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WO2020028097A1 - Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique - Google Patents

Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique Download PDF

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Publication number
WO2020028097A1
WO2020028097A1 PCT/US2019/043042 US2019043042W WO2020028097A1 WO 2020028097 A1 WO2020028097 A1 WO 2020028097A1 US 2019043042 W US2019043042 W US 2019043042W WO 2020028097 A1 WO2020028097 A1 WO 2020028097A1
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formula
inhibitors
xrpd
crystalline form
peaks
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Inventor
Ernest A. Carra
Darryl Kato
Kenneth Stanley Matthews
Jennifer R. Zhang
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Gilead Sciences Inc
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Gilead Sciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel solid forms of (R)-l l-(methoxymethyl)-l2-(3- methoxypropoxy)-3,3-dimethyl-8-oxo-2,3,8,l3b-tetrahydro-lH-pyrido[2,l-a]pyrrolo[l,2- c]phthalazine-7-carboxylic acid, the pharmaceutical formulations, and the therapeutic uses thereof in treating viral infections.
  • HBV hepatitis B virus
  • HBV hepatitis B virus
  • Initial symptoms of infection may include vomiting, jaundice, lethargy, dark urine, and abdominal pain.
  • Chronic HBV infection can result in cirrhosis and liver cancer.
  • therapies can inhibit replication of the virus and minimize liver damage; however, there are no currently available therapies that can clear an HBV infection.
  • the present disclosure is directed to novel forms of Formula I.
  • the present disclosure is directed to crystalline forms of (R)-l 1-
  • the present disclosure is directed to (R)-l l-(Methoxymethyl)- l2-(3-methoxypropoxy)-3,3-dimethyl-8-oxo-2,3,8,l3b-tetrahydro-lH-pyrido[2,l-a]pyrrolo[l,2- c]phthalazine-7-carboxylic acid Form I (Formula I Form I).
  • the present disclosure is directed to (R)-l l-(Methoxymethyl)- l2-(3-methoxypropoxy)-3,3-dimethyl-8-oxo-2,3,8,l3b-tetrahydro-lH-pyrido[2,l-a]pyrrolo[l,2- c]phthalazine-7-carboxylic acid Form II (Formula I Form II).
  • the present disclosure is directed to an amorphous form of (R)- 1 l-(Methoxymethyl)-l2-(3-methoxypropoxy)-3,3-dimethyl-8-oxo-2,3,8,l3b-tetrahydro-lH- pyrido[2, 1 -a]pyrrolo[ 1 ,2-c]phthalazine-7-carboxylic acid.
  • the present disclosure is directed to methods of treating a hepatitis B virus infection by administering a compound of Formula I provided herein.
  • FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form I of Formula I.
  • FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form I of Formula I.
  • FIG. 3 shows a thermogravimetric analysis (TGA) graph of crystalline Form I of Formula I.
  • FIG. 4 shows a dynamic vapor sorption (DVS) plot of crystalline Form I of Formula I.
  • FIG. 5 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form II of Formula I.
  • FIG. 6 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form II of Formula I.
  • FIG. 7 shows a thermogravimetric analysis (TGA) graph of crystalline Form II of Formula I.
  • FIG. 8 shows a dynamic vapor sorption (DVS) plot of crystalline Form II of Formula I.
  • FIG. 9 shows an X-ray powder diffraction (XRPD) pattern of an amorphous solid form of Formula I.
  • FIG. 10 shows a differential scanning calorimetry (DSC) thermogram of an amorphous solid form of Formula I.
  • FIG. 11 shows a thermogravimetric analysis (TGA) graph of an amorphous solid form of Formula I.
  • Embodiments that reference throughout this specification to“a Compound of Formula I” includes the crystalline, amorphous, co-crystal, and solvate, e.g ., hydrate, forms of the formulas and/or compounds disclosed herein.
  • the appearance or the phrase“a Compound of Formula I” comprises crystalline Forms I-II, amorphous, and mixtures of crystalline and/or amorphous forms thereof.
  • the invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of Formula I being isotopically-labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 ⁇ 4, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
  • Certain isotopically-labeled compounds of Formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 ⁇ 4, and carbon-l4, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.
  • Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed.
  • “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • A“pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g. , humans. Such a medium includes all pharmaceutically acceptable excipients therefor.
  • A“treatment” or“treating” is an approach for obtaining beneficial or desired results.
  • beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom associated with a disease or condition.
  • “treatment” or“treating” includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g, stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g, causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
  • slowing or arresting the development of one or more symptoms associated with the disease or condition e.g, stabilizing the disease or condition, delaying the worsening or progression of the disease or condition
  • relieving the disease or condition e.g, causing
  • A“prevention” or“preventing” refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop.
  • “prevention” relates to administration of a therapy (e.g, administration of a therapeutic substance) to a subject before signs of the disease are detectable in the subject (e.g,
  • a therapeutic substance to a subject in the absence of detectable infectious agent (e.g, virus) in the subject).
  • the subject may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder.
  • the term“preventing HBV infection” refers to administering to a subject who does not have a detectable HBV infection an anti -HBV therapeutic substance. It is understood that the subject for anti-HBV preventative therapy may be an individual at risk of contracting the HBV virus.
  • the term“therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the effective amount will vary depending on the particular compound, and characteristics of the subject to be treated, such as age, weight, etc.
  • the effective amount can include a range of amounts.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g ., additive or synergistic effects) of the compounds.
  • “co-administration” includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes.
  • a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g, 1-12 hours), by administration of a unit dose of a compound of the present disclosure.
  • Reference to“about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • description referring to“about X” includes description of“X”.
  • the singular forms "a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • Unit dosage forms are physically discrete units suitable as unitary dosages for subjects (e.g, human subjects and other mammals), each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the term“substantially as set forth in” when referring, for example, to an XRPD pattern, a DSC thermogram, a DVS plot, or a TGA graph includes a pattern, thermogram or graph that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art.
  • the term“substantially pure” or“substantially free” with respect to a particular solid form of a compound means that the composition comprising the solid form contains less than 99%, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other solid forms and/or impurities.
  • “substantially pure” or“substantially free of’ refers to a substance free of other substances, including other solid forms and/or impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other solid forms, water, and solvents.
  • a solid form may have properties such as bioavailability, stability, purity, and/or manufacturability at certain conditions that may be suitable for medical or pharmaceutical uses.
  • Solid forms of Formula I including substantially pure forms and mixtures of substantially pure forms, may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical composition. Variations in the crystal structure of a
  • pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g, ease of handling, ability to consistently prepare doses of known strength), and stability (e.g, thermal stability, shelf life, etc.) of a pharmaceutical drug product or active ingredient.
  • dissolution rate which may affect bioavailability, etc.
  • manufacturability e.g, ease of handling, ability to consistently prepare doses of known strength
  • stability e.g, thermal stability, shelf life, etc.
  • Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solutions or solid oral dosage form including tablets and capsules.
  • a solid form e.g, a crystalline form, may provide desired or suitable hygroscopicity, particle size controls, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and/or process control.
  • Solid forms of Formula I may provide advantages such as: improving the manufacturing process of an active agent, e.g, by enhancing the removal of impurities, or the stability or storability of a drug product form of the compound or an active ingredient, and/or having suitable bioavailability and/or stability as an active agent.
  • the compound name provided above is named according to IUPAC rules or using ChemBioDraw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols.
  • the compound may be named or identified with common names, systematic or non-systematic names.
  • the nomenclature systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and
  • crystalline forms of Formula I are disclosed.
  • the crystalline form is solvated, e.g ., by methanol.
  • the crystalline form is non-solvated.
  • the crystalline form of Formula I is Form I.
  • the crystalline form of Formula I is Form II.
  • the amorphous solid form of Formula I is disclosed.
  • the solid forms are characterized by the interlattice plane intervals determined by an X-ray powder diffraction pattern (XRPD).
  • XRPD X-ray powder diffraction pattern
  • the diffractogram of XRPD is typically represented by a diagram plotting the intensity of the peaks versus the location of the peaks, i.e., diffraction angle 2Q (two-theta) in degrees.
  • the characteristic peaks of a given XRPD can be selected according to the peak locations and their relative intensity to distinguish one crystalline structure from others.
  • the measurements of the XRPD peak locations and / or intensity for a given crystalline form of the same compound will vary within a margin of error.
  • the values of degree 2Q allow appropriate error margins.
  • the error margins are represented by“ ⁇ ” or“+/-”.
  • the degree 2Q of about“8.7 ⁇ 0.3” denotes a range from about 8.7+0.3, i.e., about 9.0, to about 8.7-0.3, i.e., about 8.4.
  • the appropriate error of margins for a XRPD can be ⁇ 0.5; ⁇ 0.4; ⁇ 0.3; ⁇ 0.2; ⁇ 0.1; ⁇ 0.05; or less.
  • the XRPD margin of error is ⁇ 0.2.
  • the XRPD margin of error is ⁇ 0.5.
  • a crystalline form of Formula I In some embodiments, provided is a crystalline form of Formula I. In some embodiments, the crystalline form is non-solvated. In some embodiments, the crystalline form is Form I of Formula I (Formula I Form I).
  • crystalline Formula I Form I has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight of the degree 20-reflections with the greatest intensity' as the XRPD pattern substantially as shown in FIG. 1.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having one or more peaks at 8.0°, 8.7°, 16.0°, 11.4°, 12.1°, 12.9°, 13.6°, 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • Form I is characterized by an X-ray powder diffraction (XRPD) pattern having two or more peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1°, 12.9°, 13.6°, 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • Form I is characterized by an X-ray powder diffraction (XRPD) pattern having three or more peaks at 8.0°, 8.7°, 16.0°, 11.4°, 12.1°, 12.9°, 13.6°, 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • Form I is characterized by an X-ray powder diffraction (XRPD) pattern having four or more peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1 °, 12.9°, 13.6°, 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • Form I is characterized by an X-ray powder diffraction (XRPD) pattern having five or more peaks at 8.0°, 8.7°, 16.0°, 11.4°, 12.1°, 12.9°, 13.6°, 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • Form I is characterized by an X-ray powder diffraction (XRPD) pattern having six or more peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1 °, 12.9°, 13.6°, 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • Form I is characterized by an X-ray powder diffraction (XRPD) pattern having seven or more peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1°, 12.9°, 13 6°, 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • Form I is characterized by an X-ray powder diffraction (XRPD) pattern having eight or more peaks at 8.0°, 8.7°, 16.0°, 1 1 .4°, 12.1°, 12.9°, 13.6°, 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • Form I i s characterized by an X-ray powder diffraction (XRPD) pattern having nine or more peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1 °, 12.9°, 13.6°, 26.8°, 24.3°, or 1 5.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q. In some embodiments, crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and one or more peaks at 1 1.4°, 12.1°, 12.9°, or 13.6° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and two or more peaks at 1 1.4°, 12.1 °, 12.9°, or 13.6° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I i s characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and three or more peaks at 11.4°, 12.1°, 12.9°, or 13.6° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and one peak at 1 1.4°, 12.1 °, 12.9°, or 13.6° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and two peaks at 11.4°, 12.1°, 12.9°, or 13.6° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and three peaks at 11.4°, 12.1°, 12.9°, or 13.6° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0° 2Q ⁇ 0.2° 2Q and further peaks at 1 1.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having further peaks at 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and one or more peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and two or more peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and one peak at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, and 16.0° 2Q ⁇ 0.2° 2Q and two peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0° 2Q ⁇ 0.2° 2Q and further peaks at 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I i s characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1°, 12 9°, and 13.6° 2Q ⁇ 0.2° 2Q and one or more peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and two or more peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and one peak at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and two peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 1 1.4°, 12.1 °, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 11.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and one or more peaks at 8.0°, 8.7°, or 16.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 1 1.4°, 12.1 °, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and two or more peaks at 8.0°, 8.7°, or 16.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 11.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and one peak at 8.0°, 8.7°, or 16.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 1 1.4°, 12.1 °, 12 9°, and 13 6° 2Q ⁇ 0 2° 2Q and two peaks at 8.0°, 8.7°, or 16 0° 2Q ⁇ 0 2° 2Q
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0°, 1 1.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 11.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and one or more peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 11.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and two or more peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 1 1.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and one peak at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 1 1.4°, 12.1°, 12.9°, and 13.6° 2Q ⁇ 0.2° 2Q and two peaks at 26.8°, 24.3°, or 15.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 11.4°, 12.1 °, 12.9°, 13.6°, 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q. In some embodiments, crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q and one or more peaks at 8.0°, 8.7°, or 16.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q and two or more peaks at 8.0°, 8.7°, or 16.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q and one peak at 8.0°, 8.7°, or 16.0° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q and two peaks at 8.0°, 8.7°, or 16.0° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0°, 11.4°, 12.1°, 12.9°, 13.6°, 26.8°, 24.3°, and 15.0° 2Q ⁇ 0.2° 2Q.
  • Formula I Form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram peak with an onset at about 131 °C.
  • DSC Differential Scanning Calorimetry
  • the crystalline Formula I Form I is characterized by one or more of the following: an X-ray powder diffraction (XRPD) pattern having peaks at 8.0°, 8.7°, 16.0°, 11.4°, 12.1°, 12.9°, 13.6°, 26.8°, 24.3°, and 15.0° 20 ⁇ 0.2° 20; a Differential Scanning
  • crystalline Formula I Form I is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 1.
  • crystalline Formula I Form I is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 2.
  • crystalline Formula I Form I is characterized by a
  • thermogravimetric analysis (TGA) pattern substantially as set forth in FIG. 3.
  • crystalline Formula I Form I is characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 4.
  • DVD dynamic vapor sorption
  • crystalline Formula I Form I at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply: (a) crystalline Form I has an XRPD pattern substantially as set forth in FIG.
  • the crystalline form is solvated. In some embodiments, the crystalline form is a methanol solvate. In some embodiments, the crystalline form is Form II of Formula I (Formula I Form II).
  • crystalline Formula I Form II has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight of the degree 20-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 5.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having one or more peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, or 15.4° 20 ⁇ 0.2° 2Q.
  • Form II is characterized by an X- ray powder diffraction (XRPD) pattern having two or more peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 20.
  • Form II is characterized by an X-ray powder diffraction (XRPD) pattern having three or more peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • Form II is characterized by an X-ray powder diffraction (XRPD) pattern having four or more peaks at 8 1°, 9.4°, 8.8°,
  • Form II is characterized by an X-ray powder diffraction (XRPD) pattern having five or more peaks at 8 1°, 9.4°, 8.8°, 16 3°, 26.5°, 19 2°, 12.9°, 14.8°, or 15.4° 20 ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • Form II is characterized by an X-ray powder diffraction (XRPD) pattern having six or more peaks at 8 1 °, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, or 15.4° 20 ⁇ 0.2° 2Q.
  • Form II is characterized by an X-ray powder diffraction (XRPD) pattern having seven or more peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • Form II is characterized by an X-ray powder diffraction (XRPD) pattern having eight or more peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, and 8.8° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, and 8 8° 2Q ⁇ 0.2° 2Q and one or more peaks at 16.3°, 26.5°, or 19.2° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, and 8.8° 2Q ⁇ 0.2° 2Q and two or more peaks at 16.3°, 26.5°, or 19.2° 20 ⁇ 0.2° 20.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, and 8.8° 20 ⁇ 0.2° 20 and one peak at 16.3°, 26.5°, or 19.2° 20 ⁇ 0.2° 20.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, and 8.8° 20 ⁇ 0.2° 20 and two peaks at 16.3°, 26.5°, or 19.2° 20 ⁇ 0.2° 20.
  • crystalline Formula I Form His characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1 °,
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having further peaks at 12.9°, 14.8°, and 15.4° 20 ⁇ 0.2° 20.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, and 8.8° 2Q ⁇ 0.2° 2Q and one or more peaks at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1 °, 9.4°, and 8.8° 2Q ⁇ 0.2° 2Q and two or more peaks at 12.9°, 14.8°, or 1 5.4° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8 1°, 9 4°, and 8 8° 2Q ⁇ 0 2° 2Q and one peak at 12 9°, 14 8°, or 15 4° 2Q ⁇ 0 2° 2Q
  • crystalline Formula I Form II i s characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8 1 °, 9 4°, and 8 8° 2Q ⁇ 0 2° 2Q and two peaks at 12 9°, 14 8°, or 15 4° 2Q ⁇ 0 2° 2Q
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 84 °, 9 4°, and 8 8° 2Q ⁇ 0 2° 2Q and further peaks at 12 9°, 14 8°, and 1 5 4° 2Q ⁇ 0 2°
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and one or more peaks at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and two or more peaks at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and one peak at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and two peaks at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and one peak at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 1 6 3°, 26 5°, and 19 2° 2Q ⁇ 0 2° 2Q
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and one or more peaks at 8.1°, 9.4°, or 8.8° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and two or more peaks at 8.1°, 9.4°, or 8.8° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and one peak at 8.1°, 9.4°, or 8.8° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and two peaks at 8.1°, 9.4°, or 8.8° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and one or more peaks at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and two or more peaks at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and one peak at 12.9°,
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II is
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, and 19.2° 2Q ⁇ 0.2° 2Q and two peaks at 12.9°, 14.8°, or 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q, and one or more peaks at 8.1°, 9.4°, or 8.8° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q, and two or more peaks at 8.1°, 9.4°, or 8.8° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q, and one peak at 8.1°, 9.4°, or 8.8° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q, and two peaks at 8.1°, 9.4°, or 8.8° 2Q ⁇ 0.2° 2Q.
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II is characterized by a Differential Scanning Calorimetry (DSC) thermogram peak with an onset at about 174 °C.
  • DSC Differential Scanning Calorimetry
  • crystalline Formula I Form II is characterized by one or more of the following: an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q; and a Differential Scanning
  • crystalline Formula I Form II is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 5.
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 6.
  • crystalline Formula I Form II is characterized by a
  • thermogravimetric analysis (TGA) pattern substantially as set forth in FIG. 7.
  • crystalline Formula I Form II is characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 8.
  • DVD dynamic vapor sorption
  • crystalline Formula I Form II has an X-ray powder diffraction (XRPD) pattern having peaks at 8.1°, 9.4°, 8.8°, 16.3°, 26.5°, 19.2°, 12.9°, 14.8°, and 15.4° 2Q ⁇ 0.2° 2Q;
  • XRPD X-ray powder diffraction
  • crystalline Formula I Form II has an XRPD pattern substantially as set forth in FIG. 5;
  • crystalline Formula I Form II has a DSC thermogram substantially as set forth in FIG. 6;
  • crystalline Formula I Form II has a TGA graph substantially as set forth in FIG. 7; and
  • crystalline Formula I Form II has a DVS graph substantially as set forth in FIG. 8.
  • amorphous solid form of Formula I is provided.
  • the amorphous form is characterized by an X-ray powder diffraction (XRPD) pattern having an absence of sharp peaks.
  • amorphous Formula I is characterized by a Differential Scanning Calorimetry (DSC) thermogram having a glass transition starting at about 48 °C. In some embodiments, amorphous Formula I is characterized by a Differential Scanning Calorimetry (DSC) thermogram having a glass transition starting at about 48 °C. In some embodiments, amorphous Formula I is characterized by a Differential Scanning Calorimetry (DSC) thermogram having a glass transition starting at about 48 °C. In some embodiments, amorphous Formula I is characterized by a Differential Scanning
  • amorphous Formula I is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 9.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • amorphous Formula I is characterized by a thermogravimetric analysis (TGA) pattern substantially as set forth in FIG. 11.
  • amorphous Formula I is characterized by a Differential Scanning Calorimetry (DSC) thermogram having a glass transition starting at about 48 °C;
  • DSC Differential Scanning Calorimetry
  • amorphous Formula I has an XRPD pattern substantially as set forth in FIG. 9;
  • amorphous Formula I has a DSC thermogram substantially as set forth in FIG. 10;
  • amorphous Formula I has a TGA graph substantially as set forth in FIG. 11.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises one or more additional therapeutic agents, as described in more detail below.
  • compositions comprising the compounds disclosed herein may be prepared with one or more pharmaceutically acceptable excipients which may be selected in accord with ordinary practice.
  • “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • compositions are provided as a solid dosage form, including a solid oral dosage form, such as a tablet.
  • Tablets may contain excipients including glidants, fillers, binders and the like.
  • Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic. All compositions may optionally contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 6 th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • compositions disclosed herein include those suitable for various administration routes, including oral administration.
  • the compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g ., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients.
  • the compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and
  • compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • the pharmaceutical composition is a tablet.
  • compositions disclosed herein comprise one or more compounds disclosed herein together with a pharmaceutically acceptable excipient and optionally other therapeutic agents.
  • Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, microcrystalline cellulose, starch,
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • compositions of the invention may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, reverse osmosis water so as to form a solution.
  • a surfactant or other solubilizing excipient may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
  • a solid pharmaceutical composition intended for oral administration can be prepared by mixing a therapeutically effective amount of a compound of the invention with at least one suitable pharmaceutically acceptable excipient to form a solid preformulation composition, which then may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. Accordingly, in some embodiments, a pharmaceutical composition is provided, which includes a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
  • a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient varies from about 5 to about 95% of the total compositions (weightweight).
  • compositions comprising a crystalline form as described herein, wherein the compound of Formula I within the composition is substantially pure (i.e., substantially pure compound of Formula I described herein).
  • compositions comprising a crystalline form of Formula I, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Formula I present in the composition is one of the crystalline forms disclosed herein.
  • the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of one of the crystalline forms of Formula I.
  • compositions comprising a crystalline form disclosed herein, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of Formula I present in the composition are other amorphous or crystal forms of Formula I and/or impurities.
  • impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the crystalline forms present.
  • Impurities may, for example, include by-products from synthesizing Formula I, contaminants, degradation products, other crystalline forms, amorphous form, water, and solvents.
  • impurities include by-products from the process of synthesizing Formula I.
  • impurities include contaminants from the process of synthesizing Formula I.
  • impurities include degradation products of Formula I.
  • impurities include other crystalline forms of Formula I.
  • impurities include water or solvent.
  • impurities are selected from the group consisting of by-products from synthesizing Formula I, contaminants, degradation products, other crystalline forms, water, solvents and combinations thereof.
  • the present disclosure provides methods of treating or preventing an HBV infection.
  • a method of treating or preventing an HBV infection comprises administering to an individual (e.g. a human) a therapeutically effective amount a compound disclosed herein, e.g. , a compound of Formula I.
  • the present disclosure also provides methods for treating an HBV infection comprising administering to an individual (e.g. a human) infected with HBV a therapeutically effective amount a compound disclosed herein.
  • the individual is chronically infected with HBV.
  • the individual is acutely infected with HBV.
  • a method of treating an individual (e.g. a human) infected with HBV comprises inhibiting HBsAg secretion and/or production.
  • a compound disclosed herein, e.g. , a compound of Formula I, for use in medical therapy is provided.
  • the disease or condition is an HBV infection.
  • a compound disclosed herein for use in treating or preventing an HBV infection is provided.
  • the use of a compound of the present disclosure, e.g, a compound of Formula I, for the manufacture of a medicament for treating or preventing HBV infection is provided.
  • a compound of the present disclosure for the manufacture of a medicament for treating or preventing an HBV infection is provided.
  • additional therapeutic agent(s) administered with one or more additional therapeutic agent(s) to an individual (e.g. a human) infected with HBV.
  • the additional therapeutic agent(s) can be administered to the infected individual (e.g. a human) at the same time as a compound disclosed herein or before or after administration of a compound disclosed herein.
  • a compound disclosed herein when used to treat or prevent a HBV infection, is administered with one or more additional therapeutic agent(s) selected from the group consisting of HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, Toll-like receptor 7 and 8 modulators, Toll-like receptor 3 modulators, interferon alpha ligands, HBsAg inhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), hepatitis B virus E antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core), HBV DNA polymerase
  • the present disclosure provides a method for ameliorating a symptom associated with an HBV infection, wherein the method comprises administering to an individual (e.g. a human) infected with hepatitis B virus a therapeutically effective amount of a compound of the present disclosure, e.g. , a compound of Formula I, wherein the therapeutically effective amount is sufficient to ameliorate a symptom associated with the HBV infection.
  • an individual e.g. a human
  • hepatitis B virus e.g. a human
  • a therapeutically effective amount e.g. a compound of Formula I
  • Such symptoms include the presence of HBV virus particles in the blood, liver inflammation, jaundice, muscle aches, weakness and tiredness.
  • the present disclosure provides a method for reducing the rate of progression of a hepatitis B viral infection in an individual (e.g. a human), wherein the method comprises administering to an individual (e.g. a human) infected with hepatitis B virus a therapeutically effective amount of a compound disclosed herein, e.g. , a compound of Formula I, wherein the therapeutically effective amount is sufficient to reduce the rate of progression of the hepatitis B viral infection.
  • the rate of progression of the infection can be followed by measuring the amount of HBV virus particles in the blood.
  • the present disclosure provides a method for reducing the viral load associated with HBV infection, wherein the method comprises administering to an individual (e.g . a human) infected with HBV a therapeutically effective amount of a compound of the present disclosure, e.g., a compound of Formula I, wherein the therapeutically effective amount is sufficient to reduce the HBV viral load in the individual.
  • a method of treating an individual (e.g. a human) infected with hepatitis B virus comprises reducing the viral load associated with HBV infection as measured by PCR testing.
  • Compounds disclosed herein can be administered by any route appropriate for use in a method described herein. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like.
  • Compounds disclosed herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least one week, at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.
  • the dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • Therapeutically effective amounts of compounds disclosed herein are from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day, or such as from about 0.3 pg to about 30 mg per day, or such as from about 30 pg to about 300 pg per day.
  • a compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g, from 1 mg to 1000 mg of compound).
  • Therapeutically effective amounts of the compound of Formula (I) can range from about 0.01 mg per dose to about 1000 mg per dose, such as from about 0.01 mg per dose to about 100 mg per dose, or such as from about 0.1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose.
  • Other therapeutically effective amounts of the compound of Formula (I) are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose.
  • Other therapeutically effective amounts of the compound of Formula (I) are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose.
  • a single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks. In certain embodiments, a single dose can be administered once every week. A single dose can also be administered once every month. In some embodiments, a compound disclosed herein is administered once daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in a method disclosed herein.
  • the frequency of dosage of a compound disclosed herein will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of a compound continues for as long as necessary to treat an HBV infection.
  • a compound disclosed herein can be administered to a human being infected with HBV for a period of from 20 days to 180 days or, for example, for a period of from 20 days to 90 days or, for example, for a period of from 30 days to 60 days.
  • Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of a compound disclosed herein, followed by a period of several or more days during which a patient does not receive a daily dose of the compound.
  • a patient can receive a dose of a compound every other day, or three times per week.
  • a patient can receive a dose of a compound each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period ( e.g ., from 1 to 14 days) during which the patient again receives a daily dose of the compound.
  • Alternating periods of administration of the compound, followed by non-administration of the compound can be repeated as clinically required to treat the patient.
  • a method for treating or preventing an HBV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g ., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g ., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • a method for treating an HBV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • the present disclosure provides a method for treating an HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g, one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents which are suitable for treating an HBV infection.
  • a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g, one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents which are suitable for treating an HBV infection.
  • compositions comprising a compound of the present disclosure, e.g, a compound of Formula I, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable excipient are provided.
  • a compound disclosed herein is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein is combined with four additional therapeutic agents.
  • the one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents.
  • the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes.
  • a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g ., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1- 12 hours), by administration of a unit dose of a compound disclosed herein.
  • a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
  • a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV.
  • the tablet can contain another active ingredient for treating HBV.
  • such tablets are suitable for once daily dosing.
  • the compounds described herein may be used or combined with one or more of a chemotherapeutic agent, an immunomodulator, an immunotherapeutic agent, a therapeutic antibody, a therapeutic vaccine, a bispecific antibody and“antibody-like” therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), an antibody- drug conjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases , TALENs), cell therapies such as CAR- T (chimeric antigen receptor T-cell ), and TCR-T (an engineered T cell receptor) agent or any combination thereof.
  • a chemotherapeutic agent such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives
  • ADC antibody- drug conjugate
  • gene modifiers or gene editors such as C
  • a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV.
  • the tablet can contain another active ingredient for treating HBV, such as 3- dioxygenase (IDO) inhibitors, Apolipoprotein Al modulator, arginase inhibitors, B- and T- lymphocyte attenuator inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist and modulator, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitor, Endonuclease modulator, epigenetic modifier
  • IDO 3- dioxygenase
  • NTCP cotransporting polypeptide
  • natural killer cell receptor 2B4 inhibitors NOD2 gene stimulator
  • Nucleoprotein inhibitor nucleoprotein modulators
  • PD-l inhibitors PD-L1 inhibitors
  • Peptidylprolyl isomerase inhibitor phosphatidylinositol-3 kinase (PI3K) inhibitors
  • Retinoic acid-inducible gene 1 stimulator Reverse transcriptase inhibitor
  • Ribonuclease inhibitor RNA DNA polymerase inhibitor
  • SLC10A1 gene inhibitor SMAC mimetics
  • Src tyrosine kinase inhibitor stimulator of interferon gene (STING) agonists, stimulators of NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surface glycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand, Tim-3 inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 gene stimulator,
  • combination drugs for the treatment of HBV include TRUVADA ® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN-alpha; ABX-203 adefovir, and PEG-IFNalpha; and INO-1800 (INO-9112 and RG7944).
  • Examples of other drugs for the treatment of HBV include alpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine nucleosides, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), JNJ-56136379, nitazoxanide, birinapant,
  • HBV vaccines include both prophylactic and therapeutic vaccines.
  • HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B ® , recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine
  • HBV therapeutic vaccines include HBsAG-HBIG complex, ARB- 1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP -based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-l7909, AdTG-l79lO AdTG-l8202
  • HBV DNA polymerase inhibitors include adefovir (HEPSERA ® ), emtricitabine (EMTRIVA ® ), tenofovir disoproxil fumarate (VIREAD ® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil , tenofovir dipivoxil fumarate, tenofovir octadecyloxy ethyl ester, CMX-157, besifovir, entecavir (BARACLETDE ® ), entecavir maleate, telbivudine
  • TYZEKA ® filocilovir, pradefovir, clevudine, ribavirin, lamivudine
  • EPIVIR-HBV ® phosphazide
  • famciclovir fusolin, metacavir
  • SNC-019754 FMCA
  • AGX-1009 AR-II-04-26
  • HPM302 tenofovir disoproxil aspartate
  • tenofovir disoproxil orotate and HS-10234.
  • immunomodulators include rintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440,WF-l0,AB-452, ribavirin, IL-12, INO-9112, polymer polyethyleneimine (PEI), Gepon, VGV-l, MOR-22, CRV- 431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, GS-9688, RO-7011785, RG-7854, AB- 506 ,RO-687l765, AIC-649, and IR-103.
  • TLR Toll-like Receptor
  • TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.
  • TLR3 modulators include rintatolimod, poly-ICLC, RIBOXXON ® , Apoxxim, RIBOXXIM ® IPH-33, MCT-465, MCT-475, and ND- 1.1.
  • TLR7 modulators include GS-9620, GSK -2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M- 052, Limtop, D, telratolimod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences).
  • TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688 and the compounds disclosed in
  • TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-l 179, AZD-1419, leftolimod (MGN-1703), litenimod, and CYT-003-QbGl0.
  • TLR7, TLR8 and TLR9 modulators include the compounds disclosed in WO2017047769 (Teika Seiyaku), W02015014815 (Janssen), W02018045150 (Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc), WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche),
  • W020l7l06607(Merck) W020l7l06607(Merck)
  • WO2017061532 Suditomo Dainippon Pharma
  • W02016023511 Choia Tai Tianqing Pharmaceutical
  • WO2017076346 Choia Tai Tianqing Pharmaceutical
  • W02017046112 Roche
  • WO2018078149 (Roche)
  • W02017040233 3M Co
  • W02016141092 Gilead Sciences
  • W02018049089 BristolMyers Squibb
  • WO2015057655 (Eisai Co Ltd), W02017001307 (Roche), W02018005586 (BristolMyers Squibb), W020l704023(3M Co), WO2017163264 (Council of Scientific and Industrial Research (India)), WO2018046460 (GlaxoSmithKline Biologicals), WO2018047081 (Novartis), WO2016142250 (Roche), WO2015168269 (Novartis), WO201804163 (Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co Ltd), W02017202704 (Roche), W02018026620
  • interferon alpha receptor ligands examples include interferon alpha-2b (INTRON A ® ), pegylated interferon alpha-2a (PEGASYS ® ), PEGylated interferon alpha-lb, interferon alpha lb (ELAPGEN ® ), Veldona, Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG- rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co
  • hyaluronidase inhibitors examples include astodrimer.
  • HsAg Hepatitis B Surface Antigen
  • HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2l39-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, and REP-9 AC'.
  • HBsAg secretion inhibitors include BM601. Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors
  • Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-l 155.
  • cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and ETS20130344029 (Gilead Sciences).
  • HBV viral entry inhibitors examples include Myrcludex B.
  • antisense oligonucleotide targeting viral mRNA examples include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.
  • RNAs Short Interfering RNAs (siRNA) and ddRNAi
  • siRNA examples include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB- nRNA, ARC-520, ARC-521, ARB-1740, and ARB-1467.
  • ddRNAi DNA-directed RNA interference
  • BB-HB-331 DNA-directed RNA interference
  • Examples of endonuclease modulators include PGN-514.
  • inhibitors of ribonucleotide reductase include Trimidox.
  • HBV E antigen inhibitors include wogonin.
  • Examples of cccDNA inhibitors include BSBI-25, and CHR-101.
  • Farnesoid X receptor agonists include BSBI-25, and CHR-101.
  • Examples of farnesoid x receptor agonist such as EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297 and GS-8670
  • HBV antibodies targeting the surface antigens of the hepatitis B virus include GC-l 102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed).
  • HBV antibodies including monoclonal antibodies and polyclonal antibodies
  • examples of HBV antibodies include Zutectra, Shang Sheng Gan Di, Ehnan Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).
  • Fully human monoclonal antibodies include HBC-34.
  • CCR2 chemokine antagonists include propagermanium.
  • thymosin agonists include Thymalfasin, recombinant thymosin alpha 1 (GeneScience).
  • cytokines examples include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and celmoleukin.
  • Nucleoprotein modulators may be either HBV core or capsid protein inhibitors.
  • nucleoprotein modulators examples include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109, morphothiadine mesilate, ARB-168786, ARB-880, JNJ- 379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158 and
  • capsid inhibitors include the compounds disclosed in ETS20140275167 (Novira Therapeutics), ETS20130251673 (Novira Therapeutics), ETS20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), W02014033170 (Janssen), WO2014033167 (Janssen),
  • WO2017048954 (Assembly Biosciences)
  • WO2017048962 (Assembly Biosciences)
  • transcript inhibitors include the compounds disclosed in W02017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta).
  • W02017001853 Redex Pharma
  • WO2017211791 (Roche)
  • WO2017216685 Novartis
  • WO2017216686 Novartis
  • WO2018019297 Ginkgo Pharma
  • WO2018022282 Newave Pharma
  • US20180030053 Novartis
  • W02018045911 Zajiang Pharma
  • Examples of stimulators of retinoic acid-inducible gene 1 include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100.
  • Examples of stimulators of NOD2 include SB-9200.
  • PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, puquitinib mesylate,
  • IDO inhibitors examples include epacadostat (INCB24360), resminostat
  • Examples of PD-l inhibitors include cemiplimab, nivolumab, pembrolizumab, pidilizumab, BGB-108, STI-A1014, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, JNJ-63723283, CA-170, durvalumab, atezolizumab and mDX-400, JS-001,
  • Camrelizumab Sintilimab, Sintilimab, tislelizumab, BCD-l00,BGB-A333 JNJ-63723283, GLS-010 (WBP-3055), CX-072, AGEN-2034, GNS-1480 (Epidermal growth factor receptor antagonist; Programmed cell death ligand 1 inhibitor), CS-1001, M-7824 (PD-Ll/TGF-b bifunctional fusion protein), Genolimzumab, BMS-936559
  • Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP -224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, GS-4224, CX-072, and BMS-936559.
  • Examples of PD-l inhibitors include the compounds disclosed in WO2017112730 (Incyte Corp), WO20l7087777(Incyte Corp), WO2017017624, WO2014151634 (BristolMyers Squibb Co), WO201317322 (BristolMyers Squibb Co), WO2018119286 (Incyte Corp),
  • WO2018119266 (Incyte Corp), WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO2018119221 (Incyte Corp), WO2018118848 (BristolMyers Squibb Co),
  • WO20161266460 (BristolMyers Squibb Co), WO2017087678 (BristolMyers Squibb Co), WO2016149351 (BristolMyers Squibb Co), WO2015033299 (Aurigene Discovery
  • WO20l7066227 (BristolMyers Squibb Co), WO2016142886 (Aurigene Discovery Technologies Ltd), WO20l6l42852(Aurigene Discovery Technologies Ltd), WO2016142835 (Aurigene Discovery Technologies Ltd; Individual), WO2016142833 (Aurigene Discovery Technologies Ltd), W02018085750 (BristolMyers Squibb Co), W02015033303 (Aurigene Discovery Technologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co; Individual; Texas A&M University System), W02015160641 (BristolMyers Squibb Co), WO2017079669 (Incyte Corp), W02015033301 (Aurigene Discovery Technologies Ltd), W02015034820 (BristolMyers Squibb Co), WO2018073754 (Aurigene Discovery Technologies Ltd), WO2016077518 (BristolMyers Squibb Co), WO2016057624 (
  • WO2017192961 (Incyte Corp), WO2017106634 (Incyte Corp), WO2013132317 (Aurigene Discovery Technologies Ltd), WO2012168944 (Aurigene Discovery Technologies Ltd), WO2015036927 (Aurigene Discovery Technologies Ltd), WO2015044900 (Aurigene Discovery Technologies Ltd), WO2018026971 (Arising International).
  • Examples of recombinant thymosin alpha- 1 include NL-004 and PEGylated thymosin alpha- 1.
  • BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP- 0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and the compounds disclosed in US20140330015 (Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), and US20130217880 (Ono Pharmaceutical).
  • KDM5 inhibitors include the compounds disclosed in WO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092 (Genentech/Constellation
  • KDM1 inhibitors include the compounds disclosed in US9186337B2 (Oryzon Genomics), GSK-2879552, and RG-6016.
  • STING agonists include SB-l 1285, AdVCA0848, STINGVAX, amd the compounds disclosed in WO 2018065360 ("Biolog Life Science Institute Klaslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), ETS 20170158724 (GlaxoSmithKline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), WO2018098203 (Janssen),
  • NRTI Non-nucleoside reverse transcriptase inhibitors
  • NNRTI examples include the compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), W02017100108 (Idenix), WO2017027434 (Merck), W02017007701 (Merck), and W02008005555 (Gilead).
  • hepatitis B virus replication inhibitors include isothiafludine, IQP-HBV, RM-5038, and Xingantie.
  • Arginase inhibitors include CB-l 158, C-201, and resminostat.
  • Gene therapy and cell therapy includes the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient’s own immune system to enhance the immune response to infected cells, or activate the patient’s own immune system to kill infected cells, or find and kill the infected cells; and genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection.
  • Examples of genome editing systems include a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system; e.g ., cccDNA elimination via targeted cleavage, and altering one or more of the hepatitis B virus (HBV) viral genes.
  • CRISPR/Cas9 e.g., a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system
  • cccDNA elimination via targeted cleavage e.g ., cccDNA elimination via targeted cleavage
  • HBV hepatitis B virus
  • Altering e.g, knocking out and/or knocking down
  • the PreC, C, X, PreSI, PreS2, S, P or SP gene refers to (1) reducing or eliminating PreC, C, X, PreSI, PreS2, S, P or SP gene expression, (2) interfering with Precore, Core, X protein, Long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and/or Hepatitis B spliced protein function (HBe, HBc, HBx, PreSl, PreS2, S, Pol, and/or HBSP or (3) reducing or eliminating the intracellular, serum and/or intraparenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and/or HBSP proteins. Knockdown of one or more of the PreC, C, X, PreSI, PreS2, S, P and/or SP gene(s) is performed by
  • CAR T cell therapy includes a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HBV antigen binding domain.
  • the immune effector cell is a T cell or an NK cell.
  • the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof.
  • Cells can be autologous or allogeneic.
  • TCR T cell therapy includes T cells expressing HBV-specific T cell receptors.
  • TCR-T cells are engineered to target HBV derived peptides presented on the surface of virus-infected cells.
  • the T-cells express HBV surface antigen (HBsAg)-specific TCR.
  • HBV surface antigen (HBsAg)-specific TCR examples include LTCR-H2-1.
  • a compound disclosed herein is combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from the group consisting of immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody- like” therapeutic proteins (such as DARTs®, DETOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid- inducible gene 1, stimulators of RIG-I like receptors, PD-l inhibitors, PD-L1 inhibitors,
  • Arginase inhibitors PI3K inhibitors, IDO inhibitors, and stimulators ofNOD2, and one or two additional therapeutic agents selected from the group consisting of HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).
  • HBV viral entry inhibitors NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).
  • a compound disclosed herein is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs ® , DUOBODIES ® , BITES ® , XmAbs ® , TandAbs ® , Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I like receptors, PD-l inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of NOD2.
  • a second additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, H
  • a compound disclosed herein is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).
  • a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).
  • a compound disclosed herein is combined with a compound such as one disclosed in U.S. Publication No. 2010/0143301 (Gilead Sciences), U.S. Publication No. 2011/0098248 (Gilead Sciences), U.S. Publication No. 2009/0047249 (Gilead Sciences), U.S. Patent No. 8722054 (Gilead Sciences), U.S. Publication No. 2014/0045849 (Janssen), U.S. Publication No. 2014/0073642 (Janssen), WO2014/056953 (Janssen),
  • a compound as disclosed herein may be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents in any dosage amount of the compound of Formula I (e.g, from 10 mg to 1000 mg of compound).
  • one or more e.g., one, two, three, four, one or two, one to three, or one to four
  • additional therapeutic agents in any dosage amount of the compound of Formula I (e.g, from 10 mg to 1000 mg of compound).
  • a compound disclosed herein is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • a compound disclosed herein is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • a compound as disclosed herein e.g, a compound of Formula I
  • a compound disclosed herein is combined with 100-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • a compound disclosed herein is combined with 100-150; 100-200, 100- 250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200- 350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • a compound disclosed herein is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, e.g ., a compound of Formula I, is combined with 250 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein is combined with 150 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • a compound as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g, from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • a method of producing a composition comprising one or more solid forms of Formula I e.g., a crystalline Form of Formula I
  • the method comprises combining a compound of Formula I with a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more solid forms of the compound of Formula I.
  • another method of producing a composition comprising one or more solid forms of Formula I wherein the method comprises combining Formula I with a suitable solvent or a mixture of suitable solvents.
  • Solvents suitable for crystal formation may include, for example, water, methanol, ethanol,
  • the presence of impurities affects the formation favoring one solid form of Formula I over another.
  • the form is prepared by a process comprising Formula I having impurities.
  • the form is prepared by a process comprising substantially pure Formula I.
  • a method of producing a composition comprising crystalline Form I wherein the method comprises combining Formula I with a solvent to produce a composition comprising crystalline Formula I Form I, wherein the solvent is water.
  • a method of preparing crystalline Formula I Form I comprising contacting Formula I and water, wherein Formula I remains substantially insoluble in water, under conditions suitable to prepare crystalline Form I.
  • crystalline Formula I Form I produced by combining Formula I with a solvent, wherein the solvent is water.
  • a method of producing a composition comprising crystalline Formula I Form I wherein the method comprises combining Formula I with a solvent to produce a composition comprising crystalline Formula I Form I, wherein the solvent comprises ethanol and water.
  • a method of preparing crystalline Formula I Form I comprising contacting Formula I and a solvent mixture comprising ethanol and aqueous base to form a Formula I mixture, and adding the Formula I mixture to an aqueous acid, under conditions suitable to prepare Form I of Formula I.
  • a method of preparing crystalline Formula I Form I comprising contacting Formula I and a solvent mixture comprising ethanol and aqueous base to form a Formula I mixture, and adding an aqueous acid to the Formula I mixture, under conditions suitable to prepare Form I of Formula I.
  • the water comprises an aqueous base, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, or mixtures thereof, e.g ., sodium hydroxide.
  • the aqueous base can be of any concentration ranging from about 0.1 N to about 10 N, such as about 0.1, 0.2, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or about 10 N.
  • the aqueous base is 1 N sodium hydroxide.
  • the aqueous base is lithium hydroxide.
  • the amount of aqueous base is sufficient to produce a molar amount of the carboxylate salt of the compound of Formula I.
  • the amount of aqueous base is from about 1.01 to about 3 molar equivalents compared with the amount of the compound of Formula I in the solvent mixture, e.g. , about 1.01, 1.05, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.5, 2.6, 2.8 or about 3 molar equivalents.
  • the amount of aqueous base is about 2.6 molar equivalents compared with the amount of the compound of Formula I in the solvent mixture.
  • the amount of aqueous base is about 1.3 molar equivalents compared with the amount of the compound of Formula I in the solvent mixture.
  • the ethanol and aqueous base can be present in the solvent mixture in any suitable ratio.
  • Representative ratios of the ethanol and aqueous base include from about 3 : 1 to about 1 :5 (V/V), or from about 2: 1 to about 1 :4 (V/V), or from about 1.5: 1 to about 1 :3 (V/V), or from about 1.5: 1 to about 1 :2 (V/V) , or from about 1 : 1 to about 1 :2 (V/V).
  • Representative ratios of the ethanol and aqueous base include about 3 : 1 (V/V), as well as 2.5: 1, 2.2: 1, 2: 1, 1.8:1, 1.6: 1, 1.5: 1, 1.3:1, 1.2: 1, 1.1 : 1, 1 : 1.1, 1 : 1.2, 1 : 1.3, 1 : 1.5, or 1 :2 (V/V).
  • the solvent mixture includes ethanol and aqueous base in a ratio of from about 1.5:1 to about 1 :2 (V/V).
  • the solvent mixture includes ethanol and aqueous base in a ratio of from about 1 : 1 to about 1 :2 (V/V).
  • the solvent mixture includes ethanol and aqueous base in a ratio of at least 1 : 1 (V/V). In some embodiments, the solvent mixture includes ethanol and aqueous base in a ratio of about 4:3 (V/V).
  • the method of making crystalline Formula I Form I can be performed at any suitable temperature. Representative temperatures for preparation of crystalline Formula I Form I include about 5 °C, or 10, 15, 20, 25, 30, 35, 40, 45, or about 50 °C. Representative temperatures for preparation of crystalline Formula I Form I include about 5 °C, or 10, 15, 20, 25, 30, 35, 40, 45, or about 50 °C. Representative temperatures for preparation of crystalline Formula I Form I include about 5 °C, or 10, 15, 20, 25, 30, 35, 40, 45, or about 50 °C. Representative
  • temperatures ranges include 5 °C to 50 °C, or 5 °C to 40 °C, 10 °C to 40 °C, 20 °C to 40 °C, 20 °C to 30 °C, or 15 °C to 30 °C.
  • the contacting step is performed at a temperature of from about 15 °C to about 40 °C. In some embodiments, the contacting step is performed at a temperature of from about 20 °C to about 30 °C. In some embodiments, the contacting step is performed at a temperature of about 20 °C.
  • the method further comprises adding the Formula I mixture to an aqueous acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, or methanesulfonic acid, or mixtures thereof, e.g ., hydrochloric acid.
  • aqueous acid can be of any concentration ranging from about 0.1 N to about 10 N, such as about 0.1, 0.2, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or about 10 N.
  • the aqueous acid is 1 N hydrochloric acid.
  • the amount of aqueous acid is sufficient to acidify the solvent or solvent mixture comprising the compound of Formula I.
  • the amount of aqueous acid is from about 1.01 to about 3 molar equivalents compared with the amount of aqueous base in the solvent mixture, e.g, about 1.01, 1.05, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.5, 2.8 or about 3 molar equivalents.
  • the amount of aqueous acid is from about 1.2 molar equivalents compared with the amount of aqueous base in the solvent mixture.
  • the method further comprises adding seed crystals of Formula I Form I to the aqueous acid before adding the Formula I mixture.
  • crystalline Formula I Form I produced by combining Formula I with a solvent mixture, wherein the solvent mixture comprises ethanol and water, e.g, ethanol and an aqueous base.
  • the crystalline Formula I Form I is prepared substantially free of Form II and/or the amorphous form.
  • a method of preparing crystalline Formula I Form I comprising contacting Formula I and methanol, wherein Formula I remains substantially insoluble in methanol, under conditions suitable to prepare crystalline Form II.
  • crystalline Formula I Form II produced by combining Formula I with a solvent, wherein the solvent comprises methanol.
  • the crystalline Formula I Form II is prepared substantially free of Form I and/or the amorphous form.
  • a method of producing a composition comprising amorphous Formula I comprising combining Formula I with a solvent to produce a composition comprising amorphous Formula I, wherein the solvent comprises acetonitrile and water.
  • a method of preparing an amorphous form of Formula I comprising contacting Formula I and a solvent mixture comprising acetonitrile and water, and lyophilizing under conditions suitable to prepare the amorphous form of Formula I.
  • amorphous solid Formula I produced by combining Formula I with a solvent mixture, wherein the solvent mixture comprises acetonitrile and water.
  • the amorphous form of Formula I is prepared substantially free of Form I and/or Form II.
  • a compound of Formula I is used in the manufacture of an active pharmaceutical ingredient.
  • Formula I Form I is used in the manufacture of an active pharmaceutical ingredient.
  • Formula I Form II is used in the manufacture of an active pharmaceutical ingredient.
  • amorphous Formula I is used in the manufacture of an active pharmaceutical ingredient.
  • a mixture of forms of Formula I is used in the manufacture of an active pharmaceutical ingredient.
  • compositions comprising one or more of the compounds of Formula I described herein and formulated in one or more pharmaceutically acceptable excipients or other ingredients can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of one or more of the compounds of Formula I described herein and a label containing instructions for use of the compound(s).
  • the article of manufacture is a container comprising a dosage form of one or more of the compounds of Formula I described herein, and one or more pharmaceutically acceptable excipients or other ingredients.
  • the dosage form is a solution.
  • Kits also are contemplated.
  • a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition.
  • a kit may comprise multiple individual dosage forms, each comprising a therapeutically effective amount of a compound as described herein, and instructions for their administration to a human in need thereof.
  • Each of the individual dosage forms may comprise a therapeutically effective amount of a compound as described herein in combination with at least one pharmaceutically effective excipient.
  • the individual dosage forms may be in the form of, as examples, a solution, a tablet, a pill, a capsule, a sachet, a sublingual medicament, a lyophilized powder, a spray-dried powder, or a liquid composition for oral, parenteral, or topical administration.
  • the instructions for use in the kit may be for treating a hepatitis B virus infection in a human.
  • the instructions may be directed to any of the viral infections and methods described herein.
  • the instructions may be for prophylaxis or the treatment of an existing viral infection.
  • the solid forms described herein may potentially exhibit improved properties.
  • a solid form described herein may potentially exhibit improved stability.
  • Such improved stability could have a potentially beneficial impact on the manufacture of the compound of Formula I, such as for example offering the ability to store process intermediate for extended periods of time.
  • Improved stability could also potentially benefit a composition or pharmaceutical composition of the compound of Formula I.
  • the solid form described herein may also potentially result in improved yield of the compound of Formula I, or potentially result in an improvement of the quality of the compound of Formula I.
  • the solid form and solvate forms described herein may also exhibit improved pharmacokinetic properties and/or potentially improved bioavailability.
  • kits comprising a compound disclosed herein in combination with one or more (e.g ., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided.
  • Procedure 1 To a flask was charged with about 7 grams of Formula I, about 28 mL of ethanol, and about 21 mL of 1 N NaOH. Separately, to a lOO-mL reactor was charged about 38.5 mL water, about 24.5 mL of 1 N HC1, and about 70 mg 1 wt% of Formula I Form I seeds. The contents of the lOO-mL reactor were then adjusted to about 20 °C. The resulting ethanol/NaOH solution in the flask was transferred to the contents of the lOO-mL reactor over the course of about 4 hours, and the resulting solids were filtered. Formula I Form I was washed 3 times with about 35 mL of water. The crystalline Formula I Form I solids were dried at room temperature and pressure and then at about 20 °C under vacuum.
  • Procedure 2 To a 50 mL flask was charged about 17 grams of Formula I, about 69 mL of ethanol, and about 52 mL of 1 N NaOH. The resulting solution was charged over about 1 hour at about 20 °C to a reactor equipped with overhead agitation containing about 95 mL of water, about 60 mL 1 N HC1, and about 183 mg of Formula I Form I seeds. The resulting suspension was filtered, and the solids were washed 3 times with about 86 mL of water. The isolated Formula I Form I was dried at room temperature and pressure and then dried at about 20 °C under vacuum.
  • Procedure 3 To a glass bottle equipped with a magnetic stir bar was charged with about 360 grams of Formula I Form I, about 1440 mL of ethanol, and about 1080 mL of 1 N NaOH. The contents of the bottle were agitated for about 20 minutes, and the resulting solution was polish filtered. To a glass lined reactor equipped with overhead agitation was charged with about 1980 mL of water, about 1260 mL of 1 N HC1, and about 3.6 grams of Formula I Form I seeds. The contents of the reactor were then adjusted to about 30 °C. The polish filtered ethanol/ NaOH solution was transferred to the contents of the reactor over the course of about 2 hours, and then the temperature was adjusted to about 20 °C over the course of about 1.5 hours. The resulting suspension was filtered, and the Formula I Form I was washed 3 times with about 1800 mL of water. The isolated Formula I Form I was dried at room temperature and pressure and then dried at about 50 °C under vacuum.
  • Procedure 4 To a solution of about 38 g Formula I in about 156 mL ethanol and about 120 mL of 1 N aqueous NaOH was added about 124.4 mL 1 N HC1, resulting in a reaction mixture with a pH of about 3. About 40 mg of Formula I Form I seeds were added, and the reaction contents were cooled to about 45 °C. The reactor contents were heated to about 50 °C and about 1 mL of 1 N HC1 was added to the reactor. About 40 mg of additional Formula I Form I seeds were added, at which point the reactor contents were cooled to about 45 °C. About 78 mL water was added via syringe pump over 2 h.
  • the reactor contents were aged for about 60 min at 45 °C, then cooled to 20 °C at a rate of about 5 °C/h.
  • the reactor contents were agitated at about 20 °C overnight.
  • the resulting slurry was filtered, washed with about 117 mL of 25% ethanol/water, and about three times with about 195 mL water.
  • the isolated Formula I Form I was dried at room temperature and pressure and then dried at about 50 °C under vacuum.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA therm ogravimetric analysis
  • DFS dynamic vapor sorption
  • the XRPD pattern for Formula I Form I is represented in FIG. 1.
  • the XRPD pattern for Formula I Form II is represented in FIG. 5.
  • the DSC for Formula I Form I is represented in FIG. 2, which shows a sharp endothermic event with an onset temperature of about 131 °C with an associated enthalpy of about 54 J/g.
  • the exemplary DSC of Form I is characterized by a sharp peak with an onset at about 131 °C.
  • the DSC for Formula I Form II is represented in FIG. 6, which shows an endothermic event with an onset temperature of about 174 °C with an associated enthalpy of about 120 J/g.
  • the exemplary DSC of Form II is characterized by a sharp peak with an onset at about 174 °C.
  • the DSC for amorphous Formula I is represented in FIG. 10, which shows a shift in the baseline beginning at about 48 °C and ending at about 60 °C, consistent with a glass transition.
  • Thermogravimetric analysis was used to evaluate sample weight loss as a function of temperature by loading 1-10 mg of material onto an aluminum weigh pan (TA Instruments, New Castle, DE) and heated the sample to 300 °C or above at a rate of 10 °C/min.
  • the sample and reference pans were under a 60 mL/min and 40 mL/min nitrogen purge, respectively.
  • Data analysis was completed using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE).
  • TGA for Formula I Form I is represented in FIG. 3, which shows a mass loss of 0.43 wt% by 150 °C.
  • TGA for Formula I Form II is represented in FIG. 7, which shows a mass loss of 6.4 wt% by 200 °C.
  • the TGA for amorphous Formula I is represented in FIG. 11, which shows a gradual loss of mass starting at about 25 °C, with a total mass loss of about 5.8 wt% by 150 °C.
  • Dynamic vapor sorption Hygroscopicity was studied using DVS (TA Q5000 SA, TA Instruments, New Castle, DE or DVS Intrinsic, Surface Measurement Systems, London, UK). A sample (2-20 mg) was placed in an aluminum DVS pan and loaded on the sample side of the twin pan balance. The water sorption and desorption were studied as a function of relative humidity (RH) at 25°C. In 10% RH increments, the relative humidity was increased from 5% RH to 95% RH and then decreased back to 5%. Each relative humidity increment had an equilibration time of 180 minutes, unless weight change % was less than 0.002% in 30 minutes. Data analysis was performed using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE) for TA DVS runs and Microsoft Excel for SMS DVS runs.
  • RH relative humidity
  • the DVS for Formula I Form I is represented in FIG. 4, which shows 1.1 wt% water uptake at 95% RH at 25 °C, with minimal hysteresis.
  • the DVS for Formula I Form II is represented in FIG. 8, which shows 0.3 wt% water uptake at 90% RH at 25 °C, with minimal hysteresis.
  • Solubility ⁇ To a vial equipped with a magnetic stir bar was charged about 100 mg of solid Formula I. To the same vial was charged an amount of solvent until a mobile slurry was obtained. The vial mixture was allowed to agitate for about 4 h to about 24 h at room temperature. The vial mixture was filtered, the resulting mother liquor was assayed using ultra- pressure liquid chromatography.
  • Stability ⁇ An accelerated stability study was staged at 40 °C and 75% relative humidity or 80 °C and 75% relative humidity to access the stability of the solid form and determine levels of degradants under the experimental conditions over time. Purity level of Formula I was determined by UPLC.

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Abstract

La présente invention concerne de nouvelles formes cristallines d'acide (R)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-oxo -2,3,8,13b-tétrahydro-1H-pyrido[2, 1-a]pyrrolo[1,2-c]phtalazine-7-carboxylique à utiliser dans le traitement d'infections virales. Dans certains modes de réalisation, l'infection virale est provoquée par un virus de l'hépatite B.
PCT/US2019/043042 2018-08-01 2019-07-23 Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique Ceased WO2020028097A1 (fr)

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