DNA repair gene.
  • the DNA repair gene is a homologous recombinant gene.
  • the DNA repair gene is a gene in the homologous recombination (HR) dependent deoxyribonucleic acid (DNA) double strand break (DSB) repair pathway.
  • the DNA repair gene is a homologous recombinant (HR) or non-homologous end joining (NHEJ) gene.
  • the DNA repair gene is a gene in the homologous recombination (HR) or non-homologous end joining (NHEJ) dependent deoxyribonucleic acid (DNA) double strand break (DSB) repair pathway.
  • the DNA repair gene is one or more genes selected from the group consisting of BRCA-1, BRCA-2, ATM, ATR, CHK1, CHK2, Rad51, RPA and XRCC3.
  • cancer treated or ameliorated by the said method comprises cancer cells harboring defects in BRCA1 gene (breast cancer type 1), BRCA2 (breast cancer type 2), and/or other members of the homologous recombination pathway.
  • the cancer cells are deficient in BRCA1 and/or BRCA2.
  • the cancer cells are homozygous for a mutation in BRCA1 and/or BRCA2.
  • the cancer cells are heterozygous for a mutation in BRCA1 and/or BRCA2.
  • cancer treated or ameliorated by any one of the methods as disclosed herein is BRCA2 deficient.
  • the Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in the formulation induces more apoptotic cell death in BRCA2 deficient or BRCA2 knockout cells relative to BRCA2 proficient or BRCA2 wild type cells.
  • the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof are selectively toxic to BRCA2 deficient or BRCA2 knockout cells over BRCA2 proficient or BRCA2 wild type cells.
  • BRCA2 deficient or BRCA2 knockout cells exhibit higher sensitivity to the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as compared to BRCA2 proficient or BRCA2 wild type cells.
  • Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof induces more apoptotic cell death in BRCA2 deficient or BRCA2 knockout cells relative to BRCA2 proficient or BRCA2 wild type cells.
  • Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof are selectively toxic to BRCA2 deficient or BRCA2 knockout cells over BRCA2 proficient or BRCA2 wild type cells.
  • BRCA2 deficient or BRCA2 knockout cells exhibit higher sensitivity to Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as compared to BRCA2 proficient or BRCA2 wild type cells.
  • cancer treated or ameliorated by any one of the methods as disclosed herein is BRCA mutant or BRCA-like mutant cancer.
  • the BRCA mutant or BRCA-like mutant cancer is a BRCA2-mutated cancer.
  • the BRCA mutant or BRCA-like mutant cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • the BRCA mutant or BRCA-like mutant cancer is breast cancer or prostate cancer.
  • cancer treated or ameliorated by any one of the methods as disclosed herein is BRCA mutant cancer.
  • the BRCA mutant cancer is a BRCA2-mutated cancer.
  • the BRCA mutant cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • the BRCA mutant cancer is breast cancer or prostate cancer.
  • the present disclosure relates to a method for treating or ameliorating cell proliferation disorder in a human subject, comprising administering to a subject in need thereof a therapeutically effective amount of a formulation which is a reconstituted solution from a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as disclosed herein.
  • the human subject carries a BRCA mutation.
  • the human subject carries a BRCA2 mutation.
  • the human subject is homozygous for a mutation in BRCA2.
  • the present disclosure relates to a method for treating or ameliorating cell proliferation disorder in a human subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof.
  • the human subject carries a BRCA mutation.
  • the human subject carries a BRCA2 mutation.
  • the human subject is homozygous for a mutation in BRCA2.
  • the present disclosure relates to methods for treating cancers, cancer cells, tumors, or tumor cells comprising administering a therapeutically effective amount of a formulation which is a reconstituted solution from a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as disclosed herein.
  • the present disclosure also relates to methods for treating cancers, cancer cells, tumors, or tumor cells comprising administering a therapeutically effective amount of at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, to a subject in need thereof.
  • Non limiting examples of cancer that may be treated by the methods of this disclosure include cancer or cancer cells of: colorectum, breast, ovary, cervix, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, kidney, osteosarcoma, bone (e.g., Ewing's sarcoma), blood and heart (e.g., leukemia, lymphoma, carcinoma), uterine, gastrointestinal malignancies, and carcinomas of the larynx and oral cavity.
  • Non limiting examples of tumors that may be treated by the methods of this disclosure include tumors and tumor cells of: colorectum, breast, ovary, cervix, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, kidney, osteosarcoma, bone (e.g., Ewing's sarcoma), blood and heart (e.g., leukemia, lymphoma, carcinoma), uterine, gastrointestinal malignancies, and carcinomas of the larynx and oral cavity.
  • tumors and tumor cells of: colorectum, breast, ovary, cervix, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, kidney, osteosarcoma, bone (e.g., Ewing's sarcoma), blood and heart (e.g., leukemia, lymphoma, carcinoma), uterine, gastrointestinal malignancies, and carcinomas of the larynx and oral cavity.
  • the present invention also provides methods of decreasing Pol I transcription comprising administering a formulation which is a reconstituted solution from a solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof as disclosed herein, to a subject in need.
  • the inhibition of Pol I transcription is in peripheral blood mononuclear cells (PBMC).
  • PBMC peripheral blood mononuclear cells
  • the inhibition of Pol I transcription can be observed in PBMC at one hour post-IV infusion of a dose comprising a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the dose comprises a therapeutically effective amount of a Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the inhibition of Pol I transcription in PBMC 1 hour post-infusion is at an average level of about 15% inhibition or greater. In another embodiment, the Pol I transcription in PBMC 1 hour post-infusion is at an average level of about 5% inhibition or greater, about 10% inhibition or greater, about 15% inhibition or greater, about 20% inhibition or greater, about 25% inhibition or greater, about 30% inhibition or greater, about 35% inhibition or greater, about 40% inhibition or greater, about 45% inhibition or greater, about 50% inhibition or greater, about 55% inhibition or greater, about 65% inhibition or greater, or about 70% inhibition or greater.
  • the inhibition of Pol I transcription can be observed in MACS (magnetic-activated cell sorting) sorted tumor cells.
  • administering can be effected or performed using any of the various methods known to those skilled in the art.
  • Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, or a composition comprising thereof can be administered, for example, subcutaneously, intravenously, parenterally, intraperitoneally, intradermally, intramuscularly, topically, enteral (e.g., orally), rectally, nasally, buccally, sublingually, vaginally, by inhalation spray, by drug pump or via an implanted reservoir in dosage formulations containing conventional non-toxic, physiologically acceptable carriers or vehicles.
  • a formulation or a composition reconstituted from the solid lyophilized form can be administered, for example, subcutaneously, intravenously, parenterally, intraperitoneally, intradermally, intramuscularly, topically, enteral (e.g., orally), rectally, nasally, buccally, sublingually, vaginally, by inhalation spray, by drug pump or via an implanted reservoir in dosage formulations containing conventional non-toxic, physiologically acceptable carriers or vehicles.
  • the composition of the present disclosure is administered intravenously.
  • Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, or a composition comprising thereof can be administered to a localized area in need of treatment.
  • a formulation or a composition reconstituted from the presently disclosed lyophilized forms can be administered to a localized area in need of treatment.
  • Administration to a localized area can be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, transdermal patches, by injection, by catheter, by suppository, or by implant (the implant can optionally be of a porous, non-porous, or gelatinous material), including membranes, such as sialastic membranes or fibers.
  • compositions comprising thereof, or the formulation or the composition in which the solid lyophilized form is administered (e.g., syrup, elixir, capsule, tablet, foams, emulsion, gel, etc.) will depend in part on the route by which it is administered.
  • mucosal e.g., oral mucosa, rectal, intestinal mucosa, bronchial mucosa
  • nose drops, aerosols, inhalants, nebulizers, eye drops or suppositories can be used.
  • Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, or a composition comprising thereof, and the solid lyophilized form can also be used to coat bioimplantable materials to enhance neurite outgrowth, neural survival, or cellular interaction with the implant surface.
  • Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, or a composition comprising thereof; or the solid lyophilized forms disclosed herein can be administered together with other biologically active agents, such as anticancer agents, analgesics, anti-inflammatory agents, anesthetics and other agents which can control one or more symptoms or causes of a disorder or a condition characterized by cell proliferation.
  • the solid lyophilized form of Compound I, or pharmaceutically acceptable salt and/or solvate of Compound I, as disclosed herein, can be administered in combination with one or more therapeutically active agent.
  • the one or more therapeutically active agent is an anticancer agent.
  • the one or more therapeutically active anticancer agents include, but are not limited to, paclitaxel, vinblastine, vincristine, etoposide, doxorubicin, hercepztin, lapatinib, gefitinib, erlotinib, tamoxifen, fulvestrant, anastrazole, lectrozole, exemestane, fadrozole, cyclophosphamide, taxotere, melphalan, chlorambucil, mechlorethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, carboplatin, dactinomycin (actinomycin D), doxorubici(adriamycin), daunorubicin
  • the one or more therapeutically active anticancer agents include, but are not limited to, PARP (poly (DP-ribose)polymerase) inhibitors.
  • PARP inhibitors include, but are not limited to, 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1 (2H)-one (olaparib, AZD2281, Ku-0059436), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (Veliparib, ABT-888), (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (talazoparib, BMN 673), 4-i
  • the one or more therapeutically active agent is an immunotherapeutic agent.
  • the one or more immunotherapeutic agents includes, but are not limited to, a monoclonal antibody, an immune effector cell, adoptive cell transfer, an immunotoxin, a vaccine, a cytokine, and the like.
  • Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, or a composition comprising thereof can be administered in combination with radiotherapy.
  • the solid lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate of Compound I, as disclosed herein can be administered in combination with radiotherapy.
  • administration can comprise administering to the subject a plurality of dosages over a suitable period of time.
  • administration regimens can be determined according to routine methods, upon a review of the instant disclosure.
  • Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, of the invention are generally administered in a dose of about 0.01 mg/kg/dose to about 100 mg/kg/dose.
  • the dose can be from about 0.1 mg/kg/dose to about 10 mg/kg/dose; or about 1 mg/kg/dose to 10 mg/kg/dose.
  • Time release preparations may be employed or the dose may be administered in as many divided doses as is convenient.
  • solid lyophilized forms are administered to the affected tissue at a rate from about 0.05 to about 10 mg/kg/hour, alternately from about 0.1 to about 1 mg/kg/hour.
  • topically administered formulations are administered in a dose of about 0.5 mg/kg/dose to about 10 mg/kg/dose range.
  • topical formulations are administered at a dose of about 1 mg/kg/dose to about 7.5 mg/kg/dose or even about 1 mg/kg/dose to about 5 mg/kg/dose.
  • Lyophilized forms of the invention are generally administered in a dose of about 0.01 mg/kg/dose to about 100 mg/kg/dose. Alternately the dose can be from about 0.1 mg/kg/dose to about 10 mg/kg/dose; or about 1 mg/kg/dose to 10 mg/kg/dose. Time release preparations may be employed or the dose may be administered in as many divided doses as is convenient. When other methods are used (e.g. intravenous administration), solid lyophilized forms are administered to the affected tissue at a rate from about 0.05 to about 10 mg/kg/hour, alternately from about 0.1 to about 1 mg/kg/hour. Such rates are easily maintained when these solid lyophilized forms are intravenously administered as discussed herein.
  • topically administered formulations are administered in a dose of about 0.5 mg/kg/dose to about 10 mg/kg/dose range.
  • topical formulations are administered at a dose of about 1 mg/kg/dose to about 7.5 mg/kg/dose or even about 1 mg/kg/dose to about 5 mg/kg/dose.
  • a range of from about 0.1 to about 100 mg/kg is appropriate for a single dose.
  • Continuous administration is appropriate in the range of about 0.05 to about 10 mg/kg.
  • Drug doses can also be given in milligrams per square meter of body surface area rather than body weight, as this method achieves a good correlation to certain metabolic and excretionary functions.
  • a dosage form of the present invention may contain at least one of Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as disclosed herein, in an amount of about 5 mg to about 500 mg.
  • a dosage form of the present invention may contain at least one of Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, as disclosed herein, in an amount of about 5 mg to about 500 mg.
  • a dosage form of the present invention may contain Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 425 mg, 430 mg, 440 mg, 450 mg,
  • the lyophilized forms of the invention are generally administered in a dose of about 1 mg/m 2 to about 2000 mg/m 2 of Compound I, or a pharmaceutically acceptable salt and/or solvate of Compound I, as disclosed herein. In one embodiment, the lyophilized forms of the invention are administered in a dose of about 10 mg/m 2 to about 1500 mg/m 2 of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof. In another embodiment, the lyophilized forms of the invention are administered in a dose of about 200 mg/m 2 to about 800 mg/m 2 of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the lyophilized forms of the invention are administered in a dose of about 20 mg/m 2 to about 300 mg/m 2 of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the dose can vary dependent on the type of diseases or conditions which Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is being administered for (e.g., cancer or solid tumor).
  • the dose can vary depending on the health of the patients or the patient's sensitivity to Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the lyophilized forms of the invention are administered in a dose of about 25 mg/m 2 to about 2000 mg/m 2 of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the lyophilized forms of the invention can be administered in a dose of about 25 mg/m 2 , about 30 mg/m 2 , about 35 mg/m 2 , about 40 mg/m 2 , about 45 mg/m 2 , about 50 mg/m 2 , about 55 mg/m 2 , about 60 mg/m 2 , about 65 mg/m 2 , about 70 mg/m 2 , about 75 mg/m 2 , about 80 mg/m 2 , about 85 mg/m 2 , about 90 mg/m 2 , about 95 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 125 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/
  • the lyophilized forms of the invention can be generally administered in a dose of about less than about 500 mg/m 2 of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the lyophilized forms of the invention are generally administered in a dose of less than about 500 mg/m 2 , less than about 490 mg/m 2 , less than about 480 mg/m 2 , less than about 475 mg/m 2 , less than about 470 mg/m 2 , less than about 460 mg/m 2 , less than about 450 mg/m 2 , less than about 440 mg/m 2 , less than about 430 mg/m 2 , less than about 420 mg/m 2 , less than about 410 mg/m 2 , less than about 400 mg/m 2 , less than about 390 mg/m 2 , less than about 380 mg/m 2 , less than about 375 mg/m 2 , less than about 370 mg/m 2 , less than about 360 mg/m 2 ,
  • the lyophilized forms of the invention can be administered to a cancer patient in a dose of less than about 750 mg/m 2 , less than about 700 mg/m 2 , less than about 600 mg/m 2 , less than about 500 mg/m 2 , less than about 475 mg/m 2 , less than about 400 mg/m 2 , less than about 325 mg/m 2 , less than about 300 mg/m 2 , less than about 200 mg/m 2 , less than about 170 mg/m 2 , or any subranges therein, of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the lyophilized forms of the invention can be administered to a cancer patient in a dose of less than about 170 mg/m 2 of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, every three weeks.
  • the cancer patient is a heme cancer patient.
  • the lyophilized forms of the invention can be administered to a cancer patient in about 50 mg/m 2 to about 1550 mg/m 2 , about 150 mg/m 2 to about 1250 mg/m 2 , about 250 mg/m 2 to about 1050 mg/m 2 , about 350 mg/m 2 to about 950 mg/m 2 , about 375 mg/m 2 to about 850 mg/m 2 , about 425 mg/m 2 to about 850 mg/m 2 , about 450 mg/m 2 to about 800 mg/m 2 , or about 500 mg/m 2 to about 750 mg/m 2 , or any subranges therein, of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the lyophilized forms of the invention can be administered to a cancer patient in a dose of less than about 750 mg/m 2 of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof. In other embodiments, the lyophilized forms of the invention can be administered to a cancer patient in any of the dosing frequency, dosing cycle or dosing regimen described herein. In one embodiment, the treatment is for solid tumors.
  • a dosage form of the present invention containing Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.
  • a dosage form of the present invention containing Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein is administered in a four-week treatment cycle comprising one administration weekly (QW ⁇ 4).
  • a dosage form of the present invention containing Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein is administered in a four-week treatment cycle comprising one administration weekly for two weeks followed by two weeks of rest period (no treatment) (QW ⁇ 2).
  • a dosage form of the present invention containing Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein is administered in a three-week treatment cycle comprising one administration weekly for two weeks followed by one week of rest period.
  • a dosage form of the present invention containing Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein is administered once every three weeks.
  • a dosage form of the present invention containing Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein is administered once every three weeks by IV infusion.
  • the treatment regimen with Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein can last from 1 cycle to 20 cycles or greater period of time.
  • An appropriate length of the treatment can be determined by a physician.
  • T max of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof for human subjects who received a first dose of IV infusion administration at about 25 mg/m 2 to about 1000 mg/m 2 of the lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is about 0.25 hour to about 1.25 hour. In another embodiment, T max is about 0.5 hour to about 1.0 hour.
  • the mean elimination half-life (T 1/2 ) of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof for human subjects who received a first dose of IV infusion administration at about 25 mg/m 2 to about 1000 mg/m 2 of the lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is about 20 hours to about 95 hours.
  • the mean elimination half-life (T 1/2 ) of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof for human subjects who received a first dose of IV infusion administration at about 50 mg/m 2 to about 1000 mg/m 2 of the lyophilized form of Compound I, or a pharmaceutically acceptable salt and/or solvate thereof is about 20 hours to about 50 hours.
  • the unbound Compound I in area under the concentration-time curve for each dosing interval every 168 hours after steady-state exposures have been achieved is about 2 ng ⁇ hr/mL to about 300 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 50 mg/m 2 to about 1550 mg/m 2 .
  • the AUC ss ⁇ is about 5 ng ⁇ hr/mL to about 200 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 150 mg/m 2 to about 1050 mg/m 2 .
  • the AUC ss ⁇ is about 10 ng ⁇ hr/mL to about 150 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 250 mg/m 2 to about 950 mg/m 2 . In one embodiment, the AUC ss ⁇ is about 15 ng ⁇ hr/mL to about 140 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 350 mg/m 2 to about 850 mg/m 2 .
  • the AUC ss ⁇ is about 15 ng ⁇ hr/mL to about 150 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 450 mg/m 2 to about 750 mg/m 2 . In one embodiment, the AUC ss ⁇ is about 20 ng ⁇ hr/mL to about 120 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 450 mg/m 2 to about 750 mg/m 2 . In some embodiments, the subject is on QW ⁇ 4 cycle dosing regimen.
  • the AUC ss ⁇ is about 2 ng ⁇ hr/mL to about 250 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 50 mg/m 2 to about 1550 mg/m 2 . In one embodiment, the AUC ss ⁇ is about 5 ng ⁇ hr/mL to about 150 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 150 mg/m 2 to about 1050 mg/m 2 .
  • the AUC ss ⁇ is about 10 ng ⁇ hr/mL to about 150 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 250 mg/m 2 to about 950 mg/m 2 . In one embodiment, the AUC ss ⁇ is about 15 ng ⁇ hr/mL to about 130 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 350 mg/m 2 to about 850 mg/m 2 .
  • the AUC ss ⁇ is about 15 ng ⁇ hr/mL to about 130 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 450 mg/m 2 to about 750 mg/m 2 . In one embodiment, the AUC ss ⁇ is about 20 ng ⁇ hr/mL to about 120 ng ⁇ hr/mL for subjects who received Compound I, or a pharmaceutically acceptable salt and/or solvate thereof in about 450 mg/m 2 to about 750 mg/m 2 . In some embodiments, the subject is on QW ⁇ 2 four-week cycle dosing regimen.
  • a dosage form of the present invention may contain Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein, in an amount of about 5 mg to about 500 mg. That is, a dosage form of the present invention may contain Compound I in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 375 mg, 380 mg, 390 mg,
  • a dosage form of the present invention may contain Compound I, or a pharmaceutically acceptable salt and/or solvate thereof, as disclosed herein, in an amount of about 500 mg to about 1000 mg. That is, a dosage form of the present invention may contain Compound I in an amount of about 500 mg, 510 mg, 520 mg, 525 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 575 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 625 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 675 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 725 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 775 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 825 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 875 mg, 880 mg, 890 mg,
  • a dosage form of the present invention may be administered, hourly, daily, weekly, or monthly.
  • the dosage form of the present invention may be administered twice a day or once a day.
  • the dosage form of the present invention may be administered with food or without food.
  • the crystalline forms or the solid lyophilized forms disclosed herein can take the form of a mimetic or fragment thereof, it is to be appreciated that the potency, and therefore dosage of an effective amount can vary. However, one skilled in the art can readily assess the potency of a crystalline form or a solid lyophilized form of the type presently envisioned by the present application.
  • a gradually progressive disorder or condition characterized by cell proliferation In settings of a gradually progressive disorder or condition characterized by cell proliferation, Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, or a composition comprising thereof, of the present application is generally administered on an ongoing basis.
  • a gradually progressive disorder or condition characterized by cell proliferation a formulation or a composition reconstituted from a solid lyophilized form of the present application is generally administered on an ongoing basis.
  • administration of a formulation or a composition reconstituted from a lyophilized form disclosed herein can commence prior to the development of disease symptoms as part of a strategy to delay or treat the disease.
  • Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, or a composition comprising thereof is administered after the onset of disease symptoms as part of a strategy to slow or reverse the disease process and/or part of a strategy to improve cellular function and reduce symptoms.
  • a formulation or a composition reconstituted from a solid lyophilized form disclosed herein is administered after the onset of disease symptoms as part of a strategy to slow or reverse the disease process and/or part of a strategy to improve cellular function and reduce symptoms.
  • dosage range will depend on the particular composition comprising Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, and its potency.
  • the dosage range will depend on the particular lyophilized form, and its potency.
  • the dosage range is understood to be large enough to produce the desired effect in which the neurodegenerative or other disorder and the symptoms associated therewith are ameliorated and/or survival of the cells is achieved, but not be so large as to cause unmanageable adverse side effects.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific composition comprising Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
  • the specific composition comprises lyophilized form of Compound I. The dosage can also be adjusted by the individual physician in the event of any complication.
  • An effective amount of Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, disclosed herein comprise amounts sufficient to produce a measurable biological response.
  • Actual dosage levels of active ingredients can be varied so as to administer an amount of Compound I or Compounds 1-12, or a pharmaceutically acceptable salt or ester thereof, that is effective to achieve the desired therapeutic response for a particular subject and/or application.
  • an effective amount of the solid lyophilized forms disclosed herein comprise amounts sufficient to produce a measurable biological response.
  • Actual dosage levels of active ingredients in a therapeutic solid lyophilized form of the present application can be varied so as to administer an amount of the solid lyophilized form that is effective to achieve the desired therapeutic response for a particular subject and/or application.
  • a minimal dose is administered, and the dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of a therapeutically effective dose, as well as evaluation of when and how to make such adjustments, are known to those of ordinary skill in the art.
  • a preferred subject is a vertebrate subject.
  • a preferred vertebrate is warm-blooded; a preferred warm-blooded vertebrate is a mammal.
  • the subject treated by the presently disclosed methods is desirably a human, although it is to be understood that the principles of the present application indicate effectiveness with respect to all vertebrate species which are included in the term “subject.”
  • a vertebrate is understood to be any vertebrate species in which treatment of a neurodegenerative disorder is desirable.
  • the term “subject” includes both human and animal subjects.
  • veterinary therapeutic uses are provided in accordance with the present application.
  • the present application provides for the treatment of mammals such as humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and/or animals of social importance to humans, such as animals kept as pets or in zoos or farms.
  • animals include but are not limited to: carnivores such as cats and dogs; swine, including pigs, hogs, and wild boars; ruminants and/or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels; and horses.
  • domesticated fowl i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economic importance to humans.
  • livestock including, but not limited to, domesticated swine, ruminants, ungulates, horses (including race horses), poultry, and the like.
  • Compound I or a pharmaceutically acceptable salt, solvate, and/or prodrug can be synthesized by known synthetic routes or by chemistry known by one skilled in the art (see, e.g., U.S. Pat. Nos. 7,928,100 and 8,853,234).
  • Non-lyophilized Compound I was formulated into ready-to-use solution having the following composition:
  • Compound I was dissolved in monosodium phosphate buffer solution, the pH was adjusted to 6 with 1M HCl, and sterile filtration was carried out. The filtered solution was filled into 10 mL vials and sealed with stoppers and flip-off seals.
  • the ready-to-use formulation prepared with non-lyophilized Compound I showed more than 1% impurity under the tested storage conditions. Under the accelerated conditions (Table 1), the impurities increased to about 1.5% in one month, to about 2.5% at 3 months, and about 4% by 6 months. The non-lyophilized Compound I was determined to not have adequate stability at 25° C. and at 40° C.
  • the solution was filtered through a filter chain (1 ⁇ 0.45 ⁇ m and 2 ⁇ 0.2 ⁇ m in series).
  • the filtered solution was pumped into 30 mL vials (approximately 5 g or 5 mL each), partially stoppered and placed in the freeze dryer chamber.
  • the freeze dry cycle used is shown in Table 3.
  • the primary drying process is complete after 4900 minutes. In some embodiments, the total cycle time is about 4.4 days.
  • Free drying microscope was used to determine the collapse temperature of the solid lyophilized form of Compound I as prepared according to Example 2. Analysis was performed with and without an annealing step. Each analysis was performed using a 10 ⁇ objective lens with bright field transmitted light. A summary of the key observations from each analysis performed are shown in Table 4. Two runs were performed; run 1 with an annealing step ( ⁇ 15° C.) and run 2 without the annealing step.
  • the solution containing the solid lyophilized form of Compound I as prepared according to Example 2 was analyzed by differential scanning calorimetry (DSC), with and without annealing, using the parameters shown in Table 5.
  • Run 1 was conducted without an annealing step. On cooling, a large well defined freezing exotherm ( ⁇ 15.59° C.) and a second smaller exotherm was detected ( ⁇ 31.7° C.). Without bound to any theory, the second exotherm is thought to be a result of the partial crystallization of mannitol. On warming, a small exotherm was observed at approximately ⁇ 25° C. before reaching the large broad melting endoderm which had an onset temperature at ⁇ 2.43° C. DSC thermogram of Run 1 is shown in FIGS. 1-3 .
  • Run 2 was conducted with an annealing step at ⁇ 15° C., which was held for 10 minutes.
  • the observations from the DSC thermogram were similar to Run 1.
  • On cooling a large well defined freezing exotherm and a secondary smaller exotherm were observed at ⁇ 20.42° C. and ⁇ 31.53° C., respectively.
  • On warming a small exotherm, thought to represent mannitol crystallization, was detected at ⁇ 26° C. Following annealing at ⁇ 15° C. the crystallization exotherm is not observed.
  • a small endotherm was observed at ⁇ 16° C. Without bound to any theory, this endotherm was thought to be a result of a small melt. With continued heating, a larger broad melting endoderm was observed which had an onset temperature at ⁇ 2.69° C.
  • DSC thermogram of Run 2 is shown in FIGS. 4-7 .
  • Run 3 was conducted with an annealing step at ⁇ 20° C., which was held for 10 minutes. On cooling, a large well defined freezing exotherm and a secondary smaller exotherm were observed at ⁇ 21.36° C. and ⁇ 35.39° C., respectively. After annealing, a small endotherm was observed at ⁇ 17.28° C. before the major melt at ⁇ 3.91° C. DSC thermogram of Run 3 is shown in FIGS. 8 and 9 .
  • Run 4 was conducted with an annealing step at ⁇ 10° C., which was held for 10 minutes. On cooling, a large well defined freezing exotherm and a secondary smaller exotherm were observed at ⁇ 18.23° C. and ⁇ 27.26° C., respectively. The exotherm observed at approximately ⁇ 28° C. before annealing could no longer be observed on heating after the annealing step. The endotherms, previously found in Runs 1-3 (at approximately ⁇ 16° C.) that were, without bond to any theory, thought to be due to minor melts of mannitol were no longer observed. This suggests that annealing at ⁇ 10° C. could promote better crystallization of mannitol, and therefore remove this minor melting event. DSC thermogram of Run 4 is shown in FIGS. 10 and 11 .
  • the formulation should be cooled to at least ⁇ 40° C. during freezing and the temperature should be kept below ⁇ 16° C. during first drying step.
  • an annealing temperature of about ⁇ 10° C. is also recommended to prevent the endotherm at approximately ⁇ 16° C.
  • lyophilization cycle (conservative cycle, e.g., each stage of lyophilization was conducted for a greater period of time to assure that it goes to completion before the next stage was initiated) was repeated for the formulation as described in Table 6.
  • citrate buffer which is also a suitable buffer for the target pH range around 4.5. It was also observed that most of the cakes prepared according to Table 6 turned pale yellowish upon storage indicative of oxidation.
  • mannitol formulations were assayed in stability test at room temperature before lyophilization (“Pre-lyo”), 7 days after lyophilization, and 14 days after lyophilization (Table 7). Each formulation was analyzed via reverse-phase (RP) HPLC using parameters shown below.
  • Compound 1, 7, 8, 9, and 10 has the following relative retention times when using RP-HPLC method discussed directly above.
  • the EDTA containing formulations showed more than 2% degradation within three weeks at RT at either pH. All the formulation cakes had a distinct yellow color. The impurity at RRT 1.07 for these formulations was correspondingly higher (greater than 0.5%). The pH did not seem to affect the behavior of the formulations containing EDTA.
  • Sucrose and trehalose were evaluated as alternative bulking agent to mannitol. These two sugars are essentially disaccharides and do not contain reducing functions that may possibly react with amines as in the case of mannitol which may contain traces of reducing functions present during its manufacture. Initially, trehalose was evaluated at 2% w/v and 5% w/v in the presence of citrate buffer and ascorbic acid as antioxidant. The stability of these formulations was evaluated at RT and 50° C. and the results are summarized in Table 11.
  • trehalose/ascorbic acid formulations were found to be stable at RT for three weeks (Tables 12 and 13). Each formulation was analyzed via reverse-phase (RP) HPLC using parameters as discussed in Example 5 at room temperature before lyophilization (“Pre-lyo”), 4 days after lyophilization, 10 days after lyophilization, 21 days after lyophilization, and 28 days after lyophilization, and at 50° C. at 28 days after lyophilization.
  • Pre-lyo room temperature before lyophilization
  • the impurity at RRT 1.05 was ⁇ 0.15 and negligible at RRT 1.07. However, after four weeks, some of these formulations turned reddish brown at 50° C. When these formulations were analyzed by RT-HPLC, N-oxide peak at RRT 1.05 was seen as increased but no change in the ketone peak at RRT 1.07. The browning in the vials was random and was considerably high at 50° C. For trehalose formulations with 5% ascorbic acid, within four weeks the N-oxide impurity increased significantly from 0.134% to 0.631% at both RT and 50° C. It does seem that ascorbic acid reacts with the drug at higher temperatures which results in poor stability of the formulation. Additionally, the vial-to-vial variability may have been due to moisture variability within the individual vials.
  • sucrose and trehalose formulations were lyophilized with 0, 0.5, and 1% ascorbic acid without any buffer (pH was adjusted with either HCl or NaOH). Additionally, formulations without any bulking agent, buffer or antioxidant were also lyophilized (to see if the yellow color formation was due to the excipients). These formulations are summarized in Table 14.
  • Formulations SC05, SC1, and TC1 as discussed in Table 14 were analyzed via reverse-phase (RP) HPLC using parameters as discussed in Example 5 at room temperature and at 50° C., 4 days after lyophilization, 14 days after lyophilization, and 28 days after lyophilization.
  • RP reverse-phase
  • Formulations HOM, SC0, and TC0 as discussed in Tables 14 and 16 were analyzed via reverse-phase (RP) HPLC using parameters as discussed in Example 5 at room temperature and at 50° C., 14 days after lyophilization, 28 days after lyophilization, 42 days after lyophilization, and/or 96 days after lyophilization (Tables 17a and 17b).
  • RP reverse-phase
  • sucrose and trehalose remain amorphous in the interstitial freeze concentrate and impart stability to the drug from oxidation, possibly by matrix dilution effect.
  • Mannitol solution was prepared by weighing 200 g+1.0 g of mannitol into glass beaker, adding approximately 1500 mL of WFI (water for injection) to the beaker and stirring until mannitol was dissolved. The mannitol solution was transferred to a 2 L volumetric flask and made to volume with WFI, then poured back to the original beaker to sir and mix further. 1M HCl solution was prepared by adding 16.4 mL of HCl (37%) to a 200 mL volumetric flask containing approximately 100 mL of WFI, adding WFI to make 200 mL in volume, and inverting to mix the prepared solution.
  • WFI water for injection
  • the final solution (pH adjusted and diluted) was filtered (chain including PVD Fmembrane filter 0.45 m and 0.22 m; peristaltic filtration pump by Watson Marlow) in the Bigneat and the bottle containing the filtered solution was sealed.
  • the filtered solution was pumped (Watson Marlow Flexicon PF6-B pump; 100 RPM) into 30 mL Schott Clear Glass vials (10.0 mL filtered solution each).
  • the glass vials were partially stoppered with 20 mm Freeze Dry Stopper Flurotec (Daikyo Seiko) one vial at a time with sterilized utensils inside a fume hood (Envair B101+1.5R) and placed on freeze dryer trays.
  • the freeze dryer trays were transferred into freeze dry chamber and vial probe was positioned (Lyostar II; FTS Kinetics). Lyophilization was performed using the lyophilization cycle listed below. After lyophilization cycle finished, the vials were back filled with N 2 and the stopper was placed in situ, wiped down with isopropanol in the fume hood once removed from the freeze dryer, reconciled, then crimped. Seven vials out of 186 sample vials placed under the lyophilization cycle had smashed in the freeze dryer. Stability data for samples prepared by Method A is shown in Tables 18a and 18b.
  • the resulting solution was sparged with N 2 while stirring until dissolved oxygen content was ⁇ 1 ppm (approx. 30 min).
  • the headspace of the Schott bottle containing mannitol and HCl was purged with N 2 for 3 minutes and the bottle was sealed.
  • the pH of the Compound I solution (in Schott bottle) was measured then adjusted to pH 4.5 ⁇ 0.1 using 2 M HCl and 2 M NaOH solutions in a stepwise manner. After each addition of HCl or NaOH solutions, the solution was stirred for several minutes prior to verifying the pH.
  • the pH adjusted Compound I solution was transferred to a 1000 mL volumetric flask and to a 500 mL volumetric flask and the flasks were filled with degassed WFI to the mark. Diluted solutions were transferred back to the original 2 L Schott bottle and sparged N 2 while stirring until dissolved oxygen content was ⁇ 1 ppm (approx. 30 min).
  • the headspace of the Schott bottle was purged with N 2 for 3 minutes and the bottle was sealed.
  • the final solution (pH adjusted and diluted) was filtered (chain including PVDF membrane filter 1 ⁇ 0.45 m and 2 ⁇ 0.22 m in series; peristaltic filtration pump) in the Big Neat and CTS cabinets and the bottle containing the filtered solution was sealed (The peristalitic pump filtration steps were not performed under N 2 ).
  • the filtered solution was pumped (Watson Marlow Flexicon PF6-B pump; 100 RPM) into 30 mL Schott Clear Glass vials (5.0 mL filtered solution each).
  • the glass vials were partially stoppered with 20 mm Freeze Dry Stopper Flurotec (West Pharma) one vial at a time with sterilized utensils inside a fume hood and placed on freeze dryer trays.
  • the freeze dryer trays were transferred into freeze dry chamber and vial probe was positioned. Lyophilization was performed using the lyophilization cycle according to Table 3, Example 2. After lyophilization cycle finished, the vials were back filled with N 2 and the stopper was placed in situ, wiped down with isopropanol in the fume hood once removed from the freeze dryer, reconciled, then crimped. No vials failed (out of 258 sample vials) during the lyophilization cycle (e.g., no vials smashed in the freeze dryer).
  • Composition for Lyophilization of Compound I Ingredient Amount/mL Rationale for use Compound I 30 mg Active Sucrose, USP/EP 20 mg Stabilizer Hydrochloric acid, NF/EP QS for pH pH adjustment (as 1 N solution) Sodium Hydroxide, NF/EP QS for pH pH adjustment (as 1 N solution) Water for injection, USP* QS to 1 mL Vehicle *Removed during lyophilization
  • Tg′ glass transition temperature
  • the lyophilization parameters during the primary drying were chosen such that the product temperature remained below ⁇ 30° C. during the sublimation phase of the drying.
  • a thermal treatment step during freezing was included at ⁇ 15° C. for approximately 1 hour to ensure consistent thermal behavior amongst the vials.
  • the shelf temperature was raised to 0 and then to 25° C. and maintained at 25° C. during the rest of the drying cycle to ensure that the secondary (desorption) drying phase was complete and dry product was obtained with very low residual moisture level.
  • the lyophilization process parameters are disclosed in Table 20.
  • Post Stoppered vials may be held in the Lyophilizer at Stoppering +25° C. ⁇ 3° C. for up to 24 hours. Hold:
  • the product temperature did remain below its critical temperature of about ⁇ 30° C. during the early part of the sublimation drying.
  • the duration of the primary drying is longer due to the fact that the volume of the solution to be lyophilized is 5 mL. This is indicated by the rise in the temperature of the thermocouple containing vials once the ice was sublimed and the heat received was used to raise the temperature of the cake. The additional hold at the primary drying temperature was to ensure that the vials from the entire lot have completed the primary drying before the shelf temperature is raised to the secondary drying temperatures.
  • Example 10 Preparation of Liquid Formulation Comprising Compound I and Sucrose and Preparation of Lyophilized Form of Compound I with Sucrose for Injection 30 mg/mL (150 mg/Vial)
  • a standard sterile filtration operation was designed to perform sterilization of the compounded bulk solution by membrane filtration through two 0.22 ⁇ M hydrophilic polyvinylidene fluoride (PVDF) membranes contained in a polycarbonate housing.
  • PVDF polyvinylidene fluoride
  • the compounded bulk passed through the two sterilizing membranes in series, as is typical in sterile filtration operations, to provide redundant sterilizing capability.
  • the Compound I sterile solution was filled into 20-cc clean, de-pyrogenated glass vials, with periodic weight checks to assure that the target fill quantity (5.05 g/vial) was maintained, and the vials were semi-stoppered with sterile elastomeric closures to provide a sample of Formulation A.
  • the filled vials are then transferred onto the shelves of the lyophilizer chamber for lyophilization to provide a sample of lyophilized Formulation B. Samples of Formulation A and Formulation B were analyzed using the RP-HPLC Chromatography (base mobile phase) as shown below.
  • the density of the Compound I bulk solution for lyophilization was determined using the Mettler Toledo Density meter (Densito 30 PX) at room temperature and was found to be 1.005 g/mL.
  • the lyophile displacement volume is the volume of re-constituted solution in milliliters, displaced by 1.0 g of the lyophilized dry material (that contains the dried Compound I and excipients).
  • the displacement volume is required for the determination of overfill necessary to achieve a 15 mg/mL solution upon reconstitution with exactly 10.0 mL of WFI (water for injection).
  • the displacement volume for lyophilized Compound I for Injection was determined by placing 1000 mg of lyophilized material into a 10 mL volumetric flask and then adding 10.0 mL of water. The volume of the solution, in excess of 10.0 mL caused by displacement due to the solid content was then measured. Approximately 0.73 mL of water was found displaced when 1 ⁇ m of the lyophilized material was dissolved.
  • the displacement value of the lyophilized cake was calculated as follows: The total weight of Compound I (150 mg) plus the added sucrose (100 mg) per vial is 250 mg. Therefore, for a 10.0 mL reconstitution volume to achieve concentration of 15.0 mg/mL of Compound I, the displacement value of the dried material will be 0.18 mL (250 mg ⁇ 0.73) resulting in 10.18 mL total volume or 14.73 mg/mL of Compound I. To account for this discrepancy caused by the displacement volume, one must fill about 5.1 mL of the solution to be lyophilized. The resulting dry product will then contain enough of Compound I in the reconstituted solution to deliver the targeted concentration of 15 mg/mL.
  • the lyophilization composition prepared with sucrose can be beneficial compared to composition prepared with mannitol because the amount of solid content was significantly reduced from 500 mg mannitol to 100 mg sucrose (per 150 mg of Compound I). This significant reduction of solid content when using sucrose can be beneficial in reducing fill volumes of the lyophilization solution in lyophilization vials.
  • sucrose can be a useful bulking agent for preparing solid lyophilized forms of Compound I with good stability.
  • the lyophilized composition prepared with sucrose can also be beneficial compared to composition prepared with mannitol in reducing or eliminating vial breakage during the lyophilization cycle as, without bound to any theory, sucrose did not expand as much as mannitol, which was one cause in vial breakages.
  • Compound I The effect of Compound I on cell viability was assessed by Alamar Blue assay of metabolic activity in various cancer cell lines.
  • Table 22 shows Compound I demonstrate broad spectrum antiproliferative activity in multiple cancer cell lines, while being significantly less active in normal cells.
  • TNBC triple-negative breast cancer
  • PDX patient-derived xenograft
  • Compound I was tested at different concentrations for their anti-proliferative effects using Horizon's precisely engineered isogenic cell line pairs, DLD1 and isogenic BRCA2 ⁇ / ⁇ cell lines. This study was conducted in vitro. Compound I has shown to be selectively toxic to BRCA2 deficient cancer cell lines (Compound I is selectively toxic to BRCA2 knockout cells but not to BRCA2 proficient wild type cells, e.g., BRCA2 +/+ and BRCA2 +/ ⁇ ). The sensitivity of DLD1 Parental and BRCA2 ⁇ / ⁇ isogenic cell lines to Compound I as a single agent was also evaluated to look for evidence of synthetic lethality.
  • Compound I The activity of Compound I was evaluated with short (48 hours) and long (6 days) endpoints using CellTiter-Glo® (Promega). Incubation times were 6 days (144 h) in the presence of Compound I. Test compounds were dissolved in NaH 2 PO 4 .
  • the DLD1 BRCA2 ⁇ / ⁇ line was significantly more sensitive to Compound I in the 6-day proliferation assay relative to the parental line, which is indicative of a synthetic lethal effect.
  • TGI Tumor growth inhibition
  • NGS Next Generation Sequencing revealed BRCA1 mutation (non-deleterious).
  • CTG-0012 sBRCA1m The PDX tumor was derived from a 36 year old (Y978*) Caucasian woman with Stage IV TNBC. Prior to the gBRCA2m PDX tumor harvesting, she was treated with Docetaxel (N372H) for a duration of 12 months before her disease progressed. The patient was subsequently treated with Capecitabine/Bevacizumab and Vinorelbine/Bevacizumab but failed both treatments. NGS Data revealed a deleterious somatic mutation in BRCA1 as well as a germline mutation in BRCA2.
  • the PDX tumor was derived from a 43 year old (X3030X- Caucasian woman with Stage III TNBC. Prior to PDX frameshift) tumor harvesting, she was treated with gBRCA1m Cyclophosphamide/Doxorubicin/Paclitaxel for a (K1183R; S1634G; duration of 9 months. NGS data revealed a deleterious P871L; E1038G) somatic mutation in BRCA2 and germline mutations in BRCA1.
  • the CTG-0888 implanted Harlan mice received a once weekly for 4 weeks dosing regimen (62.5 mg/kg)
  • the CTG-0888 implanted mice demonstrated 99.88% TGI compared to vehicle-treated control which is predictive for clinical response ( FIG. 14C ).
  • TNBC is a particularly aggressive breast cancer and currently lacks effective treatment.
  • the PDX data suggested that Compound I has an increased likelihood of eliciting a clinical response in TNBC patients with deleterious BRCA mutations who had received other chemotherapies. ( FIGS. 14A-14C ).
  • V ss steady-state volumes of distribution
  • the plasma concentrations in the mouse are magnitude higher than in rat, dog and monkey. These trends are qualitatively similar to those seen in the plasma protein binding assays. Compound I is highly bound (>99%) to human plasma proteins, and this binding is independent of drug concentration. Compound I (1 ⁇ M) partitioning to blood cells compared to plasma was evaluated in human whole blood, and was determined to prefer plasma ( ⁇ 65%) to the cellular compartment ( ⁇ 30%).
  • TK toxicokinetic
  • AUC 0-inf was found to be approximately dose proportional across the dose range, and terminal half-life determined across the doses ranged from approximately 7 to 16.8 hours.
  • TK parameters were calculated for each animal, using individual plasma concentration-time data of Compound I. TK parameters derived for the first (Day 1) dose were tabulated and summarized by sex within dose group (Table 27).
  • AUC last area under the concentration-time curve from time 0 to the last observation postdose
  • AUC last increased with dose level.
  • the response was not dose proportional across the dose range, with higher values of AUC last /dose at 15 mg/kg than at the 30 mg/kg and 45 mg/kg dose levels.
  • Terminal half-life determined across the doses ranged from approximately 7 to 18.2 hours.
  • the non-clinical safety program included single and repeat dose toxicology studies in rats and dogs. These acute and subacute dose-ranging studies conducted in rats and dogs permitted the characterization of the toxicity of single and multiple doses of IV administration of Compound I using various dosing schedules, and also provided the rationale for the selection of doses to be studied in the single dose study with recovery after a 21-day non-dosing period in these species.
  • the dose limiting toxicity observed with single and multiple doses of IV administration of Compound I in rats and dogs was decreased blood cell count in leukocyte, erythrocyte and megakaryocyte cell lines. This toxicity is spontaneously reversible within three weeks following an IV dose of Compound I, and this influenced the selection of a clinical dosing schedule of once every three weeks. At higher dose exposures, a hypersensitivity-like reaction consistent with mast cell degranulation was also encountered. In dogs, this reaction resulted in urticarial or hive-like rash around the ears, eyes and muzzle, which resolved with antihistamine drug. This reaction was also noted to be transient, and had fully resolved by three hours following the dose, with or without antihistamine treatment.
  • the current population analysis utilized non-linear mixed effects modeling to quantify the PK and pharmacodynamics (PD) of Compound I.
  • This approach involved estimation of fixed-effect (mean) parameters, together with inter-individual and residual variability for each of the models developed. Where relevant, covariate effects were incorporated to potentially explain the random sources of variability.
  • An additional benefit of this modeling approach is the ability to appropriately handle sparse or unbalanced data, particularly where practical considerations prohibit intensive sampling.
  • non-linear mixed effects modeling allows for the stochastic simulation of PK-PD to assist with dose recommendation in target populations of interest.
  • Two of the objectives of this analysis were to develop population models that 1) describe the PK of Compound I in non-tumor-bearing mice using data from different dosing and sampling regimens, and 2) characterize the PK-PD relationships between Compound I exposure and antitumor response in patient-derived mouse xenograft models.
  • mice A total of four non-clinical studies were used to characterize PK of Compound I in mice.
  • the dosing regimens included both intravenous (IV) and oral (PO) routes of administration at various dosing schedules.
  • mice with patient-derived xenografts were utilized to elucidate the relationships between Compound I exposure and antitumor activity in mice with patient-derived xenografts (PDX). These studies only included data from nu/nu immunocompromised mice in 5 different PDX models (CTG-0012, CTG0888, HBCx-10, HBCx-15, and HBCx-14). A summary of studies used in the population PK-PD analysis is provided in Table 29.
  • FIGS. 15A-15B A composite display of the mouse Compound I concentration-time data across dose regimen and route of administration is presented in FIGS. 15A-15B for Study 1-4.
  • routes of administration included intravenous (IV, left panel) and oral (PO, right panel) dosing of Compound I to ICR or athymic nude mice.
  • the panels are further stratified by dose at 5, 10, 25, 62.5, 65, 75, 125, or 150 mg/kg across Study 1-4 (Table 28).
  • For the antitumor PK-PD studies (Study 5-8, Table 29), data across each of the PDX models are shown in FIGS. 16A-16E .
  • corresponding lines represent the median respective data.
  • mice All pre-dose concentrations and observations reported as ‘N/A’ were excluded from the analyses. The following outliers were excluded from the PK analysis in mice:
  • ⁇ i ⁇ pop ⁇ ( Weight ⁇ ⁇ ( kg ) i 70 ) p ( 1 )
  • weight (kg) i is the total weight for subject i
  • p is the allometric exponent
  • 70 kg is a standardized human adult bodyweight. Exponents of 3 ⁇ 4 and 1 were assumed for all clearances and volumes of distribution, respectively.
  • Equations 2 to 6 Differential equations for the above structural PK model are described by Equations 2 to 6.
  • ⁇ dA 1 dt - k a ⁇ A 1 + k HRC ⁇ A 5 ⁇ FLAG ( 2 )
  • dA 2 dt k a ⁇ A 1 - CL D ⁇ ⁇ 1 V C ⁇ A 2 + CL D ⁇ ⁇ 1 V P ⁇ ⁇ 1 ⁇ A 3 - CL D ⁇ ⁇ 2 V C ⁇ A 2 + CL D ⁇ ⁇ 2 V P ⁇ ⁇ 2 ⁇ A 4 - CL V C ⁇ A 2 ( 3 )
  • compartments 1 to 5 represent the PO dosing, central (plasma), 1 st peripheral, 2 nd peripheral, and gall bladder, respectively.
  • the FLAG component in Equations 2 and 6 is a reserved variable in the modeling software used that allows for estimation of the start and end times of enterohepatic recycling. All parameters are defined in Table 31.
  • Equation 7 The differential equation for the TGI model is described by Equation 7:
  • dXEN dt k growth ⁇ A XEN + k drug ⁇ fcp ⁇ A XEN ( 7 )
  • XEN represents the xenograft compartment
  • k growth is the rate constant for tumor growth
  • k drug is the rate constant for drug-induced antitumor inhibition
  • fcp is the predicted unbound concentration of Compound I in plasma.
  • the PD effect was driven using the free (not total) concentration of Compound I obtained using the developed mouse PK model.
  • An averaged unbound fraction of 0.2% (99.8% bound) was used based on measured values for protein binding in mouse plasma.
  • Five different xenograft types (CTG-0012, CTG-0888, HBCx-10, HBCx-14, and HBCx-15) were used in the development of the Compound I TGI model.
  • Enterohepatic recirculation was included to support the known pharmacology of Compound I. However, only limited data were available to support the robust estimation of this kinetic pathway. Where necessary, parameters describing enterohepatic recirculation were fixed to allow for model convergence and to retain parsimony.
  • the unbound fraction to drive response in the PK-PD model was calculated using plasma protein binding data from mouse, dog and human species.
  • Model selection was based on the plausibility of parameter estimates, diagnostic scatter plots, and the Objective Function Value (OBJ; calculated using ⁇ 2 ⁇ log-likelihood).
  • OBJ Objective Function Value
  • a ⁇ 2 distribution was used for comparison of nested models, where a decrease in the OBJ of 3.84 units ( ⁇ 0.05) was defined as statistically significant.
  • ⁇ i represents the PK parameter for subject i
  • ⁇ pop is the population mean estimate
  • ⁇ ⁇ ,i is the subject-specific random effect.
  • Y ij is the j th observed value for the i th subject
  • C ij is the corresponding prediction
  • ⁇ 1,ij and ⁇ 2,ij are the proportional and additive residual errors, respectively.
  • Examples of potential sources of residual variability include assay error, model misspecification, and incorrect dosing or sampling.
  • Categorical covariates (mouse strain, gender, or xenograft type) were assessed using the general equation:
  • ⁇ i is a direct proportionality constant.
  • ⁇ i was fixed to 1 for a select reference subgroup and was estimated for other test subgroups.
  • Reference groups for the above categorical covariates were ICR mouse strain, male gender, or CTG-0012 xenograft type.
  • VPC visual predictive check
  • Covariate analysis identified mouse strain as a significant demographic factor in describing the PK of Compound I.
  • the estimated clearance and central volume were approximately 4- and 5-fold higher, respectively, in nu/nu relative to the ICR wild-type strain.
  • VPC is stratified to demonstrate the predictive performance following IV and in FIG. 17B , VPC is stratified to demonstrate the predictive performance following PO.
  • IV intravenous
  • PI prediction interval
  • PO oral
  • VPC visual predictive check.
  • a population analysis approach was used to simultaneously model the kinetics of tumor growth (control xenografts) and drug-induced inhibition (treatment groups).
  • Data from 67 nu/nu mice with implanted PDX were used for the development of the TGI model.
  • the predicted plasma concentrations were obtained by fixing population mean values from the PK model developed in nu/nu mice. This assumption was required because drug concentrations were not available from the same animal in which tumor response was measured.
  • Five different xenograft types CTG-0888, HBCx-10, HBCx-14, and HBCx-15) were used to characterize the TGI of Compound I.
  • the inhibition effect of Compound I was described using an immediate effect PK-PD model, which captured the re-growth of HBCx-10 tumors. Delayed effects (using an effect compartment) were investigated but produced model instability or implausibility in parameter estimates.
  • mice PK model and PK-PD model established herein can be combined with human PK model to simulate the effect of Compound I in human patients, which can be useful in predicting dosing, efficacy, and toxicity margins of Compound I.
  • Such simulation is reasonable because the xenografts implanted in mice in this Example were derived from actual breast cancer tumors in human patients.
  • Pharmacokinetic studies and dose escalation studies were conducted in adult patients with advanced hematologic cancers at 25, mg/m 2 (ready-to-use formulation), 50 mg/m 2 (ready-to-use formulation), 100 mg/m 2 (ready-to-use formulation), 170 mg/m 2 (lyophilized formulation), and 250 mg/m 2 (lyophilized formulation) dose levels of Compound I.
  • Each patient received one dose over 1 hour by IV infusion, once every three weeks ⁇ 2 days (Cohort 1).
  • Dose escalations were planned in 7 cohorts (25-450 mg/m2), in an accelerated design, with change to 3+3 design based on predefined toxicity criteria.
  • 16 patients (6 myeloma, 2 Hodgkin lymphoma, 6 Non Hodgkin lymphoma (NHL), 1 TPLL, 1 CLL) were treated in 5 cohorts (25-250 mg/m2), for a median of 2 (1-18) cycles.
  • Example 2 250 mg/m 2 dose of Compound I was prepared according to Example 2 (lyophilized composition with mannitol) and reconstituted with 5% glucose in sterile water for IV infusion.
  • the maximum tolerated dose was determined to be 170 mg/m 2 .
  • RNA-FISH peripheral blood mononuclear cells
  • a reference standard stock solution of Compound I was prepared by weighing the reference standard and dissolving it in a solution of 50:50:0.1 (v/v) mixture of ACN: deionized water:formic acid, followed by vortex-mixing and sonication. This stock solution was used for preparation of the calibration standards.
  • Another stock solution of Compound I was prepared following the same procedure and was used for preparation of the QC samples. Both stock solutions were prepared previously and stored at refrigeration (2° C. to 8° C.) prior to use on the day of assay. Compound I stock solution was found to be stable in this storage condition for 385 days. Both solutions were used within the established stability timeframe.
  • each of the stock solutions was further diluted with a solution of 50:50:0.1 (v/v) mixture of ACN:deionized water:formic acid to provide a series of working solutions for spiking calibration standards and QC samples.
  • the internal standard stock solution was previously prepared by weighing Compound A (2-(4-Methyl-piperazin-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide) and dissolving it in a solution of 50:50:0.1 (v/v) mixture of ACN:deionized water:formic acid.
  • This stock solution was stored at refrigeration (2° C. to 8° C.) prior to use.
  • Compound A stock solution was found to be stable in this storage condition for 384 days. This solution was used within the established stability timeframe. On the day of assay, this solution was further diluted with a solution of 50:50:0.1 (v/v) mixture of ACN:deionized water:formic acid into a solution for spiking.
  • Calibration standards and QC samples were prepared by spiking the appropriate working solution and the internal standard spiking solution into blank human plasma (NaHep). Each sample was extracted with ACN and then centrifuged at 13700 ⁇ g (12000 rpm) for 5 minutes. The extracted top layer was transferred to another disposable glass tube and evaporated to complete dryness in a water-bath at 40° C. under a stream of air or nitrogen. The dried sample was reconstituted with a solution of 50:50:0.1 (v/v) mixture of ACN:deionized water:formic acid. The reconstituted sample was transferred to a LC vial for LC/MS/MS analysis.
  • Each of the prospective test samples will be spiked with the internal standard solution, and then extracted, dried, and reconstituted following the same procedures for calibration standards and QC samples as described above.
  • the reconstituted sample will be transferred to a LC vial for LC/MS/MS analysis along with calibration standards and QC samples
  • This assay method was based on a nominal quantitation range of 5.00 ng/mL to 5000 ng/mL. Validation results met their acceptance criteria for the assessments of calibration range, assay accuracy and precision, hemolysis matrix effects, lipidemic matrix effects, selectivity and specificity, dilution integrity, and assay ruggedness with respect to changing analysts and instrument, and over the run time anticipated for a prospective test sample run. Chromatographic carryover was not observed. A 6-minute assay run time was validated. Compound I was found to be stable in sodium heparinised human plasma for 31 days at nominal ⁇ 70° C. ( ⁇ 63° C. to ⁇ 77° C.) and following 4 cycles of freeze/thaw.
  • HPLC-MS high performance liquid chromatography-mass spectrometry
  • Compound I was subjected to stress conditions.
  • Mobile phase B Option 1-3 ml of NH 4 OH in 1000 ml of Acetonitrile ( ⁇ 0.1% wt); Option 2-3 ml of NH 4 OH in 1000 ml of Acetonitrile ( ⁇ 0.1% wt)
  • Mass Spectrometry Sample prepared in 0.1% formic acid/50% methanol solution. Positive mode.
  • Injection volume 20 ⁇ L.
  • the aqueous layer was extracted with 100 ml of DCM.
  • the combined organic layer was extracted with 850 ml of 0.7 N HCl(aq).
  • the aqueous layer was added 900 ml of DCM.
  • To the mixture was added 150 ml of 30% NaOH(aq) to adjust pH to 14.
  • the organic layer was evaporated to dryness to get solid.
  • the solid was added 240 ml of MeOH and 30 ml of H 2 O for slurry.
  • the wet cake was vacuum dried at 40° C.
  • the mixture was added 1000 ml of 2 N NaOH(aq) for extraction.
  • the aqueous layer was extracted with 300 ml of DCM.
  • the combined aqueous layer was added 900 ml of DCM.
  • the mixture was added 30% NaOH(aq) to adjust pH to 14.
  • the aqueous layer was extracted with 300 ml of DCM.
  • the combined organic layer was evaporated to dryness.
  • the residue was added 500 ml of THF for slurry at 40° C. and then added 500 ml of n-heptane.
  • the aqueous layer was extracted with 500 ml of DCM.
  • the combine organic layer was extracted with 600 ml of 0.15% NH 3 (aq).
  • the organic layer was collected and the emulsion layer was discarded.
  • the organic layer was evaporated to dryness.
  • the residue was added 60 ml of DMSO and sonicated for 10 min to precipitate the product.
  • the mixture was filtrated and the wet cake was washed with 10 ml MeOH.
  • the wet cake was added 10 ml of DCM for slurry and then evaporated to dryness to remove the residual MeOH.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US16/277,089 2018-02-15 2019-02-15 Quinolone analogs and their salts, compositions, and method for their use Abandoned US20190374550A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/277,089 US20190374550A1 (en) 2018-02-15 2019-02-15 Quinolone analogs and their salts, compositions, and method for their use
US17/394,541 US11524012B1 (en) 2018-02-15 2021-08-05 Quinolone analogs and their salts, compositions, and method for their use

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201862631171P 2018-02-15 2018-02-15
US201862631174P 2018-02-15 2018-02-15
US16/277,089 US20190374550A1 (en) 2018-02-15 2019-02-15 Quinolone analogs and their salts, compositions, and method for their use

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/394,541 Continuation US11524012B1 (en) 2018-02-15 2021-08-05 Quinolone analogs and their salts, compositions, and method for their use

Publications (1)

Publication Number Publication Date
US20190374550A1 true US20190374550A1 (en) 2019-12-12

Family

ID=67805108

Family Applications (2)

Application Number Title Priority Date Filing Date
US16/277,089 Abandoned US20190374550A1 (en) 2018-02-15 2019-02-15 Quinolone analogs and their salts, compositions, and method for their use
US17/394,541 Active US11524012B1 (en) 2018-02-15 2021-08-05 Quinolone analogs and their salts, compositions, and method for their use

Family Applications After (1)

Application Number Title Priority Date Filing Date
US17/394,541 Active US11524012B1 (en) 2018-02-15 2021-08-05 Quinolone analogs and their salts, compositions, and method for their use

Country Status (11)

Country Link
US (2) US20190374550A1 (ko)
EP (1) EP3752149A4 (ko)
JP (1) JP7445597B2 (ko)
KR (1) KR20200131251A (ko)
CN (1) CN112334133A (ko)
AU (1) AU2019227294B2 (ko)
CA (1) CA3088998A1 (ko)
IL (1) IL276513A (ko)
RU (1) RU2020130050A (ko)
TW (1) TW202000195A (ko)
WO (1) WO2019168688A2 (ko)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10857156B2 (en) 2015-11-20 2020-12-08 Senhwa Biosciences, Inc. Combination therapy of tetracyclic quinolone analogs for treating cancer
WO2021030671A1 (en) * 2019-08-14 2021-02-18 Senhwa Biosciences, Inc. Tetracyclic compounds and their salts, compositions, and methods for their use
WO2021030686A1 (en) * 2019-08-14 2021-02-18 Senhwa Biosciences, Inc. Crystalline forms of quinoline analogs and salts thereof, compositions, and their methods for use
US11524012B1 (en) 2018-02-15 2022-12-13 Senhwa Biosciences, Inc. Quinolone analogs and their salts, compositions, and method for their use

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220062294A1 (en) * 2020-09-02 2022-03-03 Senhwa Biosciences, Inc. Pharmaceutical compositions of tetracyclic quinolone analogs and their salts
WO2023059148A1 (ko) * 2021-10-08 2023-04-13 기초과학연구원 항암 치료 개선을 위한 2-클로로-n,n-디에틸에틸아민 염산염의 용도
CN118005653A (zh) * 2023-04-23 2024-05-10 信义核新(北京)生物科技有限公司 喹诺酮类似物及其用途

Family Cites Families (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4559157A (en) 1983-04-21 1985-12-17 Creative Products Resource Associates, Ltd. Cosmetic applicator useful for skin moisturizing
LU84979A1 (fr) 1983-08-30 1985-04-24 Oreal Composition cosmetique ou pharmaceutique sous forme aqueuse ou anhydre dont la phase grasse contient un polyether oligomere et polyethers oligomeres nouveaux
US4820508A (en) 1987-06-23 1989-04-11 Neutrogena Corporation Skin protective composition
US4992478A (en) 1988-04-04 1991-02-12 Warner-Lambert Company Antiinflammatory skin moisturizing composition and method of preparing same
US4938949A (en) 1988-09-12 1990-07-03 University Of New York Treatment of damaged bone marrow and dosage units therefor
US5703055A (en) 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
WO2000059882A1 (en) 1999-04-07 2000-10-12 Gray Lloyd S Anticancer calcium channel blockers
WO2003050107A1 (en) 2001-12-13 2003-06-19 Wockhardt Limited New generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
US6900224B2 (en) 2002-07-31 2005-05-31 The Procter & Gamble Company Antimicrobial quinolones, their compositions and uses
EA009469B1 (ru) 2003-03-12 2007-12-28 Кудос Фармасеутикалс Лимитед Производные фталазинона
MXPA06000993A (es) 2003-07-25 2006-08-31 Cancer Rec Tech Ltd Inhbidores triciclicos de parp.
US20050118291A1 (en) 2003-09-10 2005-06-02 Mian-Ying Wang Formulations and methods for treating breast cancer with Morinda citrifolia and methylsulfonymethane
ES2321722T3 (es) 2003-09-22 2009-06-10 Janssen Pharmaceutica Nv Naftiridonas y quinolonas 7-amino alquilidenil-heterociclicas.
CN102107008B (zh) 2003-12-01 2013-04-03 库多斯药物有限公司 用于治疗癌症的dna损伤修复抑制剂
ES2605792T3 (es) 2004-05-13 2017-03-16 Icos Corporation Quinazolinona usada como inhibidor de la fosfatidilinositol 3-quinasa delta humana
CA2580749C (en) 2004-09-17 2014-01-28 Cylene Pharmaceuticals, Inc. Quinolone analogs
DK1928887T3 (en) 2005-08-05 2015-03-23 Senhwa Biosciences Inc Methods for preparing quinolonanaloger
JP2009504192A (ja) 2005-08-19 2009-02-05 サイリーン ファーマシューティカルズ インコーポレーティッド ヒトリボソームＤＮＡ（ｒＤＮＡ）およびリボソームＲＮＡ（ｒＲＮＡ）核酸ならびにそれらの使用
AR057555A1 (es) 2005-10-27 2007-12-05 Merck Frosst Canada Ltd Un inhibidor de fosfodiesterasa-4 4-oxo-1-(3-sustituido fenil-1,4-dihidro-1,8-naftiridin-3-carboxamida y un procedimiento de preparacion del mismo
WO2007056113A2 (en) 2005-11-02 2007-05-18 Cylene Pharmaceuticals, Inc. Methods for targeting quadruplex sequences
EP2023720A4 (en) 2006-05-17 2009-06-10 Cylene Pharmaceuticals Inc TETRACYCLIC IMIDAZOLE ANALOGS
WO2007146831A2 (en) 2006-06-08 2007-12-21 Cylene Pharmaceuticals, Inc. Quinolone analogs derivatized with sulfonic acid, sulfonate or sulfonamide
WO2007146813A2 (en) 2006-06-08 2007-12-21 Cylene Pharmaceuticals, Inc. Pyridinone analogs as cell proliferation inhibitors
GB0701992D0 (en) 2007-02-02 2007-03-14 7Tm Pharma As Grehlin Receptor Modulators
WO2008131134A1 (en) 2007-04-17 2008-10-30 Cylene Pharmaceuticals, Inc. Hydrazide compounds and uses thereof
WO2009046383A1 (en) 2007-10-05 2009-04-09 Cylene Pharmaceuticals, Inc. Quinolone analogs and methods related thereto
AU2008201871A1 (en) 2008-04-16 2009-11-26 Deutsches Krebsforschungszentrum Stiftung Des Oeffentlichen Rechts Inhibition of angiogenesis and tumor metastasis
US9359605B2 (en) 2011-03-11 2016-06-07 Sarissa Inc. Method of treating cancer by inhibition of DNA repair proteins
CN103533934B (zh) 2011-03-17 2016-03-30 特尔汗什莫尔医学基础设施研究和服务公司 用于治疗自身免疫性疾病的喹诺酮类似物
WO2013133876A1 (en) 2011-12-07 2013-09-12 The Regents Of The University Of California Biomarkers for prediction of response to parp inhibition in breast cancer
US9044421B2 (en) 2012-03-28 2015-06-02 Genus Oncology, Llc Treating MUC1-expressing cancers with combination therapies
CN104470949A (zh) 2012-05-15 2015-03-25 百时美施贵宝公司 通过破坏pd-1/pd-l1信号传输的免疫治疗
US20160145355A1 (en) 2013-06-24 2016-05-26 Biomed Valley Discoveries, Inc. Bispecific antibodies
EP3074391B1 (en) 2013-11-28 2019-07-31 Tel Hashomer Medical Research Infrastructure And Services Ltd. Rna polymerase i inhibitors and uses thereof
CN106132438B (zh) 2014-02-21 2020-03-03 尼克塔治疗印度私人有限公司 与抗CTLA-4抗体或抗PD-1抗体组合的IL-2Rβ选择性激动剂
RU2752506C2 (ru) 2015-11-20 2021-07-28 Сэньхва Байосайенсиз, Инк. Комбинированная терапия тетрациклическими аналогами хинолона для лечения рака
US9957282B2 (en) * 2015-12-14 2018-05-01 Senhwa Biosciences, Inc. Crystalline forms of quinolone analogs and their salts
JP2018537486A (ja) 2015-12-14 2018-12-20 センワ バイオサイエンシズ インコーポレイテッド キノロン類似体及びその塩の結晶形
US20180369143A1 (en) 2015-12-15 2018-12-27 British Columbia Cancer Agency Branch Metal complexed therapeutic agents and lipid-based nanoparticulate formulations thereof
WO2017205832A1 (en) * 2016-05-26 2017-11-30 Fred Hutchinson Cancer Research Center L-myc pathway targeting as a treatment for small cell lung cancer
KR20200131251A (ko) 2018-02-15 2020-11-23 센화 바이오사이언시즈 인코포레이티드 퀴놀론 유사체 및 이의 염, 조성물, 및 이들의 사용 방법
TW202115091A (zh) 2019-08-14 2021-04-16 生華生物科技股份有限公司 喹啉類似物之結晶型及其鹽類、組合物、及彼等之使用方法
JP7566010B2 (ja) 2019-08-14 2024-10-11 センワ バイオサイエンシズ インコーポレイテッド 四環式化合物及びそれらの塩、組成物、ならびにそれらの使用方法
US20220062294A1 (en) 2020-09-02 2022-03-03 Senhwa Biosciences, Inc. Pharmaceutical compositions of tetracyclic quinolone analogs and their salts

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10857156B2 (en) 2015-11-20 2020-12-08 Senhwa Biosciences, Inc. Combination therapy of tetracyclic quinolone analogs for treating cancer
US11229654B2 (en) 2015-11-20 2022-01-25 Senhwa Biosciences, Inc. Combination therapy of tetracyclic quinolone analogs for treating cancer
US11524012B1 (en) 2018-02-15 2022-12-13 Senhwa Biosciences, Inc. Quinolone analogs and their salts, compositions, and method for their use
WO2021030671A1 (en) * 2019-08-14 2021-02-18 Senhwa Biosciences, Inc. Tetracyclic compounds and their salts, compositions, and methods for their use
WO2021030686A1 (en) * 2019-08-14 2021-02-18 Senhwa Biosciences, Inc. Crystalline forms of quinoline analogs and salts thereof, compositions, and their methods for use

Also Published As

Publication number Publication date
IL276513A (en) 2020-09-30
CN112334133A (zh) 2021-02-05
AU2019227294A1 (en) 2020-09-10
EP3752149A4 (en) 2022-03-02
EP3752149A2 (en) 2020-12-23
AU2019227294B2 (en) 2023-06-15
WO2019168688A3 (en) 2019-10-10
WO2019168688A2 (en) 2019-09-06
WO2019168688A9 (en) 2019-11-14
RU2020130050A (ru) 2022-03-15
JP7445597B2 (ja) 2024-03-07
JP2021513986A (ja) 2021-06-03
TW202000195A (zh) 2020-01-01
CA3088998A1 (en) 2019-09-06
US11524012B1 (en) 2022-12-13
KR20200131251A (ko) 2020-11-23

Similar Documents

Publication Publication Date Title
US11524012B1 (en) Quinolone analogs and their salts, compositions, and method for their use
TW201534305A (zh) 使用組合療法治療癌症之方法
US9682082B2 (en) Combinations of AKT and MEK inhibitor compounds, and methods of use
JP7566010B2 (ja) 四環式化合物及びそれらの塩、組成物、ならびにそれらの使用方法
US20240307398A1 (en) Formulations, methods, kits, and dosage forms for treating atopic dermatitis and for improved stability of an active pharmaceutical ingredient
US20210046082A1 (en) Crystalline forms of quinoline analogs and salts thereof, compositions, and their methods for use
NZ760233A (en) Compositions and methods for treatment of abnormal cell growth
US20220062294A1 (en) Pharmaceutical compositions of tetracyclic quinolone analogs and their salts
KR20190126291A (ko) 옥사진 유도체를 포함하는 약제학적 조성물 및 알츠하이머병의 치료 또는 예방에 있어서 그의 용도
US20140275234A1 (en) Compositions and methods of using crystalline forms of wortmannin analogs
US20210269479A1 (en) Use of cyclosporine analogues for treating cancer
NZ617243B2 (en) Combinations of akt and mek inhibitor compounds, and methods of use

Legal Events

Date Code Title Description
AS Assignment

Owner name: SENHWA BIOSCIENCES, INC., TAIWAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LIU, HSHIOU-TING;SOONG, JOHN;SIGNING DATES FROM 20190429 TO 20190501;REEL/FRAME:049089/0629

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STCV Information on status: appeal procedure

Free format text: NOTICE OF APPEAL FILED

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION