Solid Forms of Isoquinolinones, Methods for their Preparation, Compositions Containing them, and Methods of Use

Abstract

The present invention describes solid forms and complexes of chemical compounds that modulate kinase activity, including PI3 kinase activity, pharmaceutical compositions, and methods of treating diseases and disorders associated with kinase activity, including PI3 kinase activity. The present invention also provides methods for preparing compounds, polymorphic forms, co-crystals and their amorphous forms, and pharmaceutical compositions thereof.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 218,486, filed on September 14, 2015, and U.S. Provisional Application No. 62 / 218,493, filed on September 14, 2015, the entire contents of which are incorporated herein by reference. 1. BACKGROUND OF THE INVENTION

[0003] Cell activity can be regulated by external signals that stimulate or inhibit intracellular events. The process of transmitting a stimulatory or inhibitory signal into and within a cell to elicit an intracellular response is called signal transduction. During the past several decades, cascades of signal transduction events have been elucidated and found to play important roles in a variety of biological responses. Defects in various components of signal transduction pathways have been found to account for a large number of diseases, including multiple forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al., Current Medicinal Chemistry (2007) 14:2214-2234).

[0004] Kinases represent an important class of signal transduction molecules. Kinases can generally be classified into protein kinases and lipid kinases, and certain kinases exhibit dual specificity. Protein kinases are enzymes that phosphorylate other proteins and / or themselves (i.e., autophosphorylation). Based on the substrates used by protein kinases, protein kinases can generally be divided into three main groups: tyrosine kinases that primarily phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), serine / threonine kinases that primarily phosphorylate substrates on serine and / or threonine residues (e.g., mTorC1, mTorC2, ATM, ATR, DNA-PK, Akt), and dual specificity kinases that phosphorylate substrates on tyrosine, serine, and / or threonine residues.

[0005] Lipid kinases are kinases that catalyze the phosphorylation of lipids. These enzymes, as well as the resulting phosphorylated lipids and lipid-derived biologically active organic molecules, play roles in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation. Certain lipid kinases are membrane-associated and catalyze the phosphorylation of lipids contained within or associated with the cell membrane. Examples of such enzymes include phosphoinositide kinases (e.g., PI3-kinase, PI4-kinase), diacylglycerol kinase, and sphingosine kinase.

[0006] Phosphoinositide 3-kinase (PI3K) constitutes a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group of phosphatidylinositols or phosphoinositides. The PI3K family includes 15 kinases with different substrate specificities, expression patterns, and regulatory modes. Class I PI3Ks (p110α, p110β, p110δ, or p110γ) are typically activated by tyrosine kinases or G-protein-coupled receptors to generate lipid products called PIP3, which engages downstream effectors such as those in the Akt / PDK1 pathway, mTOR, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play key roles in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.

[0007] The PI3K signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling is also a key factor in many other diseases and disorders in humans. PI3K signaling is involved in many disorders, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, disorders associated with diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.

[0008] Numerous PI3K inhibitors have been prepared. Although such compounds are typically initially evaluated for their activity in solution, solid-state characteristics such as polymorphs play an important role. Polymorphic forms of drug substances such as PI3K inhibitors can have different chemical and physical properties, including crystallinity, melting point, chemical reactivity, solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct impact on the processing or manufacturing capabilities of the drug substance and drug product. Moreover, polymorphism is often a factor in the regulatory review of "identical" drug products from different manufacturers. For example, the polymorphism of compounds such as warfarin sodium, famotidine, and ranitidine has been evaluated. Polymorphism can affect the quality, safety, and / or efficacy of drug products such as kinase inhibitors. Therefore, in the development of active pharmaceutical ingredients (APIs), research into the polymorphs of PI3K inhibitors and methods for preparing the polymorphs of PI3K inhibitors represents a significantly useful area of research.

[0009] In addition, PI3K inhibitors have been used to treat a variety of human diseases and conditions (e.g., in clinical trials). For the preparation of drug substances intended for human use, current Good Manufacturing Practice (GMP) is applicable. There is a need for in-situ methods that can control impurity levels and ensure the production of API products that consistently meet their predefined specification standards. Accordingly, there is a significant need for a method of preparing PI3K inhibitors suitable for human use, particularly on an industrial scale, i.e., a method of preparation that is, inter alia, safe, scalable, economically viable, and / or has other desirable properties. Among other entities, polymorphs of PI3K inhibitors are disclosed herein that address these needs and provide exemplary advantages.

[0010] 2. BRIEF DESCRIPTION OF THE INVENTION

[0011] Provided herein are compounds of formula (I) (also referred to herein as Compound 1):

[0012]

[0013] or salts, or solvates (e.g., hydrates) or solvates of salts, or solid forms of mixtures thereof. Also provided herein are methods for synthesizing said solid forms.

[0014] The solid forms provided herein include, but are not limited to, hydrates, anhydrates, solvates, salts, and co-crystals of Compound 1. The solid forms provided herein are used as active pharmaceutical ingredients for the preparation of formulations for animals or humans. Accordingly, the embodiments herein encompass the use of these solid forms as final drug products. Certain embodiments provide solid forms for the preparation of final dosage forms having improved properties, such as powder flow properties, compaction properties, tableting properties, stability properties, and excipient compatibility properties, etc., which are required for the preparation, processing, formulation, and / or storage of final drug products. Certain embodiments herein provide pharmaceutical compositions comprising single-component crystal forms and / or multi-component crystal forms of a compound of formula (I) and pharmaceutically acceptable diluents, excipients, or carriers.

[0015] In one embodiment, the solid form is a crystalline form. In one embodiment, the solid form further comprises a coformer. In one embodiment, the solid form comprises Compound 1 and the coformer is a co-crystal. In another embodiment, the solid form is an amorphous form.

[0016] Also provided herein are pharmaceutical compositions, single unit dosage forms, dosing regimens, and kits comprising the amorphous forms provided herein.

[0017] The present invention also provides methods for treating, preventing, and controlling various disorders using the compositions and amorphous forms provided herein. The methods include administering to a patient in need of such treatment or control a therapeutically effective amount of a compound provided herein. Further provided are methods for preventing various diseases and disorders, which include administering to a patient in need of such prevention a prophylactically effective amount of a compound provided herein.

[0018] The present invention further provides methods for preparing a compound of formula (I), or a salt, or a solvate (e.g., hydrate), or a solvate of a salt, or a mixture thereof.

[0019] The present invention further provides methods for analyzing the presence or amount of a solid form provided herein in a substance, including providing a substance comprising a compound of formula (I), or a salt, solvate (e.g., hydrate), or a solvate of a salt, or a mixture thereof; and using a characterization method to determine an identification characteristic associated with the solid form present in the substance by comparing a characteristic obtained from the substance with a reference identification characteristic; wherein the presence of a characteristic that is substantially the same as the reference identification characteristic indicates the presence of the solid form in the substance.

[0020] 3. Incorporation by Reference

[0021] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference in their entirety, to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. 4. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is a representative X-ray powder diffraction (XRPD) pattern of Form 1 of Compound 1.

[0024] Figure 2 is a representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 1 of Compound 1.

[0025] Figure 3 is a representative gravimetric vapor sorption (GVS) isotherm plot of Form 1 of Compound 1.

[0026] Figure 4 is a representative XRPD pattern of Form 2 of Compound 1.

[0027] Figure 5 is a representative overlay of the TGA and DSC thermograms of Form 2 of Compound 1.

[0028] Figure 6 is a representative GVS isotherm plot of Form 2 of Compound 1.

[0029] Figure 7 Another representative overlay plot of the TGA and DSC thermal analysis diagrams of Form 2 of Compound 1.

[0030] Figure 8 Another representative XRPD pattern of Form 2 of Compound 1.

[0031] Figure 9 Representative XRPD pattern of Form 3 of Compound 1.

[0032] Figure 10 Representative overlay plot of the TGA and DSC thermal analysis diagrams of Form 3 of Compound 1.

[0033] Figure 11 Representative XRPD pattern of Form 4 of Compound 1.

[0034] Figure 12 Representative overlay plot of the TGA and DSC thermal analysis diagrams of Form 4 of Compound 1.

[0035] Figure 13 Representative XRPD pattern of Form 5 of Compound 1.

[0036] Figure 14 Representative overlay plot of the TGA and DSC thermal analysis diagrams of Form 5 of Compound 1.

[0037] Figure 15 Representative XRPD pattern of Form 6 of Compound 1.

[0038] Figure 16 Representative overlay plot of the TGA and DSC thermal analysis diagrams of Form 6 of Compound 1.

[0039] Figure 17 Representative GVS isotherm plot of Form 6 of Compound 1.

[0040] Figure 18 Representative XRPD pattern of Form 7 of Compound 1.

[0041] Figure 19 Representative overlay plot of the TGA and DSC thermal analysis diagrams of Form 7 of Compound 1.

[0042] Figure 20 Representative XRPD pattern of Form 8 of Compound 1.

[0043] Figure 21 Representative ORTEP plot of Form 2 of Compound 1.

[0044] Figure 22Representative XRPD pattern of Form P1C3 of the co-crystal of Compound 1 and L-tartaric acid.

[0045] Figure 23 Representative TGA and DSC analyses of Form P1C3 of the co-crystal of Compound 1 and L-tartaric acid.

[0046] Figure 24 Representative XRPD of Form P1C9 of the co-crystal of Compound 1 and salicylic acid.

[0047] Figure 25 Representative TGA versus DSC analysis of Form P1C9 of the co-crystal of Compound 1 and salicylic acid.

[0048] Figure 26 Representative XRPD analysis of Form P2C9 of the co-crystal of Compound 1 and salicylic acid.

[0049] Figure 27 Representative TGA and DSC analyses of Form P2C9 of the co-crystal of Compound 1 and salicylic acid.

[0050] Figure 28 Representative GVS analysis of Form P1C3 of the co-crystal of Compound 1 and L-tartaric acid.

[0051] Figure 29 Shows the solubility of Compound 1 in ethanol / water and the corresponding ethanol content in the isolated Compound 1.

[0052] Figure 30 Representative crystal structure of Form 1 of Compound 1 obtained by heating a solution of 13.5 mg / mL of Compound 1 in 80% ethanol / water to 60 °C and then cooling to room temperature.

[0053] Figure 31 Representative TGA analysis of spray-dried Compound 1.

[0054] Figure 32 Representative TGA analysis of spray-dried Compound 1 and PVP / VA 64.

[0055] Figure 33 Representative TGA analysis of spray-dried Compound 1 and HPMC-AS.

[0056] Figure 34A Shows the conversion rate (% area) of the coupling reaction of 4-iodo-1-methyl-1H-pyrazole with trimethylsilylacetylene at 2 hours; Figure 34B Shows the reaction conversion rate (% area) at 24 hours; Figure 34C Shows the product / diyne ratio (% area) at 24 hours; andFigure 34D The content of diyne (%) area shown in 24 hours.

[0057] 5. Detailed description

[0058] 5.1 Definition

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0060] Unless the context clearly dictates otherwise, the singular forms of the indefinite articles “a”, “an” and the definite article “the” as used in the specification and claims include plural referents.

[0061] When ranges are used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formula), all combinations and sub-combinations of ranges as well as specific embodiments therein are contemplated. As used herein, the terms “about” or “approximately” when used in combination with a numerical value or numerical range mean that the value or numerical range can deviate from what would be reasonable to a person of ordinary skill in the art, e.g., within experimental variation (or within statistical experimental error), such that the numerical value or numerical range can vary, for example, between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, and between 0.5% and 1% of the stated numerical value or numerical range. Embodiments of a given value are also included where a numerical value or numerical range is preceded by the term “about” as disclosed herein. For example, “about 3 °C” discloses an embodiment where the temperature is “3 °C”. Throughout the specification, the terms “about” and “approximately” are used interchangeably. The term “between” includes the endpoint numbers of the range limits. For example, “between 3 and 5” describes a range that includes the numbers “3” and “5”. The tilde (i.e., “~”) preceding a numerical value or numerical range as used herein means “about” or “approximately”.

[0062] As used herein and unless otherwise specified, “agent” or “bioactive agent” or “second active agent” refers to a biological, pharmaceutical or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins or chemotherapeutic compounds. A variety of compounds can be synthetic, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides) and synthetic organic compounds based on various parent nuclear structures. Additionally, a variety of natural sources can provide compounds for screening, such as plant or animal extracts and the like. One of ordinary skill in the art can readily recognize that the structural nature of the reagents of the present disclosure is not limited in any way.

[0063] As used herein, and unless otherwise specified, the term "agonist" refers to a compound capable of eliciting or enhancing the biological function of a target protein or polypeptide (whether enhancing or eliciting the activity or expression of the target protein). Thus, the term "agonist" is defined in the context of the biological action of the target protein. While the agonists provided herein specifically interact (e.g., bind) with the target, the definition also expressly includes compounds that elicit or enhance the biological activity of the target protein by interacting with other members of a signal transduction pathway (wherein the target protein is a member of the pathway).

[0064] As used herein, and unless otherwise specified, the terms "antagonist" and "inhibitor" refer to a compound capable of inhibiting the biological function of a target protein (whether inhibiting the activity of the target protein or inhibiting its expression). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological action of the target protein. While the antagonists provided herein specifically interact (e.g., bind) with the target, the definition also expressly includes compounds that inhibit the biological activity of the target protein by interacting with other members of a signal transduction pathway (wherein the target protein is a member of the pathway). In one embodiment, the biological activities inhibited by the antagonist are those associated with the development, growth or spread of a tumor or an unwanted immune response such as manifested in, for example, an autoimmune disease.

[0065] As used herein, and unless otherwise specified, the terms "anticancer agent", "antineoplastic agent" or "chemotherapeutic agent" refer to any agent useful in the treatment of a tumor disorder. One class of anticancer agents includes chemotherapeutic agents. As used herein, and unless otherwise specified, the term "chemotherapy" refers to the administration of one or more chemotherapeutic drugs and / or other agents to a cancer patient by various methods including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation, or in the form of a suppository.

[0066] As used herein, and unless otherwise specified, the term "cell proliferation" refers to the phenomenon in which the number of cells changes due to division. In one embodiment, the term also encompasses cell growth such that the cell morphology changes in accordance with the proliferation signal (e.g., an increase in size).

[0067] As used herein, and unless otherwise specified, the terms "co-administer", "administer in combination" and their grammatical equivalents include the administration of two or more agents to a subject. In one embodiment, the agent and / or its metabolite(s) are present in the animal simultaneously. In one embodiment, co-administration includes simultaneous administration in the form of separate compositions, administration at different times in the form of separate compositions, or administration in the form of a composition in which both agents are present.

[0068] As used herein and unless otherwise specified, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to achieve the intended application as defined herein, the intended application including but not limited to the treatment of diseases. The therapeutically effective amount can vary depending on the following factors: the intended application (in vivo or in vitro), or the subject being treated and the disease condition, e.g., the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term can also apply to the dose that will induce a specific response (e.g., reduce platelet adhesion and / or cell migration) in a target cell. The specific dose will vary depending on the following factors: the specific compound selected, the dosing regimen followed, whether administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system that transports it.

[0069] As used herein and unless otherwise specified, the terms "treatment", "treating", "palliating", and "ameliorating" are used interchangeably herein and refer to a method of obtaining a beneficial or desired result (including but not limited to a therapeutic benefit). In one embodiment, a therapeutic benefit refers to eradicating or ameliorating the underlying disorder being treated. In one embodiment, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, but the patient may still have the underlying disorder.

[0070] As used herein and unless otherwise specified, the terms "prevention" and "preventing" refer to a method of obtaining a beneficial or desired result (including but not limited to a preventive benefit). In one embodiment, a preventive benefit includes delaying or the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, stopping, or reversing the progression of a disease or disorder, or any combination thereof. For a preventive benefit, a pharmaceutical composition can be administered to a patient at risk of having a particular disease or to a patient reporting one or more physiological symptoms of a disease, even if the disease may or may not have been diagnosed.

[0071] As used herein and unless otherwise specified, "signal transduction" is the process by which a stimulatory or inhibitory signal is transmitted into a cell and elicits an intracellular response within the cell. A "modulator" of a signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins that localize to the same specific signal transduction pathway. A modulator can enhance (agonist) or inhibit (antagonist) the activity of a signal transduction molecule.

[0072] As used herein and unless otherwise specified, the terms "selective inhibition" or "selectively inhibit" as applied to a bioactive agent refer to the ability of an agent to selectively reduce target signal transduction activity compared to off-target signal transduction activity via direct or indirect interaction with a target.

[0073] As used herein and unless otherwise specified, the term "in vivo" refers to an event occurring within an object.

[0074] As used herein and unless otherwise specified, the term "in vitro" refers to an event occurring outside of an object. For example, in vitro assays encompass any assay conducted outside of an object assay. In vitro assays encompass cell-based assays, where live or dead cells are employed. In one embodiment, in vitro assays also include cell-free assays, where intact cells are not employed.

[0075] An "object" to which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, pediatric objects (e.g., infants, children, adolescents) or adult objects (e.g., young adults, middle-aged adults or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or avians, including commercially relevant avians such as chickens, ducks, geese, quails, and / or turkeys.

[0076] As used herein and unless otherwise specified, "radiotherapy" refers to exposing a patient to a radiation emitter, such as a radionuclide emitting alpha particles (e.g., actinium and thorium radionuclides), a low linear energy transfer (LET) radiation emitter (e.g., a beta emitter), a conversion electron emitter (e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation, including but not limited to x-rays, gamma rays, and neutrons, using conventional methods and compositions known to a practitioner.

[0077] As used herein, the term "mixing" refers to forming a combination of one or more chemical entities with one or more additional chemical entities. Mixing includes the process of adding one or more compounds to a solid, liquid, or gaseous mixture, or a liquid solution or a multiphase liquid mixture, of one or more compounds (the same or other chemical entities). The actions of mixing include steps in which one or more compounds react with one or more compounds (the same or other chemical entities) (e.g., bond formation or cleavage; salt formation, solvate formation, chelation, or other alteration of non-bonded associations). The actions of mixing can include altering one or more compounds, such as by isomerization (e.g., tautomerization, resolution of one isomer from another, or racemization).

[0078] As used herein and unless otherwise indicated, the term "one-pot" method refers to a method for preparing a desired product, wherein all reactants are added simultaneously or sequentially, and wherein no isolation, separation, and / or purification of any intermediates formed is carried out until the formation of the desired product is substantially complete. The "one-pot" method is preferably carried out in a single vessel, but may be carried out in more than one vessel.

[0079] As used herein, the term "recover" includes, but is not limited to, the act of obtaining one or more compounds by collection during and / or after the method steps disclosed herein, and the act of separating one or more compounds from one or more other chemical entities during and / or after the method steps disclosed herein to obtain one or more compounds. The term "collect" refers to any act known in the art for this purpose, including, but not limited to, filtration, decanting a mother liquor from a solid to obtain one or more compounds, and evaporating the liquid medium in a solution or other mixture to obtain a solid, an oil, or other residue comprising one or more compounds. The solid may be a crystal, a single crystal, a partial crystal, an amorphous substance, containing one or more polymorphs, powders, granules of different particle sizes, uniform particle sizes, and other characteristics known in the art. The color and viscosity of the oil may vary and include one or more solid forms in a non-uniform mixture, and other characteristics known in the art. The term "separate" refers to any act known in the art for this purpose, including, but not limited to, using, for example, seeded or unseeded crystallization or other precipitation techniques (e.g., adding an anti-solvent to a solution to induce precipitation of a compound; heating a solution and then cooling it to induce precipitation of a compound; scraping the surface of a solution with a tool to induce precipitation of a compound) and distillation techniques to separate one or more compounds from a solution or mixture. Recovering one or more compounds may include preparing its salts, solvates, hydrates, chelates, or other complexes, and then collecting or separating as described above.

[0080] The "pharmaceutically acceptable forms" of formula (I) as disclosed herein include, but are not limited to, its pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives, and mixtures thereof. Thus, the term "chemical entity" also encompasses pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives, and mixtures thereof. In certain embodiments, the pharmaceutically acceptable forms of formula (I) disclosed include its salts, solvates, or hydrates.

[0081] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which, within the scope of sound medical judgment, are suitable for contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Inorganic acids from which salts can be derived include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed by reaction of an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods employed in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, besylates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, gluconates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. In certain embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0082] Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1–4 alkyl) 4- Salts. Inorganic bases from which salts can be derived include, but are not limited to, sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Organic bases from which salts can be derived include, but are not limited to, primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., examples including, but not limited to, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In certain embodiments, the pharmaceutically acceptable base addition salts are ammonium salts, potassium salts, sodium salts, calcium salts or magnesium salts. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. When appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Organic bases from which salts can be derived include, but are not limited to, primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In certain embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Di-salts (i.e., two counterions) and higher order salts (e.g., three or more counterions) are encompassed within the meaning of pharmaceutically acceptable salts.

[0083] Alternatively, if the compounds of the present invention are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acidic salt. Conversely, if the product is a free base, pharmaceutically acceptable addition salts can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional methods for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic methods available for preparing non-toxic pharmaceutically acceptable addition salts.

[0084] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further includes a solvent, either stoichiometric or non-stoichiometric, bound by non-covalent intermolecular forces. The solvate can be the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that can include, for example, from 1 to about 100, or from 1 to about 10, or from 1 to about 2, about 3, or about 4 solvent or water molecules. In certain embodiments, the solvate can be a channel solvate. It should be understood that as used herein, the term "compound" includes the compound and the solvate of the compound, as well as mixtures thereof.

[0085] As used herein, and unless otherwise specified, a "prodrug" refers to a compound that can be converted or solvolyzed under physiological conditions to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a pharmaceutically active compound. A prodrug may be inactive when administered to a subject, but is converted to the active compound in vivo, e.g., by hydrolysis. In certain embodiments, prodrug compounds generally offer the advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire contents of both of which are incorporated herein by reference. The term "prodrug" also means to include any covalently bonded carrier that releases the active formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein can be prepared by modifying the functional groups present in the active formula (I) in such a way that the modification is cleaved in a conventional operation or in vivo to the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxyl, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols in the active compound; or acetamide, formamide, and benzamide derivatives of amine functional groups, etc. Other examples of prodrugs include compounds containing -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can generally be prepared using well-known methods, such as those described in Burger’s Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995) and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985).

[0086] For example, if the disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, the prodrug may include a pharmaceutically acceptable ester formed by replacing the hydrogen atom of the acid group with a group such as (C1-C8) alkyl, (C2-C 12 ) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, di-N,N-(C1-C2) alkylamino (C2-C3) alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2) alkyl, N,N-di(C1-C2) alkylcarbamoyl-(C1-C2) alkyl, and piperidino-, pyrrolidino- or morpholino-(C2-C3) alkyl.

[0087] Similarly, if the disclosed compound or a pharmaceutically acceptable form of the compound contains an alcohol functional group, the prodrug may be formed by replacing the hydrogen atom of the alcohol group with a group such as (C1-C6) alkanoyloxymethyl, 1-((C1-C6) alkanoyloxy)ethyl, 1-methyl-1-((C1-C6) alkanoyloxy)ethyl (C1-C6) alkoxycarbonyloxymethyl, N-(C1-C6) alkoxycarbonylaminomethyl, succinyl, (C1-C6) alkanoyl, α-amino (C1-C4) alkanoyl, arylcarbonyl, and α-aminoacyl or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6) alkyl)2 or a glycosyl group (a group obtained by removing the hydroxyl group of the hemiacetal form of the sugar).

[0088] If the disclosed compound or a pharmaceutically acceptable form of formula (I) includes an amine functional group, the prodrug may be formed by replacing the hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl (where R and R' are each independently (C1-C 10 ) alkyl, (C3-C7) cycloalkyl, benzyl, a natural α-aminoacyl or a natural α-aminoacyl-natural α-aminoacyl), -C(OH)C(O)OY 1 (where Y 1 is H, (C1-C6) alkyl or benzyl), -C(OY 2 ) Y 3(wherein Y 2 is a (C1-C4) alkyl and Y 3 is a (C1-C6) alkyl, carboxy (C1-C6) alkyl, amino (C1-C4) alkyl or mono-N- or di-N,N-(C1-C6) alkylaminoalkyl), -C(Y 4 )Y 5 (wherein Y 4 is H or methyl and Y 5 is mono-N- or di-N,N-(C1-C6) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl).

[0089] In certain embodiments, the pharmaceutically acceptable form is an isomer. An "isomer" is a different compound having the same molecular formula. A "stereoisomer" is an isomer that differs only in the spatial arrangement of atoms. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomer" includes geometric cis and trans isomers of double bonds, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (1)-isomers, their racemic mixtures; and other mixtures falling within the scope of the present disclosure.

[0090] Substituents around a carbon-carbon double bond may optionally be referred to as "cis" or "trans", where "cis" means that the substituents are on the same side of the double bond and "trans" means that the substituents are on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring may also be designated as "cis" or "trans". The term "cis" means that the substituents are on the same side of the ring plane and the term "trans" means that the substituents are on opposite sides of the ring plane. A mixture of compounds in which the substituents are on both the same side and opposite sides of the ring plane is designated as "cis / trans".

[0091] "Enantiomers" are stereoisomers that are non-superimposable mirror images of each other. A mixture of enantiomers in any proportion can be called a "racemic" mixture. When appropriate, the term "(±)" is used to indicate a racemic mixture. "Diastereomers" are stereoisomers that have at least two asymmetric atoms and are not mirror images of each other. Absolute stereochemistry can be assigned according to the Cahn-Ingold-Prelog R-S system. When the formula (I) is an enantiomer, the stereochemistry at each chiral carbon can be designated as R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) according to the direction (right or left) in which it rotates plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined according to the absolute stereochemistry at each asymmetric atom, such as (R)- or (S)-. This chemical entity, pharmaceutical composition, and method are intended to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents or resolved using conventional techniques.

[0092] As used herein, and unless otherwise specified, the term "stereoisomerically pure" means that a composition or substance includes one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure composition of a compound having one chiral center should be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure composition of a compound having two chiral centers should be substantially free of other stereoisomers of the compound (e.g., diastereomers or enantiomers, or syn or anti isomers, or cis or trans isomers). Typical stereoisomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound.

[0093] As used herein, and unless otherwise specified, the term "enantiomerically pure" means a stereoisomerically pure composition of a compound having one or more chiral centers.

[0094] As used herein and unless otherwise indicated, the terms "enantiomeric excess" and "diastereomeric excess" are used interchangeably herein. In certain embodiments, a compound having a single stereocenter may be considered to have an "enantiomeric excess", and those compounds having at least two stereocenters may be considered to have a "diastereomeric excess". For example, the term "enantiomeric excess" is well known in the art and is defined as:

[0095]

[0096] Thus, the term "enantiomeric excess" is related to the term "optical purity", where both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, with 0 being racemic and 100 being enantiomerically pure. A compound that could have been referred to in the past as 98% optically pure is now more precisely characterized as 96% ee. 90% ee reflects the presence of 95% of one enantiomer and 5% of the other enantiomer in the substance.

[0097] Some of the compositions described herein contain at least about 50%, 75%, 90%, 95% or 99% enantiomeric excess of the S enantiomer. In other words, the composition contains an enantiomeric excess of the S enantiomer relative to the R enantiomer. In other embodiments, some of the compositions described herein contain at least about 50%, 75%, 90%, 95% or 99% enantiomeric excess of the R enantiomer. In other words, the composition contains an enantiomeric excess of the R enantiomer relative to the S enantiomer.

[0098] For example, in certain embodiments, an isomer / enantiomer substantially free of the corresponding enantiomer may be provided, also referred to herein interchangeably as "optically enriched", "enantiomerically enriched", "enantiomerically pure", and "non-racemic". These terms refer to a composition in which the % weight of one enantiomer is greater than the amount of one enantiomer in a control mixture of a racemic composition (e.g., greater than about 1:1 by weight). For example, an enantiomerically enriched preparation of the S enantiomer refers to a preparation of a compound having greater than about 50% weight relative to the R enantiomer, such as at least about 75% weight, and further such as at least about 80% weight. In certain embodiments, the enrichment can be much higher than about 80% weight, providing a "substantially enantiomerically enriched", "substantially enantiomerically pure", or "substantially non-racemic" preparation, which refers to a preparation of a composition having at least about 85% weight, such as at least about 90% weight and further such as at least 95% weight of one enantiomer relative to the other enantiomer. In certain embodiments, the mixtures provided herein consist of at least about 90% weight of one enantiomer. In other embodiments, Formula (I) consists of at least about 95%, 98%, or 99% weight of one enantiomer.

[0099] Enantiomers can be separated from a racemic mixture by any method known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), formation and crystallization of chiral salts, or preparation by asymmetric synthesis. See, for example, Enantiomers, Racemates and Resolutions (Jacques, Ed., Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Stereochemistry of Carbon Compounds (E.L. Eliel, Ed., McGraw–Hill, NY, 1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0100] In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a type of isomer that includes two or more interconvertible compounds obtained by the migration of at least one form of a hydrogen atom and at least one change in valence (e.g., single bond to double bond, triple bond to single bond, or vice versa). "Tautomerization" includes prototropic or proton-transfer tautomerism, which is considered a subset of acid-base chemistry. "Prototropic tautomerism" or "proton-transfer tautomerism" involves the migration of a proton, accompanied by a change in bond order. The exact ratio of tautomers depends on various factors, including temperature, solvent, and pH. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. Tautomerization (i.e., the reaction that provides a pair of tautomers) can be catalyzed by an acid or a base, or can occur in the absence or presence of an external reagent. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(different) enamine tautomerism. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and the 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tautomerism. Another example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0101] As used herein, and unless otherwise specified, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to hydrogen being replaced by deuterium or tritium, or carbon being replaced by 13 C- or 14 C-enriched carbon, or nitrogen being replaced by 13 N- or 15 N-enriched nitrogen, or oxygen being replaced by 14 O-, 15 O-, 17 O- or 18 O-enriched oxygen, or chlorine being replaced by 35 Cl-, 36 Cl- or 37 Cl-enriched chlorine, compounds having the structures of the present invention are within the scope of the present disclosure.

[0102] In one embodiment, the compounds of the present disclosure may also contain atoms in unnatural proportions at one or more of the atoms that make up such compounds. For example, the compounds may be radiolabeled with a radioactive isotope, such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Some isotopically labeled disclosed compounds (e.g., with 3H and 14 those labeled with 14 are used in the analysis of the tissue distribution of compounds and / or substrates. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes allow for easy preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e., 2H) can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). Isotopically labeled compounds of the present disclosure can generally be prepared by substituting a non-isotopically labeled reagent with an isotopically labeled reagent. In certain embodiments, compounds are provided herein that also contain non-natural proportions of atomic isotopes at one or more atoms that make up such compounds. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0103] As used herein and unless otherwise specified, the terms "solvent", "organic solvent", and "inert solvent" each refer to a solvent that is inert under the reaction conditions described in connection with it, including but not limited to benzene, toluene, acetonitrile ("MeCN"), ethyl acetate ("EtOAc"), isopropyl acetate ("IPAc"), hexane, heptane, dioxane, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), dimethylacetamide ("DMA"), chloroform, methylene chloride ("DCM"), diethyl ether, methanol ("MeOH"), butanol ("1-BuOH"), methyl tert-butyl ether ("MTBE", or "TBME"), 2-butanone (”MEK”), N-methylpyrrolidone ("NMP"), pyridine, etc. Unless otherwise specified, the solvents used in the reactions described herein are inert organic solvents. Unless otherwise specified, 1 cc (or mL) of solvent constitutes a volume equivalent per gram of the limiting reagent.

[0104] As used herein and unless otherwise specified, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, etc. The use of such media and agents for pharmaceutical active substances is well known in the art. Unless any conventional media or reagents are incompatible with the active ingredient, their use in the therapeutic compositions of the present disclosure is contemplated. Supplementary active ingredients can also be added to the pharmaceutical compositions.

[0105] As used herein and unless otherwise specified, the terms "solid form" and related terms refer to physical forms that are not predominantly liquid or gaseous. Solid forms can be crystalline, amorphous, or mixtures thereof. In certain embodiments, the solid form can be a liquid crystal.

[0106] In certain embodiments, the solid forms provided herein are single-component or multi-component solid forms. A "single-component" solid form includes a compound of the formula consisting essentially of the compound of the formula. A "multi-component" solid form includes a compound of the formula that contains a significant amount of one or more additional species, such as ions and / or molecules, within the solid form. For example, a crystalline multi-component solid form that contains a compound of the formula further includes one or more species non-covalently bonded at regular sites in the lattice. The multi-component solid forms provided herein can be co-crystals.

[0107] As used herein and unless otherwise indicated, the terms "crystalline" and related terms, when used to describe a substance, variant, material, component, or product, mean that the substance, variant, material, component, or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23 rd edition, 1843 - 1844 (1995).

[0108] As used herein and unless otherwise indicated, "crystal form" and related terms mean a crystalline solid form. Crystal forms include single-component crystal forms and multi-component crystal forms, and include but are not limited to polymorphs, solvates, hydrates, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs. In certain embodiments, the crystal form of a substance can be substantially free of amorphous forms and / or other crystal forms. In certain embodiments, the crystal form of a substance can contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of one or more amorphous forms and / or other crystal forms. In certain embodiments, the crystal form of a substance can be physically and / or chemically pure. In certain embodiments, the crystal form of a substance can be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure.

[0109] As used herein and unless otherwise specified, the terms "polymorph", "polymorphic form" and related terms refer to two or more crystalline forms that are substantially composed of the same molecules or ions. Like different crystalline forms, different polymorphs can have different physical properties, such as for example melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectra, due to the arrangement or conformation of the molecules and / or ions in the crystal lattice. Differences in physical properties can affect pharmaceutical parameters such as storage stability, compressibility, and density (important in formulation and product manufacture), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors faster when composed of one polymorph than when composed of another), or mechanical changes (e.g., a tablet crumbles upon storage because a kinetically favored polymorph converts to a thermodynamically more stable polymorph), or both (e.g., a tablet of one polymorph is more prone to crumbling under high humidity). As a result of solubility / dissolution differences, in extreme cases, some solid-state transformations can cause loss of potency, or in the other extreme, cause toxicity. Additionally, physical properties can be important in processing (e.g., one polymorph may be more prone to form solvates, or may be difficult to filter and wash to remove impurities, and the particle shape and size distribution can differ between polymorphs).

[0110] As used herein and unless otherwise specified, the terms "solvate" and "solvated" refer to crystalline forms of a substance that contain a solvent. The terms "hydrate" and "hydrated" refer to solvates in which the solvent includes water. "Polymorphs of solvates" refer to the existence of more than one crystalline form for a particular solvated composition. Similarly, "polymorphs of hydrates" refer to the existence of more than one crystalline form for a particular hydrated composition. The term "desolvated solvate" as used herein refers to a crystalline form of a substance that can be prepared by removing the solvent from a solvate.

[0111] As used herein, and unless otherwise indicated, the terms “amorphous,” “amorphous form,” and related terms refer to a substance, component, or product that is substantially not crystalline as determined by X-ray diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous forms and / or crystalline forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of one or more other amorphous forms and / or crystalline forms. In certain embodiments, an amorphous form of a substance may be physically and / or chemically pure. In certain embodiments, an amorphous form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure.

[0112] Techniques for characterizing solid forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), gravimetric vapor sorption (GVS), single crystal X-ray diffraction, vibrational spectroscopy such as infrared (IR) and Raman spectroscopy, solid state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis, and Karl Fischer analysis. Characteristic unit cell parameters can be determined using one or more techniques such as, but not limited to, X-ray diffraction and neutron diffraction, including single crystal diffraction and powder diffraction. Techniques for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which can be used, for example, to analyze diffraction peaks associated with a single phase in a sample containing one solid phase. Other methods for analyzing powder diffraction data include unit cell indexing, which enables a person skilled in the art to determine unit cell parameters from a sample comprising a crystalline powder.

[0113] In certain embodiments, the solid forms described herein are substantially pure, i.e., substantially free of other solid forms and / or other chemical compounds, containing less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% by weight of one or more other solid forms and / or other chemical compounds.

[0114] Solid forms can exhibit different physical characteristic data that are unique to a particular solid form, such as the crystalline forms described herein. These characteristic data can be obtained by a variety of techniques known to those of skill in the art, including, for example, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance spectroscopy. The data provided by these techniques can be used to identify a specific solid form. One of ordinary skill in the art can determine whether a solid form is one of the forms described herein by performing one of these characterization techniques and determine whether the resulting data “matches” the reference data provided herein that is identified as being specific to the solid form. Characteristic data that “matches” the data of a reference solid form is understood by those of skill in the art to be equivalent to the same solid form as the reference solid form. In the analysis of whether the data “matches,” one of ordinary skill in the art understands that due to, for example, experimental error and analysis between conventional samples, specific characteristic data points can vary to a reasonable degree and still describe a given solid form.

[0115] The solid forms provided herein can be crystalline or intermediate forms (e.g., a mixture of crystalline and amorphous forms). Thus, the crystalline forms described herein can have varying degrees of crystallinity or lattice order. The solid forms described herein are not limited to any particular degree of crystallinity or lattice order and can be 0–100% crystalline. Methods for determining crystallinity known to those of ordinary skill in the art, such as those described in Suryanarayanan, R., X-Ray Power Diffractometry, Physical Characterization of Pharmaceutical Salts, H.G. Brittain, Editor, Mercel Dekkter, Murray Hill, N.J., 1995, pp. 187–199, are hereby incorporated by reference in their entirety. In certain embodiments, the solid forms described herein are approximately 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% crystalline.

[0116] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this application, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition (inside front cover), and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0117] As used herein, the term “alkyl” refers to a saturated, straight-chain or branched-chain, optionally substituted hydrocarbon radical derived from the aliphatic moiety of a C1-C6 (e.g., C 1-6 alkyl) alkane by removal of a single hydrogen atom. In certain embodiments, the alkyl employed contains 1-5 carbon atoms. In another embodiment, the alkyl employed contains 1-4 carbon atoms. In still other embodiments, the alkyl contains 1-3 carbon atoms. In still another embodiment, the alkyl contains 1-2 carbons. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, sec-pentyl, isopentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.

[0118] As used herein, the term "alkenyl" refers to a monovalent group derived from a straight or branched chain optionally substituted aliphatic moiety having at least one carbon-carbon double bond by removal of a single hydrogen atom. In certain embodiments, the alkenyl group contains 2 - 6 carbon atoms (e.g., C2-6 alkenyl). In certain embodiments, the alkenyl group contains 2 - 5 carbon atoms. In certain embodiments, the alkenyl group contains 2 - 4 carbon atoms. In another embodiment, the alkenyl group employed contains 2 - 3 carbon atoms. Alkenyl groups include, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0119] As used herein, the term "alkynyl" refers to a monovalent group derived from a straight or branched chain optionally substituted aliphatic moiety having at least one carbon-carbon triple bond by removal of a single hydrogen atom. In certain embodiments, the alkynyl group contains 2 - 6 carbon atoms (e.g., C 2-6 alkynyl). In certain embodiments, the alkynyl group contains 2 - 5 carbon atoms. In certain embodiments, the alkynyl group contains 2 - 4 carbon atoms. In another embodiment, the alkynyl group contains 2 - 3 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

[0120] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic and bicyclic optionally substituted ring system having a total of five to twelve ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In certain embodiments, "aryl" refers to a monocyclic and bicyclic optionally substituted ring system having a total of six to twelve ring members (e.g., C 6-12 aryl), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthryl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings (such as indanyl, phthalimido, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like).

[0121] The term "heteroaryl", used alone or as part of a larger moiety (such as "heteroaralkyl" or "heteroaralkoxy"), refers to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; sharing 6, 10, or 14 π electrons in a ring array; and having one to five atoms in addition to carbon atoms. In certain embodiments, the term "heteroaryl" refers to an optionally substituted group as defined above having 6 to 10 ring atoms (e.g., C 6-12 heteroaryl). The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, where the group or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms includes an optionally substituted ring. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently optionally substituted.

[0122] The compounds provided herein as described herein can contain "optionally substituted" moieties. Generally, whether or not placed before the term "optionally", the term "substituted" means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from the designated group, the substituents can be the same or different at each position. Combinations of substituents contemplated by the present invention are preferably those that result in a stable or chemically viable compound. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow its generation, detection, and in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0123] Suitable monovalent substituents on the replaceable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0–4 R o ; –(CH2) 0–4 OR o ; -O-(CH2) 0–4 C(O)OR o ; -(CH2) 0–4 CH(OR o )2; –(CH2) 0–4 SR o ; -(CH2) 0–4 Ph, which may be substituted by R o ; -(CH2) 0–4 O(CH2) 0–1 Ph, which may be substituted by R o ; –CH=CHPh, which may be substituted by R o ; –NO2; –CN; –N3; –(CH2) 0–4 N(R o )2; –(CH2) 0–4 N(R o )C(O)R o ; –N(R o )C(S)R o ; –(CH2) 0–4 N(R o )C(O)NR o 2; –N(R o )C(S)NR o 2; –(CH2) 0–4 N(R o )C(O)OR o ; –N(R o )N(R o )C(O)R o ; -N(R o )N(R o )C(O)NR o 2; –N(R o )N(R o )C(O)OR o ; –(CH2) 0–4 C(O)R o ; –C(S)R o ; –(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 C(O)SR o ; –(CH2) 0–4 C(O)OSiR o 3; –(CH2)0–4 OC(O)R o ; –OC(O)(CH2) 0–4 SR–, SC(S)SR o ; –(CH2) 0–4 SC(O)R o ; –(CH2) 0–4 C(O)NR o 2; –C(S)NR o 2; –C(S)SR o ; –SC(S)SR o , -(CH2) 0–4 OC(O)NR o 2; –C(O)N(OR o )R o ; –C(O)C(O)R o ; –C(O)CH2C(O)R o ; –C(NOR o )R o ; -(CH2) 0–4 SSR o ; -(CH2) 0–4 S(O)2R o ; –(CH2) 0–4 S(O)2OR o ; –(CH2) 0–4 OS(O)2R o ; –S(O)2NR o 2; -(CH2) 0–4 S(O)R o ; –N(R o )S(O)2NR o 2; –N(R o )S(O)2R o ; –N(OR o )R o ; –C(NH)NR o 2; –P(O)2R o ; -P(O)R o 2; –OP(O)R o 2; –OP(O)(OR o )2; SiR o 3; –(C 1–4 linear or branched alkylene)O–N(R o )2; or –(C 1–4 linear or branched alkylene)C(O)O–N(R o )2, where each R o can be defined as substituted and independently is hydrogen, C 1-6Alkyl, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independently occurring R o together with the atoms intervening therebetween form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0124] In R o (or the ring formed by two independently occurring R o together with the atoms intervening therebetween), suitable monovalent substituents are independently halogen, –(CH2) 0–2 R · , –(haloR · ), –(CH2) 0–2 OH, –(CH2) 0–2 OR ● , –(CH2) 0–2 CH(OR ● )2; -O(haloR · ), –CN, –N3, –(CH2) 0–2 C(O)R ● , –(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR ● , –(CH2) 0–2 SR ● , –(CH2) 0–2 SH, –(CH2) 0–2 NH2, –(CH2) 0–2 NHR ● , –(CH2) 0–2 NR · 2, –NO2, –SiR · 3, –OSiR · 3, -C(O)SR · , –(C 1–4 linear or branched alkylene)C(O)OR · or –SSR · wherein each R · is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens and is independently selected from C 1-4 alkyl, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In R oSuitable divalent substituents on the saturated carbon atoms include ═O and ═S.

[0125] Suitable divalent substituents on the saturated carbon atoms of an "optionally substituted" group include the following: ═O, ═S, ═NNR * 2, ═NNHC(O)R * , ═NNHC(O)OR * , ═NNHS(O)2R * , ═NR * , ═NOR * , –O(C(R * 2)) 2–3 O– or –S(C(R * 2)) 2–3 S–, where each independently occurring R* is selected from hydrogen, a C 1-6 aliphatic group that may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to an adjacent substitutable carbon of an "optionally substituted" group include: –O(CR * 2) 2–3 O–, where each independently occurring R* is selected from hydrogen, a C 1-6 aliphatic group that may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, and or aryl ring.

[0126] Suitable substituents on the aliphatic group of R* include halogen, –R · , -(haloR ● ), –OH, –OR ● , –O(haloR ● ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR ● , –NR ● 2 or –NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens and is independently a C 1-4 aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0127] Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include where each Independently for hydrogen, a substituted C can be defined as follows 1-6 an aliphatic group, an unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independently occurring together with the atoms intervening therebetween form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0128] In suitable substituents on the aliphatic group include halogen, –R ● , –(halogenR ● ), –OH, –OR ● , –O(halogenR · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · , –NR · 2 or -NO2, where each R · is unsubstituted or is substituted only by one or more halogens when preceded by “halo-” and is independently a C 1-4 aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0129] 5.2 Solid Forms

[0130] Potential pharmaceutical solids include crystalline solids and amorphous solids. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solids depends on the specific application; sometimes amorphous solids are selected based on, for example, improved dissolution characteristics, while crystalline solids may be required for properties such as physical or chemical stability (see, e.g., S.R. Vippagunta et al., Adv. Drug Deliv. Rev., (2001) 48:3-26; L. Yu, Adv. Drug Deliv. Rev., (2001) 48:27-42). Variations in solid form can affect a variety of physical and chemical properties, which can provide benefits or drawbacks in terms of processing, formulation, stability, and bioavailability, as well as other important pharmaceutical properties.

[0131] Whether crystalline or amorphous, potential solid forms of a pharmaceutical compound can include single-component and multi-component solids. A single-component solid consists essentially of the pharmaceutical compound and no other compounds. Diversity in single-component crystalline materials can potentially arise from polymorphism, where there are multiple three-dimensional arrangements for a particular pharmaceutical compound (see, e.g., S.R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette).

[0132] Other diversity in potential solid forms of a pharmaceutical compound can arise from the possibility of multi-component solids. Crystalline solids containing two or more ionic species are called salts (see, e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl and C.G. Wermuth, Eds., (2002), Wiley, Weinheim). Other types of multi-component solids that can potentially impart other property improvements to a pharmaceutical compound or its salt include, for example, hydrates, solvates, co-crystals, and inclusion compounds (see, e.g., S.R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Co-crystals of Compound 1 and their polymorphs are also provided herein. Multi-component crystal forms can potentially be polymorphic, where there can be more than one three-dimensional crystalline arrangement for a particular multi-component composition. The discovery of solid forms is of great significance in the development of safe, effective, stable, and marketable pharmaceutical compounds.

[0133] The solid forms provided by the present invention are used as active pharmaceutical ingredients in the preparation of formulations for animals or humans. Accordingly, embodiments herein include the use of these solid forms as the final pharmaceutical product. Certain embodiments provide solid forms for the preparation of final dosage forms with improved properties, such as powder flow properties, compaction properties, tableting properties, stability properties, and excipient compatibility properties, etc., which are required for the preparation, processing, formulation, and / or storage of the final pharmaceutical product. Certain embodiments herein provide pharmaceutical compositions that include single-component crystal forms and / or multi-component crystal forms of a compound of formula (I) and a pharmaceutically acceptable diluent, excipient, or carrier.

[0134] Solid forms and related terms refer to physical forms that are predominantly not liquid or gaseous. Solid forms can be mixtures of crystalline and amorphous forms. A "single-component" solid form comprising a particular compound consists essentially of that compound. A "multi-component" solid form comprising a particular compound includes within the solid form the compound and a significant amount of one or more additional species, such as ions and / or molecules. The solid forms provided herein can be crystalline or intermediate forms (e.g., mixtures of crystalline and amorphous forms). Thus, the crystalline forms described herein can have varying degrees of crystallinity or lattice order. The solid forms described herein are not limited to any particular degree of crystallinity or lattice order and can be 0 - 100% crystalline. Methods for determining crystallinity known to those of ordinary skill in the art, such as those described in Suryanarayanan, R., X-Ray Powder Diffractometry, Physical Characterization of Pharmaceutical Solids, H.G. Brittain, Editor, Marcel Dekker, Murray Hill, N.J., 1995, pp. 187–199, are hereby incorporated by reference in their entirety. In certain embodiments, the solid forms described herein are about 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% crystalline.

[0135] Solid forms can exhibit different physical characteristic data that are unique to a particular solid form, such as the crystalline forms described herein. These characteristic data can be obtained by various techniques known to those of skill in the art, including, for example, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance spectroscopy. The data provided by these techniques can be used to identify a specific solid form. One of ordinary skill in the art can determine whether a solid form is one of the forms described herein by performing one of these characterization techniques and determining whether the resulting data is "substantially similar" to reference data provided herein that is specific to the identified solid form. Characteristic data that is "substantially similar" to the data of a reference solid form is understood by those of ordinary skill in the art to be equivalent to the same solid form as the reference solid form. In the analysis of whether the data is "substantially similar", one of ordinary skill in the art understands that due to, for example, experimental error and normal sample-to-sample variation, specific characteristic data points can vary to a reasonable degree while still describing a given solid form.

[0136] In certain embodiments, the present invention provides solid forms that comprise a compound of formula (I):

[0137]

[0138] or a salt, solvate (e.g., hydrate) or solvate of a salt thereof, or a mixture thereof. In one embodiment, the solid form comprising the compound of formula (I) can be a crystalline form, a partially crystalline form, or a mixture of a crystalline form and an amorphous form. In one embodiment, provided herein is a solid form comprising a crystalline form of the compound of formula (I), or a salt, solvate (e.g., hydrate) or solvate of a salt thereof, or a mixture thereof. In one embodiment, the solid form further comprises a coformer. In one embodiment, the solid form comprising Compound 1 and a coformer is a cocrystal. In another embodiment, the solid form is an amorphous form. In one embodiment, the solid form is substantially pure. The compound of formula (I) has the chemical name (S)-2-amino-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. The compound of formula (I) is described in US2015 / 011874, the content of which is incorporated herein by reference.

[0139] In certain embodiments, formula (I) is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein is a mixture of compounds, wherein the individual compounds of the mixture are present predominantly in the (S)- or (R)-isomeric configuration. For example, the mixture of compounds has an (S)-enantiomeric excess greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or higher. In certain embodiments, the mixture of compounds has an (S)-enantiomeric excess greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or higher.

[0140] In other embodiments, the mixture of compounds has an (R)-enantiomeric purity greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or higher. In certain other embodiments, the mixture of compounds has an (R)-enantiomeric excess greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or higher.

[0141] 5.2.1. Solid Forms of Compound 1

[0142] Provided herein are solid forms that include a compound of formula (I):

[0143]

[0144] or a salt thereof, or a solvate (e.g., hydrate), or a solvate of a salt, or a mixture thereof.

[0145] In one embodiment, provided herein are solid forms that include the free base of Compound 1 or a solvate thereof (e.g., hydrate). In one embodiment, provided herein are solid forms that include the anhydrous free base of Compound 1. In one embodiment, provided herein are solid forms that include a solvate of the free base of Compound 1. In one embodiment, provided herein are solid forms that include a hydrate of the free base of Compound 1.

[0146] It is contemplated that Compound 1, or a salt thereof, or a solvate (e.g., hydrate), or a solvate of a salt, or a mixture thereof may exist in multiple solid forms. Such solid forms include crystalline solids (e.g., polymorphs of the anhydride of Compound 1, polymorphs of the hydrate of Compound 1, and polymorphs of the solvate of Compound 1), amorphous solids, or mixtures of crystalline and amorphous solids. In one embodiment, the solid form is substantially crystalline. In one embodiment, the solid form is crystalline.

[0147] In certain embodiments, the molar ratio of Compound 1 in solid form to solvent / water ranges from about 10:1 to about 1:10. In certain embodiments, the molar ratio of Compound 1 in solid form to solvent / water ranges from about 5:1 to about 1:5. In certain embodiments, the molar ratio of Compound 1 in solid form to solvent / water ranges from about 3:1 to about 1:3. In certain embodiments, the molar ratio of Compound 1 in solid form to solvent / water ranges from about 2:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (i.e., bis-solvate / hydrate). In another embodiment, the molar ratio is about 1:1 (i.e., mono-solvate / hydrate). In still another embodiment, the molar ratio is about 2:1 (i.e., semi-solvate / hydrate).

[0148] 5.2.1.1 Form 1 of Compound 1

[0149] In certain embodiments, provided herein is Form 1 of a compound of formula (I). In one embodiment, Form 1 of Compound 1 is the crystalline non-solvated anhydrous free base of Compound 1. In certain embodiments, Form 1 of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, Form 1 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form 1 of Compound 1 is substantially free of salts of Compound 1. In certain embodiments, Form 1 of Compound 1 is provided in a substantially pure form of Form 1 of Compound 1. In certain embodiments, one or more residual solvents (e.g., a small amount of EtOH or iPrOH) may be present in Form 1 of Compound 1, but the residual solvents do not form a solvate of Compound 1.

[0150] A representative XRPD pattern of Form 1 of Compound 1 is provided in Figure 1 .

[0151] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form 1 includes peaks at 16.8, 23.6, and 25.6 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 1 further includes at least one peak selected from 14.6 and 21.2 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 1 includes a combination of peaks at 14.6, 16.8, 21.2, 23.6, and 25.6 degrees 2θ ± 0.2 and at least one peak selected from 11.3, 15.4, 16.2, 18.4, 20.5, 22.6, 24.3, 26.6, 27.1, and 29.5 degrees 2θ ± 0.2.

[0152] In one embodiment, Form 1 is characterized by XRPD peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following positions: 11.3, 14.6, 15.4, 16.2, 16.8, 18.4, 20.5, 21.2, 22.6, 23.6, 24.3, 25.6, 26.6, 27.1 and 29.5 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0153] In certain embodiments, the above XRPD peaks (degree 2θ peaks) are observed when analyzed using Cu Kα radiation.

[0154] In one embodiment, Form 1 has an XRPD pattern substantially as Figure 1 shown.

[0155] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 1 of Compound 1 is provided in Figure 2 .

[0156] In one embodiment, Form 1 exhibits an endothermic event as characterized by DSC, having an onset temperature of about 255 °C and / or a peak temperature of about 257 °C. In one embodiment, Form 1 is characterized by a DSC thermogram substantially as shown in the DSC thermogram presented in Figure 2 . In another embodiment, Form 1 exhibits an endothermic event as characterized by DSC, having an onset temperature of about 242 °C and / or a peak temperature of about 251 °C. In still another embodiment, Form 1 exhibits an endothermic event as characterized by DSC, having an onset temperature of about 242 °C to about 255 °C.

[0157] In one embodiment, Form 1 shows a weight loss of about 0.6% when heated from about 230 °C to about 310 °C. In one embodiment, Form 1 is characterized by a TGA thermogram substantially as shown in the TGA thermogram presented in Figure 2 . In another embodiment, Form 1 shows a weight loss of about 0.4% when heated from about 25 °C to about 70 °C, and a weight loss of about 1.1% when heated from about 200 °C to about 280 °C.

[0158] Representative gravimetric vapor sorption (GVS) isotherms for Form 1 are presented in Figure 3 . In one embodiment, Form 1 shows a weight increase of about 0.5% when subjected to a relative humidity increase from about 0 to about 90% relative humidity. In one embodiment, Form 1 is characterized by a GVS thermogram substantially as shown in the GVS thermogram presented in Figure 3 .

[0159] In one embodiment, Form 1 has the following approximate unit cell dimensions: α = 90°, β = 90° and γ = 90°. In one embodiment, Form 1 has the following approximate unit cell dimensions: a = α = 90°, β = 90° and γ = 90°. In one embodiment, Form 1 has the following approximate unit cell dimensions: α = 90°, β = 90° and γ = 90°. In one embodiment, Form 1 has a unit cell of the P212121 space group. In one embodiment, Form 1 has a volume of about for the unit cell. In one embodiment, Form 1 has a Z value of 4. In one embodiment, Form 1 has a density of about 1.279 g / cm 3 .

[0160] In one embodiment, Form 1 is anhydrous. In one embodiment, Form 1 is non-hygroscopic. In one embodiment, Form 1 is stable for over 9 months after storage at 40 °C / 75% RH or 25 °C / 96% RH.

[0161] This application encompasses combinations of all the above embodiments.

[0162] 5.2.1.2 Form 2 of Compound 1

[0163] In certain embodiments, provided herein is Form 2 of a compound of formula (I). In one embodiment, Form 2 of Compound 1 is a crystalline solvate of the free base of Compound 1. In certain embodiments, Form 2 of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, Form 2 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form 2 of Compound 1 is substantially free of salts of Compound 1. In certain embodiments, Form 2 of Compound 1 is provided as substantially pure Form 2 of Compound 1.

[0164] In one embodiment, the molar ratio of Compound 1 to the solvent in Form 2 ranges from about 1:0.5 to about 1:2. In one embodiment, the molar ratio of Compound 1 to the solvent in Form 2 ranges from about 1:0.75 to about 1:1.25. In one embodiment, the molar ratio of the compound to the solvent in Form 2 ranges from about 1:0.75 to about 1:1. In one embodiment, the molar ratio of Compound 1 to the solvent in Form 2 is about 1:0.85. In one embodiment, the molar ratio of Compound 1 to the solvent in Form 2 is about 1:1.

[0165] In one embodiment, Form 2 is the acetone / DCM solvate of the free base of Compound 1. In one embodiment, the molar ratio of Compound 1∶acetone∶DCM in Form 2 is about 1:0.1:0.75. In another embodiment, the form is the 1-propanol solvate of the free base of Compound 1. In one embodiment, the molar ratio of Compound 1 to 1-propanol in Form 2 is about 1:0.85. In another embodiment, Form 2 is the DCM solvate of the free base of Compound 1. In one embodiment, the molar ratio of Compound 1 to DCM in Form 2 is about 1:1.

[0166] A representative XRPD pattern of Form 2 of Compound 1 is provided in Figure 4 In. Another representative XRPD pattern of Form 2 of Compound 1 is provided in Figure 8 In.

[0167] In one embodiment, the XRPD pattern of Form 2 includes peaks at 13.6, 14.9 and 21.0 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 2 further includes at least one peak selected from 7.4 and 16.7 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 2 includes a combination of peaks at 7.4, 13.6, 14.9, 16.7 and 21.0 degrees 2θ ± 0.2 and at least one peak selected from 9.5, 18.1, 18.4, 19.7, 20.8, 22.4, 23.2, 24.5, 26.2 and 26.8 degrees 2θ ± 0.2.

[0168] In one embodiment, Form 2 is characterized by XRPD peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the following positions: 7.4, 9.5, 13.6, 14.9, 16.7, 18.1, 18.4, 19.7, 20.8, 21.0, 22.4, 23.2, 24.5, 26.2, and 26.8 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0169] In certain embodiments, the above XRPD peaks (degrees 2θ peaks) are observed when analyzed using Cu Kα radiation.

[0170] In one embodiment, Form 2 has an XRPD pattern substantially as Figure 4 shown. In another embodiment, Form 2 has an XRPD pattern substantially as Figure 8 shown.

[0171] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 2 of Compound 1 is provided in Figure 5 .

[0172] In one embodiment, Form 2 exhibits an endothermic event as characterized by DSC, having an onset temperature of about 168 °C and / or a peak temperature of about 182 °C. In one embodiment, Form 2 is characterized by a DSC thermogram substantially as Figure 5 shown in the DSC thermogram presented in

[0173] In one embodiment, when heated from about 80 °C to about 240 °C, Form 2 shows a weight loss of about 12.9%. In one embodiment, Form 2 is characterized by a TGA thermogram substantially as Figure 5 shown in the TGA thermogram presented in

[0174] Another representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 2 of Compound 1 is provided in Figure 7 .

[0175] In one embodiment, Form 2 exhibits an endothermic event with an onset temperature of about 25 °C, an endothermic event with an onset temperature of about 151 °C, an exothermic event with an onset temperature of about 179 °C, or an endothermic event with an onset temperature of about 244 °C as characterized by DSC. In one embodiment, Form 2 exhibits an endothermic event with an onset temperature of about 25 °C, an endothermic event with an onset temperature of about 151 °C, an exothermic event with an onset temperature of about 179 °C, and an endothermic event with an onset temperature of about 244 °C as characterized by DSC. In one embodiment, Form 2 is characterized by a DSC thermogram substantially as shown in the DSC thermogram presented in Figure 7 below.

[0176] In one embodiment, Form 2 shows a weight loss of about 0.9% when heated from about 25 °C to about 75 °C, and a weight loss of about 8.5% when heated from about 75 °C to about 250 °C. In one embodiment, Form 2 is characterized by a TGA thermogram substantially as shown in the TGA thermogram presented in Figure 7 below.

[0177] A representative gravimetric vapor sorption (GVS) isotherm for Form 2 is presented in Figure 6 below. In one embodiment, Form 2 shows a weight gain of about 1.3% when subjected to a relative humidity increase from about 0 to about 90% relative humidity. In one embodiment, Form 2 is characterized by a GVS thermogram substantially as shown in the GVS thermogram presented in Figure 6 below.

[0178] In one embodiment, Form 2 is non-hygroscopic.

[0179] In one embodiment, Form 2 has the following approximate unit cell dimensions: α = 90°, β = 90° and γ = 90°. In one embodiment, Form 2 has the following approximate unit cell dimensions: α = 90°, β = 90° and γ = 90°. In one embodiment, Form 2 has the following approximate unit cell dimensions: α = 90°, β = 90° and γ = 90°. In one embodiment, Form 2 has a unit cell with the space group P212121. In one embodiment, Form 2 has a volume of about for the unit cell. In one embodiment, Form 2 has a Z value of 4. In one embodiment, Form 2 has a density of about 1.360 Mg / m 3 ³.

[0180] This application encompasses combinations of all the above embodiments.

[0181] 5.2.1.3 Form 3 of Compound 1

[0182] In certain embodiments, provided herein is Form 3 of a compound of Formula (I). In one embodiment, Form 3 of Compound 1 is a crystalline solvate of the free base of Compound 1. In certain embodiments, Form 3 of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, Form 3 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form 3 of Compound 1 is substantially free of salts of Compound 1. In certain embodiments, Form 3 of Compound 1 is provided as substantially pure Form 3 of Compound 1.

[0183] In one embodiment, the molar ratio of Compound 1 to the solvent in Form 3 ranges from about 1:0.2 to about 1:1. In one embodiment, Form 3 is the 2-methyl-1-propanol solvate of the free base of Compound 1. In one embodiment, the molar ratio of Compound 1 to 2-methyl-1-propanol in Form 3 is about 1:0.79. In another embodiment, Form 3 is the MEK solvate of the free base of Compound 1. In one embodiment, the molar ratio of Compound 1 to MEK in Form 3 is about 1:0.25.

[0184] A representative XRPD pattern of Form 3 of Compound 1 is provided in Figure 9 .

[0185] In one embodiment, the XRPD pattern of Form 3 includes peaks at 17.9, 20.6, and 25.8 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 3 further includes at least one peak selected from 11.7 and 23.5 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 3 includes a combination of peaks at 11.7, 17.9, 20.6, 23.5, and 25.8 degrees 2θ ± 0.2 and at least one peak selected from 7.4, 10.2, 13.5, 19.3, 19.5, 21.0, 21.5, 22.4, 23.7, and 26.5 degrees 2θ ± 0.2.

[0186] In one embodiment, Form 3 is characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the following positions: 7.4, 10.2, 11.7, 13.5, 17.9, 19.3, 19.5, 20.6, 21.0, 21.5, 22.4, 23.5, 23.7, 25.8, and 26.5 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0187] In certain embodiments, when analyzed using Cu Kα radiation, the above XRPD peaks (degree 2θ peaks) are observed.

[0188] In one embodiment, Form 3 has an XRPD pattern substantially as Figure 9 shown.

[0189] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 3 of Compound 1 is provided in Figure 10 herein.

[0190] In one embodiment, Form 3 shows endothermic events with onset temperatures of approximately 29 °C, approximately 126 °C, approximately 148 °C, an exothermic event with an onset temperature of approximately 181 °C, and an endothermic event with an onset temperature of approximately 246 °C as characterized by DSC. In one embodiment, Form 3 shows endothermic events with onset temperatures of approximately 29 °C, approximately 126 °C, approximately 148 °C, an exothermic event with an onset temperature of approximately 181 °C, and an endothermic event with an onset temperature of approximately 246 °C as characterized by DSC. In one embodiment, Form 3 is characterized by a DSC thermogram substantially as Figure 10 presented in the DSC thermogram shown in

[0191] In one embodiment, Form 3 exhibits endothermic events with onset temperatures of approximately 30 °C, approximately 127 °C, approximately 137 °C, an exothermic event with an onset temperature of approximately 169 °C, an endothermic event with an onset temperature of approximately 207 °C, or an endothermic event with an onset temperature of approximately 250 °C, as characterized by DSC. In one embodiment, Form 3 exhibits endothermic events with onset temperatures of approximately 30 °C, approximately 127 °C, approximately 137 °C, an exothermic event with an onset temperature of approximately 169 °C, an endothermic event with an onset temperature of approximately 207 °C, and an endothermic event with an onset temperature of approximately 250 °C, as characterized by DSC.

[0192] In one embodiment, Form 3 exhibits a weight loss of approximately 0.8% when heated from approximately 25 °C to approximately 75 °C, and a weight loss of approximately 10.4% when heated from approximately 75 °C to approximately 300 °C. In one embodiment, Form 3 is characterized by a TGA thermogram substantially as Figure 10 shown in the TGA thermogram presented in

[0193] In one embodiment, Form 3 exhibits a weight loss of approximately 2.0% when heated from approximately 25 °C to approximately 80 °C, and a weight loss of approximately 3.4% when heated from approximately 80 °C to approximately 300 °C.

[0194] This application encompasses combinations of all of the above embodiments.

[0195] 5.2.1.4 Form 4 of Compound 1

[0196] In certain embodiments, provided herein is Form 4 of the compound of formula (I). In one embodiment, Form 4 of Compound 1 is a crystalline solvate of the free base of Compound 1. In certain embodiments, Form 4 of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, Form 4 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form 4 of Compound 1 is substantially free of salts of Compound 1. In certain embodiments, Form 4 of Compound 1 is provided as substantially pure Form 4 of Compound 1.

[0197] In one embodiment, the molar ratio of Compound 1 to the solvent in Form 4 ranges from about 1:0.75 to about 1:1. In one embodiment, the molar ratio of Compound 1 to the solvent in Form 4 ranges from about 1:0.83 to about 1:0.9. In one embodiment, Form 4 is an isopropanol solvate of the free base of Compound 1. In one embodiment, the molar ratio of Compound 1 to isopropanol in Form 4 is about 1:0.9. In another embodiment, the molar ratio of Compound 1 to isopropanol in Form 4 is about 1:0.83.

[0198] A representative XRPD pattern of Form 4 of Compound 1 is provided in Figure 11 .

[0199] In one embodiment, the XRPD pattern of Form 4 has peaks located at 7.4, 18.0, and 20.7 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 4 further includes at least one peak selected from 11.9 and 13.6 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 4 includes a combination of peaks located at 7.4, 11.9, 13.6, 18.0, and 20.7 degrees 2θ ± 0.2 and at least one peak selected from 10.3, 19.3, 19.6, 19.8, 21.0, 21.8, 23.6, 23.8, 26.0, and 26.6 degrees 2θ ± 0.2.

[0200] In one embodiment, Form 4 is characterized by XRPD peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the following positions: 7.4, 10.3, 11.9, 13.6, 18.0, 19.3, 19.6, 19.8, 20.7, 21.0, 21.8, 23.6, 23.8, 26.0, and 26.6 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0201] In certain embodiments, the above XRPD peaks (degrees 2θ peaks) are observed when analyzed using Cu kα radiation.

[0202] In one embodiment, Form 4 has an XRPD pattern substantially as Figure 11 shown.

[0203] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 4 of Compound 1 is provided in Figure 12 as follows.

[0204] In one embodiment, Form 4 exhibits an endothermic event with an onset temperature of about 30 °C, an endothermic event with an onset temperature of about 156 °C, an exothermic event with an onset temperature of about 190 °C, or an endothermic event with an onset temperature of about 245 °C, as characterized by DSC. In one embodiment, Form 4 exhibits an endothermic event with an onset temperature of about 30 °C, an endothermic event with an onset temperature of about 156 °C, an exothermic event with an onset temperature of about 190 °C, and an endothermic event with an onset temperature of about 245 °C, as characterized by DSC. In one embodiment, Form 4 is characterized by a DSC thermogram substantially as shown in the DSC thermogram presented in Figure 12 as follows.

[0205] In one embodiment, Form 4 exhibits an endothermic event with an onset temperature of about 28 °C, an endothermic event with an onset temperature of about 156 °C, an exothermic event with an onset temperature of about 201 °C, or an endothermic event with an onset temperature of about 247 °C, as characterized by DSC. In one embodiment, Form 4 exhibits an endothermic event with an onset temperature of about 28 °C, an endothermic event with an onset temperature of about 156 °C, an exothermic event with an onset temperature of about 201 °C, and an endothermic event with an onset temperature of about 247 °C, as characterized by DSC.

[0206] In one embodiment, Form 4 shows a weight loss of about 0.7% when heated from about 25 °C to about 75 °C, and a weight loss of about 9.3% when heated from about 75 °C to about 225 °C. In one embodiment, Form 4 is characterized by a TGA thermogram substantially as shown in the TGA thermogram presented in Figure 12 as follows.

[0207] In one embodiment, Form 4 shows a weight loss of about 0.8% when heated from about 25 °C to about 75 °C, and a weight loss of about 8.6% when heated from about 75 °C to about 250 °C.

[0208] This application encompasses combinations of all the above embodiments.

[0209] 5.2.1.5.1 Form 5 of Compound 1

[0210] In certain embodiments, provided herein is Form 5 of the compound of formula (I). In one embodiment, Form 5 of Compound 1 is a crystalline solvate of the free base of Compound 1. In certain embodiments, Form 5 of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, Form 5 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form 5 of Compound 1 is substantially free of salts of Compound 1. In certain embodiments, Form 5 of Compound 1 is provided as substantially pure Form 5 of Compound 1.

[0211] In one embodiment, the molar ratio of Compound 1 to the solvent in Form 5 ranges from about 1:0.1 to about 1:0.2. In one embodiment, Form 5 is an anisole solvate of the free base of Compound 1. In one embodiment, the molar ratio of Compound 1 to anisole in Form 5 is about 1:0.12.

[0212] A representative XRPD pattern of Form 5 of Compound 1 is provided in Figure 13 .

[0213] In one embodiment, the XRPD pattern of Form 5 includes peaks located at 21.0, 22.1 and 25.2 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 5 further includes at least one peak selected from 14.5 and 19.2 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 5 includes a combination of peaks located at 14.5, 19.2, 21.0, 22.1 and 25.2 degrees 2θ ± 0.2 and at least one peak selected from 7.9, 11.0, 12.7, 16.6, 18.0, 23.3, 27.7, 28.5, 29.1 and 29.2 degrees 2θ ± 0.2.

[0214] In one embodiment, Form 5 is characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following positions: 7.9, 11.0, 12.7, 14.5, 16.6, 18.0, 19.2, 21.0, 22.1, 23.3, 25.2, 27.7, 28.5, 29.1 and 29.2 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0215] In certain embodiments, when analyzed using Cu Kα radiation, the above XRPD peaks (degree 2θ peaks) are observed.

[0216] In one embodiment, Form 5 has an XRPD pattern substantially as Figure 13 shown.

[0217] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 5 of Compound 1 is provided in Figure 14 .

[0218] In one embodiment, Form 5 exhibits an endothermic event with an onset temperature of about 126 °C or an endothermic event with an onset temperature of about 254 °C as characterized by DSC. In one embodiment, Form 5 exhibits an endothermic event with an onset temperature of about 126 °C and an endothermic event with an onset temperature of about 254 °C as characterized by DSC. In one embodiment, Form 5 is characterized by a DSC thermogram substantially as shown in the DSC thermogram presented in Figure 14 .

[0219] In one embodiment, Form 5 shows a weight loss of about 2.1% when heated from about 175 °C to about 300 °C. In one embodiment, Form 5 is characterized by a TGA thermogram substantially as shown in the TGA thermogram presented in Figure 14 .

[0220] This application encompasses combinations of all the above embodiments.

[0221] 5.2.1.6 Form 6 of Compound 1

[0222] In certain embodiments, provided herein is Form 6 of the compound of formula (I). In one embodiment, Form 6 of Compound 1 is a crystalline hydrate of the free base of Compound 1. In certain embodiments, Form 6 of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, Form 6 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form 6 of Compound 1 is substantially free of salts of Compound 1. In certain embodiments, Form 6 of Compound 1 is provided as substantially pure Form 6 of Compound 1.

[0223] In one embodiment, the molar ratio of Compound 1 to water in Form 6 ranges from about 1:2 to about 1:4. In one embodiment, the molar ratio of Compound 1 to water in Form 6 is about 1:3.3.

[0224] A representative XRPD pattern of Form 6 of Compound 1 is provided in Figure 15 .

[0225] In one embodiment, Form 6 has an XRPD pattern that includes peaks at 4.8, 19.9, and 26.7 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 6 further includes at least one peak selected from 11.9 and 24.8 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 6 includes a combination of peaks at 4.8, 11.9, 19.9, 24.8, and 26.7 degrees 2θ ± 0.2 and at least one peak selected from 12.2, 12.4, 14.1, 16.0, 17.7, 18.1, 18.9, 20.9, 24.0, and 27.1 degrees 2θ ± 0.2.

[0226] In one embodiment, Form 6 is characterized by XRPD peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the following positions: 4.8, 11.9, 12.2, 12.4, 14.1, 16.0, 17.7, 18.1, 18.9, 19.9, 20.9, 24.0, 24.8, 26.7, and 27.1 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0227] In certain embodiments, the above XRPD peaks (2θ degree peaks) are observed when analyzed using Cu Kα radiation.

[0228] In one embodiment, Form 6 has an XRPD pattern that is substantially as Figure 15 shown.

[0229] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 6 of Compound 1 is provided in Figure 16 .

[0230] In one embodiment, Form 6 exhibits an endothermic event with an onset temperature of about 46 °C, an endothermic event with an onset temperature of about 154 °C, or an endothermic event with an onset temperature of about 243 °C as characterized by DSC. In one embodiment, Form 6 exhibits an endothermic event with an onset temperature of about 46 °C, an endothermic event with an onset temperature of about 154 °C, and an endothermic event with an onset temperature of about 243 °C as characterized by DSC. In one embodiment, Form 6 is substantially asFigure 16 Characterization of the DSC thermal analysis chart shown in the DSC thermal analysis chart presented in

[0231] In one embodiment, Form 6 shows a weight loss of about 10.3% when heated from about 30 °C to about 100 °C. In one embodiment, Form 6 is characterized by a TGA thermal analysis chart substantially as shown in the TGA thermal analysis chart presented in Figure 16

[0232] The representative gravimetric vapor sorption (GVS) isotherm of Form 6 is presented in Figure 17 In one embodiment, Form 6 shows a weight gain of about 14% when subjected to a relative humidity increase from about 0 to about 90% relative humidity. In one embodiment, Form 6 is characterized by a GVS thermal analysis chart substantially as shown in the GVS thermal analysis chart presented in Figure 17

[0233] This application encompasses combinations of all the above embodiments.

[0234] 5.2.1.7 Form 7 of Compound 1

[0235] In certain embodiments, provided herein is Form 7 of a compound of formula (I). In one embodiment, Form 7 of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, Form 7 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form 7 of Compound 1 is substantially free of salts of Compound 1. In certain embodiments, Form 7 of Compound 1 is provided as substantially pure Form 7 of Compound 1.

[0236] The representative XRPD pattern of Form 7 of Compound 1 is provided in Figure 18

[0237] In one embodiment, the XRPD pattern of Form 7 has peaks located at 7.5, 12.3 and 20.7 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 7 further includes at least one peak selected from 13.7 and 17.2 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 7 includes a combination of peaks located at 7.5, 12.3, 13.7, 17.2 and 20.7 degrees 2θ ± 0.2 and at least one peak selected from 11.8, 14.9, 18.0, 18.4, 19.6, 20.2, 21.1, 23.5, 23.6 and 25.9 degrees 2θ ± 0.2.

[0238] ​​​In one embodiment, Form 7 is characterized by XRPD peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following positions: 7.5, 11.8, 12.3, 13.7, 14.9, 17.2, 18.0, 18.4, 19.6, 20.2, 20.7, 21.1, 23.5, 23.6 and 25.9 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0239] In certain embodiments, when analyzed using Cu Kα radiation, the above XRPD peaks (degrees 2θ peaks) are observed.

[0240] In one embodiment, Form 7 has an XRPD pattern substantially as Figure 18 shown.

[0241] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 7 of Compound 1 is provided in Figure 19 below.

[0242] In one embodiment, Form 7 shows an endothermic event with an onset temperature of about 30 °C, an endothermic event with an onset temperature of about 127 °C, an endothermic event with an onset temperature of about 137 °C, an exothermic event with an onset temperature of about 169 °C, an endothermic event with an onset temperature of about 207 °C, or an endothermic event with an onset temperature of about 250 °C, as characterized by DSC. In one embodiment, Form 7 shows an endothermic event with an onset temperature of about 30 °C, an endothermic event with an onset temperature of about 127 °C, an endothermic event with an onset temperature of about 137 °C, an exothermic event with an onset temperature of about 169 °C, an endothermic event with an onset temperature of about 207 °C, and an endothermic event with an onset temperature of about 250 °C, as characterized by DSC. In one embodiment, Form 7 is characterized by a DSC thermogram substantially as Figure 19 presented in the DSC thermogram shown in

[0243] In one embodiment, Form 7 shows a weight loss of about 2.0% when heated from about 10 °C to about 90 °C, and a weight loss of about 3.4% when heated from about 90 °C to about 190 °C. In one embodiment, Form 7 is characterized by a DSC thermogram substantially as Figure 19TGA thermal analysis characterization shown in the TGA thermal analysis chart presented in

[0244] This application covers combinations of all the above embodiments.

[0245] 5.2.1.8 Form 8 of Compound 1

[0246] In certain embodiments, provided herein is Form 8 of a compound of formula (I). In one embodiment, Form 8 of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, Form 8 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form 8 of Compound 1 is substantially free of salts of Compound 1. In certain embodiments, Form 8 of Compound 1 is provided in a substantially pure form of Compound 1.

[0247] A representative XRPD pattern of Form 8 of Compound 1 is provided in Figure 20 .

[0248] In one embodiment, the XRPD pattern of Form 8 has peaks located at 18.8, 20.8, and 24.5 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 8 further includes at least one peak selected from 16.0 and 17.9 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form 8 includes a combination of peaks located at 16.0, 17.9, 18.8, 20.8, and 24.5 degrees 2θ ± 0.2 and at least one peak selected from 5.4, 9.4, 11.0, 12.3, 12.7, 14.2, 16.4, and 22.0 degrees 2θ ± 0.2.

[0249] In one embodiment, Form 8 is characterized by XRPD peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following positions: 5.4, 9.4, 11.0, 12.3, 12.7, 14.2, 16.0, 16.4, 17.9, 18.8, 20.8, 22.0, and 24.5 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0250] In certain embodiments, when analyzed using Cu Kα radiation, the above XRPD peaks (degree 2θ peaks) are observed.

[0251] In one embodiment, Form 8 has an XRPD pattern substantially as Figure 20 shown.

[0252] In one embodiment, Form 8 is an unsolvated solid form of Compound 1.

[0253] In one embodiment, Form 8 exhibits an endothermic event as characterized by DSC, having an onset temperature of about 156 °C.

[0254] This application encompasses combinations of all of the above embodiments.

[0255] In one embodiment, the particles of the solid forms provided herein (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, or Form 8) have a diameter of from about 0.1 μm to about 150 μm, from about 0.1 μm to about 125 μm, from about 0.1 μm to about 100 μm, from about 0.1 μm to about 75 μm, from about 0.1 μm to about 50 μm, from about 1 μm to about 50 μm, from about 0.1 μm to about 10 μm, from about 0.1 μm to about 7 μm, or from about 0.5 μm to about 5 μm. In one embodiment, the diameter is from about 0.5 μm to about 5 μm. In another embodiment, the diameter is from about 0.6 μm to about 4.8 μm.

[0256] In one embodiment, the present application provides a composition comprising a solid form of a compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof, wherein the compound has a purity of greater than 98.0% as determined by HPLC. In one embodiment, the compound of formula (I) has a purity of about 98.5%, about 99.0%, about 99.5%, about 99.6%, about 99.9%, or about 99.91%.

[0257] 5.2.2. Method for preparing the solid forms of Compound 1

[0258] The present application provides a method for preparing a compound of formula (I), wherein the compound is a polymorphic Form 1 of a compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof; the method comprises:

[0259] (i) exposing a composition comprising at least one polymorph of a compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof that is not Form 1 to one or more solvents for a period of time sufficient to convert at least about 50% of the total amount of the non-Form 1 polymorphs into Form 1 of the compound of formula (I); and

[0260] (ii) recovering the polymorphic Form 1.

[0261] In one embodiment, the Form 1 polymorph of the compound of formula (I) is exposed to a solvent. In one embodiment, the Form 1 polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the Form 1 polymorph of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is an alcohol. In one embodiment, the solvent is ethanol, 2-methoxyethanol, methanol, ethylene glycol, or isopropanol. In one embodiment, the solvent is ethyl acetate, methyl isobutyl ketone, toluene, 1,2-dimethoxyethane, N,N-dimethylformamide, acetonitrile, ethylene glycol, anisole, or water. In one embodiment, the solvent is ethanol. In one embodiment, the solvent system comprises a mixture of two solvents. In one embodiment, the solvent system is a mixture of two solvents. In one embodiment, the mixture of two solvents is a mixture of anisole and isopropanol, a mixture of anisole and ethanol, a mixture of anisole and toluene, a mixture of acetonitrile and water, a mixture of toluene and ethanol, a mixture of acetone and water, a mixture of isopropanol and water, a mixture of ethanol and water, a mixture of N,N-dimethylformamide and water, a mixture of N,N-acetamide and water, a mixture of dimethyl sulfoxide and water, or a mixture of anisole and methanol. In one embodiment, the mixture of two solvents is a mixture of isopropanol and water. In one embodiment, the volume ratio of isopropanol to water is from about 1:4 to about 4:1. In one embodiment, the volume ratio of isopropanol to water is about 1:1 or about 3:2. In one embodiment, the volume ratio of isopropanol to water is about 1:2. In one embodiment, the mixture of two solvents is a mixture of acetone and water. In one embodiment, the mixture of two solvents is a mixture of ethanol and water. In one embodiment, the mixture of two solvents is a mixture of acetonitrile and water. In one embodiment, the volume ratio of acetonitrile to water is from about 1:4 to about 8:1. In one embodiment, the volume ratio of acetonitrile to water is about 4:1. In one embodiment, the volume ratio of acetonitrile to water is about 2:3. In one embodiment, the solvent system comprises a mixture of three solvents. In one embodiment, the mixture of three solvents is a mixture of ethanol, water, and DCM.

[0262] In one embodiment, the Form 1 polymorph is the amorphous compound of formula (I). In one embodiment, the Form 1 polymorph is Form 2 of the compound of formula (I). In one embodiment, a period of time sufficient to convert at least about 50% of the total amount of the Form 1 polymorph to Form 1 of the compound of formula (I) is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0263] In one embodiment, an amorphous polymorph of the compound of formula (I) is exposed to isopropyl alcohol and water, for example, in a 1:1 volume ratio. An additional volume of water is added at about 60 °C such that the final volume ratio of isopropyl alcohol to water is 1:2. The mixture is aged at about 60 °C for about 30 minutes, 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0264] In one embodiment, at about 50 °C to about 60 °C, an amorphous polymorph of the compound of formula (I) is exposed to acetone and water, for example, in a 4:1 volume ratio. The solvent is replaced from acetone / water to isopropyl alcohol to a final volume of about 30 volumes. The mixture is aged at about 60 °C for about 30 minutes, 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 14 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0265] In one embodiment, Form 1 is prepared by crystallization or recrystallization of the compound of formula (I) from one or more solvents. In one embodiment, the solvent is ethanol, 2-methoxyethanol, methanol, ethylene glycol, or isopropyl alcohol. In one embodiment, the solvent is ethyl acetate, methyl isobutyl ketone, toluene, 1,2-dimethoxyethane, N,N-dimethylformamide, acetonitrile, ethylene glycol, anisole, or water. In one embodiment, the solvent is ethanol.

[0266] In one embodiment, Form 1 is prepared by crystallization or recrystallization of the compound of formula (I) from a solvent comprising an alcohol. In one embodiment, the solvent is isopropyl alcohol. In one embodiment, the solvent is ethanol.

[0267] In one embodiment, Form 1 is prepared by solvent crystallization or recrystallization of the compound of formula (I) from a solvent comprising a mixture of two solvents. In one embodiment, the mixture of two solvents is a mixture of anisole and isopropanol, a mixture of anisole and ethanol, a mixture of anisole and toluene, a mixture of acetonitrile and water, a mixture of toluene and ethanol, a mixture of acetone and water, a mixture of isopropanol and water, a mixture of ethanol and water, a mixture of N,N-dimethylformamide and water, a mixture of N,N-acetamide and water, a mixture of dimethyl sulfoxide and water, or a mixture of anisole and methanol. In one embodiment, the mixture of two solvents is a mixture of isopropanol and water. In one embodiment, the volume ratio of isopropanol to water is from about 1:4 to about 4:1. In one embodiment, the volume ratio of isopropanol to water is about 1:1 or about 3:2. In one embodiment, the volume ratio of isopropanol to water is about 1:2. In one embodiment, the mixture of two solvents is a mixture of acetone and water. In one embodiment, the mixture of two solvents is a mixture of ethanol and water. In one embodiment, the mixture of two solvents is a mixture of acetonitrile and water.

[0268] In one embodiment, Form 1 is prepared by crystallization or recrystallization of the compound of formula (I) from a solvent comprising a mixture of an alcohol and water. In one embodiment, the solvent is a mixture of about 30% to about 90% alcohol in water. In one embodiment, the solvent is a mixture of about 40% to about 80% alcohol in water. In one embodiment, the solvent is a mixture of isopropanol and water. In one embodiment, the solvent is a mixture of isopropanol and water in a ratio of about 3:2. In one embodiment, the solvent is a mixture of ethanol and water. In one embodiment, the solvent is a mixture of about 20% to about 90% ethanol in water. In one embodiment, the solvent is a mixture of about 40% to about 80% ethanol in water. In one embodiment, the solvent is a mixture of about 40% ethanol in water. In one embodiment, the solvent is a mixture of about 60% ethanol in water. In one embodiment, the solvent is a mixture of about 80% ethanol in water. In one embodiment, the solvent further comprises DCM. In one embodiment, the crystallization or recrystallization comprises one or more (e.g., 1, 2, 3, 4, 5 or 6) heating and cooling cycles. In one embodiment, the crystallization or recrystallization comprises 3 heating and cooling cycles. In one embodiment, the crystallization or recrystallization comprises 4 heating and heating cycles. In one embodiment, the heating stage comprises heating at about 50°C to about 60°C for a period of time (e.g., about 1 hour to about 6 hours, e.g., about 3 hours). In one embodiment, the cooling period comprises holding at room temperature for a period of time (e.g., about 1 hour to about 6 hours, e.g., about 2 hours).

[0269] In one embodiment, Form 1 is prepared by crystallizing or recrystallizing the compound of formula (I) from a solvent comprising a mixture of acetonitrile and water. In one embodiment, the volume ratio of acetonitrile to water is from about 1:4 to about 8:1. In one embodiment, the volume ratio of acetonitrile to water is about 4:1. In one embodiment, the volume ratio of acetonitrile to water is about 2:3.

[0270] Provided herein is a method for preparing a compound of formula (I), wherein the compound is a polymorphic Form 2 of the compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof; the method comprising:

[0271] (i) exposing a composition comprising at least one non-Form 2 polymorph of the compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof to one or more solvents for a period of time sufficient to convert at least about 50% of the total amount of the non-Form 2 polymorph into Form 2 of the compound of formula (I); and

[0272] (ii) recovering the polymorphic Form 2.

[0273] In one embodiment, the non-Form 2 polymorph of the compound of formula (I) is exposed to one solvent. In one embodiment, the non-Form 2 polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-Form 2 polymorph of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is dichloromethane, acetone, tetrahydrofuran, water, 1-propanol or chloroform. In one embodiment, the mixture of two solvents is a mixture of dichloromethane and acetone, a mixture of tetrahydrofuran and water, a mixture of dichloromethane and ethanol, or a mixture of dichloromethane and methanol. In one embodiment, the mixture of two solvents is a mixture of dichloromethane and acetone. In one embodiment, the non-Form 2 polymorph of the compound of formula (I) is exposed to a mixture of three solvents. In one embodiment, the mixture of three solvents is a mixture of dichloromethane, ethanol and water. In one embodiment, the non-Form 2 polymorph is an amorphous compound of formula (I). In one embodiment, the period of time sufficient to convert at least about 50% of the total amount of the non-Form 2 polymorph into Form 2 of the compound of formula (I) is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours or about 72 hours.

[0274] In one embodiment, Form 2 is obtained by aging, for example, in 1-propanol, acetone, or dichloromethane, or a mixture of dichloromethane and acetone, or a mixture of tetrahydrofuran and water. In one embodiment, Form 2 is obtained from dichloromethane at about 5 °C.

[0275] The present invention provides a method for preparing a compound of formula (I), wherein the compound is a polymorphic form 3 of the compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof; the method comprises:

[0276] (i) exposing a composition comprising at least one compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof that is not in polymorphic form 3 to one or more solvents for a period of time sufficient to convert at least about 50% of the total amount of the non-form 3 polymorphs into form 3 of the compound of formula (I); and

[0277] (ii) recovering the polymorphic form 3.

[0278] In one embodiment, the non-form 3 polymorph of the compound of formula (I) is exposed to one solvent. In one embodiment, the non-form 3 polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-form 3 polymorph of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is methyl ethyl ketone, tert-butyl methyl ether, 2-methyl-1-propanol, 2-methyltetrahydrofuran, isopropanol, ethanol, toluene, 1-propanol, acetone, or acetonitrile. In one embodiment, the mixture of two solvents is a mixture of 2-methyltetrahydrofuran and isopropanol, a mixture of 2-methyltetrahydrofuran and ethanol, a mixture of 2-methyltetrahydrofuran and toluene, or a mixture of acetonitrile and water. In one embodiment, the non-form 3 polymorph is an amorphous compound of formula (I). In one embodiment, the period of time sufficient to convert at least about 50% of the total amount of the non-form 3 polymorphs into form 3 of the compound of formula (I) is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0279] In one embodiment, Form 3 is obtained by aging in one solvent or a mixture of one or more solvents. In one embodiment, Form 3 is obtained at about 5 °C.

[0280] The present invention provides a method for preparing a compound of formula (I), wherein the compound is a polymorphic form 4 of the compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof; the method comprises:

[0281] (i) Exposing a composition comprising at least one compound of formula (I), or a salt, solvate, solvate of a salt, or mixture thereof, in the non-form 4 polymorphic form to one or more solvents for a period of time sufficient to convert at least about 50% of the total amount of the non-form 4 polymorphic form into form 4 of the compound of formula (I); and

[0282] (ii) Recovering the polymorphic form 4.

[0283] In one embodiment, the non-form 4 polymorphic form of the compound of formula (I) is exposed to one solvent. In one embodiment, the non-form 4 polymorphic form of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-form 4 polymorphic form of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is 1-propanol, acetone, 2-methyl-1-propanol, 1,4-dioxane, chloroform, tetrahydrofuran, 2-methoxyethanol, isopropanol, water, anisole, toluene, or dimethyl sulfoxide. In one embodiment, the mixture of two solvents is an isopropanol mixture of anisole and tetrahydrofuran, a mixture of toluene and tetrahydrofuran, a mixture of toluene and isopropanol, or a mixture of isopropanol and water. In one embodiment, the non-form 4 polymorphic form is an amorphous compound of formula (I). In one embodiment, the period of time sufficient to convert at least about 50% of the total amount of the non-form 4 polymorphic form into form 4 of the compound of formula (I) is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0284] In one embodiment, form 4 is obtained by aging in one solvent or a mixture of one or more solvents. In one embodiment, form 4 is obtained at about 5 °C.

[0285] Provided herein is a method for preparing a compound of formula (I), wherein the compound is polymorphic form 5 of the compound of formula (I), or a salt, solvate, solvate of a salt, or mixture thereof; the method comprising:

[0286] (i) Exposing a composition comprising at least one compound of formula (I), or a salt, solvate, solvate of a salt, or mixture thereof, in the non-form 5 polymorphic form to one or more solvents for a period of time sufficient to convert at least about 50% of the total amount of the non-form 5 polymorphic form into form 5 of the compound of formula (I); and

[0287] (ii) Recovering the polymorphic form 5.

[0288] In one embodiment, the polymorph of the compound of formula (I) in Form 5 is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is anisole. In one embodiment, the polymorph in Form 5 is the amorphous compound of formula (I). In one embodiment, a period of time sufficient to convert at least about 50% of the total amount of the polymorph in Form 5 into Form 5 of the compound of formula (I) is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours or about 72 hours.

[0289] In one embodiment, Form 5 is obtained by aging in a solvent or a mixture of one or more solvents. In one embodiment, Form 5 is obtained at about 5 °C.

[0290] The present invention provides a method for preparing a compound of formula (I), wherein the compound is a polymorphic Form 6 of the compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof; the method comprises:

[0291] (i) exposing a composition comprising a polymorph of Form 6 of at least one compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof, to one or more solvents for a period of time sufficient to convert at least about 50% of the total amount of the polymorph of Form 6 into Form 6 of the compound of formula (I); and

[0292] (ii) recovering the polymorphic Form 6.

[0293] In one embodiment, the polymorph of the compound of formula (I) in Form 6 is exposed to one solvent. In one embodiment, the polymorph of the compound of formula (I) in Form 6 is exposed to a mixture of two solvents. In one embodiment, the polymorph of the compound of formula (I) in Form 6 is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is nitromethane, acetonitrile or water. In one embodiment, the solvent is nitromethane. In one embodiment, the mixture of two solvents is a mixture of nitromethane and water or a mixture of acetonitrile and water. In one embodiment, the mixture of two solvents is a mixture of acetonitrile and water. In one embodiment, the volume ratio of acetonitrile to water is 1:1. In one embodiment, the polymorph in Form 6 is the amorphous compound of formula (I). In one embodiment, a period of time sufficient to convert at least about 50% of the total amount of the polymorph of Form 6 into Form 6 of the compound of formula (I) is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours or about 72 hours.

[0294] In one embodiment, Form 6 is obtained by aging in a solvent or a mixture of one or more solvents. In one embodiment, Form 6 is obtained at about 5 °C.

[0295] Provided herein is a method for preparing a compound of formula (I), wherein the compound is polymorphic Form 7 of the compound of formula (I), or a salt, solvate, solvate of a salt, or a mixture thereof; the method comprising:

[0296] (i) exposing a composition comprising at least one non-Form 7 polymorph of the compound of formula (I), or a salt, solvate, solvate of a salt, or a mixture thereof, to one or more solvents for a period of time sufficient to convert at least about 50% of the total amount of the non-Form 7 polymorph into Form 7 of the compound of formula (I); and

[0297] (ii) recovering the polymorphic Form 7.

[0298] In one embodiment, the non-Form 7 polymorph of the compound of formula (I) is exposed to one solvent. In one embodiment, the non-Form 7 polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-Form 7 polymorph of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is methyl ethyl ketone, 1-propanol, acetone, or tert-butyl methyl ether. In one embodiment, the non-Form 7 polymorph is an amorphous compound of formula (I). In one embodiment, the period of time sufficient to convert at least about 50% of the total amount of the non-Form 7 polymorph into Form 7 of the compound of formula (I) is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0299] Provided herein is a method for preparing a compound of formula (I), wherein the compound is polymorphic Form 8 of the compound of formula (I), or a salt, solvate, solvate of a salt, or a mixture thereof; the method comprising:

[0300] (i) exposing a composition comprising at least one non-Form 8 polymorph of the compound of formula (I), or a salt, solvate, solvate of a salt, or a mixture thereof, to heating for a period of time sufficient to convert at least about 50% of the total amount of the non-Form 8 polymorph into Form 8 of the compound of formula (I); and

[0301] (ii) recovering the polymorphic Form 8.

[0302] In one embodiment, the polymorph of Form 8 is the compound of Form 6 of formula (I). In one embodiment, a period of time sufficient to convert at least about 50% of the total amount of the polymorph of Form 8 into the compound of formula (I) of Form 8 is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 80 hours, about 40 hours, about 48 hours, or about 72 hours.

[0303] 5.2.3. Solid forms comprising Compound 1 and coformers

[0304] In certain embodiments, the solid forms provided herein further comprise a coformer. In certain embodiments, the solid forms provided herein comprise the compound of formula (I)

[0305]

[0306] or a salt thereof, or a solvate (e.g., hydrate), or a solvate of a salt, or a mixture thereof, and a coformer.

[0307] In one embodiment, the solid forms provided herein comprise the free base of Compound 1, or a solvate thereof (e.g., hydrate) and a coformer. In one embodiment, the solid forms provided herein comprise an unsolvated solid form of Compound 1 and a coformer. In one embodiment, the solid forms provided herein comprise an anhydrous solid form of Compound 1 and a coformer. In one embodiment, the solid forms provided herein comprise a solvated solid form of Compound 1 and a coformer. In one embodiment, the solid forms provided herein comprise a hydrated solid form of Compound 1 and a coformer.

[0308] It is contemplated that Compound 1, or a salt thereof, or a solvate (e.g., hydrate), or a solvate of a salt, or a mixture thereof and a coformer may exist in a variety of solid forms. Such solid forms include crystalline solids or mixtures of crystalline and amorphous solids. In one embodiment, the solid form is substantially crystalline. In one embodiment, the solid form is a co-crystal.

[0309] In certain embodiments, the molar ratio of Compound 1 to solvent / water in the solid form ranges from about 10:1 to about 1:10. In certain embodiments, the molar ratio of Compound 1 to solvent / water in the solid form ranges from about 5:1 to about 1:5. In certain embodiments, the molar ratio of Compound 1 to solvent / water in the solid form ranges from about 3:1 to about 1:3. In certain embodiments, the molar ratio of Compound 1 to solvent / water in the solid form ranges from about 2:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (i.e., bis-solvate / hydrate). In another embodiment, the molar ratio is about 1:1 (i.e., mono-solvate / hydrate). In still another embodiment, the molar ratio is about 2:1 (i.e., semi-solvate / hydrate).

[0310] The ratio of Compound 1 to the co-former can be stoichiometric or non-stoichiometric. In one embodiment, the ratio of Compound 1 to the co-former ranges from about 5:1 to about 1:5. In one embodiment, the ratio of Compound 1 to the co-former is about 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4 or 1:5. In one embodiment, the ratio of Compound 1 to the co-former is about 1:1. In one embodiment, the co-crystal comprises more than one co-former. In one embodiment, the co-crystal comprises two co-formers.

[0311] In one embodiment, the co-former is one or more of the following: citric acid, L-malic acid, L-tartaric acid, fumaric acid, succinic acid, maleic acid, sorbic acid, ketoglutaric acid, salicylic acid, benzoic acid, 3-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 4-aminobenzoic acid, orotic acid, urea, nicotinic acid, isonicotinic acid, nicotinamide, isonicotinamide, saccharin, L-lactic acid, L-serine, L-proline, glycine, maltol, succinimide, sulfacetamide, and p-toluenesulfonic acid monohydrate.

[0312] In one embodiment, the co-former is L-tartaric acid. In another embodiment, the co-former is salicylic acid.

[0313] 5.2.3.1 Form P1C3 of the solid form comprising Compound 1 and L-tartaric acid

[0314] In certain embodiments, provided herein is Form P1C3, a solid form comprising Compound 1 and L-tartaric acid. In one embodiment, Form P1C3 is a crystalline hydrate solid form comprising Compound 1 and L-tartaric acid. In certain embodiments, Form P1C3 is substantially free of amorphous Compound 1. In certain embodiments, Form P1C3 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form P1C3 is provided as substantially pure Form P1C3.

[0315] In one embodiment, the molar ratio of Compound 1 to L-tartaric acid in Form P1C3 ranges from about 1:2 to 2:1. In one embodiment, the molar ratio of Compound 1 to L-tartaric acid in Form P1C3 is about 1:1. In one embodiment, Form P1C3 further comprises water. In one embodiment, the molar ratio of Compound 1 to water in Form P1C3 ranges from about 1:2 to 2:1. In one embodiment, the molar ratio of Compound 1 to water in Form P1C3 is about 1:1. In one embodiment, Compound 1:L-tartaric acid:water in Form P1C3 is about 1:1:1.

[0316] A representative XRPD pattern of Form P1C3 is provided in Figure 22 .

[0317] In one embodiment, the XRPD pattern of Form P1C3 comprises peaks located at 11.2, 17.4, and 17.7 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form P1C3 further comprises at least one peak selected from 21.2 and 22.5 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form P1C3 comprises a combination of peaks located at 11.2, 17.4, 17.7, 21.2, and 22.5 degrees 2θ ± 0.2 and at least one peak selected from 10.7, 11.6, 17.0, 20.6, 20.8, 21.4, 22.2, 23.2, 23.6, and 24.2 degrees 2θ ± 0.2.

[0318] In one embodiment, Form P1C3 is characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following positions: 10.7, 11.2, 11.6, 17.0, 17.4, 17.7, 20.6, 20.8, 21.2, 21.4, 22.2, 22.5, 23.2, 23.6 and 24.2 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0319] In certain embodiments, when analyzed using Cu Kα radiation, the above XRPD peaks (degrees 2θ peaks) are observed.

[0320] In one embodiment, Form P1C3 has an XRPD pattern substantially as Figure 22 shown.

[0321] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form P1C3 of Compound 1 is provided in Figure 23 .

[0322] In one embodiment, Form P1C3 exhibits an endothermic event as characterized by DSC, having an onset temperature of about 129 °C and / or a peak temperature of about 149 °C. In one embodiment, Form P1C3 is characterized by a DSC thermogram substantially as Figure 23 presented in the DSC thermogram shown in

[0323] In one embodiment, Form P1C3 shows a weight loss of about 0.5% when heated from about 30 °C to about 100 °C, a weight loss of about 1.9% when heated from about 100 °C to about 160 °C, and a weight loss of about 15.9% when heated from about 170 °C to about 260 °C. In one embodiment, Form P1C3 is characterized by a TGA thermogram substantially as Figure 23 presented in the TGA thermogram shown in

[0324] A representative gravimetric vapor sorption (GVS) isotherm of Form P1C3 is presented in Figure 28In. In one embodiment, Form P1C3 shows a weight increase of about 3.7% when subjected to a relative humidity increase from about 0 to about 90% relative humidity. In one embodiment, Form P1C3 is characterized by a GVS thermal analysis chart substantially as shown in the GVS thermal analysis chart presented in Figure 28 In.

[0325] In one embodiment, the preparation of Form P1C3 includes grinding a mixture of Compound 1 and L-tartaric acid in the presence of a solvent. In one embodiment, the solvent is nitromethane. In one embodiment, the nitromethane is not anhydrous, i.e., contains a certain amount (e.g., about 5%) of water. In one embodiment, the preparation of Form P1C3 includes grinding a 1:1 mixture of Compound 1 and L-tartaric acid in the presence of nitromethane.

[0326] In one embodiment, the preparation of Form P1C3 includes slowly cooling a solution of Compound 1 and L-tartaric acid in the presence of a solvent. In one embodiment, the solvent is nitromethane. In one embodiment, the nitromethane is not anhydrous, i.e., contains a certain amount (e.g., about 5%) of water. In one embodiment, the preparation of Form P1C3 includes slowly cooling a 1:1 solution of Compound 1 and L-tartaric acid in nitromethane containing about 5% water. In one embodiment, the solution is cooled from about 50 °C to about 5 °C at a rate of about 0.1 to about 0.25 °C / min.

[0327] This application encompasses combinations of all the above embodiments.

[0328] 5.2.3.2 Form P1C9, a solid form comprising Compound 1 and salicylic acid

[0329] In certain embodiments, provided herein is Form P1C9, a solid form comprising Compound 1 and salicylic acid. In one embodiment, Form P1C9 is a crystalline hydrate solid form comprising Compound 1 and salicylic acid. In certain embodiments, Form P1C9 is substantially free of amorphous Compound 1. In certain embodiments, Form P1C9 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form P1C9 is provided in substantially pure form P1C9.

[0330] In one embodiment, the molar ratio of Compound 1 to salicylic acid in Form P1C9 ranges from about 1:1 to 3:1. In one embodiment, the molar ratio of Compound 1 to salicylic acid in Form P1C9 is about 2:1. In one embodiment, Form P1C9 further comprises water. In one embodiment, the molar ratio of Compound 1 to water in Form P1C9 ranges from about 1:3 to 1:5. In one embodiment, the molar ratio of Compound 1 to water in Form P1C9 is about 1:4. In one embodiment, Compound 1:salicylic acid:water in Form P1C9 is about 1:0.5:4.

[0331] A representative XRPD pattern of Form P1C9 is provided in Figure 24 .

[0332] In one embodiment, the XRPD pattern of Form P1C9 has peaks located at 6.9, 10.1, and 12.0 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form P1C9 further comprises at least one peak selected from 17.8 and 20.0 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form P1C9 includes a combination of peaks located at 6.9, 10.1, 12.0, 17.8, and 20.0 degrees 2θ ± 0.2 and at least one peak selected from 4.7, 6.0, 12.7, 13.7, 15.0, 16.2, 24.2, 24.6, 26.1, and 28.3 degrees 2θ ± 0.2.

[0333] In one embodiment, Form P1C9 is characterized by XRPD peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the following positions: 4.7, 6.0, 6.9, 10.1, 12.0, 12.7, 13.7, 15.0, 16.2, 17.8, 20.0, 24.2, 24.6, 26.1, and 28.3 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0334] In certain embodiments, the above XRPD peaks (degrees 2θ peaks) are observed when analyzed using Cu kα radiation.

[0335] In one embodiment, Form P1C9 has an XRPD pattern substantially as Figure 24 shown.

[0336] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form P1C9 of Compound 1 is provided in Figure 25 .

[0337] In one embodiment, Form P1C9 exhibits an endothermic event having an onset temperature of about 43 °C and / or a peak temperature of about 75 °C, or an endothermic event having an onset temperature of about 120 °C and / or a peak temperature of about 127 °C, as characterized by DSC. In one embodiment, Form P1C9 exhibits an endothermic event having an onset temperature of about 43 °C and / or a peak temperature of about 75 °C, or an endothermic event having an onset temperature of about 120 °C and / or a peak temperature of about 127 °C, as characterized by DSC. In one embodiment, Form P1C9 is characterized by a DSC thermogram substantially as shown in the DSC thermogram presented in Figure 25 .

[0338] In one embodiment, Form P1C9 shows a weight loss of about 10.15% when heated from about 30 °C to about 100 °C. In one embodiment, Form P1C9 is characterized by a TGA thermogram substantially as shown in the TGA thermogram presented in Figure 25 .

[0339] In one embodiment, the preparation of Form P1C9 includes sonication of a mixture of Compound 1 and salicylic acid in the presence of a solvent. In one embodiment, the solvent is a mixture of acetonitrile and water. In one embodiment, the solvent is a 1:1 mixture of acetonitrile and water. In one embodiment, the preparation of Form P1C9 includes sonication of a 1:1 mixture of Compound 1 and salicylic acid in the presence of a 1:1 mixture of acetonitrile and water. In one embodiment, the preparation further includes sedimenting the material for a period of time from the sonication step. In one embodiment, the sedimentation time is less than about 2 hours. In one embodiment, the sedimentation time is about 30 minutes.

[0340] This application encompasses combinations of all of the above embodiments.

[0341] 5.2.3.3 Form P2C9, a solid form comprising Compound 1 and salicylic acid

[0342] In certain embodiments, provided herein is Form P2C9, a solid form comprising Compound 1 and salicylic acid. In one embodiment, Form P2C9 is a crystalline solvate solid form comprising Compound 1 and salicylic acid. In one embodiment, Form P2C9 is a crystalline acetonitrile solvate solid form comprising Compound 1 and salicylic acid. In certain embodiments, Form P2C9 is substantially free of amorphous Compound 1. In certain embodiments, Form P2C9 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In certain embodiments, Form P2C9 is provided as substantially pure Form P2C9.

[0343] In one embodiment, the molar ratio of Compound 1 to salicylic acid in Form P2C9 ranges from about 1:2 to 2:1. In one embodiment, the molar ratio of Compound 1 to salicylic acid in Form P2C9 is about 1:1. In one embodiment, Form P2C9 further comprises acetonitrile. In one embodiment, the molar ratio of Compound 1 to acetonitrile in Form P2C9 ranges from about 1:1 to 3:1. In one embodiment, the molar ratio of Compound 1 to acetonitrile in Form P2C9 is about 1:0.5. In one embodiment, the molar ratio of Compound 1∶salicylic acid∶acetonitrile in Form P2C9 is about 1:1:0.5.

[0344] A representative XRPD pattern of Form P2C9 is provided in Figure 26 .

[0345] In one embodiment, the XRPD pattern of Form P2C9 comprises peaks at 11.4, 13.4, and 24.0 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form P2C9 further comprises at least one peak selected from 25.1 and 26.9 degrees 2θ ± 0.2. In one embodiment, the XRPD pattern of Form P2C9 comprises peaks at 11.4, 13.4, 24.0, 25.1, and 26.9 degrees 2θ ± 0.2, in combination with at least one peak selected from 8.5, 12.7, 16.0, 16.8, 18.7, 19.9, 21.7, 23.6, 28.3, and 28.7 degrees 2θ ± 0.2.

[0346] In one embodiment, Form P2C9 is characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following positions: 8.5, 11.4, 12.7, 13.4, 16.0, 16.8, 18.7, 19.9, 21.7, 23.6, 24.0, 25.1, 26.9, 28.3 and 28.7 degrees 2θ ± 0.2. In one embodiment, the solid form is characterized by 3 of said peaks. In one embodiment, the solid form is characterized by 5 of said peaks. In one embodiment, the solid form is characterized by 7 of said peaks. In one embodiment, the solid form is characterized by 9 of said peaks. In one embodiment, the solid form is characterized by 11 of said peaks. In one embodiment, the solid form is characterized by 13 of said peaks. In one embodiment, the solid form is characterized by all of said peaks.

[0347] In certain embodiments, when analyzed using CuKα radiation, the above XRPD peaks (2θ degree peaks) are observed.

[0348] In one embodiment, Form P2C9 has an XRPD pattern substantially as Figure 26 shown.

[0349] A representative overlay of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form P2C9 of Compound 1 is provided in Figure 27 herein.

[0350] In one embodiment, Form P2C9 shows an endothermic event characterized by DSC having an onset temperature of about 78 °C and / or a peak temperature of about 96 °C. In one embodiment, Form P2C9 is characterized by a DSC thermogram substantially as Figure 27 presented in the DSC thermogram shown in

[0351] In one embodiment, Form P2C9 shows a weight loss of about 5.6% when heated from about 30 °C to about 130 °C. In one embodiment, Form P2C9 is characterized by a TGA thermogram substantially as Figure 27 presented in the TGA thermogram shown in

[0352] In one embodiment, the preparation of Form P2C9 comprises sonication of a mixture of Compound 1 and salicylic acid in the presence of a solvent. In one embodiment, the solvent is a mixture of acetonitrile and water. In one embodiment, the solvent is a 1:1 mixture of acetonitrile and water. In one embodiment, the preparation of Form P2C9 comprises sonication of a 1:1 mixture of Compound 1 and salicylic acid in the presence of a 1:1 mixture of acetonitrile and water. In one embodiment, the preparation further comprises sedimenting the substance for a period of time from the sonication step. In one embodiment, the sedimentation time is at least about 2 hours.

[0353] This application encompasses combinations of all of the above embodiments.

[0354] In one embodiment, the particle diameter of the solid forms provided herein (e.g., Form P1C9, Form P1C9, or Form P2C9), wherein the particle diameter of the compound is from about 0.1 μm to about 150 μm, from about 0.1 μm to about 125 μm, from about 0.1 μm to about 100 μm, from about 0.1 μm to about 75 μm, from about 0.1 μm to about 50 μm, from about 1 μm to about 50 μm, from about 1 μm to about 50 μm, from about 0.1 μm to about 10 μm, from about 0.1 μm to about 7 μm, or from about 0.5 μm to about 5 μm. In one embodiment, the diameter is from about 0.5 μm to about 5 μm. In one embodiment, the diameter is from about 0.6 μm to about 4.8 μm.

[0355] In one embodiment, the compositions provided herein comprise a solid form of a compound of formula (I), or a salt, solvate, or solvate of a salt thereof, or a mixture thereof, wherein the compound has a purity of greater than about 98.0% as determined by HPLC. In one embodiment, the compound of formula (I) has a purity of about 98.5%, about 99.0%, about 99.5%, about 99.6%, about 99.9%, or about 99.91%.

[0356] 5.2.4 Methods for Analyzing Substances

[0357] In certain embodiments, the present application also provides methods for analyzing the presence or amount of the solid forms provided herein in a substance, comprising providing a substance comprising a compound of formula (I), or a salt, solvate (e.g., hydrate), or solvate of a salt thereof, or a mixture thereof; and using a characterization method to determine whether an identification feature associated with the solid form is present in the substance by comparing a feature obtained from the substance with a reference identification feature; wherein the presence of a feature that is substantially the same as the reference identification feature indicates the presence of the solid form in the substance.

[0358] In one embodiment, the method further comprises selecting a lot for assay results based on comparison with a reference standard. In one embodiment, the method further comprises determining the quality of the substance. In one embodiment, the method further comprises determining whether to use the substance to prepare a pharmaceutical composition. In one embodiment, the method further comprises determining whether to use the substance to treat a PI3K-mediated disorder.

[0359] In one embodiment, the characterization method is one or more of XRPD, TGA, DSC, GVS, FT-IR or NMR.

[0360] 5.2.5. Preparation method of the amorphous form of Compound 1

[0361] The present invention provides a method for preparing an amorphous form of a compound of formula (I), wherein the amorphous form is prepared via a crystalline form. In one embodiment, the present invention provides a method for preparing an amorphous form of a compound of formula (I), wherein the amorphous form is prepared via polymorphic form 1 of the compound of formula (I), or its salt, or solvate, or solvate of salt, or a mixture thereof.

[0362] In one embodiment, the method comprises:

[0363] (i) dissolving a solid form comprising a compound of formula (I), or its salt, or solvate, or solvate of salt, or a mixture thereof in one or more solvents to form a solution; and

[0364] (ii) removing the solvent of the solution to obtain an amorphous form of the compound of formula (I).

[0365] In one embodiment, the polymorphic form is polymorphic form 1.

[0366] In one embodiment, the solid form further comprises an amorphous form of the compound of formula (I).

[0367] In one embodiment, the method comprises:

[0368] (i) dissolving a solid form comprising polymorphic form 1 of a compound of formula (I), or its salt, or solvate, or solvate of salt, or a mixture thereof in one or more solvents to form a solution; and

[0369] (ii) removing the solvent of the solution to obtain an amorphous form of the compound of formula (I).

[0370] In one embodiment, the method comprises:

[0371] (i) exposing a composition comprising at least one compound of formula (I), or a salt, or solvate, or solvate of a salt, or a mixture thereof, in a non-form 1 polymorphic or amorphous form to one or more solvents for a period of time sufficient to convert at least about 50% of the total amount of the non-form 1 polymorph into form 1 of the compound of formula (I); and

[0372] (ii) recovering the polymorphic form 1;

[0373] (iii) dissolving the polymorphic form 1 in one or more solvents to form a solution; and

[0374] (iv) removing the solvent from the solution to obtain an amorphous form of the compound of formula (I).

[0375] In one embodiment, the solvent of the solution is removed by lyophilization. In another embodiment, the solvent of the solution is removed by spray drying.

[0376] In one embodiment, the non-form 1 polymorph of the compound of formula (I) is exposed to one solvent. In one embodiment, the non-form 1 polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-form 1 polymorph of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is an alcohol. In one embodiment, the solvent is ethanol, 2-methoxyethanol, methanol, ethylene glycol, or isopropanol. In one embodiment, the solvent is ethyl acetate, methyl isobutyl ketone, toluene, 1,2-dimethoxyethane, N,N-dimethylformamide, acetonitrile, ethylene glycol, anisole, or water. In one embodiment, the solvent is ethanol. In one embodiment, the mixture of two solvents is a mixture of anisole and isopropanol, a mixture of anisole and ethanol, a mixture of anisole and toluene, a mixture of acetonitrile and water, a mixture of toluene and ethanol, a mixture of acetone and water, or a mixture of isopropanol and water. In one embodiment, the mixture of two solvents is a mixture of isopropanol and water. In one embodiment, the volume ratio of isopropanol to water is 1:1 or 3:2. In one embodiment, the volume ratio of isopropanol to water is 1:2. In one embodiment, the mixture of two solvents is a mixture of acetone and water. In one embodiment, the non-form 1 polymorph is an amorphous compound of formula (I). In one embodiment, the period of time sufficient to convert at least about 50% of the total amount of the non-form 1 polymorph into form 1 of the compound of formula (I) is about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0377] In one embodiment, an amorphous form 1 polymorph of a compound of formula (I) is exposed to isopropanol and water, e.g., in a 1:1 volume ratio. An additional volume of water is added at about 60 °C such that the final volume ratio of isopropanol to water is 1:2. The mixture is aged at about 60 °C for about 30 minutes, 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0378] In one embodiment, an amorphous form 1 polymorph of a compound of formula (I) is exposed to acetone and water, e.g., in a 4:1 volume ratio, at about 50 °C to about 60 °C. The solvent is replaced from acetone / water to isopropanol to a final volume of about 30 volumes. The mixture is aged at about 60 °C for about 30 minutes, 1 hour, about 2 hours, about 5 hours, about 10 hours, about 12 hours, about 14 hours, about 20 hours, about 24 hours, about 30 hours, about 40 hours, about 48 hours, or about 72 hours.

[0379] In one embodiment, the solvent in which the compound of formula (I) is dissolved is DCM, an alcohol, or a mixture thereof. In one embodiment, the alcohol is MeOH. In one embodiment, the alcohol is 2-propanol. In another embodiment, a polymer is added prior to spray drying. In another embodiment, the polymer is PVP / VA 64. In another embodiment, the polymer is HPMC-AS.

[0380] 5.3 Preparation Method

[0381] In certain embodiments, provided herein is a method for preparing a compound of formula (I):

[0382]

[0383] or a salt, or solvate, or solvate of a salt, or a mixture thereof, comprising coupling a compound C of the following formula: with a carboxylic acid of formula G:

[0384]

[0385] to obtain a compound of formula (I).

[0386] In one embodiment, the coupling occurs in the presence of a coupling agent. In one embodiment, the coupling agent is a carbodiimide, triazine, phosphonium, uronium, or mixed anhydride, or a mixture thereof. In one embodiment, the coupling agent is N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 2-propane phosphonic anhydride (T3P), 1-[(dimethylamino)(morpholino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HDMA), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), (1-cyano-2-ethoxy-2-oxo-ethylideneaminooxy)dimethylamino-morpholinocarbenium hexafluorophosphate (COMU), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), diethyl phosphorocyanidate (DECP), diethyl phosphorochloridate (DEPC), diphenylphosphoryl azide (DPPA), bis(2-oxazolidinyl)phosphinic chloride (BOPCl), chlorodimethoxytriazine or its N-methylmorpholinium adduct, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), (EtO)2P(O)-Cl, (EtO)2P(O)-Oxyma, pivaloyl chloride, isobutyl chloroformate, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) or its BF4 analogue, or a mixture thereof. In one embodiment, the coupling agent is EDCI. In one embodiment, the coupling agent is DMTMM.

[0387] In one embodiment, the coupling occurs in the presence of an activator. In one embodiment, the activator is HOBt, HBTriazinone, ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma), NHS, or potassium (hydroxyimino)cyanoacetate (K-Oxyma). In one embodiment, the activator is HOBt.

[0388] In one embodiment, the coupling occurs in the presence of a base. In one embodiment, the base is Et3N, DIPEA, pyridine, NMM, DBU, NaOH, or DMAP. In one embodiment, the base is Et3N. In one embodiment, the base is DIPEA.

[0389] In one embodiment, the coupling occurs in the presence of a solvent. In one embodiment, the solvent is DMF, NMP, acetonitrile, EtOH, acetone, DCM, MeOH, or water, or a mixture thereof.

[0390] In one embodiment, the coupling occurs in the presence of a carbodiimide coupling agent. In one embodiment, the carbodiimide is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In one embodiment, the coupling occurs in the presence of hydroxybenzotriazole (HOBt). In one embodiment, the coupling occurs in the presence of a base. In one embodiment, the base is DIPEA. In one embodiment, DIPEA is in DMF. In one embodiment, the coupling occurs under an inert atmosphere.

[0391] In one embodiment, the coupling occurs in the presence of a triazine coupling agent. In one embodiment, the triazine is DMTMM. In one embodiment, the coupling occurs in the presence of a base. In one embodiment, the base is Et3N, DIPEA, pyridine, NMM, DBU, NaOH, or DMAP. In one embodiment, the base is Et3N. In one embodiment, the coupling occurs in a solvent of acetonitrile, EtOH, acetone, DCM, MeOH, or water, or a mixture thereof. In one embodiment, the solvent is a mixture of acetonitrile and water (e.g., 4:1 v / v), a mixture of EtOH and water (e.g., 3:1 v / v), a mixture of EtOH, water, and DCM (e.g., 14.4:4.8:1 v / v / v), a mixture of acetone and water (e.g., 4:1 v / v), a mixture of DCM and MeOH (e.g., 4:1 v / v), a mixture of DCM and EtOH (e.g., 4:1 v / v), or DCM. In one embodiment, the solvent is a mixture of acetonitrile and water. In one embodiment, the volume ratio of acetonitrile to water is about 4:1.

[0392] In one embodiment, the coupling occurs in the presence of T3P and DIPEA in DMF.

[0393] In certain embodiments, provided herein is a method for preparing a compound of formula (I):

[0394]

[0395] A process for or its salt, or solvate, or solvate of salt, or mixture thereof, comprising coupling a compound C of the following formula:

[0396]

[0397] with an ester of formula D:

[0398]

[0399] to obtain a compound of formula (I).

[0400] In one embodiment, the coupling occurs in the presence of one or more solvents. In another embodiment, the coupling occurs in the presence of a base and one or more solvents. In one embodiment, the amine is N,N-diisopropylethylamine (DIPEA). In one embodiment, the solvent is an organic solvent. In one embodiment, the organic solvent is selected from acetonitrile, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, and dichloromethane, or a mixture thereof. In one embodiment, the organic solvent is acetonitrile. In one embodiment, the organic solvent is a mixture of DCM and ethanol. In one embodiment, the volume ratio of DCM to ethanol is about 8:1 to about 2:1. In one embodiment, the volume ratio of DCM to ethanol is about 4:1. In one embodiment, the coupling occurs in the presence of a mixture of two solvents. In another embodiment, the solvent mixture is water and acetonitrile. In one embodiment, the volume ratio of water to acetonitrile is about 1:4. In one embodiment, the coupling occurs at a temperature of about 30 °C to about 80 °C, about 40 °C to about 70 °C, or about 55 °C to about 65 °C. In one embodiment, the temperature is about 60 °C.

[0401] In certain embodiments, provided herein is a process for preparing a compound C of the following formula:

[0402]

[0403] including coupling a compound A of the following formula:

[0404]

[0405] with an alkyne of formula E:

[0406]

[0407] In one embodiment, the coupling occurs in the presence of a catalyst, a ligand, or a catalyst / ligand complex; a base, and a solvent.

[0408] In one embodiment, the catalyst is a palladium (Pd) catalyst, a nickel (Ni) catalyst, a copper (Cu) catalyst, or a mixture thereof. In one embodiment, the catalyst is a Pd catalyst. In one embodiment, the Pd catalyst is Pd-G3, Pd2(dba)3, PdCl2(MeCN)2, Pd(OAc)2, Pd(PPh3)4, or PdCl2(PPh3)2. In one embodiment, the palladium catalyst is PdCl2(MeCN)2. In one embodiment, the palladium catalyst is Pd2(dba)3.

[0409] In one embodiment, the catalyst is a Ni catalyst. In one embodiment, the Ni catalyst is (Ph3P)2NiCl2.

[0410] In one embodiment, the catalyst is a Cu catalyst. In one embodiment, the Cu catalyst is CuI.

[0411] In one embodiment, the ligand is a phosphine ligand or a diphosphine ligand. In one embodiment, the ligand is XPhos, PCy3, PCy2Ph, P i Pr3, PCy2 t Bu, CataCXium A, P(MeOC6H4)3, PPh2(C6H4CO2H), PPh2(C6H4SO3H), SPhos, JohnPhos, DavePhos, MePhos, cBRIDP, Cy-vBRIDP, Cy-cBRIDP, i Bu Triplecage, P t Bu2Cy, P t Bu3, CataCXium PICy, P t Bu2(PhNMe2), PPh3, dppp, dppe, dppb, BINAP, DPEPhos, dppf, dbpf, XantPhos, N- t Bu2P azetine, dppm, dmpe, dippe, DIPAMP, Chiraphos, SPANphos, SEGPHOS, Me-DuPhos, or Josiphos. In one embodiment, the ligand is XPhos, CataCXium A, JohnPhos, DavePhos, MePhos, cBRIDP, CataCXium PICy, or dbpf. In one embodiment, wherein the ligand is XPhos (2-dicyclohexylphosphino 2′,4′,6′-triisopropylbiphenyl). In one embodiment, the ligand is cBRIDP.

[0412] In one embodiment, the molar ratio of the ligand to the catalyst is from about 5:1 to about 1:5. In one embodiment, the molar ratio of the ligand to the catalyst is from about 2:1 to about 1:2. In one embodiment, the molar ratio of the ligand to the catalyst is from about 2:1 to about 1:1. In one embodiment, the ligand is a monodentate ligand and the molar ratio of the ligand to the catalyst is about 2:1. In one embodiment, the ligand is a monodentate ligand and the molar ratio of the ligand to the catalyst is about 1:1. In one embodiment, the ligand is a bidentate ligand and the molar ratio of the ligand to the catalyst is about 1:1. In one embodiment, the ligand is a bidentate ligand and the molar ratio of the ligand to the catalyst is about 1:2.

[0413] In one embodiment, the catalyst loading is from about 0.5% to about 10%, from about 1% to about 10%, or from about 1% to about 5%. In one embodiment, the catalyst loading is about 5%. In one embodiment, the catalyst loading is about 4%. In one embodiment, the catalyst loading is about 3%. In one embodiment, the catalyst loading is about 2%. In one embodiment, the catalyst loading is about 1%.

[0414] In one embodiment, the ligand loading is from about 0.5% to about 20%, from about 0.5% to about 15%, from about 0.5% to about 10%, from about 1% to about 10%, from about 1% to about 5%, or from about 1% to about 3%. In one embodiment, the ligand loading is about 10%. In one embodiment, the ligand loading is about 5%. In one embodiment, the ligand loading is about 4%. In one embodiment, the ligand loading is about 3%. In one embodiment, the ligand loading is about 2%. In one embodiment, the ligand loading is about 1%.

[0415] In one embodiment, the base is an inorganic base. In one embodiment, the base is an alkali metal salt. In one embodiment, the base is an alkaline earth metal salt. In one embodiment, the base is Cs2CO3, K2CO3 or K3PO4. In one embodiment, the base is Cs2CO3. In one embodiment, the base is K2CO3. In one embodiment, the base is K3PO4.

[0416] In one embodiment, the base is an organic base.

[0417] In one embodiment, the Pd catalyst is Pd2(dba)3, the ligand is Xphos, and the base is K2CO3. In one embodiment, the Pd catalyst is Pd2(dba)3, the ligand is Xphos, and the base is K3PO4. In one embodiment, the Pd catalyst is PdCl2(MeCN)2, the ligand is Xphos, and the base is K2CO3. In one embodiment, the Pd catalyst is Pd(OAc)2, the ligand is Xphos, and the base is K2CO3.

[0418] In one embodiment, the solvent is MeCN, i PrOAc, n-propyl acetate, 2-MeTHF, EtCN, MEK or toluene. In one embodiment, the solvent is MeCN.

[0419] In one embodiment, the coupling occurs in the presence of PdCl2(MeCN)2. In one embodiment, the coupling occurs in the presence of XPhos. In one embodiment, the coupling further occurs in the presence of a base. In one embodiment, the base is Cs2CO3. In one embodiment, the coupling occurs in the presence of a solvent. In one embodiment, the solvent is an organic solvent. In one embodiment, the organic solvent is acetonitrile.

[0420] In one embodiment, the coupling occurs in the presence of PdCl2(dba)3. In one embodiment, the coupling occurs in the presence of XPhos. In one embodiment, the coupling further occurs in the presence of a base. In one embodiment, the base is K3PO4. In one embodiment, the coupling occurs in the presence of a solvent. In one embodiment, the solvent is an organic solvent. In one embodiment, the organic solvent is acetonitrile.

[0421] In certain embodiments, provided herein is a method for preparing an alkyne of formula E:

[0422]

[0423] comprising deprotecting a compound of formula F:

[0424]

[0425] In one embodiment, the deprotection occurs in the presence of a base and a solvent.

[0426] In one embodiment, the base is an inorganic base. In one embodiment, the base is an alkali metal salt. In one embodiment, the base is KOH, NaOH, NaHCO3, K3PO4 or K2CO3. In one embodiment, the base is an organic base. In one embodiment, the base is pyridine.

[0427] In one embodiment, deprotection occurs in the presence of an acid. In one embodiment, the acid is HCl, AcOH, p-TsOH or camphorsulfonic acid.

[0428] In one embodiment, deprotection occurs in the presence of a fluoride source. In one embodiment, the fluoride source is tetra-n-butylammonium fluoride (TBAF). In one embodiment, the fluoride source is pyridine-HF.

[0429] In one embodiment, deprotection occurs in the presence of a phase transfer catalyst. In one embodiment, the phase transfer catalyst is tetrabutylammonium hydroxide.

[0430] In one embodiment, the solvent is an organic solvent. In one embodiment, the organic solvent is MeOH. In one embodiment, the solvent is a mixture of water and a water-insoluble solvent. In one embodiment, the water-insoluble solvent is MTBE or DCM. In one embodiment, deprotection occurs in the presence of a mixture of about 10 wt% aqueous KOH and MTBE. In one embodiment, the solvent is acetonitrile.

[0431] In certain embodiments, provided herein is a method for preparing a compound of formula F:

[0432]

[0433] comprising coupling 4-iodo-1-methyl-1H-pyrazole with trimethylsilylacetylene.

[0434] In one embodiment, the coupling occurs in the presence of a Cu catalyst, a Pd catalyst and a base.

[0435] In one embodiment, the Cu catalyst is CuI.

[0436] In one embodiment, the Pd catalyst is Pd-G3, Pd2(dba)3, PdCl2(MeCN)2, Pd(OAc)2, Pd(PPh3)4 or PdCl2(PPh3)2. In one embodiment, the Pd catalyst is PdCl2(PPh3)2.

[0437] In one embodiment, the molar ratio of the Pd catalyst to the Cu catalyst is from about 1:20 to about 10:1, about 1:10 to about 5:1, about 1:7.5 to about 1:1, or about 1:6 to about 1:2. In one embodiment, the molar ratio of the Pd catalyst to the Cu catalyst is about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, or about 2:1. In one embodiment, the molar ratio of the Pd catalyst to the Cu catalyst is about 1:6. In one embodiment, the molar ratio of the Pd catalyst to the Cu catalyst is about 1:2.

[0438] In one embodiment, the loading of the Pd catalyst is from about 0.0005 equivalents to about 0.1 equivalents, about 0.001 equivalents to about 0.05 equivalents, about 0.002 equivalents to about 0.02 equivalents, or about 0.003 equivalents to about 0.01 equivalents. In one embodiment, the loading of the Pd catalyst is about 0.003 equivalents. In one embodiment, the loading of the Pd catalyst is about 0.01 equivalents.

[0439] In one embodiment, the loading of the Cu catalyst is from about 0.001 equivalents to about 0.2 equivalents, about 0.005 equivalents to about 0.1 equivalents, about 0.01 equivalents to about 0.05 equivalents, or about 0.0175 equivalents to about 0.02 equivalents. In one embodiment, the loading of the Cu catalyst is about 0.0175 equivalents. In one embodiment, the loading of the Cu catalyst is about 0.02 equivalents.

[0440] In one embodiment, the loading of the Pd catalyst is about 0.01 equivalents and the loading of the Cu catalyst is about 0.02 equivalents. In one embodiment, the loading of the Pd catalyst is about 0.003 equivalents and the loading of the Cu catalyst is about 0.0175 equivalents.

[0441] In one embodiment, the base is DIPA, DIPEA, or N-methylmorpholine (NMM). In one embodiment, the base is DIPA. In one embodiment, the base is DIPEA. In one embodiment, the base is NMM. In one embodiment, the base (e.g., DIPA) also serves as a solvent.

[0442] In one embodiment, the coupling occurs in the solvent DCM, toluene, 2-methyl-tetrahydrofuran, or DIPA, or a mixture thereof. In one embodiment, the coupling occurs in the solvent DCM. In one embodiment, the coupling occurs in the solvent toluene. In one embodiment, the coupling occurs in the solvent 2-methyl-tetrahydrofuran.

[0443] In one embodiment, the compound of formula F is used to prepare the alkyne compound of formula E without purification. In one embodiment, the compound of formula F is purified before being used to prepare the alkyne compound of formula E.

[0444] In one embodiment, the coupling produces less than about 5%, less than about 4%, less than about 4%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of the by-product of formula .

[0445] In certain embodiments, the carboxylic acid of formula G is prepared according to the methods described in PCT Publication Nos. WO 2011 / 003065 and WO 2015 / 073267. An exemplary synthetic scheme is shown below. The overall average yield is from about 10% to about 25%.

[0446]

[0447] In certain embodiments, an alternative method for preparing the carboxylic acid of formula G is provided herein. An exemplary synthetic scheme is shown below. The alternative method gives an overall yield of about 40 - 45% and gives a yellowish-white product.

[0448]

[0449] In certain embodiments, the carboxylic acid of formula G is prepared by a method comprising hydrolyzing the compound of formula H:

[0450]

[0451] In one embodiment, the hydrolysis occurs in the presence of a base. In one embodiment, the base is LiOH, NaOH, or KOH. In one embodiment, the base is LiOH.

[0452] In certain embodiments, the compound of formula H is prepared by a method comprising reacting the compound of formula J

[0453]

[0454] with 1,1,3,3 - tetramethoxypropane.

[0455] In one embodiment, the reaction between the compound of formula J and 1,1,3,3 - tetramethoxypropane occurs in the solvent AcOH. In one embodiment, the compound of formula H is used to prepare the compound of formula G and, after removing the solvent AcOH, no further purification is required.

[0456] In one embodiment, the reaction between the compound of formula J and 1,1,3,3 - tetramethoxypropane occurs in the presence of HCl.

[0457] In certain embodiments, provided herein is a method for preparing a compound of formula J:

[0458]

[0459] comprising cyclizing a compound of formula K:

[0460]

[0461] In one embodiment, the cyclization occurs by refluxing in the solvent 1 - propanol for about 2 days to about 4 days. In one embodiment, the cyclization occurs by refluxing in the solvent 1 - propanol for about several days.

[0462] In one embodiment, the cyclization occurs by refluxing in the solvent 1 - butanol for about 24 hours to about 48 hours. In one embodiment, the cyclization occurs by refluxing in the solvent 1 - butanol for about 36 hours.

[0463] In one embodiment, the compound of formula K is prepared by a method comprising reacting a compound of formula L:

[0464]

[0465] with hydrazine or hydrazine hydrate.

[0466] In one embodiment, the reaction between the compound of formula L and hydrazine or hydrazine hydrate occurs by refluxing in the solvent 1 - propanol.

[0467] In one embodiment, the reaction between the compound of formula L and hydrazine or hydrazine hydrate occurs by heating from about 60 °C to about 80 °C in the solvent 1 - butanol.

[0468] In one embodiment, the compound of formula L is prepared by a method comprising reacting a compound of formula M:

[0469]

[0470] with NH3 or NH4OH.

[0471] In one embodiment, the reaction between the compound of formula M and NH3 or NH4OH occurs at room temperature.

[0472] In one embodiment, the preparation of the compound of formula L, the compound of formula K, and the compound of formula J occurs in one pot.

[0473] In one embodiment, the compound of formula M is prepared by a method comprising reacting a 2-cyanoacetate with 2-chloroethyl chloroformate.

[0474] In one embodiment, the reaction between the 2-cyanoacetate and 2-chloroethyl chloroformate occurs in the presence of a base. In one embodiment, the base is an inorganic base. In one embodiment, the base is an alkali metal salt. In one embodiment, the base is an alkaline earth metal salt. In one embodiment, the base is LiOH, NaOH or KOH. In one embodiment, the base is NaOH.

[0475] In one embodiment, the reaction between the 2-cyanoacetate and 2-chloroethyl chloroformate occurs in the solvent MeCN.

[0476] In one embodiment, the compound of formula M is purified by recrystallization from MeOH. In one embodiment, the compound of formula M is purified by trituration in 1-propanol. In one embodiment, the compound of formula M is purified by crystallization from 1-butanol.

[0477] 5.4. Pharmaceutical Compositions

[0478] In certain embodiments, the present disclosure provides pharmaceutical compositions comprising a solid form of a compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof, and a filler (filler or carrier), and optionally a disintegrant and a lubricant. In certain embodiments, the present disclosure provides pharmaceutical compositions comprising a solid form of a compound of formula (I), or a salt, or a solvate, or a solvate of a salt, or a mixture thereof, and a pharmaceutically acceptable excipient, diluent or carrier (including inert solid diluents and fillers, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers and adjuvants). In one embodiment, the present disclosure provides pharmaceutical compositions comprising the solid forms provided herein and their pharmaceutically acceptable excipients. In one embodiment, the present disclosure provides pharmaceutical compositions consisting essentially of the solid forms provided herein. In one embodiment, the solid form is present in the composition in an amount of at least about 80% by weight. In one embodiment, the solid form is present in the composition in an amount of at least about 90% by weight.

[0479] In one embodiment, the solid form in the pharmaceutical composition is a polymorphic or co-crystalline form provided herein. In one embodiment, the solid form is Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form P1C3, Form P1C9 or Form P2C9 of Compound 1. In one embodiment, the solid form is Form 1.

[0480] In one embodiment, the solid form in the pharmaceutical composition is the amorphous form of Compound 1. In one embodiment, the amorphous form of Compound 1 is prepared by the method provided herein. In one embodiment, the amorphous form of Compound 1 is prepared as follows: dissolving Form 1 of Compound 1 in one or more solvents to form a solution; and removing the solvent of the solution to obtain the amorphous form of Compound 1. In one embodiment, the solvent is removed by spray drying.

[0481] In one embodiment, the pharmaceutical composition comprises one or more excipients selected from fillers (or bulking agents), disintegrants, lubricants, and capsule shells. In one embodiment, the filler is mannitol or pregelatinized starch. In another embodiment, the disintegrant is sodium carboxymethylcellulose cross-linked. In another embodiment, the lubricant is magnesium stearate. In one embodiment, the capsule shell is an HPMC capsule shell. In one embodiment, the pharmaceutical composition comprises one or more excipients selected from mannitol, pregelatinized starch, sodium carboxymethylcellulose cross-linked, magnesium stearate, and HPMC capsule shell.

[0482] In one embodiment, the content of Compound 1 in the pharmaceutical composition is about 1 mg to about 100 mg, about 1 mg to about 75 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 30 mg, about 5 mg to about 10 mg, about 5 mg or about 30 mg. In one embodiment, the content is about 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 75 mg or 100 mg. In one embodiment, the content is about 5 mg or 30 mg. In one embodiment, the content of Compound 1 in the pharmaceutical composition is about 1.5% to about 25% w / w, about 1.5% to about 15% w / w, about 1.5% to about 10% w / w, about 1% to about 25% w / w, about 1% to about 15% w / w or about 1% to about 10% w / w. In one embodiment, the content of Compound 1 in the pharmaceutical composition is about 1% to about 10% w / w. In one embodiment, the content of Compound 1 in the pharmaceutical composition is about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10% w / w. In one embodiment, the content of Compound 1 in the pharmaceutical composition is about 1.9% or about 9.4%. In one embodiment, the content of Compound 1 is about 1.92% to about 9.38%.

[0483] In one embodiment, the filler (or bulking agent) (e.g., starch and mannitol) in the pharmaceutical composition is from about 80% to about 95% w / w, from about 85% to about 95% w / w, or from about 90% to about 95% w / w. In one embodiment, the filler (or bulking agent) (e.g., starch and mannitol) in the pharmaceutical composition is about 80%, about 85%, about 90% or about 95% w / w. In one embodiment, the filler (or bulking agent) (e.g., starch and mannitol) in the pharmaceutical composition is about 93% w / w, about 86% w / w, about 92.3% w / w or about 85.1% w / w. In one embodiment, the filler is about 93% w / w. In one embodiment, the filler is about 85% w / w. In one embodiment, the filler is starch, mannitol or a mixture thereof. In one embodiment, the filler is a mixture of starch and mannitol. In one embodiment, the weight ratio of starch to mannitol is from about 1:3 to about 3:1. In one embodiment, the filler is an approximately 1:1 mixture of starch and mannitol. In one embodiment, the starch is pregelatinized starch.

[0484] In one embodiment, the disintegrant (e.g., croscarmellose sodium) in the pharmaceutical composition is from about 1% to about 20% w / w, from about 1% to about 15% w / w, from about 1% to about 10% w / w, from about 2.5% to about 7.5% w / w, from about 1% to about 5% w / w or about 5% w / w. In one embodiment, the disintegrant is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% w / w. In one embodiment, the disintegrant is about 5% w / w.

[0485] In one embodiment, the lubricant (e.g., magnesium stearate) in the pharmaceutical composition is from about 0.1% to about 10% w / w, from about 0.1% to about 5% w / w or from about 0.1% to about 1% w / w. In one embodiment, the lubricant is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1% w / w. In one embodiment, the lubricant is about 0.5% w / w.

[0486] In one embodiment, provided herein is a method for preparing a pharmaceutical composition provided herein, comprising mixing a solid form of a compound of formula (I) with a pharmaceutically acceptable excipient or carrier; wherein the solid form is Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form P1C3, Form P1C9 or Form P2C9. In one embodiment, provided herein is a pharmaceutical composition prepared by the above method.

[0487] In one embodiment, the present invention provides a pharmaceutical composition comprising an amorphous form of a compound of formula (I), or a salt, solvate, solvate of a salt, or a mixture thereof, a filler (bulking agent or carrier), and optionally a disintegrant and a lubricant. In one embodiment, the present invention provides a pharmaceutical composition comprising from about 1% to about 10% w / w of an amorphous form of a compound of formula (I), or a salt, solvate, solvate of a salt, or a mixture thereof, from about 80% to about 95% w / w of a filler, from about 2.5% to about 7.5% w / w of a disintegrant, and from about 0.1% to about 1% w / w of a lubricant.

[0488] In one embodiment, the present invention provides a pharmaceutical composition comprising from about 5 to 30 mg of Compound 1 (e.g., amorphous), pregelatinized starch, and mannitol. In one embodiment, the pharmaceutical composition further comprises croscarmellose sodium and magnesium stearate.

[0489] In one embodiment, the pharmaceutical composition is formulated as follows: about 5 mg of Compound 1 (e.g., amorphous), about 120 mg of pregelatinized starch, about 120 mg of mannitol, about 13 mg of croscarmellose sodium, and about 1.3 mg of magnesium stearate. In an embodiment, the pharmaceutical composition is formulated into capsules. In one embodiment, the pharmaceutical composition is formulated as follows: about 5 mg of Compound 1 (e.g., amorphous), about 120.35 mg of pregelatinized starch, about 120.35 mg of mannitol, about 13.00 mg of croscarmellose sodium, and about 1.3 mg of magnesium stearate. In an embodiment, the pharmaceutical composition is formulated into capsules.

[0490] In one embodiment, the pharmaceutical composition is formulated as follows: about 30 mg of Compound 1 (e.g., amorphous), about 136 mg of pregelatinized starch, about 136 mg of mannitol, about 16 mg of croscarmellose sodium, and about 1.6 mg of magnesium stearate. In one embodiment, the pharmaceutical composition is formulated as follows: about 30 mg of Compound 1 (e.g., amorphous), about 136.20 mg of pregelatinized starch, about 136.20 mg of mannitol, about 16.00 mg of croscarmellose sodium, and about 1.60 mg of magnesium stearate. In an embodiment, the pharmaceutical composition is formulated into capsules.

[0491] In certain embodiments, the pharmaceutical compositions described herein comprise a second active agent such as an additional therapeutic agent (e.g., a chemotherapeutic agent).

[0492] In certain embodiments, provided herein are pharmaceutical compositions for oral administration (e.g., capsules), comprising: (a) about 5 mg of amorphous Compound 1; (b) about 120.35 mg of pregelatinized starch; (c) about 120.35 mg of mannitol; (d) about 13 mg of croscarmellose sodium; and (e) about 1.3 mg of magnesium stearate.

[0493] In certain embodiments, provided herein are pharmaceutical compositions for oral administration (e.g., capsules), comprising: (a) about 30 mg of amorphous Compound 1; (b) about 136.2 mg of pregelatinized starch; (c) about 136.2 mg of mannitol; (d) about 16 mg of croscarmellose sodium; and (e) about 1.6 mg of magnesium stearate.

[0494] In one embodiment, the pharmaceutical composition is an oral dosage form. In one embodiment, the oral dosage form is a capsule. In another embodiment, the oral dosage form is a tablet. In one embodiment, the capsule shell is Swedish orange or white.

[0495] 5.4.1. Formulations

[0496] The pharmaceutical compositions can be formulated particularly for administration in solid or liquid form, including those suitable for: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., for buccal, sublingual, and systemic absorption), capsules, pills, powders, granules, pastes for application to the tongue and duodenal routes; parenteral administration, including intravenous, intra-arterial, subcutaneous, intramuscular, intra-vascular, intraperitoneal, or infusion, in the form of, for example, sterile solutions or suspensions, or sustained release formulations; topical application, e.g., to the skin in the form of creams, ointments, or controlled release patches or sprays; intravaginal or rectal administration, e.g., in the form of vaginal suppositories, creams, stents, or foams; sublingual administration; ocular administration; pulmonary administration; local delivery via catheter or stent; intrathecal administration or nasal administration.

[0497] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oil olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained by using coating materials such as lecithin, by maintaining the desired particle size in the dispersion, and by using surfactants.

[0498] In one embodiment, suitable carriers that can be used in the pharmaceutical composition include mannitol, pregelatinized starch, croscarmellose sodium, magnesium stearate, and HPMC capsule shells.

[0499] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants and / or antioxidants. Prevention of microbial action on the compounds described herein can be ensured by including a variety of antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the compositions. In addition, extended absorption of injectable drug forms can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0500] Methods for preparing these formulations or compositions include the step of combining the compounds and / or chemotherapeutic agents described herein with a carrier and optionally one or more accessory ingredients. Generally, formulations are prepared by uniformly and intimately bringing the compounds disclosed herein into association with a liquid carrier or a comminuted solid carrier or both, and then shaping the product, if necessary.

[0501] The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.;Knoben, James E.;Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002;Pratt and Taylor, eds., Principles of Drug Action, 3rd Edition, Churchill Livingston, New York, 1990;Katzung, ed., Basic and Clinical Pharmacology, 12th Edition, McGraw Hill, 2011;Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th Edition, McGraw Hill, 2001;Remingtons Pharmaceutical Sciences, 20th Edition., Lippincott Williams & Wilkins., 2000;Martindale, The Extra Pharmacopoeia, 32nd Edition (The Pharmaceutical Press, London, 1999);the entire contents of all of which are incorporated herein by reference. The use of excipients is contemplated within the scope of the present disclosure unless any conventional excipient medium is incompatible with the compounds provided herein, such as producing any undesirable biological effects or interacting in a detrimental manner with any other component of the pharmaceutically acceptable composition.

[0502] In certain embodiments, the concentration of one or more compounds provided in the disclosed pharmaceutical compositions is equal to or less than about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002% or about 0.0001% w / w, w / v or v / v.

[0503] In certain embodiments, the concentration of one or more compounds as provided herein is greater than about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%, about 19.50%, about 19.25%, about 19%, about 18.75%, about 18.50%, about 18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%, about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about 15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about 14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%, about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about 11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about 10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%, about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about 7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%, about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%, about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about 3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about 1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002% or about 0.0001% w / w, w / v or v / v.

[0504] In certain embodiments, the concentration range of one or more compounds as provided herein is from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0505] In certain embodiments, the concentration range of one or more compounds as provided herein is from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0506] In certain embodiments, the amount of one or more compounds as provided herein is equal to or less than about 10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g, about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about 3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2 g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g, about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g, about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006 g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about 0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g, about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about 0.0001 g. In certain embodiments, the amount of one or more compounds as provided herein in the pharmaceutical compositions provided herein is about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.

[0507] In certain embodiments, the amount of one or more compounds as provided herein is greater than about 0.0001 g, about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about 0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g, about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045 g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095 g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

[0508] In certain embodiments, the amount of one or more compounds as provided herein is in the range of from about 0.0001 to about 10 g, from about 0.0005 to about 9 g, from about 0.001 to about 8 g, from about 0.005 to about 7 g, from about 0.01 to about 6 g, from about 0.05 to about 5 g, from about 0.1 to about 4 g, from about 0.5 to about 4 g, or from about 1 to about 3 g.

[0509] 5.4.1.1 Preparations for oral administration

[0510] In certain embodiments, the present disclosure provides a pharmaceutical composition for oral administration, comprising a compound as provided herein and a pharmaceutical excipient suitable for oral administration. In certain embodiments, the present disclosure provides a pharmaceutical composition for oral administration, comprising: (i) an effective amount of the disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for oral administration. In certain embodiments, the pharmaceutical composition further comprises: (iv) an effective amount of a third agent.

[0511] In certain embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions suitable for oral administration can be provided as discrete dosage forms, such as capsules, cachets, or tablets, or as liquids or aerosol sprays, solutions or suspensions in aqueous or non-aqueous liquids, water-in-oil emulsions or oil-in-water liquid emulsions, each containing a predetermined amount of the active ingredient as a powder or granules. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more ingredients. Generally, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a comminuted solid carrier or both, and then, if necessary, shaping the product into the desired form. For example, tablets can be prepared by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in free-flowing form, such as a powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surface-active or dispersing agents. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0512] Since water can promote the degradation of some compounds, the present disclosure also includes anhydrous pharmaceutical compositions and dosage forms containing the active ingredient. For example, in the pharmaceutical field, water (e.g., about 5%) can be added as a means of simulating long-term storage to determine the characteristics of the formulation over time, such as shelf life or stability. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. For example, if significant exposure to moisture and / or humidity is expected during production, packaging, and / or storage, pharmaceutical compositions and dosage forms containing lactose can be made anhydrous. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Thus, anhydrous pharmaceutical compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0513] The active ingredient can be combined with a pharmaceutical carrier into a compact mixture according to conventional pharmaceutical compounding techniques. The carrier can assume various forms depending on the form of the dosage form desired for administration. When preparing a pharmaceutical composition for an oral dosage form, any commonly used pharmaceutical vehicle can be employed as the carrier, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used in the case of oral solid preparations, and lactose is not used in some embodiments. For example, in the case of solid oral preparations, suitable carriers include powders, capsules, and tablets. In some embodiments, tablets can be coated by standard aqueous or non-aqueous techniques.

[0514] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums (such as gum arabic), sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0515] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0516] Disintegrants can be used in the pharmaceutical compositions provided herein to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant can result in tablets that disintegrate in the bottle. Too little may be insufficient to cause disintegration, thereby altering the rate and extent of release of the active ingredient from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient can be used to form the dosage forms of the compounds provided herein. The amount of disintegrant used can vary depending on the type of formulation and the mode of administration, and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant or about 1 to about 5 weight percent of disintegrant can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacrilate, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other alginates, other celluloses, gums, or mixtures thereof.

[0517] Lubricants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other diols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, aggregated aerosols of synthetic silica, or mixtures thereof. The lubricant can optionally be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0518] When an aqueous suspension and / or elixir is desired for oral administration, the active ingredient therein can be combined with various sweetening or flavoring agents, coloring substances or dyes, and, for example, emulsifying and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerol, and various combinations thereof.

[0519] Tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be employed. Preparations for oral use can also be in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil.

[0520] Surfactants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, compounds of hydrophilic surfactants can be employed, mixtures of lipophilic surfactants can be employed, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.

[0521] Suitable hydrophilic surfactants generally can have an HLB value of at least about 10, while suitable lipophilic surfactants generally can have an HLB value of less than about 10. The empirical parameter used to characterize the hydrophilicity and hydrophobicity of relatively nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values have higher lipophilicity or hydrophobicity and higher solubility in oil, while surfactants with higher HLB values have higher hydrophilicity and higher solubility in aqueous solutions. Hydrophilic surfactants are generally regarded as those compounds having an HLB value greater than about 10, and the HLB measure generally is not applicable to anionic, cationic, or zwitterionic compounds. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide generally used to achieve the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0522] Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glycerol ester derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysophosphatidylcholine and hydrogenated lysophosphatidylcholine; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[0523] Among the above groups, ionic surfactants include, for example: lecithin, lysophosphatidylcholine, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[0524] The ionic surfactant may be the ionized form of the following substances: lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactate, 2-stearoyl lactate, stearoyl lactate, succinylated monoglyceride, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, dioctyl sulfosuccinate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine and their salts and mixtures.

[0525] The hydrophilic nonionic surfactant may include, but is not limited to, alkyl glucoside; alkyl maltoside; alkyl thioglucoside; lauryl polyglycol glycerol ester; polyoxyalkylene alkyl ether, such as polyethylene glycol alkyl ether; polyoxyalkylene alkyl phenol, such as polyethylene glycol alkyl phenol; polyoxyalkylene alkyl phenol fatty acid ester, such as polyethylene glycol fatty acid monoester and polyethylene glycol fatty acid diester; polyethylene glycol glycerol fatty acid ester; polyglycerol fatty acid ester; polyoxyalkylene sorbitan fatty acid ester, such as polyethylene glycol sorbitan fatty acid ester; hydrophilic transesterification products of polyol and at least one member of glyceride, vegetable oil, hydrogenated vegetable oil, fatty acid and sterol; polyoxyethylene sterol, its derivatives and analogs; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymer; and their mixtures; polyethylene glycol sorbitan fatty acid ester; and hydrophilic transesterification products of polyol and at least one member of triglyceride, vegetable oil and hydrogenated vegetable oil. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or sugar.

[0526] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprylic / capric glycerides, PEG-8 caprylic / capric glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 stigmasterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0527] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and diglycerides; hydrophobic transesterification products of polyols with at least one member of glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, non-limiting examples of lipophilic surfactants include fatty acid glycerol esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of polyols with at least one member of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0528] In one embodiment, the pharmaceutical composition may include a solubilizer to ensure good solubilization and / or dissolution of the compounds provided herein, minimizing precipitation of the compounds. This may be particularly important for pharmaceutical compositions for non-oral use, for example, pharmaceutical compositions for injection. Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components (such as surfactants), or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion.

[0529] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, diethylene glycol monoethyl ether (transcutol), dimethyl isosorbitol ether, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (tetrahydrofuryl polyethylene glycol ether (glycofurol)) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidones, N-hydroxyalkylpyrrolidones, N-alkylpiperidones, N-alkylcaprolactams, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetylcitrate, tributyl acetylcitrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, glyceryl triacetate, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethyl isosorbitol ether, N-methylpyrrolidone, monocaprylin, diethylene glycol monoethyl ether and water.

[0530] Mixtures of solubilizers may also be used. Examples include, but are not limited to, glyceryl triacetate, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, tetrahydrofuryl polyethylene glycol ether, ethylene glycol monoethyl ether (transcutol), propylene glycol and dimethyl isosorbitol ether. In certain embodiments, the solubilizer includes sorbitol, glycerol, glyceryl triacetate, ethanol, PEG-400, tetrahydrofuryl polyethylene glycol ether and propylene glycol.

[0531] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biocompatible amount, which can be readily determined by those skilled in the art. In some cases, it may be advantageous to include far in excess of the biocompatible amount of solubilizer, for example to maximize the drug concentration, where the excess solubilizer is removed using conventional techniques (such as distillation or evaporation) prior to providing the pharmaceutical composition to a subject. Thus, if present, the weight ratio of solubilizer based on the combined weight of the drug and other excipients can be about 10%, 25%, 50%, 100% or up to about 200% by weight. If desired, very small amounts of solubilizer can also be used, such as about 5%, 2%, 1% or even lower. Generally, the solubilizer can be present in an amount of about 1% to about 100% by weight, more typically in an amount of about 5% to about 25% by weight.

[0532] The pharmaceutical composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adhesives, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity modifiers, flavoring agents, coloring agents, oils, fragrances, opacifying agents, suspending agents, binders, fillers, plasticizers, lubricants and mixtures thereof.

[0533] Exemplary preservatives can include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include, but are not limited to, α-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimonium bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, parabens, and phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, β-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopheryl acetate, deteroximemesylate, cetrimonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phcnonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0534] Exemplary oils include, but are not limited to, almond oil, apricot kernel oil, avocado oil, babassu palm oil, bergamot oil, blackcurrant seed oil, borage oil, cade oil, chamomile oil, canola oil, coriander oil, carnauba wax, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, flaxseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate oil, jojoba oil, macadamia nut oil, hybrid lavender oil, lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, camellia oil, spearmint oil, seabuckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, tsubakioil, vetiver oil, walnut oil, and wheat germ oil. Exemplary oils also include, but are not limited to, butyl stearate, tricaprylin, tricaprin, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0535] In addition, an acid or a base can be added to the pharmaceutical composition to facilitate processing, to enhance stability or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)-aminomethane (TRIS), and the like. Bases that are salts of pharmaceutically acceptable acids are also suitable, such acids as acetic acid, acrylic acid, adipic acid, alginic acid, alkylsulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid, uric acid, and the like. Polyacid salts can also be used, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. When the base is a salt, the cation can be any suitable and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0536] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkylsulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid, uric acid, and the like.

[0537] 5.4.1.2 Preparations for Parenteral Administration

[0538] In certain embodiments, the present disclosure provides pharmaceutical compositions for parenteral administration, comprising a compound as provided herein and a pharmaceutical excipient suitable for parenteral administration. In certain embodiments, the present disclosure provides pharmaceutical compositions for parenteral administration, comprising (i) an effective amount of the disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for parenteral administration. In certain embodiments, the pharmaceutical composition further comprises: (iv) an effective amount of a third agent.

[0539] The disclosed pharmaceutical compositions can be incorporated into forms for administration by injection, including aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical solvents.

[0540] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used.

[0541] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. The desired particle size can be maintained, for example, by using a coating such as lecithin in the case of a dispersant, and the proper fluidity can be maintained by using a surfactant. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0542] A sterile injectable solution can be prepared by incorporating a compound as provided herein in an amount required into a suitable solvent having various other ingredients as enumerated above, and then, if desired, filter sterilizing it. Generally, dispersions are prepared by incorporating the various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and the appropriate other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, some of the methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any other ingredients from its previously sterile-filtered solution.

[0543] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium before use. The injectable compositions can contain from about 0.1 to about 5% w / w of the compounds as disclosed herein.

[0544] 5.4.1.3 Formulations for topical administration

[0545] In certain embodiments, the present disclosure provides pharmaceutical compositions for topical (e.g., transdermal) administration, containing a compound as provided herein and a pharmaceutical excipient suitable for topical administration. In certain embodiments, the present disclosure provides pharmaceutical compositions for topical administration, containing (i) an effective amount of the disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for topical administration. In certain embodiments, the pharmaceutical composition further contains: (iv) an effective amount of a third agent.

[0546] The pharmaceutical compositions provided herein can be formulated into preparations in solid, semi-solid or liquid forms suitable for topical administration, such as gels, hydrogels, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethyl sulfoxide (DMSO)-based solutions. Generally, carriers with higher densities enable longer exposure of the area to the active ingredient. In contrast, solution formulations can provide faster exposure to the selected area.

[0547] The pharmaceutical composition may also include suitable solid or gel phase carriers or excipients that enhance the penetration or assist the delivery of the therapeutic molecule through the stratum corneum permeability barrier of the skin. Many of these penetration enhancing molecules are known to those skilled in the art of topical formulations. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), diols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glyceryl monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0548] Another exemplary formulation for use in the disclosed methods employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a continuous or non - continuous infusion of the compounds provided herein in a controlled amount, in the presence or absence of additional agents.

[0549] The structure and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed to deliver pharmaceutical agents continuously, pulsatilely, or on demand.

[0550] Suitable devices for intradermal delivery of the pharmaceutically acceptable compositions described herein include short needle devices such as those described in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496 and 5,417,662. The intradermal composition can be administered by a device that limits the effective length of the needle insertion into the skin, such as that described in PCT Publication WO 99 / 34850 and its functional equivalents. Jet injection devices that deliver a liquid vaccine to the dermis via a liquid jet injector and / or via a needle that pierces the stratum corneum and creates a jet that reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Pat. Nos. 5,480,381, 5,599,302, 5,334,144, 5,993,412, 5,649,912, 5,569,189, 5,704,911, 5,383,851, 5,893,397, 5,466,220, 5,339,163, 5,312,335, 5,503,627, 5,064,413, 5,520,639, 4,596,556, 4,790,824, 4,941,880, 4,940,460 and PCT Publications WO 97 / 37705 and WO 97 / 13537. Ballistic powder / particle delivery devices that use compressed gas to accelerate a vaccine in powder form through the outer layer of the skin to the dermis are suitable. Optionally or additionally, a conventional syringe can be used for the classical mantoux method of intradermal administration.

[0551] The locally administrable preparation can, for example, contain from about 1% to about 10% (w / w) of the compound provided herein relative to the total weight of the preparation, but the concentration of the compound provided herein in the preparation can be as high as the solubility limit of the compound in the solvent. In certain embodiments, the locally administrable preparation can, for example, contain from about 1% to about 9% (w / w) of the compound provided herein, such as from about 1% to about 8% (w / w), further such as from about 1% to about 7% (w / w), further such as from about 1% to about 6% (w / w), further such as from about 1% to about 5% (w / w), further such as from about 1% to about 4% (w / w), further such as from about 1% to about 3% (w / w) and further such as from about 1% to about 2% (w / w) of the compound provided herein. The preparation for local administration can further contain one or more of the additional pharmaceutically acceptable excipients described herein.

[0552] 5.4.1.4 Preparations for inhalation administration

[0553] In certain embodiments, the present disclosure provides pharmaceutical compositions for inhalation administration, comprising a compound as provided herein and a pharmaceutical excipient suitable for topical administration. In certain embodiments, the present disclosure provides pharmaceutical compositions for enteral inhalation administration, comprising (i) an effective amount of the disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for inhalation administration. In certain embodiments, the pharmaceutical composition further comprises: (iv) an effective amount of a third agent.

[0554] Pharmaceutical compositions for inhalation or insufflation include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid pharmaceutical compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the pharmaceutical composition is administered by the oral or nasal respiratory route for local or systemic effects. Pharmaceutical compositions in pharmaceutically acceptable solvents may be atomized using an inert gas. The atomized composition may be inhaled directly from the atomizing device, or the atomizing device may be connected to a face mask tent or intermittent positive pressure ventilator. Solution, suspension or powder pharmaceutical compositions may be administered orally or nasally, for example, in a suitable manner, from a device for delivering the formulation.

[0555] 5.4.1.5 Preparations for ophthalmic administration

[0556] In certain embodiments, the present invention provides pharmaceutical compositions for treating ophthalmic disorders. The pharmaceutical composition may contain an effective amount of a compound as provided herein and a pharmaceutical excipient suitable for ophthalmic administration. Pharmaceutical compositions suitable for ophthalmic administration may be in discrete dosage forms, such as drops or sprays each containing a predetermined amount of the active ingredient, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions. Other forms of administration include intraocular injection, intravitreal injection, topical or by using a drug irrigation device, microcapsules, implants or microfluidic devices. In some cases, a compound as provided herein is administered together with a carrier or excipient that enhances the intraocular penetration of the compound, such as an oil-in-water emulsion of colloidal particles having an oily core surrounded by an interfacial membrane. All local routes of administration to the eye are contemplated, including topical, subconjunctival, peribulbar, retrobulbar, subtenon, intracameral, intravitreal, intraocular, subretinal, episcleral and suprachoroidal administration. Systemic or parenteral administration is possible, including but not limited to, intravenous, subcutaneous and oral delivery. Exemplary methods of administration will be intravitreal or subconjunctival injection of a solution or suspension, or intravitreal or subconjunctival placement of a bioerodible or non-bioerodible device, or topical ophthalmic administration of a solution or suspension, or posterior episcleral administration of a gel or cream formulation.

[0557] Eye drops can be prepared by dissolving the active ingredient in a sterile aqueous solution (such as physiological saline, buffer solution, etc.), or by combining a powder composition to be dissolved before use. Other solvents can be selected as known in the art, including but not limited to: balanced salt solutions; saline solutions; water-soluble polyethers, such as polyethylene glycol; polyethylenes, such as polyvinyl alcohol and polyvinylpyrrolidone; cellulose derivatives, such as methylcellulose and hydroxypropylmethylcellulose; petroleum derivatives, such as mineral oil and white petrolatum; animal fats, such as lanolin; polymers of acrylic acid, such as carboxypolymethylene gel; vegetable fats, such as peanut oil; and polysaccharides, such as dextran; and glucosaminoglycans, such as sodium hyaluronate. In certain embodiments, additives commonly used in eye drops can be added. Such additives include isotonic agents (e.g., sodium chloride, etc.), buffers (e.g., boric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.), preservatives (e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.), thickeners (e.g., sugars, such as lactose, mannitol, maltose, etc.; e.g., hyaluronic acid or its salts, such as sodium hyaluronate, potassium hyaluronate, etc.; e.g., mucopolysaccharides, such as chondroitin sulfate, etc.; e.g., sodium polyacrylate, carboxyethyl polymer, cross-linked polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose or other reagents known to those skilled in the art).

[0558] In some cases, the colloidal particles comprise at least one cationic reagent and at least one non-ionic surfactant, such as poloxamer, tyloxapol, polysorbate, polyoxyethylene castor oil derivatives, sorbitan esters or polyoxyl stearate. In some cases, the cationic reagent is an alkylamine, a tertiary alkylamine, a quaternary ammonium compound, a cationic lipid, an amino alcohol, a biguanide, a cationic compound or a mixture thereof. In some cases, the cationic reagent is a biguanide, such as chlorhexidine, polyaminopropyl biguanide, phenformin, alkyl biguanide or a mixture thereof. In some cases, the quaternary ammonium compound is benzalkonium halide, lauralkonium halide, cetrimonium bromide, cetyltrimethylammonium halide, myristyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, benzalkoniumhalide, cetalkonium halide, cetethyldimoniumhalide, cetylpyridinium halide, benzododeciniumhalide, chlorallyl methenaminehalide, myristylalkonium halide, stearalkonium halide or a mixture of two or more thereof. In some cases, the cationic reagent is benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethonium chloride, cetyltrimethylammonium bromide, myristyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. In some cases, the oil phase is mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil; hydrogenated oils, including hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives, including polyoxyethylene-40 hydrogenated castor oil, polyoxyethylene-60 hydrogenated castor oil or polyoxyethylene-100 hydrogenated castor oil.

[0559] 5.4.1.6 Formulations for controlled release drug delivery

[0560] In certain embodiments, provided herein are pharmaceutical compositions for controlled release administration, comprising a compound as provided herein and a pharmaceutical excipient suitable for controlled release administration. In certain embodiments, provided herein are pharmaceutical compositions for controlled release administration, comprising: (i) an effective amount of the disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for controlled release administration. In certain embodiments, the pharmaceutical composition further comprises: (iv) an effective amount of a third agent.

[0561] An active agent such as the compound provided herein can be administered by a controlled release means or by a delivery device well known to those of ordinary skill in the art. Examples include but are not limited to those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500, which are hereby incorporated by reference herein. Such dosage forms can use, for example, hydroxypropyl methylcellulose, other polymeric matrices, gels, osmotic membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide sustained or controlled release of one or more active agents to provide a desired release profile in different proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active agents provided herein. Accordingly, the pharmaceutical compositions provided include single unit dosage forms suitable for oral administration, such as, for example, but not limited to, tablets, capsules, caplets, and cachets suitable for controlled release.

[0562] All controlled release pharmaceuticals share a common goal: to improve therapy beyond that achieved by their non-controlled counterparts. In certain embodiments, the use of controlled release formulations in medical therapy is characterized by treating or controlling a disease, disorder, or condition with the least amount of active ingredient in the shortest period of time. Advantages of controlled release formulations include extended drug activity, reduced dosing frequency, and improved patient compliance. In addition, controlled release formulations can be used to affect the onset time or other characteristics, such as the blood level of a drug, and can thus affect the occurrence of side effects (e.g., adverse effects).

[0563] In certain embodiments, a controlled release formulation is designed to initially release a certain amount of a compound as provided herein that rapidly produces the desired therapeutic effect, and to gradually and continuously release additional amounts of the compound to maintain that level of therapeutic or prophylactic effect over an extended period of time. To maintain that constant level of compound in the body, the compound should be released from the dosage form at a rate that will replace the amount of drug that is metabolized and excreted from the body. Controlled release of the active agent can be stimulated by a variety of conditions, including but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0564] In certain embodiments, the pharmaceutical composition can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In one embodiment, a pump can be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used. In still another embodiment, the controlled release system can be placed in a suitable site in the subject determined by one of ordinary skill in the art, i.e., such that only a fraction of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, 115-138 (vol. 2, 1984)). Other controlled release systems are discussed in the review by Langer, Science 249:1527-1533 (1990). One or more active agents can be dispersed within a solid inner matrix such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acids), collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed crosslinked polyvinyl acetate, which is surrounded by an outer polymeric membrane insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyl oxyethanol copolymer. One or more active agents then diffuse through the outer polymeric membrane in a rate controlling step. The percentage of active agent in such parenteral compositions is highly dependent on its specific nature and the needs of the subject.

[0565] 5.4.2 Dosage

[0566] The compounds described herein can be delivered in the form of a pharmaceutically acceptable composition, which comprises a therapeutically effective amount of one or more of the compounds described herein and / or one or more additional therapeutic agents (such as chemotherapeutic agents), formulated together with one or more pharmaceutically acceptable excipients. In some cases, the compounds described herein and the additional therapeutic agents are administered in separate pharmaceutical compositions and can be administered by different routes (e.g., due to different physical and / or chemical properties) (e.g., one therapeutic agent is administered orally and another is administered intravenously). In other instances, the compounds described herein and the additional therapeutic agents can be administered individually, but by the same route (e.g., both orally or intravenously). In still other instances, the compounds described herein and the additional therapeutic agents can be administered in the same pharmaceutical composition.

[0567] The selected dosage level will depend upon a variety of factors including, for example, the activity of the specific compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the art.

[0568] Generally, the suitable daily dose of the compounds and / or chemotherapeutic agents described herein will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect in certain embodiments. Such effective doses will generally depend on the factors described above. Generally, when administered to achieve the displayed effects, the dose of the compounds described herein for a patient will be from about 0.0001 mg to about 100 mg per day, or from about 0.001 mg to about 100 mg per day, or from about 0.01 mg to about 100 mg per day, or from about 0.1 mg to about 100 mg per day, or from about 0.0001 mg to about 500 mg per day, or from about 0.001 mg to about 500 mg per day, or from about 0.01 mg to 1000 mg, or from about 0.01 mg to about 500 mg per day, or from about 0.1 mg to about 500 mg per day, or from about 1 mg to 50 mg per day, or from about 5 mg to 40 mg per day. An exemplary dose is from about 10 to 30 mg per day. In certain embodiments, for a 70 kg person, a suitable dose will be from about 0.05 to about 7 g / day, such as from about 0.05 to about 2.5 g / day. The actual dose level of the active ingredient in the pharmaceutical compositions described herein can be varied to obtain an amount of the active ingredient that effectively achieves the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient. In some cases, dose levels below the lower limit of the foregoing ranges are sufficient, while in other cases larger doses can be employed without causing any harmful side effects, e.g., by dividing the larger dose into several smaller doses to be administered throughout the day.

[0569] In certain embodiments, the daily dose range of the compounds described herein can be from about 0.0001 mg / kg to about 1000 mg / kg, from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 1000 mg / kg, from about 0.1 mg / kg to about 1000 mg / kg, from about 0.0001 mg / kg to about 500 mg / kg, from about 0.001 mg / kg to about 500 mg / kg, from about 0.01 mg / kg to 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.1 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to 50 mg / kg, from about 0.05 mg / kg to 20 mg / kg or from about 0.05 mg / kg to 10 mg / kg. For example, the daily dose can be about 10 mg / kg, 5 mg / kg, 1.5 mg / kg, 0.5 mg / kg, 0.15 mg / kg or about 0.05 mg / kg. For example, the daily dose can be about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg or about 10 mg / kg.

[0570] In certain embodiments, the compound can be administered once daily, every other day, three times a week, twice a week, once a week or once every two weeks. The dosing regimen can include a "drug holiday", for example, the drug can be administered as follows: administered for two weeks and then discontinued for one week; or administered for three weeks and then discontinued for one week; or administered for four weeks and then discontinued for one week, etc.; or administered continuously without a drug holiday. The compound can be administered orally, intravenously, intraperitoneally, topically, transdermally, intramuscularly, subcutaneously, intranasally, sublingually or by any other route.

[0571] In certain embodiments, the compounds provided herein are administered in multiple doses. The administration can be about once, twice, three times, four times, five times, six times or more than six times per day. The administration can be about once a month, about once every two weeks, about once a week or about once every other day. In another embodiment, the compounds provided herein and additional agents are administered together about once to about 6 times per day. In another embodiment, the administration of the compounds and agents provided herein lasts less than about 7 days. In still another embodiment, the administration lasts more than about 6 days, about 10 days, about 14 days, about 28 days, about two months, about six months or about one year. In some cases, continuous administration is achieved and maintained for the duration as needed.

[0572] Administration of the pharmaceutical compositions provided herein can be for a duration as needed. In certain embodiments, the agent provided herein is administered for more than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 14, or about 28 days. In certain embodiments, the agent provided herein is administered for less than about 28, about 14, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 day. In certain embodiments, the agent provided herein is administered for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 14, about 21, or about 28 days. In certain embodiments, the agent provided herein is administered chronically and continuously, for example, for treating chronic conditions.

[0573] Since the compounds described herein can be administered in combination with other treatments (such as additional chemical agents, radiation, or surgery), the dosage of each agent or therapy can be lower than the corresponding dosage of a single-agent therapy. The dosage of a single-agent therapy can be, for example, from about 0.0001 to about 200 mg per kilogram of body weight per day, or from about 0.001 to about 100 mg, or from about 0.01 to about 100 mg, or from about 0.1 to about 100 mg, or from about 1 to about 50 mg.

[0574] When the compounds provided herein are administered in a pharmaceutical composition comprising one or more agents, and the agent has a shorter half-life than the compounds provided herein, the unit dosage forms of the agent and the compounds provided herein can be adjusted accordingly.

[0575] 5.4.3 Kits

[0576] In certain embodiments, kits are provided herein. The kits can include the compounds or pharmaceutical compositions described herein in a suitable package, and written materials that can include instructions for use, clinical study discussions, lists of side effects, etc. Such kits can also include information, such as scientific literature reference materials, package insert materials, clinical trial results, and / or summaries of such information, that indicate or establish the activity and / or advantages of the pharmaceutical composition, and / or describe administration, dosing, side effects, drug interactions, or other information useful to a healthcare provider. Such information can be based on the results of various studies, for example, studies involving the use of in vivo models in experimental animals and studies based on human clinical trials.

[0577] In certain embodiments, a memory aid is provided to the kit, for example, in the form of numbers adjacent to tablets or capsules, such that the numbers correspond to the number of days of a course of treatment during which the designated tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, for example, as follows: "First week, Monday, Tuesday... etc... Second week, Monday, Tuesday", etc. Other variations of the memory aid will be apparent. The "daily dose" can be a single tablet or capsule or several tablets or capsules taken on a given date.

[0578] The kit may further contain additional agents. In certain embodiments, the compounds and agents provided herein are provided in separate containers in the kit as separate pharmaceutical compositions. In certain embodiments, the compounds and agents provided herein are provided in a container within the kit as a single pharmaceutical composition. Suitable packaging and additional articles for use (e.g., measuring cups for liquid formulations, foil packaging that minimizes exposure to air, etc.) are known in the art and may be included in the kit. In other embodiments, the kit may further include means for administering the active agent. Examples of such means include, but are not limited to, syringes, drip bags, patches, and inhalers. The kits described herein may be provided, sold, and / or promoted to health care providers (including physicians, nurses, pharmacists, formulators, etc.). In certain embodiments, the kits may also be sold directly to consumers.

[0579] An example of such a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). A blister pack generally consists of a relatively rigid sheet of material covered with a preferably transparent plastic material. During the packaging process, depressions are formed in the plastic foil. The depressions have the size and shape of the tablets or capsules to be packaged. Then, the tablets or capsules are placed in the depressions, and the relatively rigid sheet of material is sealed to the plastic foil at the foil side opposite to the side where the depressions are formed. Thus, the tablets or capsules are sealed in the depressions between the plastic foil and the sheet. The strength of the sheet allows the tablets or capsules to be removed from the blister pack by manually applying pressure on the depression, thereby forming an opening in the sheet at the depression. The tablets or capsules can then be removed via the opening.

[0580] The kit may further include a pharmaceutically acceptable solvent, which can be used to administer one or more active agents. For example, if the active agent is provided in a solid form that must be reconstituted for parenteral administration, the kit may include a sealed container of a suitable solvent in which the active agent can be dissolved to form a particulate-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable solvents include, but are not limited to: Water for Injection USP; aqueous solvents such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible solvents such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous solvents such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0581] The present disclosure further includes anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can promote the degradation of some compounds. For example, in the pharmaceutical art, water (e.g., about 5%) can be added as a means of simulating long-term storage to determine the characteristics of a formulation over time, such as shelf life or stability. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. For example, if significant exposure to moisture and / or humidity is anticipated during preparation, packaging, and / or storage, pharmaceutical compositions and dosage forms containing lactose can be made anhydrous. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Accordingly, anhydrous pharmaceutical compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0582] 5.5. Methods of Treatment

[0583] Provided herein is a method of treating a PI3K-mediated disorder in a subject, comprising administering to the subject a therapeutically effective amount of the solid form provided herein or the pharmaceutical composition provided herein. In one embodiment, the PI3K-mediated disorder is cancer, an inflammatory disease, or an autoimmune disease. In one embodiment, the cancer is a solid tumor.

[0584] Phosphoinositide 3-kinase (PI3K) is a member of a conserved family of lipid kinases that regulate multiple cellular functions, including proliferation, differentiation, cell survival, and metabolism. Several classes of PI3K exist in mammalian cells, including class IA subgroups (e.g., PI3K-α, β, δ), which are typically activated by receptor tyrosine kinases (RTKs); class IB (e.g., PI3K-γ), which is activated by G-protein-coupled receptors (GPCRs), etc. PI3K exerts its biological activity via the "PI3K-mediated signal transduction pathway," which includes several components that directly and / or indirectly transduce signals triggered by PI3K, including the generation of the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the plasma membrane, activation of heterotrimeric G-protein signaling, and generation of additional second messengers (such as cAMP, DAG, and IP3), all of which lead to a broad cascade of protein kinase activation (reviewed in Vanhaesebroeck, B. et al. (2001) Annu Rev Biochem. 70:535-602). For example, PI3K-δ is activated by cell receptors through interactions between the SH2 domains of the PI3K regulatory subunit (p85) or through direct interactions with RAS. The PIP3 produced by PI3K activates downstream effector pathways by interacting with enzymes containing a pleckstrin homology (PH) domain (e.g., PDK-1 and AKT [PKB]) (Fung-Leung WP. (2011) Cell Signal. 23(4):603-8). Unlike PI3K-δ, PI3K-γ is not related to the regulatory subunits of the p85 family but is related to regulatory subunits in the p101 or p84 families. PI3K-γ is associated with GPCRs and can very rapidly induce PIP3. PI3K-γ can also be activated by RAS.

[0585] In certain embodiments, provided herein are methods of modulating (e.g., selectively modulating) PI3 kinase activity by contacting a kinase with an effective amount of a compound as provided herein or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, isomer, prodrug, and isotopically labeled derivative) or a pharmaceutical composition as provided herein. The modulation can be inhibition (e.g., reduction) or activation (e.g., enhancement) of kinase activity. In certain embodiments, provided herein are methods of inhibiting kinase activity by contacting a kinase with an effective amount of a compound as provided herein in solution. In certain embodiments, provided herein are methods of inhibiting kinase activity by contacting a cell, tissue, or organ expressing the relevant kinase with a compound as provided herein. In certain embodiments, provided herein are methods of inhibiting kinase activity in a subject by administering to the subject an effective amount of a compound as provided herein or a pharmaceutically acceptable form thereof. In certain embodiments, the kinase activity when contacted with a compound as provided herein is inhibited (e.g., reduced) by greater than about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the kinase activity without such contact. In certain embodiments, provided herein are methods of inhibiting PI3 kinase activity in a subject (including a mammal, such as a human) by contacting the subject with an amount of a compound as provided herein sufficient to inhibit or reduce the PI3 kinase activity of the subject.

[0586] In certain embodiments, the kinase is a lipid kinase or a protein kinase. In certain embodiments, the kinase is selected from PI3 kinases, including different subtypes such as PI3 kinase α, PI3 kinase β, PI3 kinase γ, PI3 kinase δ; DNA-PK; TOR; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEK receptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3); platelet-derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src; epidermal growth factor receptor (EGFR); KIT; insulin receptor (IR); and IGFR.

[0587] As used herein, "PI3K-mediated disorder" refers to a disease or disorder involving an abnormal PI3K-mediated signaling pathway. In one embodiment, the present disclosure provides methods of treating a PI3K-mediated disorder in a subject, the methods comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable form thereof as provided herein, or a pharmaceutical composition as provided herein. In certain embodiments, the present disclosure provides methods of treating a PI3K-δ or PI3K-γ-mediated disorder in a subject, the methods comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable form thereof as provided herein, or a pharmaceutical composition as provided herein. In certain embodiments, the present disclosure provides methods of inhibiting at least one of PI3K-δ and PI3K-γ, the methods comprising contacting a cell expressing PI3K with an effective amount of a compound or composition provided herein, either in vitro or in vivo. PI3K is associated with a variety of disorders, including immune diseases, cancer, and thrombosis (reviewed in Vanhaesebroeck, B. et al. (2010) Current Topics in Microbiology and Immunology, DOI 10.1007 / 82_2010_65). For example, class I PI3Ks, particularly the PI3K-γ and PI3K-δ isoforms, are highly expressed in leukocytes and are associated with adaptive and innate immunity; thus, these PI3Ks are considered to be important mediators in inflammatory disorders and hematological malignancies (reviewed in Harris, SJ et al. (2009) Curr Opin Investig Drugs 10(11):1151-62); Rommel C. et al. (2007) Nat Rev Immunol 7(3):191-201; Durand CA et al. (2009) J Immunol. 183(9):5673-84; Dil N, Marshall AJ. (2009) Mol Immunol. 46(10):1970-8; Al-Alwan MM et al. (2007) J Immunol. 178(4):2328-35; Zhang TT, et al. (2008) J Allergy Clin Immunol. 2008;122(4):811-819.e2; Srinivasan L, et al. (2009) Cell 139(3):573-86).

[0588] PI3K-γ activity

[0589] PI3K-γ is a class IB PI3K associated with the p101 and p84 (p87PIKAP) adaptor proteins and signals canonically through GPCRs. Non-canonical activation through tyrosine kinase receptors and RAS can occur. Activated PI3K-γ leads to the production of PIP3, which serves as a docking site for downstream effector proteins including AKT and BTK, bringing these enzymes to the cell membrane where they can be activated. A scaffolding role for PI3K-γ has been proposed and it may contribute to the activation of the RAS / MEK / ERK pathway. Interaction with the RAS pathway explains the lethality of kinase-dead PI3K-γ in cells or animals. PI3K-γ is essential for the function of various immune cells and pathways. Chemotactic responses (including IL-8, fMLP, and C5a) that lead to neutrophil, basophil, or monocyte migration are dependent on PI3K-γ (HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation,” Science 287:1049-1053 (2000); SASAKI et al., “Function of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration,” Science 287:1040-1046 (2000); LI et al., “Roles of PLC-β2 and –β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction,” Science 287:1046-1049 (2000)). The failure of arthritis development in the K / BXN serum transfer arthritis model in PI3K-γ knockout mice demonstrated the requirement for PI3K-γ-dependent neutrophil migration (Randis et al., Eur. J. Immunol., 2008, 38(5), 1215–24). Similarly, mice failed to develop cellular inflammation and airway hyperreactivity in an ovalbumin-induced asthma model (Takeda et al., J. Allergy Clin. Immunol., 2009; 123, 805-12). PI3K-γ-deficient mice may also have defects in T-helper cell function. Responsive activated T-cell cytokine production and proliferation are reduced, and T helper cell-dependent viral clearance is defective (Sasaki et al., Science, 2000, 287, 1040-46).T cell-dependent inflammatory disease models, including EAE, also do not develop in PI3K-γ-deficient mice, and defects in T-cell activation and cell migration can contribute to efficacy in this model (Comerfold, PLOS One, 2012, 7, e45095). The imiquimod psoriasis model has also been used to demonstrate the importance of PI3K-γ in the inflammatory response. In this model, the use of PI3K-γ-deficient mice blocked the accumulation of γδ T cells in the skin, as well as dendritic cell maturation and migration (ROLLER et al., “Blockade ofPhosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ Reduces IL-17 and AmelioratesImiquimod-Induced Psoriasis-like Dermatitis,” J. Immunol. 189:4612-4620 (2012)). The role of PI3K-γ in cell trafficking can also be demonstrated in oncology models, where tumor inflammation is important for cancer growth and metastasis. In the Lewis lung cancer model, monocyte activation, migration, and differentiation in the tumor are defective. This defect results in reduced tumor growth and extended survival in PI3K-γ-deficient mice (Schmid et al., Cancer Cell, 2011, 19, 715-27) or reduced tumor growth and extended survival in PI3K-γ-deficient mice when treated with an inhibitor targeting PI3K-γ. In pancreatic cancer, PI3K-γ can be inappropriately expressed, and in this solid tumor cancer or other cancers in which PI3K-γ plays a functional role, inhibition of PI3K-γ can be beneficial.

[0590] For example, although not wishing to be bound by theory, PI3K-γ is expressed in Gr1+CD11b+ myeloid cells and directly promotes myeloid cell invasion and thus immunosuppression in pancreatic ductal carcinoma. Hardamon et.al., Proceedings: AACR 103rd Annual Meeting 2012, Cancer Research: April 15, 2012; Vol. 72, No. 8, Supplement 1. Inhibition of PI3K-γ also shows promise in treating hematological malignancies. In a T-ALL model with T cell-directed knockout of pten, both PI3K-δ and PI3K-γ are necessary for the proper development of the disease, as shown by gene deletion of both genes (Subramaniam et al. Cancer Cell 21, 459–472, 2012). Additionally, in this TALL model, treatment of both kinases with a small molecule inhibitor led to extended survival of these mice. In CLL, the chemokine network supports a pseudo-follicular microenvironment including nurse-like cells, stromal cells, and T-helper cells. The role of PI3K-γ in normal chemokine signaling and T cell biology suggests the value of inhibiting this target in CLL (BURGER, “Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr. Mematol. Malig. Rep. 7:26-33 (2012)). Thus, PI3K-γ inhibitors are of therapeutic interest for diseases of the immune system important for cell trafficking and T cell or myeloid cell function. In oncology, solid tumors dependent on tumor inflammation or tumors with high levels of PI3K-γ expression can be targeted. For blood cancers, the specific roles of the PI3K-γ and PI3K-δ isoforms in TALL and potentially in CLL suggest targeting these PI3Ks in these diseases.

[0591] Without being bound by a particular theory, PI3K-γ has been shown to play a role in, for example, inflammation, arthritis, asthma, allergy, multiple sclerosis (MS), and cancer (e.g., Ruckle et al., Nature Rev., Drug Discovery, 2006, 5, 903–18; Schmid et al., “Myeloid cells in tumor inflammation,” Vascular Cell, 2012, doi:10.1186 / 2045-824X-4-14). For example, PI3K-γ function is involved in leukocyte activation and migration in multiple signaling pathways. PI3K-γ has been shown to drive the priming and survival of autoreactive CD4+ T cells during the model of MS - experimental autoimmune encephalomyelitis (EAE). When administered starting at the onset of EAE, PI3K-γ inhibitors have been shown to result in the suppression and reversal of clinical disease, and a reduction in demyelination and cellular pathology in the CNS (Comerford et al., PLOS One, 2012, 7, e45095). PI3K-γ also regulates thymocyte development, T cell activation, neutrophil migration, and oxidative burst (Sasaki et al., Science, 2000, 287, 1040–46). Additionally, allergic airway hyperreactivity, inflammation, and remodeling have not been formed in PI3K-γ-deficient mice (Takeda et al., J. Allergy Clin. Immunol., 2009; 123, 805–12). PI3K-γ has been shown to be required for chemoattractant-induced production of phosphatidylinositol 3,4,5-trisphosphate and has an important role in chemoattractant-induced superoxide production and chemotaxis in murine neutrophils and in the production of T cell-independent antigen-specific antibodies composed of immunoglobulin λ light chains (Li et al., Science, 2000, 287, 1046–49). PI3K-γ has been reported as a key signaling molecule required for macrophage accumulation in inflammation (Hirsch et al., Science, 2000, 287, 1049–53). In cancer, pharmacological or genetic blockade of p110γ inhibits the inflammation, growth, and metastasis of transplanted and spontaneous tumors, indicating that PI3K-γ can be an important therapeutic agent in oncology (Schmid et al., Cancer Cell, 2011, 19, 715–27). For example, PI3K-γ has been shown to have tumor-specific high accumulation in human pancreatic ductal adenocarcinoma (PDAC), indicating the role of PI3K-γ in pancreatic cancer (Edling et al., Human Cancer Biology, 2010, 16(2), 4928–37).

[0592] In certain embodiments, provided herein are methods of treating or preventing PI3K-γ-mediated disorders in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a selective PI3K-γ inhibitor, such as Compound 1 or a pharmaceutically acceptable form thereof.

[0593] In one embodiment, the subject has or is at risk of having a PI3K-γ-mediated disorder selected from cancer, an inflammatory disease, or an autoimmune disease. In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is selected from one or more of the following: lung cancer, brain cancer, gastrointestinal cancer, skin cancer, urinary tract cancer, pancreatic cancer, lung cancer, medulloblastoma, basal cell carcinoma, glioma, breast cancer, prostate cancer, testicular cancer, esophageal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, ovarian cancer, melanoma, neuroectodermal tumor, head and neck cancer, sarcoma, soft tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, leiomyosarcoma, cervical cancer, uterine cancer, endometrial cancer, carcinoma, bladder cancer, epithelial cancer, squamous cell carcinoma, adenocarcinoma, bronchial carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, neuroendocrine carcinoma, carcinoid tumor, diffuse giant cell tumor, and glioblastoma multiforme.

[0594] In one embodiment, the cancer is a hematological cancer.

[0595] In one embodiment, the inflammatory disease is arthritis.

[0596] In one embodiment, the subject is human. In one embodiment, the subject is determined to have or be at risk of having a PI3K-γ-mediated disorder by using a biomarker.

[0597] In one embodiment, the therapeutically effective dose is about 2 mg, about 1 - 3 mg, about 1 - 5 mg, about 1 - 10 mg, about 0.5 - 20 mg, about 0.1 - 50 mg / day, about 0.1 - 75 mg / day, about 0.1 - 100 mg / day, about 0.1 - 250 mg / day, about 0.1 - 500 mg / day, about 0.1 - 1000 mg / day, about 1 - 50 mg / day, about 1 - 75 mg / day, about 1 - 100 mg / day, about 1 - 250 mg / day, about 1 - 500 mg / day, about 1 - 1000 mg / day, about 10 - 50 mg / day, about 10 - 75 mg / day, about 10 - 100 mg / day, about 10 - 250 mg / day, about 10 - 500 mg / day, about 10 - 1000 mg / day, about 100 - 500 mg / day or about 100 - 1000 mg / day. In one embodiment, the therapeutically effective dose is about 0.029 mg / kg, about 0.014 - 0.14 mg / kg, about 0.02 - 0.04 mg / kg, about 0.01 - 0.05 mg / kg, about 0.01 - 0.1 or about 0.01 - 0.5 mg / kg. In one embodiment, the compound is administered once every two days. In one embodiment, the compound is administered once a day. In one embodiment, the compound is administered twice a day.

[0598] In one embodiment, the compound is administered at a dose such that, during at least 70%, 80%, 90%, 95%, 97%, 98% or 99% of a selected time period, e.g., 6 hours, 12 hours, 24 hours or 48 hours immediately following administration, the level of the compound in the subject is higher than the IC of the PI3K-γ inhibition of the compound 50 . In one embodiment, the compound is administered at a dose such that, during at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98% or 99% of a selected time period, e.g., 6 hours, 12 hours, 24 hours or 48 hours immediately following administration, the level of the compound in the subject is higher than the IC of the PI3K-γ inhibition of the compound 90 . In one embodiment, the compound is administered at a dose such that, within a selected time period, e.g., 6 hours, 12 hours, 24 hours or 48 hours immediately following administration, the level of the compound in the subject does not increase to be higher than the IC of the PI3K-δ inhibition of the compound 20 or IC 50。In one embodiment, the level of the compound is measured from the plasma of the subject. In one embodiment, the level of the compound is measured from the tissue of the subject. In one embodiment, the compound is administered at a dose such that the compound provides at least 50% PI3K-γ inhibition in the subject but less than 10% or 20% PI3K-δ inhibition in the subject.

[0599] In one embodiment, the subject is human and the compound has a half-life of about 10 - 13 hours in the subject. In one embodiment, the method further comprises administering to the subject a second therapeutic agent, which is a P-gp substrate. In one embodiment, the second therapeutic agent is Norvir (ritonavir).

[0600] PI3K-δ and / or PI3K-γ activity

[0601] PI3K-δ has a role in B cell signal transduction and formation impairment, antibody production, T cell function, Th1 and Th2 differentiation, and mast cell and basophil degranulation. Without being bound by a particular theory, PI3K-γ has a role in T-cell function, neutrophil and macrophage recruitment, macrophage activation, neutrophil oxidative burst, and dendritic cell migration. Inhibition of the PI3K-δ and / or PI3K-γ isoforms can result in efficacy against inflammation and cancer, for example, in arthritis, asthma, multiple sclerosis (MS), and tumor models.

[0602] For example, deficiency of PI3K-δ and / or PI3K-γ can result in efficacy in the K / BxN arthritis model (Kyburz et al., Springer Semin. Immunopathology, 2003, 25, 79–90) or the K / BxN serum transfer model of arthritis (Randis et al., Eur. J. Immunol., 2008, 38(5), 1215–24), where it is shown that recognition of immune complexes depends on both PI3K-δ and PI3K-γ, while cell migration depends on PI3K-γ. Deficiency of PI3K-δ or PI3K-γ can also result in efficacy in murine ovalbumin (OVA)-induced allergic asthma models (Lee et al., FASEB J., 2006, 20, 455–65; Takeda et al., J. Allergy Clin. Immunol., 2009; 123, 805–12), where it is shown that inhibition of either PI3K-δ or PI3K-γ can inhibit ovalbumin-induced lung infiltration and improve airway reactivity. Deficiency of PI3K-δ or PI3K-γ can also result in efficacy in murine experimental autoimmune encephalomyelitis (a model of MS), where it is shown that PI3K-γ deficiency can provide better efficacy compared to PI3K-δ deficiency (Haylock-Jacob et al., J. Autoimmunity, 2011, 36, 278–87; Comerford et al., PLOS One, 2012, 7, e45095), including reduced T-cell receptor-induced CD4+ T cell activation, leukocyte infiltration, and Th1 / Th17 responses, and dendritic cell migration (Comerfold, PLOS One, 2012, 7, e45095). Further, inhibition of PI3K-γ can result in reduced tumor inflammation and growth (e.g., Lewis lung carcinoma model, Schmid et al., Cancer Cell, 2011, 19(6), 715–27). PI3K-γ deficiency in combination with PI3K-δ deficiency results in improved survival in T cell acute lymphoblastic leukemia (T-ALL) (Subramaniam et al., Cancer Cell, 2012, 21, 459-72). Inhibitors of both PI3K-δ and PI3K-γ also show efficacy in PTEN-deficient T-ALL cell lines (MOLT-4). In the absence of the PTEN phosphatase tumor suppressor function, either PI3K-δ or PI3K-γ alone can support leukemogenesis, while activation of both subtypes inhibits tumor formation.Thus, inhibitors of PI3K-δ and / or PI3K-γ are useful in treating inflammation, such as arthritis, allergic asthma, and MS; and, for example, are useful in treating cancer due to effects such as reduction of inflammation associated with solid tumors, angiogenesis, and tumor progression.

[0603] The importance of PI3K-δ in B cell development and function is supported by inhibitor studies and genetic models. PI3K-δ is an important mediator of B cell receptor (BCR) signal transduction and is upstream of the activation of AKT, calcium flux, PLCγ, MAP kinases, P70S6k, and FOXO3a. PI3K-δ is also important in IL4R, S1P, and CXCR5 signal transduction and has been shown to regulate responses to toll-like receptors 4 and 9. Inhibitors of PI3K-δ have shown the importance of PI3K-δ in B cell development (marginal zone and B1 cells), B cell activation, chemotaxis, migration, and homing to lymphoid tissues, as well as the control of immunoglobulin class switching leading to the production of IgE. Clayton E et al. (2002) J Exp Med. 196(6):753-63; Bilancio A, et al. (2006) Blood 107(2):642-50; Okkenhaug K. et al. (2002) Science 297(5583):1031-4; Al-Alwan MM et al. (2007) J Immunol. 178(4):2328-35; Zhang TT, et al. (2008) J Allergy Clin Immunol. 2008;122(4):811-819.e2; Srinivasan L, et al. (2009) Cell 139(3):573-86).

[0604] In T cells, PI3K-δ has been shown to have a role in T cell receptor and cytokine signal transduction and is upstream of AKT, PLCγ, and GSK3b. In PI3K-δ-deficient or kinase-inactive knock-in mice or in inhibitor studies, T cell defects including proliferation, activation, and differentiation have been observed, resulting in reduced T helper cell 2 (TH2) responses, memory T cell-specific defects (reduced DTH), defects in antigen-dependent cell trafficking, and chemotaxis / migration to chemokines (e.g., S1P, CCR7, CD62L). ( F. et al. (2008) Blood 111(3):1464-71; Okkenhaug K et al. (2006). J Immunol. 177(8):5122-8; Soond DR, et al. (2010) Blood 115(11):2203-13; Reif K, (2004). J Immunol. 2004; 173(4):2236-40; Ji H. et al. (2007) Blood 110(8):2940-7; Webb LM, et al. (2005) J Immunol. 175(5):2783-7; Liu D, et al. (2010) J Immunol. 184(6):3098-105; Haylock-Jacobs S, et al. (2011) J Autoimmun. 2011; 36(3-4):278-87; Jarmin SJ, et al. (2008) J Clin Invest. 118(3):1154-64).

[0605] A number of publications support the role of PI3K-δ and PI3K-γ in the differentiation, maintenance, and activation of immune and malignant cells, as described in more detail herein.

[0606] The PI3K-δ and PI3K-γ isoforms are preferably expressed in white blood cells, where they have distinct and non-overlapping roles in immune cell formation and function. See, for example, PURI and GOLD, “Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory disease and B-cell malignancies,” Front. Immunol. 3:256 (2012); BUITENHUIS et al., “The role of the PI3K-PKB signaling module in regulation of hematopoiesis,” Cell Cycle 8(4):560-566 (2009); HOELLENRIEGEL and BURGER, “Phosphoinositide 3'-kinase delta: turning off BCR signaling in Chronic Lymphocytic Leukemia,” Oncotarget 2(10):737-738 (2011); HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation,” Science 287:1049-1053 (2000); LI et al., “Roles of PLC-β2 and –β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction,” Science 287:1046-1049 (2000); SASAKI et al., “Function of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration,” Science 287:1040-1046 (2000); CUSHING et al., “PI3Kδ and PI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med. Chem.55:8559-8581(2012); MAXWELL et al., "Attenuation of phosphoinositide 3-kinase δ signaling restrains autoimmune disease," J. Autoimmun. 38:381-391(2012); HAYLOCK-JACOBS et al., "PI3Kδ drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation," J. Autoimmun. 36:278-287(2011); SOOND et al., "PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans," Blood 115(11):2203-2213(2010); ROLLER et al., "Blockade of Phosphatidylinositol 3-Kinase(PI3K)δ or PI3Kγ Reduces IL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis," J. Immunol. 189:4612-4620(2012); CAMPS et al., "Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis," Nat. Med.11(9):936-943(2005). As key enzymes in leukocyte signal transduction, PI3K-δ and PI3K-γ promote normal B-cell, T-cell, and myeloid cell functions, including differentiation, activation, and migration. See, for example, HOELLENRIEGEL and BURGER, “Phosphoinositide 3'-kinase delta: turning off BCR signaling in Chronic Lymphocytic Leukemia,” Oncotarget 2(10):737-738(2011); CUSHING et al., “PI3Kδ and PI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med. Chem. 55:8559-8581(2012). PI3K-δ or PI3K-γ activity is critical for preclinical models of autoimmune and inflammatory diseases. See, for example, HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation,” Science 287:1049-1053(2000); LI et al., “Roles of PLC-β2 and –β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction,” Science 287:1046-1049(2000); SASAKI et al., “Function of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration,” Science 287:1040-1046(2000); CUSHING et al., “PI3Kδ and PI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med. Chem. 55:8559-8581(2012); MAXWELL et al., “Attenuation of phosphoinositide 3-kinase δ signaling restrains autoimmune disease,” J. Autoimmun.38:381-391(2012); Haylock-Jacobs et al., "PI3Kδ drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation," J. Autoimmun. 36:278-287(2011); Soond et al., "PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans," Blood 115(11):2203-2213(2010); Roller et al., "Blockade of Phosphatidylinositol 3-Kinase (PI3K) δ or PI3Kγ Reduces IL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis," J. Immunol. 189:4612-4620(2012); Camps et al., "Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis," Nat. Med.11(9):936-943(2005). Considering the crucial roles of PI3K-δ and PI3K-γ in immune function, inhibitors of PI3K-δ and / or γ have therapeutic potential in immune-related inflammatory or neoplastic diseases. PI3K-δ and PI3K-γ are important for the growth and survival of B- and T-cell malignancies, and inhibition of these isoforms can effectively limit these diseases. See, e.g., SUBRAMANIAM et al., “Targeting Nonclassical Oncogenes for Therapy in T-ALL,” Cancer Cell 21:459-472(2012); LANNUTTI et al., “CAL-101 a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability,” Blood 117(2):591-594(2011). PI3K-δ and PI3K-γ support the growth and survival of certain B-cell malignancies by mediating intracellular BCR signal transduction and the interaction between tumor cells and their microenvironment. See, e.g., PURI and GOLD, “Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory disease and B-cell malignancies,” Front. Immunol. 3:256(2012); HOELLENRIEGEL et al., “The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia,” Blood 118(13):3603-3612(2011); BURGER, “Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr. Mematol. Malig.Rep.7:26-33(2012). Enhanced BCR signal transduction is an important pathological mechanism of B-cell malignancies, and PI3K activation is a direct consequence of BCR pathway activation. See, e.g., BURGER, “Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr. Mematol. Malig. Rep. 7:26-33(2012); HERISHANU et al., “The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia,” Blood 117(2):563-574(2011); DAVIS et al., “Chronic active B-cell-receptor signaling in diffuse large B-cell lymphoma,” Nature 463:88-92(2010); PIGHI et al., “Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling,” Cell Oncol. (Dordr) 34(2):141-153(2011); RIZZATTI et al., “Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFβ signaling pathways,” Brit. J. Haematol. 130:516-526(2005); MARTINEZ et al., “The Molecular Signature of Mantle Cell Lymphoma Reveals Multiple Signals Favoring Cell Survival,” Cancer Res.63:8226-8232(2003). Interactions between malignant B-cells and supportive cells (e.g., stromal cells, nurse-like cells) in the tumor microenvironment are important for tumor cell survival, proliferation, homing, and tissue rete...

Claims

1. A method for preparing a compound of formula (I): or a salt thereof, comprising coupling a compound C of the following formula: with a carboxylic acid of formula G: to form a compound of formula (I), wherein said compound C is obtained by coupling a compound A of the following formula: with an alkyne of formula E: prepared wherein the coupling between said compound A and the alkyne of formula E occurs in the presence of a catalyst, a ligand, or a catalyst / ligand complex; a base; and a solvent, wherein the catalyst, the catalyst in the catalyst / ligand complex, or the catalyst / ligand complex is Pd-G3, Pd2(dba)3, PdCl2(MeCN)2, Pd(OAc)2, Pd(PPh3)4, or PdCl2(PPh3)2, and the loading of the catalyst is about 0.5% to about 10%, and the loading of the ligand is about 0.5% to about 20%.

2. The method of claim 1, wherein the coupling between said compound C and the carboxylic acid of formula G occurs in the presence of a coupling agent.

3. The method of claim 2, wherein the coupling agent is a carbodiimide, a triazine, a phosphonium, a uronium, or a mixed anhydride, or a mixture thereof.

4. The method of claim 2, wherein the coupling agent is N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, 2-propane phosphonic anhydride, 1-[(dimethylamino)(morpholino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxo-ethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, diethyl cyanophosphonate, diethyl chlorophosphate, diphenylphosphoryl azide, bis(2-oxazolidinyl)phosphinic chloride, chlorodimethoxytriazine or its N-methylmorpholinium adduct, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one, bromotris(dimethylamino)phosphonium hexafluorophosphate), (EtO)2P(O)-Cl, (EtO)2P(O)-Oxyma, pivaloyl chloride, isobutyl chloroformate, 2-chloro-4,6-dimethoxy-1,3,5-triazine or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or its BF4 analogue or a mixture thereof.

5. The method of claim 4, wherein the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

6. The method of claim 4, wherein the coupling agent is 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride.

7. The method of claim 1, wherein the coupling between the compound C and the carboxylic acid of formula G occurs in the presence of an activator.

8. The method of claim 7, wherein the activator is hydroxybenzotriazole, HBTriazinone, ethyl 2-cyano-2-(hydroxyimino)acetate, NHS, or potassium (hydroxyimino)cyanoacetate.

9. The method of claim 8, wherein the activator is hydroxybenzotriazole.

10. The method of claim 1, wherein the coupling between the compound C and the carboxylic acid of formula G occurs in the presence of a base.

11. The method of claim 10, wherein the base is Et3N, DIPEA, pyridine, NMM, DBU, NaOH or DMAP.

12. The method of claim 1, wherein the coupling between the compound C and the carboxylic acid of formula G occurs in the presence of the solvent DMF, NMP, acetonitrile, EtOH, acetone, DCM, MeOH or water, or a mixture thereof.

13. A method for preparing a compound of formula (I): or a salt thereof, comprising coupling a compound C of the following formula: ester of formula D∶ forms a compound of formula (I), wherein the compound C is obtained by coupling a compound A of the following formula: with an alkyne of formula E: prepared, wherein the coupling between the compound A and the alkyne of formula E occurs in the presence of a catalyst, a ligand or a catalyst / ligand complex; a base; and a solvent, wherein the catalyst, the catalyst in the catalyst / ligand complex, or the catalyst / ligand complex is Pd-G3, Pd2(dba)3, PdCl2(MeCN)2, Pd(OAc)2, Pd(PPh3)4 or PdCl2(PPh3)2, and the loading of the catalyst is about 0.5% to about 10%, and the loading of the ligand is about 0.5% to about 20%.

14. The method of claim 13, wherein the coupling between the compound C and the ester of formula D occurs in the presence of a base and a solvent.

15. The method of claim 14, wherein the base is an amine.

16. The method of claim 15, wherein the amine is N,N-diisopropylethylamine.

17. The method of claim 14, wherein the solvent is an organic solvent.

18. The method of claim 17, wherein the organic solvent is acetonitrile.

19. The method of claim 17, wherein the organic solvent is a mixture of DCM and ethanol.

20. The method of claim 13, wherein the coupling between the compound C and the ester of formula D occurs at a temperature of about 30 °C to about 80 °C, about 40 °C to about 70 °C, or about 55 °C to about 65 °C.

21. The method of claim 20, wherein the temperature is about 60 °C.

22. The method of claim 13, wherein the ester of formula D is prepared by a method comprising coupling a carboxylic acid of formula G with N-succinimide.

23. The method according to any one of claims 1-22, wherein the catalyst is PdCl2(MeCN)2.

24. The method according to any one of claims 1-22, wherein the catalyst is Pd2(dba)3.

25. The method according to any one of claims 1-22, wherein the catalyst is Pd(OAc)2.

26. The method according to any one of claims 1-22, wherein the ligand is a phosphine ligand or a diphosphine ligand.

27. The method of claim 26, wherein the ligand is XPhos, PCy3, PCy2Ph, P i Pr3, PCy2 t Bu, CataCXium A, P(MeOC6H4)3, PPh2(C6H4CO2H), PPh2(C6H4SO3H), SPhos, JohnPhos, DavePhos, MePhos, cBRIDP, Cy-vBRIDP, Cy-cBRIDP, i Bu Triplecage, P t Bu2Cy, P t Bu3, CataCXium PICy, P t Bu2(PhNMe2), PPh3, dppp, dppe, dppb, BINAP, DPEPhos, dppf, dbpf, XantPhos, N- t Bu2P azetine, dppm, dmpe, dippe, DIPAMP, Chiraphos, SPANphos, SEGPHOS, Me-DuPhos or Josiphos.

28. The method of claim 27, wherein the ligand is XPhos, CataCXium A, JohnPhos, DavePhos, MePhos, cBRIDP, CataCXium PICy or dbpf.

29. The method of claim 28, wherein the ligand is XPhos.

30. The method according to any one of claims 1-22, wherein the molar ratio of the ligand to the catalyst is from about 5:1 to about 1:

5.

31. The method of claim 30, wherein the molar ratio of the ligand to the catalyst is from about 2:1 to about 1:

1.

32. The method according to any one of claims 1-22, wherein the base is Cs2CO3, K2CO3 or K3PO4.

33. The method according to any one of claims 1-22, wherein the solvent is MeCN, i PrOAc, n-propyl acetate, 2-MeTHF, EtCN, MEK or toluene.

34. The method of claim 33, wherein the solvent is MeCN.

35. A compound of formula C:

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