Pharmaceutical forms of CD73 inhibitors

Abstract

The present disclosure relates to pharmaceutical forms of CD73 inhibitors, polymorphic forms of the pharmaceutical forms, pharmaceutical compositions comprising the pharmaceutical forms, and methods of treating a subject with cancer by administering one of the pharmaceutical forms or a pharmaceutical composition comprising one of the disclosed pharmaceutical forms.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 375,580, filed September 14, 2022, and U.S. Provisional Patent Application No. 63 / 497,323, filed April 20, 2023, which are incorporated by reference in their entireties.

[0002] CD73 is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein that catalyzes the hydrolysis of AMP to adenosine, acting in concert with CD39 to convert ATP to AMP. The resulting adenosine functions as a signaling molecule that activates P1 receptors expressed on the cell surface in various tissues. Four G protein-coupled P1 or adenosine receptors have been cloned, designated A1, A2A, A2B, and A3. Adenosine influences a wide range of physiological processes, including neuronal function, vascular perfusion, and immune response. In so doing, this metabolite regulates CNS, cardiovascular, and immune system function, to name a few.

[0003] Increasing evidence suggests that interactions between tumor cells and their microenvironment are essential for tumorigenesis. The purinergic signaling pathway, in which CD73 plays a key role, has emerged as a key factor in cancer progression. In recent years, it has become clear that adenosine is one of the most important immunosuppressive regulatory molecules in the tumor microenvironment, contributing to immune escape and tumor progression.

[0004] CD73 is a key protein molecule in cancer development and has been found to be overexpressed in many cancer cell lines and tumor types, including breast, colorectal, ovarian, gastric, and gallbladder cancers, as well as cancers associated with poor prognosis.

[0005] CD73 expression in tumors is regulated by various mechanisms. CD73 expression is negatively regulated by estrogen receptor (ER) in breast cancer. Therefore, CD73 is highly expressed in ER-negative breast cancer patients. Hypoxia-inducible factor-1α (HIF-1α) has also been shown to regulate CD73 transcription. In addition, inflammatory factors such as IFN-γ affect CD73 levels. CD73 expression is further epigenetically regulated by CpG island methylation in cell lines and clinical tumor samples.

[0006] In addition to being a prognostic biomarker in cancer patients, overexpression of CD73 has also been shown to be functionally associated with therapeutic resistance: elevated levels of CD73 were initially associated with resistance to various chemotherapeutic agents, including vincristine and doxorubicin.

[0007] CD73 has also been shown to be involved in immunotherapy resistance. This ectonucleotidase participates in the process of tumor immune evasion by inhibiting the activation, clonal expansion, and homing of tumor-specific T cells (especially T helper and cytotoxic T cells); impairing tumor cell killing by cytolytic effector T lymphocytes; enhancing the suppressive capacity of Treg and Th17 cells through the pericellular generation of adenosine; enhancing the conversion of type 1 macrophages into tumor-promoting type 2 macrophages; and promoting the accumulation of MDSCs.

[0008] Small molecule inhibitors and monoclonal antibodies targeting CD73 have demonstrated antitumor activity in various immunocompetent but not immunodeficient mouse tumor models. Overall, these studies suggest that anti-CD73 therapeutic activity depends on its ability to elicit an immune response in vivo.

[0009] Antibodies that block PD-1, PD-L1, and CTLA-4 have shown impressive objective responses in cancer patients. Recent data show that anti-CD73 mAbs significantly enhance the activity of both anti-CTLA-4 and anti-PD-1 mAbs in several mouse tumor models. In addition to checkpoint blockade, CD73-mediated generation of adenosine may contribute to resistance to additional immunotherapy modalities, including CAR-T cells and cancer vaccines.

[0010] Blocking CD73 activity represents a strategy for resensitizing tumors to therapy. Based on the association between CD73 and treatment resistance, combining anti-CD73 therapy with chemotherapy or immunotherapy is an effective approach to enhance its activity in cancer patients with high CD73 levels. In some instances, CD73 expression serves as a biomarker to identify patients who may benefit from anti-CD73 combination therapy.

[0011] In some cases, the CD39 / CD73 couple shifts ATP-driven pro-inflammatory cell activity to an adenosine-mediated anti-inflammatory state. Numerous studies have demonstrated changes in the activity of the CD39 / CD73 axis during infections induced by various microorganisms. Increased CD73 expression has been observed in the brains of mice infected with Toxoplasma gondii, which promotes the parasite life cycle through the production of adenosine. Therefore, pharmacological blockade of CD73 is a promising therapeutic approach for treating human toxoplasmosis.

[0012] Enhanced expression and activity of CD39 and CD73 have been observed in cytomegalovirus (CMV)-infected endothelial cells. Increased local adenosine production, coupled with upregulation of ectonucleotidases, creates an immunosuppressive and antithrombotic microenvironment that favors viral entry into target cells.

[0013] In some cases, CD73 inhibitors have been applied as antiviral agents by causing a decrease in adenosine production. Increased expression / activity of CD39 and CD73 on lymphocytes from individuals infected with human immunodeficiency virus (HIV) indicates a role for ectonucleotidases in the immune dysfunction associated with this disease. Indeed, an increased proportion of CD39-expressing Tregs and a positive correlation between CD39 expression on Tregs and disease progression have been observed in different cohorts of HIV-infected individuals. Furthermore, it has been shown that HIV-positive patients have a high number of CD39+ Tregs, and their Teffs exhibit increased in vitro sensitivity to the inhibitory effects of adenosine, which was associated with increased expression of the immunosuppressive A2A receptor.

[0014] In the central nervous system, adenosine plays an important role in regulating many neural functions. Via activation of P1 receptors, adenosine is involved in diverse physiological and pathological processes, including the regulation of sleep, general wakefulness and activity, local neuronal excitability, and the coupling of cerebral blood flow to energy demands. In some cases, manipulating adenosine production via CD73 inhibitors may be useful for treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric disorders such as schizophrenia and autism.

[0015] Thus, there is a need for the development of CD73 inhibitors and pharmaceutical compositions containing them that can be advantageously used to treat cancer and infectious diseases in subjects in need thereof. Summary of the Invention

[0016] Compound 1:

[0017] [ka] Provided herein are pharmaceutically acceptable forms of Compound 1, wherein the pharmaceutically acceptable form is selected from a gentisate salt form and a succinate salt form. Also provided herein are polymorphic forms of the gentisate salt form and the succinate salt form of Compound 1. In some embodiments, the gentisate salt form comprises a gentisate salt. In some embodiments, the gentisate salt form comprises a co-crystal of gentisate salt. In some embodiments, the gentisate salt form comprises a salt and a co-crystal. In some embodiments, the succinate salt form comprises a succinate salt. In some embodiments, the succinate salt form comprises a co-crystal of succinate salt. In some embodiments, the succinate salt form comprises a salt and a co-crystal. Further provided herein are pharmaceutical compositions comprising an amount of a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from a gentisate salt form and a succinate salt form. Some embodiments disclosed herein provide a method of inhibiting the activity of CD73 in a cell, comprising contacting CD73 in the cell with an effective amount of a pharmaceutically acceptable form of Compound 1 disclosed herein. Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1 disclosed herein. In some embodiments, the cancer is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, kidney cancer, multiple myeloma, or lymphoma. In other embodiments, the cancer expresses CD73. In yet further embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1 disclosed herein and one or more second therapeutic agents. DETAILED DESCRIPTION OF THE INVENTION

[0018] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties such as molecular weight, melting point, or chemical properties such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is an approximation within experimental variation (or within statistical experimental error); thus, in some cases, the number or numerical range may vary by 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in certain other embodiments, embodiments, such as any composition of matter, compositions, methods, or processes consisting of the substances described herein, "consist of" or "consist essentially of" the described features.

[0019] As used in this specification and the appended claims, unless indicated to the contrary, the following terms have the meanings indicated below.

[0020] "Administering," when used in conjunction with a therapeutic agent, means administering the therapeutic agent systemically or locally, such as by direct administration into or onto a target tissue, or by administering the therapeutic agent to a subject, thereby positively affecting the tissue to which the therapeutic agent is targeted. Thus, as used herein, the term "administering," when used in conjunction with the compositions described herein, can include, but is not limited to, providing the composition into or onto the target tissue, providing the composition systemically to a subject, for example, by oral administration, thereby allowing the therapeutic agent to reach the target tissue or cell. "Administering" a composition can be accomplished by injection, topical administration, oral administration, or other methods alone or in combination with other known techniques.

[0021] The term "amorphous," as used herein, refers to a solid composition that does not have measurable long-range order in the positions of its molecules, as determined by analytical techniques known to those skilled in the art, such as x-ray powder diffraction (XRPD).

[0022] The terms "crystalline" and "crystallinity" refer to a solid composition that has some measure of long-range order in the positions of its molecules as measured by analytical techniques known to those skilled in the art, such as x-ray powder diffraction (XRPD).

[0023] The term "differential scanning calorimetry" as used herein means a calorimeter according to the U.S.P. <891> This refers to the method of thermal analysis described in

[0024] The term "gentisate salt," as used herein, refers to the salt formed between Compound 1 and gentisic acid. As used herein, the term "gentisic acid" refers to the compound having CAS Registry Number 490-79-9, the chemical name 2,5-dihydroxybenzoic acid, and the following chemical structure:

[0025] [ka] means a compound having the formula:

[0026] The term "gentisate," as used herein, refers to a form of Compound 1 associated with gentisic acid. As intended herein, gentisate may be (a) a salt form comprising Compound 1 and gentisic acid, (b) a co-crystal comprising Compound 1 and gentisic acid, or (c) a mixture of a salt comprising Compound 1 and gentisic acid and a co-crystal comprising Compound 1 and gentisic acid.

[0027] As used herein, the term "co-crystal" refers to a crystalline material comprising two or more different molecules in a defined stoichiometric ratio within the same crystal lattice associated by non-ionic and non-covalent bonds, one of which is Compound 1. In one embodiment, a co-crystal is provided comprising Compound 1 and gentisic acid. In another embodiment, a co-crystal is provided comprising Compound 1 and succinic acid.

[0028] The term "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0029] The term "pharmaceutical composition" means a composition comprising one or more active ingredients, whereby the composition is suitable for investigation in a mammal (e.g., but not limited to, a human) for a specified efficacious outcome. Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0030] The term "substantially amorphous," as used herein, refers to a composition that has little or no long-range order in the position of its molecules. For example, a substantially amorphous material has less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity). As intended herein, the term substantially amorphous refers to a composition that does not contain measurable crystalline material, as determined by analytical techniques known to those skilled in the art, such as x-ray powder diffraction (XRPD).

[0031] The term "succinate salt," as used herein, refers to the salt formed between Compound 1 and succinic acid. The term "succinic acid," as used herein, refers to CAS Registry Number 110-15-6, the chemical names 1,2-ethanedicarboxylic acid and 1,4-butanedioic acid, and the following chemical structure:

[0032] [ka] means a compound having the formula:

[0033] The term "succinate," as used herein, refers to a form of Compound 1 associated with succinic acid. As intended herein, the succinate may be (a) a salt form comprising Compound 1 and succinic acid, (b) a co-crystal comprising Compound 1 and succinic acid, or (c) a mixture of a salt comprising Compound 1 and succinic acid and a co-crystal comprising Compound 1 and succinic acid.

[0034] As used herein, the term "therapeutic agent" means an agent utilized to treat, combat, ameliorate, prevent, or ameliorate an unwanted disease or disorder in a subject.

[0035] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical physician, or other clinician, including one or more of: (1) preventing a disease, e.g., preventing a disease, illness, or disorder in an individual who is predisposed to the disease, illness, or disorder but who has not yet experienced or exhibited the pathology or symptomology of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, illness, or disorder (i.e., halting further progression of the pathology and / or symptomology) in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, illness, or disorder; and (3) ameliorating a disease, e.g., ameliorating a disease, illness, or disorder (i.e., reversing the pathology and / or symptomology) in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, illness, or disorder.

[0036] As used herein, the terms "treat," "treated," "treatment," or "treating" refer to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, where the objective is to prevent or slow (alleviate) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical result. For purposes described herein, a beneficial or desired clinical result includes, but is not limited to, alleviation of symptoms, reduction in the extent of the disease, disorder, or condition, stabilization (i.e., not worsening) of the disease, disorder, or condition, delay in the onset or slowing of progression of the disease, disorder, or condition, improvement in the disease, disorder, or condition, and remission (whether partial or total), whether detectable or undetectable, or whether enhancement or amelioration of the disease, disorder, or condition. Treating includes eliciting a clinically significant response without excessive levels of side effects. Treating also includes prolonging survival compared to expected survival if not receiving treatment. The prophylactic benefit of treatment includes preventing disease, delaying disease progression, stabilizing disease, or reducing the likelihood of disease occurrence. As used herein, "treat," "treated," "treatment," or "treating" includes prevention, in some embodiments.

[0037] As used herein, the term "x-ray powder diffraction (XRPD)" refers to the <941> By use of powder x-ray diffraction as defined in the JIS K 1995 / 10001, we mean a technique for characterizing solids as to their crystallinity or partial crystallinity.

[0038] Compound 1:

[0039] [ka] Disclosed herein are pharmaceutically acceptable forms of the compound of formula (I), wherein the pharmaceutically acceptable form is selected from a gentisate form and a succinate form.

[0040] In some embodiments, a pharmaceutically acceptable form of Compound 1 is provided that is a gentisate salt form. In some embodiments, the gentisate salt form comprises gentisate. In some embodiments, the gentisate salt form comprises a co-crystal of gentisate. In some embodiments, the gentisate salt form comprises a salt and a co-crystal. In further embodiments, a gentisate salt form of Compound 1 is provided, wherein the molar ratio of Compound 1 to gentisic acid is about 1:1. In further embodiments, a gentisate salt form of Compound 1 is provided, wherein the molar ratio of Compound 1 to gentisic acid is about 2:1. In further embodiments, a gentisate salt form of Compound 1 is provided, wherein the molar ratio of Compound 1 to gentisic acid is about 1:2. In other embodiments, a gentisate salt form of Compound 1 is provided, wherein the gentisate salt form is a hydrate. In some embodiments, the hydrate of the gentisate form of Compound 1 is selected from hemihydrate, monohydrate, and dihydrate forms. In some embodiments, the hydrate is a hemihydrate. In some embodiments, the hydrate is a monohydrate. In some embodiments, the hydrate is a dihydrate.

[0041] In further embodiments, a gentisate salt form of Compound 1 is provided, wherein the form is a solid. In some embodiments, such a solid is crystalline. In some embodiments, such a crystalline solid exhibits a peak at 9.25±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. In still further embodiments, the crystalline solid further exhibits peaks at 6.97±0.2°2θ, 20.53±0.2°2θ, and 26.08±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. In still further embodiments, the crystalline solid further exhibits peaks at 14.61±0.2°2θ and 18.89±0.2°2θ in an x-ray powder diffraction (XRPD) pattern.

[0042] In a further embodiment, a gentisate form of Compound 1 is provided, wherein the form is a crystalline solid and exhibits a peak at 9.3±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In a still further embodiment, the crystalline solid further exhibits a peak at 7.1±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In a still further embodiment, the crystalline solid further exhibits a peak at 20.1±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In a still further embodiment, the crystalline solid further exhibits a peak at 19.0±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In a still further embodiment, the crystalline solid further exhibits a peak at 26.2±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In still further embodiments, the crystalline solid further exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 4.8±0.2 degrees 2θ, 10.5±0.2 degrees 2θ, and 14.8±0.2 degrees 2θ.

[0043] In another embodiment, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline form comprises a peak in a differential scanning calorimetry pattern from about 150°C to about 170°C. In yet a further embodiment, the crystalline solid comprises a peak in a differential scanning calorimetry pattern from about 150°C to about 165°C. In yet a further embodiment, the crystalline solid comprises a peak in a differential scanning calorimetry pattern from about 161°C to about 162°C.

[0044] In another embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, which exhibits a mass loss of about 1% to about 5% in thermogravimetric analysis when heated from about 31° C. to about 150° C. In yet a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, which exhibits a mass loss of about 3% to about 5% in thermogravimetric analysis when heated from about 31° C. to about 150° C. In yet a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, which exhibits a mass loss of about 5% in thermogravimetric analysis when heated from about 31° C. to about 150° C.

[0045] In another embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C. In a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 10 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C. In a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 15 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C. In a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 20 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C. In a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 25 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0046] In another embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of about 10 mg / mL to about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C. In yet a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of about 15 mg / mL to about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C. In yet a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of about 20 mg / mL to about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C. In yet a further embodiment, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of about 25 mg / mL to about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0047] In other embodiments, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 2.5 and a temperature of 37° C. In yet further embodiments, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 7.5 mg / mL in an aqueous solution having a pH of 2.5 and a temperature of 37° C. In yet further embodiments, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 10 mg / mL in an aqueous solution having a pH of 2.5 and a temperature of 37° C.

[0048] In other embodiments, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 1 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37° C. In yet further embodiments, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 2.5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37° C. In yet further embodiments, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37° C. In yet further embodiments, a crystalline solid in the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits a solubility of at least 7.5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37° C.

[0049] In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits degradation of less than about 10% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 5° C. for at least 7 days. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits degradation of less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 5° C. for at least 1 month. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits degradation of less than about 10% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 5° C. for at least 1 month. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% degradation of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 5° C. for at least 1 month. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 5° C. for at least 3 months. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 5°C for at least 3 months.

[0050] In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits degradation of less than about 10% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 25° C. and 60% relative humidity for at least 7 days. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits degradation of less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 25° C. and 60% relative humidity for at least 7 days. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits degradation of less than about 10% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 25° C. and 60% relative humidity for at least 1 month. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% degradation of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 25° C. and 60% relative humidity for at least 1 month. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 25° C. and 60% relative humidity for at least 3 months. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 25° C. and 60% relative humidity for at least 3 months.

[0051] In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits less than about 10% degradation when the pharmaceutically acceptable form is stored at 40° C. and 75% relative humidity for at least 7 days. In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 40° C. and 75% relative humidity for at least 7 days.

[0052] In other embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits degradation of less than about 10% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 60° C. for one day or more. In still further embodiments, a crystalline solid of the gentisate salt form of Compound 1 is provided, wherein the crystalline solid exhibits degradation of less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% of the total amount of the gentisate salt form of Compound 1 when the pharmaceutically acceptable form is stored at 60° C. for one day or more.

[0053] Also provided herein is a crystalline solid in the gentisate form of Compound 1, wherein the crystalline solid exhibits a peak at 8.26±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. Further provided herein is a crystalline solid in the gentisate form of Compound 1, wherein the crystalline solid additionally exhibits a peak at 26.43±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In another embodiment, a crystalline solid in the gentisate form of Compound 1 is provided, wherein the crystalline solid additionally exhibits peaks at 15.81±0.2 degrees 2θ and 15.40±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In another embodiment, a crystalline solid in the gentisate form of Compound 1 is provided, wherein the crystalline solid additionally exhibits peaks at 14.94±0.2 degrees 2θ and 20.44±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

[0054] Also provided herein is a pharmaceutically acceptable form of Compound 1 that is a succinate salt form. In some embodiments, the succinate salt form comprises a succinate salt. In some embodiments, the succinate salt form comprises a co-crystal of a succinate salt. In further embodiments, a succinate salt form of Compound 1 is provided, wherein the molar ratio of Compound 1 to succinic acid is about 1:1. In further embodiments, a succinate salt form of Compound 1 is provided, wherein the molar ratio of Compound 1 to succinic acid is about 2:1. In further embodiments, a succinate salt form of Compound 1 is provided, wherein the molar ratio of Compound 1 to succinic acid is about 1:2. In other embodiments, such a succinate salt form of Compound 1 is provided, wherein the succinate salt form is a hydrate. In some embodiments, the hydrate of the succinate form of Compound 1 is selected from hemihydrate, monohydrate, and dihydrate forms. In some embodiments, the hydrate is a hemihydrate. In some embodiments, the hydrate is a monohydrate. In some embodiments, the hydrate is a dihydrate.

[0055] Further provided herein is a pharmaceutical composition comprising an amount of a pharmaceutically acceptable form of Compound 1 and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable form is selected from the gentisate form and the succinate form disclosed herein. In some embodiments, the gentisate form comprises gentisate. In some embodiments, the gentisate form comprises a co-crystal of gentisate. In some embodiments, the gentisate form comprises a salt and a co-crystal. In some embodiments, the succinate form comprises a succinate salt. In some embodiments, the succinate form comprises a co-crystal of succinate. In some embodiments, the succinate form comprises a salt and a co-crystal.

[0056] Also disclosed herein is a method of inhibiting the activity of CD73 in a cell, comprising contacting CD73 in the cell with an effective amount of a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from the gentisate form and the succinate form disclosed herein.

[0057] Further provided herein are methods of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate salt forms disclosed herein. In other embodiments, provided are methods of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate salt forms disclosed herein. In some embodiments, the cancer is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, kidney cancer, multiple myeloma, or lymphoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is gallbladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer, or castration-sensitive prostate cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the multiple myeloma is light-chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma, or immunoglobulin E (IgE) myeloma. In some embodiments, the cancer is lymphoma.

[0058] Further provided herein are methods of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate forms disclosed herein, and the cancer expresses CD73. In some embodiments, CD73 is upregulated in the cancer being treated. In some embodiments, the cancer expressing CD73 or the cancer in which CD73 is upregulated is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, kidney cancer, multiple myeloma, or lymphoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is gallbladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer, or castration-sensitive prostate cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the multiple myeloma is light-chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma, or immunoglobulin E (IgE) myeloma. In some embodiments, the cancer is lymphoma.

[0059] Further provided herein are methods for treating cancer in a subject, comprising administering to the subject (a) a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1, and (b) one or more second therapeutic agents, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate forms disclosed herein. In other embodiments, provided are methods for treating cancer in a subject, comprising administering to the subject (a) a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1, and (b) one or more second therapeutic agents, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate forms disclosed herein. In some embodiments, the second therapeutic agent is a chemotherapeutic agent or an immunotherapeutic agent.

[0060] In further embodiments, the subject's cancer is multiple myeloma, and the second therapeutic agent is selected from chemotherapy, corticosteroids, immunomodulatory agents, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, monoclonal antibodies against CD38, monoclonal antibodies against SLAMF7, antibody-drug conjugates, and nuclear export inhibitors. In some embodiments, the second therapeutic agent is chemotherapy selected from cyclophosphamide, etoposide (VP-16), doxorubicin, liposomal doxorubicin, melphalan, melphalan flufenamide (melflufen), and bendamustine. In other embodiments, the second therapeutic agent is selected from corticosteroids, including but not limited to dexamethasone and prednisone. In other embodiments, the second therapeutic agent is selected from immunomodulatory agents, including but not limited to thalidomide, lenalidomide, and pomalidomide. In further embodiments, the second therapeutic agent is selected from proteasome inhibitors, including but not limited to bortezomib, carfilzomib, and ixazomib. In other embodiments, the second therapeutic agent is selected from histone deacetylase (HDAC) inhibitors, including but not limited to panobinostat. In still further embodiments, the second therapeutic agent is selected from monoclonal antibodies against CD38, including but not limited to daratumumab and isatuximab. In some embodiments, the second therapeutic agent is selected from antibodies against SLAMF7, including but not limited to elotuzumab. In some embodiments, the second therapeutic agent is selected from antibody-drug conjugates, including but not limited to belantamab-mafodotin. In some embodiments, the second therapeutic agent is selected from nuclear export inhibitors, including but not limited to selinexor.

[0061] In other embodiments, methods of treating multiple myeloma in a subject are provided, comprising the step of administering to the subject (a) a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable form of Compound 1, and (b) one or more second therapeutic agents, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate forms disclosed herein, wherein the one or more second therapeutic agents include, but are not limited to, the following drug combinations: lenalidomide (or pomalidomide or thalidomide) and dexamethasone, carfilzomib (or ixazomib or bortezomib), lenalidomide and dexamethasone, bortezomib (or carfilzomib), cyclophosphamide and dexamethasone, elotuzumab (or daratumumab), ...cyclophosphamide and dexamethasone, elotuzumab (or daratumumab), lenalidomide (or pomalidomide or thalidomide) and dexamethasone, carfilzomib (or ixazomib or bortezomib), cyclophosphamide and dexamethasone, elotuzumab (or daratumumab), lenalidomide (or pomalidomide or thalidomide) and dexamethasone, carfilzomib (or ixazomib or bortezomib), cyclophosphamide and dexamethasone, bortezomib, liposomal doxorubicin and dexamethasone, panobinostat, bortezomib and dexamethasone, elotuzumab, bortezomib and dexamethasone, melphalan and prednisone (MP) with or without thalidomide or bortezomib, vincristine, doxorubicin, and dexamethasone (referred to as VAD), dexamethasone, cyclophosphamide, etoposide, and cisplatin (referred to as DCEP), dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide with or without bortezomib (referred to as DT-PACE), and selinexor, bortezomib, and dexamethasone.

[0062] Further provided herein is a method for treating an infectious disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate salt forms disclosed herein. In some embodiments, the infectious disease is a viral infection. In other embodiments, the infectious disease is a parasitic infection.

[0063] Further provided herein is a method of treating a neurodegenerative disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate forms disclosed herein. Also provided herein is a method of treating a neurodegenerative disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from the gentisate and succinate forms disclosed herein. In some embodiments, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, or autism.

[0064] Further provided herein are compositions for use in treating cancer in a subject, the compositions comprising a form of Compound 1. In some embodiments, the compositions comprise the succinate form of Compound 1. In some embodiments, the compositions comprise the gentisate form of Compound 1. In some embodiments, the compositions comprise the gentisate form of Compound 1, wherein the form is crystalline. In some embodiments, the compositions comprise the gentisate form of Compound 1, wherein the form is a crystalline solid exhibiting a peak at 9.3±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In yet further embodiments, the crystalline solid further exhibits a peak at 7.1±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In yet further embodiments, the crystalline solid further exhibits a peak at 20.1±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In yet further embodiments, the crystalline solid further exhibits a peak at 19.0±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In still further embodiments, the crystalline solid further exhibits a peak at 26.2±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In still further embodiments, the crystalline solid further exhibits peaks at 4.8±0.2 degrees 2θ, 10.5±0.2 degrees 2θ, and 14.8±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern. In some embodiments, the cancer is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, stomach cancer, gallbladder cancer, prostate cancer, kidney cancer, multiple myeloma, or lymphoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is gallbladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer, or castration-sensitive prostate cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is multiple myeloma.In some embodiments, the multiple myeloma is light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma, or immunoglobulin E (IgE) myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer expresses CD73. In some embodiments, CD73 is upregulated in the cancer being treated. In some embodiments, the cancer that expresses or in which CD73 is upregulated is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, kidney cancer, multiple myeloma, or lymphoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is gallbladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer, or castration-sensitive prostate cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the multiple myeloma is light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma, or immunoglobulin E (IgE) myeloma. In some embodiments, the cancer is lymphoma.

[0065] Also provided herein are pharmaceutical compositions comprising an amount of a pharmaceutically acceptable form of Compound 1 and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable form is selected from a gentisate form and a succinate form. In some embodiments, the gentisate form comprises gentisate. In some embodiments, the gentisate form comprises a co-crystal of gentisate. In some embodiments, the gentisate form comprises a salt and a co-crystal. In some embodiments, the succinate form comprises a succinate salt. In some embodiments, the succinate form comprises a co-crystal of succinate. In some embodiments, the succinate form comprises a salt and a co-crystal. Further provided herein are such pharmaceutical compositions, wherein the one or more pharmaceutically acceptable excipients comprise one or more diluents, binders, disintegrants, lubricants, anti-adhesives, glidants, colorants, flavorants, sweeteners, coating agents, plasticizers, wetting agents, buffers, or adsorbents.

[0066] Among the one or more diluents that may be used are lactose, mannitol, xylitol, microcrystalline cellulose, dicalcium phosphate, and starch. In some embodiments, the one or more diluents comprise about 1% to about 80%, about 10% to about 80%, about 10% to about 70%, about 15% to about 80%, about 20% to about 80%, about 15% to about 75%, about 20% to about 75%, about 25% to about 75%, about 50% to about 80%, about 50% to about 75%, about 60% to about 80%, or about 60% to about 75% of the total weight of the pharmaceutical composition. In some embodiments, the diluent is lactose. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is xylitol. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is dicalcium phosphate. In some embodiments, the diluent is starch.

[0067] Also provided herein are pharmaceutical compositions in which the one or more pharmaceutically acceptable excipients comprise one or more binders, and the one or more binders comprise about 1% to about 80%, about 10% to about 80%, about 10% to about 70%, about 15% to about 80%, about 20% to about 80%, about 15% to about 75%, about 20% to about 75%, about 25% to about 75%, about 50% to about 80%, about 50% to about 75%, about 60% to about 80%, or about 60% to about 75% of the total weight of the pharmaceutical composition. In some embodiments, the one or more binders are selected from methylcellulose, microcrystalline cellulose, starch, and gums such as guar gum and tragacanth, or mixtures thereof.

[0068] Also provided herein are pharmaceutical compositions wherein the one or more pharmaceutically acceptable excipients comprise one or more disintegrants, and the one or more disintegrants comprise about 0.1 wt % to about 10 wt %, about 0.1 wt % to about 5% by weight, about 0.1 wt % to about 4 wt %, about 0.1 wt % to about 3 wt %, about 0.1 wt % to about 2 wt %, about 0.1 wt % to about 1 wt %, about 0.1 wt % to about 0.75 wt %, about 0.2 wt % to about 1 wt %, about 0.3 wt % to about 1 wt %, about 0.4 wt % to about 1 wt %, about 0.2 wt % to about 0.8 wt %, about 0.3 wt % to about 0.75 wt %, about 0.3 wt % to about 0.7 wt %, or about 0.3 wt % to about 0.6 wt % of the total weight of the pharmaceutical composition. In some embodiments, the one or more disintegrants are selected from starch, sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, croscarmellose sodium, and crospovidone, or mixtures thereof. In some embodiments, the disintegrant is starch. In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the disintegrant is sodium alginate. In some embodiments, the disintegrant is sodium carboxymethylcellulose. In some embodiments, the disintegrant is methylcellulose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is crospovidone.

[0069] Also provided herein are pharmaceutical compositions wherein the one or more pharmaceutically acceptable excipients comprise one or more lubricants, and the one or more lubricants comprise about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.2% to about 1%, about 0.3% to about 1%, about 0.4% to about 1%, about 0.2% to about 0.8%, about 0.3% to about 0.75%, about 0.3% to about 0.7%, or about 0.3% to about 0.6% by weight of the total weight of the pharmaceutical composition. In further embodiments, the one or more lubricants are selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, and stearic acid, or mixtures thereof. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is calcium stearate. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is stearic acid.

[0070] In some embodiments, the pharmaceutical compositions disclosed herein may include additional excipients, including, but not limited to, buffers, glidants, preservatives, and colorants. Additional excipients such as bulking agents, tonicity agents, and chelating agents are also within the scope of embodiments.

[0071] Non-limiting examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, a mixture of an amino acid and a buffer, a mixture of an aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0072] In some embodiments, the pharmaceutical compositions disclosed herein may comprise a glidant. Suitable glidants include, but are not limited to, tricalcium phosphate, calcium silicate, cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, and the like. In some embodiments, the glidant is tricalcium phosphate. In some embodiments, the glidant is calcium silicate. In some embodiments, the glidant is cellulose. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is magnesium silicate. In some embodiments, the glidant is magnesium trisilicate. In some embodiments, the glidant is silicon dioxide. In some embodiments, the glidant is starch. In some embodiments, the glidant is talc.

[0073] In some embodiments, the pharmaceutical compositions disclosed herein may contain a preservative. Preservatives include antimicrobial agents, antioxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (methylparaben, ethylparaben, butylparaben), benzoic acid, potassium sorbate, vanillin, etc.

[0074] In some embodiments, the pharmaceutical compositions disclosed herein may contain coloring agents for purposes of identity and / or aesthetics of the resulting liquid form. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide, and combinations thereof.

[0075] Additional excipients are contemplated in the pharmaceutical compositions disclosed herein.These additional excipients are selected based on function and compatibility with the pharmaceutical compositions described herein, and can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975); Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980) and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), and these documents are incorporated herein by reference in their entirety.

[0076] The pharmaceutical compositions disclosed herein may be in a form suitable for oral administration to a subject in need thereof. Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules made of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. Solid dosage forms of oral administration may be presented as individual units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of Compound 1 disclosed herein and one or more pharmaceutically acceptable excipients. In another embodiment, oral administration may be in the form of a powder or granules. In another embodiment, oral dosage forms are sublingual, such as lozenges. Capsules or tablets may contain controlled-release formulations. In the case of capsules, tablets, and pills, the dosage forms may also include buffering agents or be prepared with enteric coatings. In another embodiment, oral administration may be in the form of a liquid dosage. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or flavoring agents.

[0077] Also provided herein is a tablet comprising a pharmaceutically acceptable form of Compound 1, microcrystalline cellulose, colloidal silica dioxide, sodium stearyl fumarate, crospovidone, and magnesium stearate. In some embodiments, the pharmaceutically acceptable form of Compound 1 is selected from a gentisate form and a succinate form. In some embodiments, the pharmaceutically acceptable form of Compound 1 is the gentisate form. In some embodiments, the gentisate form comprises a salt. In some embodiments, the gentisate form comprises a cocrystal. In some embodiments, the gentisate form comprises a salt and a cocrystal. In some embodiments, the pharmaceutically acceptable form of Compound 1 is the succinate form. In some embodiments, the succinate form comprises a salt. In some embodiments, the succinate form comprises a cocrystal. In some embodiments, the succinate form comprises a salt and a cocrystal. In further embodiments, the tablet disclosed herein is as set forth in Table 1.

[0078] [Table 1]

[0079] In another embodiment, the pharmaceutical compositions disclosed herein may comprise parenteral dosage forms. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Preparations for injection (for example, sterile injectable aqueous or oily suspensions) may be formulated according to known techniques using suitable dispersants, wetting agents, and / or suspending agents.

[0080] In another embodiment, the pharmaceutical compositions disclosed herein may comprise topical dosage forms. "Topical administration" includes, for example, transdermal administration via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the pharmaceutical compositions disclosed herein are administered via a transdermal device, administration is achieved using a patch, either of the reservoir and porous membrane type or of the solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, adhesive bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated, see, for example, J.Pharm.Sci., 88(10), 955-958, by Finnin and Morgan (October 1999).

[0081] For intranasal administration or inhalation administration, the pharmaceutical compositions disclosed herein are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray presentation from a pressurized container or nebulizer, using a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture with lactose in a dry blend, or as mixed-component particles mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to generate a fine mist), or nebulizer. For intranasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin.

[0082] Other carrier materials and modes of administration known in the pharmaceutical field can also be used.The pharmaceutical compositions disclosed herein can be prepared by any well-known technique in pharmacy, such as effective formulation and administration procedures.The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks.Drug formulation is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0083] Doses of compositions containing forms of Compound 1 described herein may vary depending on the patient's (e.g., human) condition, i.e., the stage of the disease, overall health, age, and other factors. Pharmaceutical compositions are administered in a manner appropriate to the disease being treated (or prevented). The appropriate dose and suitable duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic / prophylactic benefit (e.g., increased frequency of complete or partial remission, or improved clinical outcomes such as longer disease-free and / or overall survival, or reduced severity of symptoms). Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses depend on the patient's body mass, weight, or blood volume. Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0084] Compound 1 may be prepared by methods known to those skilled in the art, including but not limited to those described in Example 1.

[0085] Among the abbreviations used in the examples are rt (room temperature), min (minutes), h (hours), MeCN (acetonitrile), DMF (N,N-dimethylformamide), THF (tetrahydrofuran), MeOH (methanol), sat (saturated), and TsOH (toluenesulfonic acid). [Example]

[0086] Example 1. Preparation of ((S)-1-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-hydroxypropan-2-yl)phosphonic acid

[0087] [ka]

[0088] Step A. (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyl diacetate (1a)

[0089] [ka]

[0090] β-D-Ribofuranose 1,2,3,5-tetraacetate (5.73 g, 17.99 mmol) was heated at 90 °C for 10 min, and 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1.5 g, 17.99 mmol) and SnCl4 (60 mg) were added sequentially. The mixture was heated at 130 °C under reduced pressure for 15 min, cooled to room temperature, diluted with water, and extracted with DCM. The combined organic layers were washed with water, brine, dried, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate 10:1 to 5:1) to give the title compound (1a) (2.4 g, 68%) as a yellow solid.

[0091] Step B. (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyl diacetate (1b)

[0092] [ka]

[0093] To an oven-dried flask was added 1a (5.2 g, 11.63 mmol), followed by ethanol (53.24 mL). To this solution was added triethylamine (2.43 mL, 17.44 mmol), followed by cyclopentylamine (1.38 mL, 13.95 mmol). The mixture was stirred and heated at 50 °C for 15 min, after which it was cooled to room temperature, concentrated, and purified by column chromatography (20-45% ethyl acetate / hexane, gradient elution) to give the title compound (1b) (5.02 g, 87%) as a white solid. m / z (ESI, +ve ion) = 496.1 [M+H] + .

[0094] Step C. (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4-((tert-butoxycarbonyl)(cyclopentyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyl diacetate (1c)

[0095] [ka]

[0096] To a solution of 1b (12.6 g, 25.4 mmol) in MeCN (120 mL) was added triethylamine (5.14 g, 50.9 mmol), followed by di-tert-butyl dicarbonate (44.35 g, 203.6 mmol) and 4-dimethylaminopyridine (0.31 g, 2.54 mmol). After stirring overnight, the mixture was concentrated and partitioned between EtOAc (50 mL) and saturated NaHCO. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate: 8:1) to give the title compound (1c) (10.56 g, 70% yield) as a yellow solid. m / z (ESI, +ve ion) = 596.72 [M+H] + .

[0097] Step D. tert-Butyl (6-chloro-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1d)

[0098] [ka]

[0099] To an oven-dried flask was added 1c (10.56 g, 17.78 mmol), followed by ammonia in methanol (5.0 M, 140 mL). The mixture was stirred overnight and then concentrated. The crude oil was purified by column chromatography to give the title compound (1d) (7.39 g, 89% yield) as a yellow solid. m / z (ESI, +ve ion) = 470.3 [M+H] + .

[0100] Step E. tert-Butyl (6-chloro-1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1e)

[0101] [ka]

[0102] To a solution of 1d (7.39 g, 15.75 mmol) and 2,2-dimethoxypropane (4.92 g, 47.27 mmol) in DMF (75 mL) was added TsOH·HO (0.6 g, 3.15 mmol). The mixture was stirred at 70 °C for 1 h, then cooled and quenched with saturated NaHCO (100 mL). The mixture was extracted with EtOAc (50 mL), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude oil was purified by column chromatography (petroleum ether / ethyl acetate: 8:1) to give the title compound (1e) (5.5 g, 68% yield) as a yellow solid. m / z (ESI, +ve ion) = 510.4 [M+H] + .

[0103] Step F. Ethyl 2-(((3aR,4R,6R,6aR)-6-(4-((tert-butoxycarbonyl)(cyclopentyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-2-(diethoxyphosphoryl)acetate (1f)

[0104] [ka]

[0105] To a solution of ethyl 2-diazo-2-(diethoxyphosphoryl)acetate (13.5 g, 54.13 mmol) and 1e (5.5 g, 10.83 mmol) in toluene (80 mL) was added Rh(OAc) (0.96 g, 2.17 mmol) under N. The mixture was stirred at 95 °C overnight, then concentrated and purified by column chromatography (petroleum ether / ethyl acetate: 5:1) to give the title compound (1f) (6 g, 76% yield) as a yellow oil. m / z (ESI, +ve ion) = 732.2 [M+H] + .

[0106] Step G. Ethyl 2-[[(3aR,4R,6R,6aR)-4-[4-[tert-butoxycarbonyl(cyclopentyl)amino]-6-chloro-pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]-2-diethoxyphosphoryl-3-(2-trimethylsilylethoxy)propanoate (1g)

[0107] [ka]

[0108] To a solution of compound 1f (1.2 g, 1.64 mmol) in THF (33 mL) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 2.13 mL, 2.13 mmol) dropwise at −15° C. After stirring for 25 min at −15° C., tetra-n-butylammonium iodide (303 mg, 0.820 mmol) was added, followed immediately by the dropwise addition of 2-(chloromethoxy)ethyl(trimethyl)silane (0.863 mL, 4.92 mmol) to the solution. The mixture was stirred at the same temperature for 1 h and then quenched with saturated aqueous NH4Cl. The solution was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-30% acetone / hexane, gradient elution) to give the title compound (1g) (1.03 g, 73%) as a pale yellow oil. m / z (ESI, +ve ion) = 862.3 [M+H] + .

[0109] Step H. tert-Butyl N-[1-[(3aR,4R,6R,6aR)-6-[[1-diethoxyphosphoryl-1-(hydroxymethyl)-2-(2-trimethylsilylethoxy)ethoxy]methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-pyrazolo[3,4-d]pyrimidin-4-yl]-N-cyclopentyl-carbamate (1h)

[0110] [ka]

[0111] To a stirred solution of ethyl 2-[[(3aR,4R,6R,6aR)-4-[4-[tert-butoxycarbonyl(cyclopentyl)amino]-6-chloro-pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]-2-diethoxyphosphoryl-3-(2-trimethylsilylethoxy)propanoate (1g) (1.03 g, 1.19 mmol) in EtOH (18 mL) was added calcium dichloride (596 g, 5.37 mmol), followed by sodium borohydride (203 mg, 5.37 mmol) in one portion at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The mixture was then cooled back to 0°C, quenched with 1N aqueous HCl, and diluted with EtOAc and water. The solution was extracted (EtOAc), and the combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-5% MeOH / DCM, gradient elution) to afford the title compound (1h) (755 mg, 77%) as a white foamy solid. m / z (ESI, +ve ion) = 820.3 [M+H] + .

[0112] Step I. tert-Butyl (6-chloro-1-((3aR,4R,6R,6aR)-6-(((2-(diethoxyphosphoryl)-1-(2-(trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1i)

[0113] [ka]

[0114] To a solution of tert-butyl N-[1-[(3aR,4R,6R,6aR)-6-[[1-diethoxyphosphoryl-1-(hydroxymethyl)-2-(2-trimethylsilylethoxy)ethoxy]methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-pyrazolo[3,4-d]pyrimidin-4-yl]-N-cyclopentyl-carbamate (1h) (632 mg, 0.770 mmol) and 5-(bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazole (1.13 g, 3.85 mmol) in DMF (5.0 mL) at 0 °C, NaH (60% mineral oil, 77.0 mg, 1.93 mmol) was added in one portion. After stirring the mixture at 0°C for 30 minutes, the mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc and water. The solution was extracted (EtOAc), and the combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5-30% acetone / hexane, gradient elution) to afford the title compound (1i) (697 mg, 88%) as a pale yellow gum.

[0115] Step J. tert-Butyl (6-chloro-1-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-1-(2-(trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1j)

[0116] [ka]

[0117] The diastereomers from Step I were separated by chiral chromatography (CHIRALPAK, AD-H, 21 x 250 mm, 5 μm, 5% IPA / hexane, isocratic elution, flow rate 20 mL / min), and the second eluting isomer was identified as the title compound (1j) and collected.

[0118] Step K. Diethyl ((S)-1-((2H-tetrazol-5-yl)methoxy)-2-(((3aR,4R,6R,6aR)-6-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-3-hydroxypropan-2-yl)phosphonate (1k)

[0119] [ka]

[0120] To a solution of tert-butyl (6-chloro-1-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-1-(2-(trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1j) (325 mg, 0.315 mmol) in DCM (16 mL) was added boron trifluoride diethyl etherate (0.233 mL, 1.89 mmol) dropwise at 0° C. The reaction was allowed to warm to room temperature. After stirring at room temperature for 3.5 hours, the reaction was quenched with triethylamine (3.6 mL), and the resulting mixture was stirred at room temperature for 10 minutes. Saturated aqueous NaHCO3 (7.2 mL) was added to the mixture, and the solution was diluted with DCM and water. The solution was extracted (DCM), and the combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (0-20% MeOH / DCM, gradient elution) to afford the title compound (1k) (189 mg, 86%) as an off-white foamy solid. m / z (ESI, +ve ion) = 702.3 [M+H]+.

[0121] Step L. ((S)-1-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-hydroxypropan-2-yl)phosphonic acid (1)

[0122] [ka]

[0123] To a solution of diethyl ((S)-1-((2H-tetrazol-5-yl)methoxy)-2-(((3aR,4R,6R,6aR)-6-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-3-hydroxypropan-2-yl)phosphonate (1k) (189 mg, 0.269 mmol) in MeCN (13.5 mL) was added triethylamine (0.751 mL, 5.38 mmol) followed by bromotrimethylsilane (0.528 mL, 4.04 mmol) at room temperature under an argon atmosphere. After stirring at room temperature for 4 hours, the solution was concentrated under reduced pressure. The residue was dissolved in TFA / water (1 / 3, 10 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (15-40% ACN / HO, 0.1% TFA, gradient elution) to give the title compound (1) as an off-white solid (TFA salt, 107 mg, 55%). 1 H NMR(400MHz,methanol-d4)δ8.08(d,J=0.8Hz,1H),6.25-6.20(m,1H),4.96(s,2H),4.72-4.69(m,1H),4.57-4.47(m,2H),4.19-4.16( m / z(ESI, +ve ion)=606.1[M+H] + .

[0124] Alternatively, ((S)-1-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-hydroxypropan-2-yl)phosphonic acid of Example 1 was prepared by the following steps MO.

[0125] Step M. tert-Butyl (6-chloro-1-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-1-hydroxy-3-(2-(trimethylsilyl)ethoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1m)

[0126] [ka]

[0127] The diastereomers (1h) from step H were separated by chiral chromatography (CHIRALPAK, AD-H, 21 x 250 mm, 5 μm, 5% IPA / hexane, isocratic elution, flow rate 20 mL / min), and the second eluting isomer was identified as the title compound (1m) and collected.

[0128] Step N. tert-Butyl (6-chloro-1-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-1-(2-(trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1n)

[0129] [ka]

[0130] To a solution of tert-butyl (6-chloro-1-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-1-hydroxy-3-(2-(trimethylsilyl)ethoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1m) (2.07 g, 2.52 mmol) and 5-(bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazole (2.96 g, 10.1 mmol) in DMF (12.5 mL) at 0 °C was added NaH (60% mineral oil, 252 mg, 6.31 mmol) in one portion. After stirring the mixture at 0°C for 30 minutes, the mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc and water. The solution was extracted (EtOAc), and the combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5-30% acetone / hexane, gradient elution) to afford the title compound (1n) (2.2 mg, 84%) as a pale yellow gum.

[0131] Step O. ((S)-1-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-hydroxypropan-2-yl)phosphonic acid (1)

[0132] [ka]

[0133] tert-Butyl (6-chloro-1-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-1-(2-(trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrazolium nitrite in MeCN (300 mL) To a solution of tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (1n) (8.00 g, 7.75 mmol) was added triethylamine (16.2 mL, 116 mmol) followed by bromotrimethylsilane (10.1 mL, 77.5 mmol) at room temperature under an argon atmosphere. After stirring for 15 h, the solution was concentrated under reduced pressure and azeotroped with toluene (twice). The residue was partitioned between EtOAc and water. The organic layer was collected, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed once more with water and concentrated under reduced pressure. The crude solid was dissolved in TFA / water (1 / 1, 280 mL) and stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (15-35% ACN / HO, 0.1% TFA, gradient elution) to give the title compound (1) as a white solid (TFA salt, 3.1 g, 56%). 1 H NMR(400MHz,methanol-d4)δ8.08(d,J=0.8Hz,1H),6.25-6.20(m,1H),4.96(s,2H),4.72-4.69(m,1H),4.57-4.47(m,2H),4.19-4.16(m ,1H),4.08(dd,J=10.4,4.0Hz,1H),4.01-3.92(m,4H),3.84(dd,J=12.4,7.6Hz,1H),2.13-2.06(m,2H),1.84-1.57(m,6H);m / z(ESI,+ve ion)=606.1[M+H] + .

[0134] Example 2: Preparation of the succinate salt form of Compound 1 A slurry containing a certain amount of Compound 1 (20 mg, free base) and an equimolar amount of succinic acid in tetrahydrofuran / water (approximately 0.2 mL, 9:1, v / v) was prepared, and the resulting slurry was stirred at room temperature for 3 days and then at 5°C for an additional 3 days to obtain a clear solution. A certain amount of acetonitrile (approximately 5 mL) was then added to obtain a clear solution, which was transferred to an open container. The solvent was evaporated to obtain a solid precipitate, which was collected to obtain the succinate salt form of Compound 1.

[0135] Example 3: Preparation of Form 1, the gentisate salt form of Compound 1 A vial was charged with an amount of Compound 1 (20 mg, free base) and an equimolar amount of gentisic acid in THF / HO (9:1, v / v), and the resulting mixture was stirred at room temperature for 3 days and then at 5°C for an additional 3 days to obtain a clear solution. An amount of acetonitrile (approximately 5 mL) was then added to obtain a clear solution, which was transferred to an open container. The solvent was evaporated to obtain a solid precipitate, which was collected to obtain Form 1, the gentisate salt form of Compound 1.

[0136] Example 4: Preparation of Form 2, the gentisate salt form of Compound 1 A 5 mL glass vial was charged with a quantity of Compound 1 (50.2 mg, free base) and gentisic acid (12.5 mg). 1 mL of a mixture of tetrahydrofuran / water (9:1, v / v) was added to the vial to form a slurry, which was stirred at room temperature for 1 day until a clear solution was obtained. A quantity of acetonitrile (3 mL) was added to the solution to form a clear solution. The solvent was then evaporated at room temperature to give a solid precipitate, which was collected to give Form 2, the gentisate salt form of Compound 1.

[0137] Example 5: Preparation of Form 2, the gentisate salt form of Compound 1 To a solution of the trifluoroacetic acid form of Compound 1 from Example 1 in a mixture of water / n-propanol (2:98, 3 volumes), gentisic acid (3 molar equivalents) was added, and the resulting mixture was stirred at 25°C. Seed crystals of Form 2, the gentisate salt form of Compound 1 (which can be prepared according to a method similar to that of Example 4) (1 mol%) were added to the resulting solution, and the resulting mixture was stirred for more than 1 hour. Heptane (2 volumes) was then added over more than 1 hour, and the resulting mixture was stirred for more than 12 hours. Additional heptane (19 volumes) was added to the mixture over more than 10 hours, and the mixture was stirred for more than 8 hours. The mixture was filtered, and the solid was washed three times with a water / n-propanol / heptane mixture (1:37:100, 2 volumes), drained, and dried under vacuum at 40°C, controlling the humidity inside the dryer to 25% to 45% relative humidity, to obtain Form 2, the gentisate salt form of Compound 1.

[0138] Example 6: X-ray powder diffraction (XRPD) analysis of polymorphic forms of the gentisate salt form of Compound 1 XRPD analysis of the polymorphic form of the gentisate salt of Compound 1 was carried out using a Panalytical Empyrean and X'pert3 X-ray powder diffractometer. The sample was spread in the center of a zero-background Si holder. The parameters used for the analysis are listed in Table 2.

[0139] [Table 2]

[0140] Form 1, the gentisate salt form of Compound 1, was analyzed by XRPD as described above and showed the peaks listed in Table 3. The error associated with each °2θ position was determined to be ±0.2 °θ.

[0141] [Table 3]

[0142] Form 2, the gentisate salt form of Compound 1, was analyzed by XRPD as described above and showed the peaks listed in Table 4. The error associated with each °2θ position was determined to be ±0.2 °θ.

[0143] [Table 4]

[0144] Example 7: Thermogravimetric and Differential Scanning Calorimetry Analysis of the Gentisate Form of Compound 1 Thermogravimetric analysis (TGA) data was collected using a TA Q5000 and a Discovery TGA 5500 TGA from TA Instruments. Differential scanning calorimetry (DSC) analysis was performed using a TA Q2000 DSC from TA Instruments using the parameters listed in Table 5.

[0145] [Table 5]

[0146] Example 8: Solubility of Polymorphic Forms of the Gentisate Salt Form of Compound 1 The solubility of polymorphic forms of the gentisate salt form of Compound 1 was measured in water, simulated gastric fluid (SGF), fasting simulated intestinal fluid (FaSSIF), and 4 hours fed simulated intestinal fluid (FeSSIF) at 37°C as follows.

[0147] SGF medium was prepared by weighing 49.5 mg of NaCl and 25.4 mg of Triton X-100 into a 100 mL volumetric flask. A volume of purified water was added to the flask, and the resulting mixture was sonicated until all solids were dissolved. Approximately 1.632 mL of HCl solution (1 M) was then added, and sufficient purified water was added to the target volume to adjust the pH to 1.8. The solution was then diluted to volume with purified water, mixed well, and the pH was measured to be 1.83.

[0148] FaSSIF buffer was prepared by weighing 340.8 mg of NaH2PO4, 43.0 mg of NaOH, and 619.6 mg of NaCl into a 100 mL volumetric flask. A volume of purified water was added to the flask, and the resulting mixture was sonicated until the solids dissolved. A second volume of purified water was added to the flask to adjust the pH to 6.5. The solution was diluted with another volume of purified water, mixed, and the pH was measured to be 6.54. FaSSIF medium was prepared by weighing 110.4 mg of SIF powder into a 50 mL volumetric flask and adding a volume of FaSSIF dissolution buffer. The resulting mixture was sonicated until the SIF powder dissolved. The mixture was then diluted to a volume with FaSSIF dissolution buffer and mixed well. The FaSSIF solution was allowed to equilibrate at room temperature for 2 hours before use.

[0149] FeSSIF dissolution buffer was prepared by weighing 0.82 mL of glacial acetic acid, 404.9 mg of NaOH, and 1188.2 mg of NaCl into a 100 mL volumetric flask. A volume of purified water was added to the flask, and the mixture was sonicated until the solids were dissolved. A second volume of purified water was added to the target volume to adjust the pH to 5.0. The solution was diluted with a volume of purified water, mixed well, and the pH was measured to be 4.96. FeSSIF medium was prepared by weighing 559.6 mg of SIF powder into a 50 mL volumetric flask. A volume of FeSSIF dissolution buffer was added to the flask, and the resulting mixture was sonicated to dissolve the SIF powder. A second volume of FeSSIF dissolution buffer was added, and the resulting mixture was mixed well. The FeSSIF solution was equilibrated at room temperature for 2 hours before use.

[0150] An Agilent 1260 high performance liquid chromatography (HPLC) instrument equipped with a DAD detector, a Waters H-Class UPLC with a PDA detector was used in the solubility measurements using the conditions listed in Table 6.

[0151] [Table 6]

[0152] Approximately 10 mg of gentisate Form 2 of Compound 1 (calculated by the weight of the free base of Compound 1) was placed in a 3 mL glass vial, and 1 mL of each medium (water, SGF, FaSSIF, and FeSSIF) was added to each glass vial. Each vial was capped and rotated at 37°C (25 rpm) for 4 hours. The suspension was then extracted into a centrifuge tube, followed by centrifugation (10,000 rpm, 37°C, 5 minutes) and filtration (0.22 μm PTFE membrane). The resulting supernatant was analyzed by HPLC, and the pH was measured. The solubility of the polymorphic forms of gentisate Form 2 of Compound 1 measured above was as listed in Table 7.

[0153] [Table 7]

[0154] Example 9: Tablets containing the gentisate form of Compound 1 Tablets containing 261 mg of Compound 1 gentisate Form 2 (200 mg of Compound 1 free base) were prepared according to the following method: The amount of each ingredient used was as set forth in Table 8, and each ingredient, except for magnesium stearate and sodium stearyl fumarate, was passed through a #20 mesh sieve before use. Magnesium stearate and sodium stearyl fumarate were passed through a #35 mesh sieve before use.

[0155] [Table 8]

[0156] A 10-liter jar was charged with one-third of the sieved microcrystalline cellulose and blended at 20 rpm for 5 minutes. The jar then contained an additional one-third of the microcrystalline cellulose, the gentisate form of Compound 1, and the remaining one-third of the microcrystalline cellulose (used to rinse the bag containing the gentisate form of Compound 1), the initial amount of crospovidone Kollidon CL, the initial amount of colloidal silicon dioxide Aerosil 200 Pharma, and the initial amount of sodium stearyl fumarate. The resulting mixture was then blended at 20 rpm for 20 minutes. The blended mixture was then passed through a #20 mesh sieve, and the sieved mixture was added to the 10-liter jar and blended at 20 rpm for an additional 15 minutes. The initial amount of magnesium stearate was then added to the center of the blended mixture and blended at 20 rpm for an additional 5 minutes. The resulting mixture was then discharged into a low-density polyethylene bag.

[0157] The roller compactor was equipped with the following settings: (a) roller width: 40 mm, (b) upper roller: knurled, (c) lower roller: knurled, (d) coarse RFG screen: 2.0 mm wire, (e) fine RFG screen: 1.0 mm wire. The roller compactor feed hopper was then filled with the blended mixture, and the material was processed using the roller compactor parameters listed in Table 9. Granules (1454.25 g) were collected in a low-density polyethylene bag.

[0158] [Table 9]

[0159] The granules (1454.25 g) produced by the roller compactor were placed in a 10-liter bottle, to which sodium stearyl fumarate (7.725 g), colloidal silica dioxide Aerosil 200 Pharma (7.78 g), and crospovidone Kollidon CL (22.503 g) were added, and the resulting mixture was blended at 20 rpm for 15 minutes. Magnesium stearate (7.72 g) was added to the blended mixture, and the mixture was blended at 20 rpm for 5 minutes to obtain the final blend.

[0160] The tablet press was equipped with (a) upper punch, lower punch, and die = 19 mm x 8.51 mm, (b) punch number = 2, and (c) fill cam size = 8 mm to 14 mm. The tablet press was set with the parameters listed in Table 10 to produce tablets within the target parameters listed in Table 11.

[0161] [Table 10]

[0162] [Table 11]

[0163] Example 10: Preparation of Form 2, the gentisate salt form of Compound 1 A reactor under nitrogen at about 25°C was charged with 2.8 kg of a 2:98 mixture of water / n-propanol and 1.73 kg of the trifluoroacetic acid form of Compound 1. The resulting mixture was stirred at a temperature of about 25°C until the solids dissolved, after which 1.31 kg of 2,5-dihydroxybenzoic acid (1.31 kg) was added, followed by an additional portion of the 2:98 water / n-propanol mixture. The resulting mixture was stirred at about 25°C until the solids dissolved, after which a portion of Form 2 of the gentisate salt form of Compound 1 (about 0.02 kg) was added to the mixture, which was stirred for an additional about 30 minutes at about 25°C. n-Heptane (about 22 kg) was added to the resulting mixture, and the resulting mixture was stirred for an additional about 16 hours at about 25°C. The resulting solid was filtered, washed, and dried under vacuum in an oven set at a temperature of about 40°C to about 50°C and a relative humidity of about 30% to about 40% to yield Form 2 (about 2 kg), the gentisate salt form of Compound 1.

[0164] Example 11: X-ray Powder Diffraction (XRPD) Analysis of Form 2 of the Gentisate Salt Form of Compound 1 A sample of Form 2, the gentisate salt form of Compound 1, prepared using a method similar to that described in Example 10, was analyzed by XRPD and showed the peaks listed in Table 12. The error associated with each °2θ position was determined to be ±0.2 °θ.

[0165] [Table 12]

[0166] Example 12: Stability of Form 2 of the gentisate salt form of Compound 1 To measure the stability of Form 2 of the gentisate salt form of Compound 1 under storage conditions, samples of Form 2 of the gentisate salt form of Compound 1 were placed in double low-density polyethylene bags with a desiccant between the bags, each placed in a high-density polyethylene drum. One drum was stored at 5°C, and samples of material were taken at 1 month and 3 months. The samples were analyzed for the presence of impurities. The other drum was stored at 25°C and 60% relative humidity (RH), and samples of material were taken at 1 month and 3 months. The samples were analyzed for the presence of impurities. The amount of Form 2 of the gentisate salt form of Compound 1 and the amount of any impurities in each sample were measured by reverse-phase high-performance liquid chromatography using the test condition set and solvent gradient described in Tables 13 and 14. The samples were tested to determine the amount of Form 2 remaining at each time point, and the measurements were performed according to USP <941> X-ray powder diffraction (XRPD) was carried out according to

[0167] [Table 13]

[0168] [Table 14]

[0169] The results of the stability studies for Form 2 of the gentisate salt form of Compound 1 under both storage conditions are shown in Table 15.

[0170] [Table 15]

[0171] The results showed that Form 2, the gentisate salt form of Compound 1, was stable for up to 3 months when stored at 5°C and for up to 3 months when stored at 25°C and 60% RH.

[0172] Embodiment Embodiment 1: Compound 1:

[0173] [ka] A pharmaceutically acceptable form of the compound of formula (I) selected from the gentisate form and the succinate form.

[0174] Embodiment 2: A pharmaceutically acceptable form according to embodiment 1, which is a gentisate salt form.

[0175] Embodiment 3: A pharmaceutically acceptable form according to embodiment 2, wherein the gentisate form comprises gentisate.

[0176] Embodiment 4: The pharmaceutically acceptable form of embodiment 2, wherein the gentisate form comprises a co-crystal of gentisate.

[0177] Embodiment 5: A pharmaceutically acceptable form according to any one of embodiments 1 to 4, wherein in the gentisate form, the molar ratio of compound 1 to gentisic acid is about 1:1.

[0178] Embodiment 6: A pharmaceutically acceptable form according to any one of embodiments 1 to 5, wherein the gentisate form is a hydrate.

[0179] Embodiment 7: The pharmaceutically acceptable form of embodiment 6, wherein the hydrate is selected from a hemihydrate, a monohydrate, and a dihydrate.

[0180] Embodiment 8: The pharmaceutically acceptable form of embodiment 7, wherein the hydrate is a hemihydrate.

[0181] Embodiment 9: The pharmaceutically acceptable form of embodiment 7, wherein the hydrate is a monohydrate.

[0182] Embodiment 10: The pharmaceutically acceptable form of embodiment 7, wherein the hydrate is a dihydrate.

[0183] Embodiment 11: A pharmaceutically acceptable form according to any one of embodiments 1 to 10, which is a solid.

[0184] Embodiment 12: The pharmaceutically acceptable form of embodiment 11, wherein the solid is a crystalline solid.

[0185] Embodiment 13: The pharmaceutically acceptable form of embodiment 12, wherein the crystalline solid exhibits a peak at 9.25±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

[0186] Embodiment 14: The pharmaceutically acceptable form of embodiment 13, wherein the crystalline solid further exhibits peaks at 6.97±0.2 degrees 2θ, 20.53±0.2 degrees 2θ, and 26.08±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

[0187] Embodiment 15: The pharmaceutically acceptable form of embodiment 13 or 14, wherein the crystalline solid further exhibits peaks at 14.61±0.2 degrees 2θ and 18.89±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

[0188] Embodiment 16: The pharmaceutically acceptable form of any one of embodiments 12 to 15, wherein the crystalline solid further comprises a peak at about 150°C to about 170°C in a differential scanning calorimetry pattern.

[0189] Embodiment 17: The pharmaceutically acceptable form of embodiment 16, wherein the crystalline solid comprises a peak at about 150°C to about 165°C in a differential scanning calorimetry pattern.

[0190] Embodiment 18: The pharmaceutically acceptable form of embodiment 16, wherein the crystalline solid comprises a peak at about 161°C to about 162°C in a differential scanning calorimetry pattern.

[0191] Embodiment 19: The pharmaceutically acceptable form of any one of embodiments 12 to 18, wherein the crystalline solid exhibits a mass loss of about 1% to about 5% in thermogravimetric analysis when heated from about 31°C to about 150°C.

[0192] Embodiment 20: The pharmaceutically acceptable form of embodiment 19, wherein the crystalline solid further exhibits a mass loss of about 3% to about 5% in thermogravimetric analysis upon heating from about 31°C to about 150°C.

[0193] Embodiment 21: The pharmaceutically acceptable form of embodiment 19, wherein the crystalline solid further exhibits a mass loss of about 5% in thermogravimetric analysis upon heating from about 31°C to about 150°C.

[0194] Embodiment 22: A pharmaceutically acceptable form according to any one of embodiments 1 to 21, which exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0195] Embodiment 23: A pharmaceutically acceptable form according to embodiment 22, which exhibits a solubility of at least 10 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0196] Embodiment 24: A pharmaceutically acceptable form according to embodiment 23, which exhibits a solubility of at least 15 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0197] Embodiment 25: A pharmaceutically acceptable form according to embodiment 23, which exhibits a solubility of at least 20 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0198] Embodiment 26: A pharmaceutically acceptable form according to embodiment 23, which exhibits a solubility of at least 25 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0199] Embodiment 27: A pharmaceutically acceptable form according to any one of embodiments 1 to 21, which exhibits a solubility of about 10 mg / mL to about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0200] Embodiment 28: A pharmaceutically acceptable form according to embodiment 27, which exhibits a solubility of about 15 mg / mL to about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0201] Embodiment 29: A pharmaceutically acceptable form according to embodiment 27, which exhibits a solubility of about 20 mg / mL to about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0202] Embodiment 30: A pharmaceutically acceptable form according to embodiment 27, which exhibits a solubility of about 25 mg / mL to about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37°C.

[0203] Embodiment 31: A pharmaceutically acceptable form according to any one of embodiments 1 to 30, which exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 2.5 and a temperature of 37°C.

[0204] Embodiment 32: A pharmaceutically acceptable form according to embodiment 31, which exhibits a solubility of at least 7.5 mg / mL in an aqueous solution having a pH of 2.5 and a temperature of 37°C.

[0205] Embodiment 33: A pharmaceutically acceptable form according to embodiment 31, which exhibits a solubility of at least 10 mg / mL in an aqueous solution having a pH of 2.5 and a temperature of 37°C.

[0206] Embodiment 34: A pharmaceutically acceptable form according to any one of embodiments 1 to 33, which exhibits a solubility of at least 1 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37°C.

[0207] Embodiment 35: A pharmaceutically acceptable form according to embodiment 34, which exhibits a solubility of at least 2.5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37°C.

[0208] Embodiment 36: A pharmaceutically acceptable form according to embodiment 34, which exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37°C.

[0209] Embodiment 37: A pharmaceutically acceptable form according to embodiment 34, which exhibits a solubility of at least 7.5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37°C.

[0210] Embodiment 38: A pharmaceutically acceptable form of any one of embodiments 1 to 37, which exhibits less than about 10% degradation when stored at 25°C and 60% relative humidity for at least 7 days.

[0211] Embodiment 39: The pharmaceutically acceptable form of embodiment 38, which exhibits less than about 1% degradation when stored at 25°C and 60% relative humidity for at least 7 days.

[0212] Embodiment 40: A pharmaceutically acceptable form of any one of embodiments 1 to 39, which exhibits less than about 10% degradation when stored at 40° C. and 75% relative humidity for at least 7 days.

[0213] Embodiment 41: The pharmaceutically acceptable form of embodiment 40, which exhibits less than about 1% degradation when stored at 40°C and 75% relative humidity for at least 7 days.

[0214] Embodiment 42: A pharmaceutically acceptable form according to any one of embodiments 1 to 41, which exhibits less than about 10% degradation when stored at 60°C for one day or more.

[0215] Embodiment 43: The pharmaceutically acceptable form of embodiment 42, which exhibits less than about 1% degradation when stored at 60°C for one day or more.

[0216] Embodiment 44: The pharmaceutically acceptable form of embodiment 12, wherein the crystalline solid exhibits a peak at 8.26±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

[0217] Embodiment 45: The pharmaceutically acceptable form of embodiment 44, wherein the crystalline solid further exhibits a peak at 26.43±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

[0218] Embodiment 46: The pharmaceutically acceptable form of embodiment 44 or 45, wherein the crystalline solid further exhibits peaks at 15.81±0.2 degrees 2θ and 15.40±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

[0219] Embodiment 47: A pharmaceutically acceptable form according to any one of embodiments 44 to 46, wherein the crystalline solid further exhibits peaks at 14.94±0.2 degrees 2θ and 20.44±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

[0220] Embodiment 48: A pharmaceutically acceptable form according to embodiment 1, which is a succinate salt form.

[0221] Embodiment 49: A pharmaceutically acceptable form according to embodiment 48, wherein the succinate form comprises a succinate salt.

[0222] Embodiment 50: The pharmaceutically acceptable form of embodiment 48, wherein the succinate salt form comprises a co-crystal of succinate salt.

[0223] Embodiment 51: A pharmaceutical composition comprising an amount of a pharmaceutically acceptable form of compound 1 according to any one of embodiments 1 to 50, and one or more pharmaceutically acceptable excipients.

[0224] Embodiment 52: A method for inhibiting the activity of CD73 in a cell, comprising contacting CD73 in the cell with an effective amount of a pharmaceutically acceptable form of any one of embodiments 1 to 50.

[0225] Embodiment 53: A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable form of any one of embodiments 1 to 50.

[0226] Embodiment 54: A method of treating cancer in a subject, comprising administering to the subject the pharmaceutical composition of embodiment 51.

[0227] Embodiment 55: The method of embodiment 53 or 54, wherein the cancer is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, kidney cancer, multiple myeloma, or lymphoma.

[0228] Embodiment 56: The method of any one of embodiments 53 to 55, wherein the cancer expresses CD73.

[0229] Embodiment 57: The method of any one of embodiments 53 to 56, wherein CD73 is upregulated in the cancer being treated.

[0230] Embodiment 58: The method of any one of embodiments 52 to 57, further comprising administering one or more second therapeutic agents.

[0231] Embodiment 59: The method of embodiment 58, wherein the second therapeutic agent is a chemotherapeutic agent or an immunotherapeutic agent.

[0232] Embodiment 60: A method of treating an infection in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable form of any one of embodiments 1 to 50.

[0233] Embodiment 61: A method of treating an infection in a subject, comprising administering to the subject the pharmaceutical composition of embodiment 51.

[0234] Embodiment 62: The method of embodiment 60 or 61, wherein the infection is a viral infection.

[0235] Embodiment 63: The method of embodiment 60 or 61, wherein the infection is a parasitic infection.

[0236] Embodiment 64: A method of treating a neurodegenerative disease in a subject, comprising administering to the subject a pharmaceutically acceptable form of any one of embodiments 1 to 50.

[0237] Embodiment 65: A method of treating a neurodegenerative disease in a subject, comprising administering to the subject the pharmaceutical composition of embodiment 51.

[0238] Embodiment 66: The method of embodiment 64 or 65, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, or autism.

[0239] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. Compound 1: 【Chemical 1】 A pharmaceutically acceptable form of the compound of formula (I) selected from the gentisate form and the succinate form.

2. 2. The pharmaceutically acceptable form of claim 1, which is a gentisate salt form.

3. 3. The pharmaceutically acceptable form of claim 2, wherein the molar ratio of compound 1 to gentisic acid in the gentisate form is about 1:

1.

4. 4. The pharmaceutically acceptable form of claim 3, wherein the gentisate form is a crystalline solid.

5. 5. The pharmaceutically acceptable form of claim 4, wherein the crystalline solid exhibits a peak at 9.25±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

6. 6. The pharmaceutically acceptable form of claim 5, wherein the crystalline solid further exhibits peaks at 6.97±0.2°2θ, 20.53±0.2°2θ, and 26.08±0.2°2θ in an x-ray powder diffraction (XRPD) pattern.

7. 7. The pharmaceutically acceptable form of claim 6, wherein the crystalline solid further exhibits peaks at 14.61±0.2 degrees 2θ and 18.89±0.2 degrees 2θ in an x-ray powder diffraction (XRPD) pattern.

8. 8. The pharmaceutically acceptable form of any one of claims 5 to 7, wherein the crystalline solid further comprises a peak at about 150°C to about 170°C in a differential scanning calorimetry pattern.

9. 9. The pharmaceutically acceptable form of any one of claims 1 to 8, which exhibits less than about 10% degradation when stored at 25°C and 60% relative humidity for at least 7 days.

10. 2. The pharmaceutically acceptable form of claim 1, which is a succinate salt form.

11. A pharmaceutical composition comprising an amount of a pharmaceutically acceptable form of compound 1 according to any one of claims 1 to 10, and one or more pharmaceutically acceptable excipients.

12. 11. A method for inhibiting the activity of CD73 in a cell, comprising contacting CD73 in said cell with an effective amount of a pharmaceutically acceptable form of any one of claims 1 to 10.

13. 11. A method of treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of a pharmaceutically acceptable form according to any one of claims 1 to 10.

14. 12. A method of treating cancer in a subject, comprising administering to the subject the pharmaceutical composition of claim 11.

15. 15. The method of claim 13 or 14, wherein the cancer is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, kidney cancer, multiple myeloma, or lymphoma.

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