WO2025193759A1

WO2025193759A1 - Solid forms of an azolopyrimidine compound

Info

Publication number: WO2025193759A1
Application number: PCT/US2025/019455
Authority: WO
Inventors: Ernest CARRA
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2024-03-12
Filing date: 2025-03-11
Publication date: 2025-09-18
Anticipated expiration: 2026-09-12

Abstract

The present disclosure relates generally to salts and solid forms of etrumadenant, and compositions thereof.

Description

SOLID FORMS OF AN AZOLOPYRIMIDINE COMPOUND

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit to U.S. Provisional Patent Application No. 63/564,406, filed March 12, 2024, which is hereby incorporated by reference in its entirety.

FIELD

[0002] The present disclosure relates generally to salts and solid forms of etrumadenant, and compositions thereof.

BACKGROUND

[0003] Adenosine is a purine nucleoside compound comprising a complex of adenine and a ribose sugar molecule (ribofuranose). Adenosine occurs naturally in mammals and plays important roles in several biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate). Adenosine also serves in processes associated with vasodilation, including cardiac vasodilation, and acts as a neuromodulator (i.e., it is thought to be involved in promoting sleep). In addition to its involvement in these biochemical processes, adenosine is used as a therapeutic antiarrhythmic agent to treat, for example, supraventricular tachycardia. Tumors evade host responses by inhibiting immune function and promoting tolerance, and adenosine has been shown to play an important role in mediating tumor evasion of the immune system. Adenosine signaling through A^ARS and A2BRS, expressed on a variety of immune cell subsets and endothelial cells, has been established as having an important role in protecting tissues during inflammatory responses. As such, under certain conditions adenosine protects tumors from immune destruction (see, e.g., Fishman, P et al. (2009) Handb Exp Pharmacol 193:399-441).

[0004] The adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. The four types of adenosine receptors in humans are referred to as Ai, A2A, AZB, and A3. Modulation of Ai has been proposed for the management and treatment of, for example, neurological disorders, asthma, and heart and renal failure; A2A antagonists have been proposed for the management and treatment of, for example, Parkinson’ s disease; modulation of AZB has been proposed for the management and treatment of, for example, chronic pulmonary diseases, including asthma; and modulation of As has been proposed for the management and treatment of, for example, asthma and chronic obstructive pulmonary diseases, glaucoma, cancer, and stroke.

[0005] Historically, modulators of adenosine receptors have been nonselective. This is acceptable in certain indications, such as where the endogenous agonist adenosine, which acts on all four adenosine receptors in cardiac tissue, is administered parenterally for the treatment of severe tachycardia. However, the use of subtype selective adenosine receptor agonists and antagonists provides the potential for achieving desired outcomes while minimizing or eliminating adverse effects. [0006] Etrumadenant (also known as AB928), has been reported to be a sub-type selective adenosine receptor antagonist. Etrumadenant is a potent antagonist of AZAR and AZBR with a potency on both receptors of less than 10 nM.

SUMMARY

[0007] Provided herein are salts and solid forms of etrumadenant (Compound I):

[0008] Also disclosed herein are pharmaceutical compositions comprising salts and solid forms of Compound I and methods of using the same in the treatment of diseases, disorders, or conditions mediated at least in part by the adenosine AZA receptor and/or the adenosine AZB receptor.

[0009] Some embodiments provide for a crystalline form of a salt of Compound I.

[0010] Some embodiments provide for a crystalline form of freebase Compound I (Compound I freebase Form IV), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.9, 21.0, and 21.2 °20 as determined on a diffractometer using Cu-Ka radiation.

[0011] Some embodiments provide for a crystalline form of an oxalic acid salt of Compound I (Compound I oxalic acid salt), characterized by an X-ray powder diffractogram comprising peaks (+0.2°) at 6.7, 16.7, and 29.6 °29 as determined on a diffractometer using Cu-Ka radiation.

[0012] Some embodiments provide for a crystalline form of a benzenesulfonic acid salt of Compound I (Compound I benzenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.8, 17.7, and 22.1 °20 as determined on a diffractometer using Cu-Ka radiation.

[0013] Some embodiments provide for a crystalline form of a succinic acid salt of Compound I (Compound I succinic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 15.0, 22.1, and 31.6 °20 as determined on a diffractometer using Cu-Ka radiation.

[0014] Some embodiments provide for a crystalline form of an ethanedisulfonic acid salt of Compound I (Compound I ethanedisulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.4, 14.3, and 21.5 °20 as determined on a diffractometer using Cu-Ka radiation.

[0015] Some embodiments provide for a crystalline form of a p-toluenesulfonic acid salt of Compound I (Compound I p-toluenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.1, 8.7, and 17.9 °20 as determined on a diffractometer using Cu-Ka radiation. [0016] Some embodiments provide for a crystalline form of a 2,5-dihydroxybenzoic acid salt of Compound I (Compound I 2,5-dihydroxybenzoic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.3, 10.5, and 15.7 °20 as determined on a diffractometer using Cu-Ka radiation.

[0017] Some embodiments provide for a crystalline form of a 2-naphthalenesulfonic acid salt of Compound I (Compound 12-naphthalenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.0, 18.3, and 18.7 °20 as determined on a diffractometer using Cu-Ka radiation.

[0018] Some embodiments provide for a crystalline form of a gentisic acid salt of Compound I (Compound I gentisic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.5, 13.3, and 19.5 °20 as determined on a diffractometer using Cu-Ka radiation.

[0019] Some embodiments provide for a crystalline form of a HC1 salt of Compound I (Compound I HC1 salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 22.5, 24.4, and 26.7 °20 as determined on a diffractometer using Cu-Ka radiation.

[0020] Also provided herein are pharmaceutical compositions comprising a crystalline form of Compound I as disclosed herein and a pharmaceutically acceptable carrier.

[0021] Also provided herein are methods of treating a disease, disorder, or condition, mediated at least in part by the adenosine A2A receptor (AIAR) and/or the adenosine A^B receptor (AZB ), comprising administering a therapeutically effective amount of a crystalline form of Compound I or a pharmaceutical composition disclosed herein to a subject in need thereof.

[0022] Also provided herein are methods of treating cancer, comprising administering a therapeutically effective amount of a crystalline form of Compound I or a pharmaceutical composition disclosed herein to a subject in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of Compound I freebase Form IV.

[0024] FIG. 2 shows a differential scanning calorimetry (DSC) curve of Compound I freebase Form IV.

[0025] FIG. 3 shows thermogravimetric analysis (TGA) of Compound I freebase Form IV.

[0026] FIG. 4 shows an X-ray powder diffraction (XRPD) pattern of Compound I oxalic acid salt.

[0027] FIG. 5 shows a differential scanning calorimetry (DSC) curve of Compound I oxalic acid salt.

[0028] FIG. 6 shows thermogravimetric analysis (TGA) of Compound I oxalic acid salt.

[0029] FIG. 7 shows an X-ray powder diffraction (XRPD) pattern of Compound I benzenesulfonic acid salt. [0030] FIG. 8 shows a differential scanning calorimetry (DSC) curve of Compound I benzenesulfonic acid salt.

[0031] FIG. 9 shows thermogravimetric analysis (TGA) of Compound I benzenesulfonic acid salt.

[0032] FIG. 10 shows an X-ray powder diffraction (XRPD) pattern of Compound I succinic acid salt.

[0033] FIG. 11 shows a differential scanning calorimetry (DSC) curve of Compound I succinic acid salt.

[0034] FIG. 12 shows thermogravimetric analysis (TGA) of Compound I succinic acid salt.

[0035] FIG. 13 shows an X-ray powder diffraction (XRPD) pattern of Compound I ethanedisulfonic acid salt.

[0036] FIG. 14 shows a differential scanning calorimetry (DSC) curve of Compound I ethanedisulfonic acid salt.

[0037] FIG. 15 shows thermogravimetric analysis (TGA) of Compound I ethanedisulfonic acid salt.

[0038] FIG. 16 shows an X-ray powder diffraction (XRPD) pattern of Compound I yj-toluenesulfonic acid salt.

[0039] FIG. 17 shows a differential scanning calorimetry (DSC) curve of Compound I p-toluenesulfonic acid salt.

[0040] FIG. 18 shows thermogravimetric analysis (TGA) of Compound I /?-toluenesulfonic acid salt.

[0041] FIG. 19 shows an X-ray powder diffraction (XRPD) pattern of Compound I 2,5-dihydroxybenzoic acid salt.

[0042] FIG. 20 shows a differential scanning calorimetry (DSC) curve of Compound I 2,5- dihydroxybenzoic acid salt.

[0043] FIG. 21 shows thermogravimetric analysis (TGA) of Compound 12,5-dihydroxybenzoic acid salt.

[0044] FIG. 22 shows an X-ray powder diffraction (XRPD) pattern of Compound I 2-naphthalenesulfonic acid salt.

[0045] FIG. 23 shows a differential scanning calorimetry (DSC) curve of Compound I 2- naphthalenesulfonic acid salt.

[0046] FIG. 24 shows thermogravimetric analysis (TGA) of Compound 12-naphthalenesulfonic acid salt.

[0047] FIG. 25 shows an X-ray powder diffraction (XRPD) pattern of Compound I gentisic acid salt.

[0048] FIG. 26 shows a differential scanning calorimetry (DSC) curve of Compound I gentisic acid salt.

[0049] FIG. 27 shows thermogravimetric analysis (TGA) of Compound I gentisic acid salt.

[0050] FIG. 28 shows an X-ray powder diffraction (XRPD) pattern of Compound I HC1 salt.

[0051] FIG. 29 shows a differential scanning calorimetry (DSC) curve of Compound I HC1 salt. [0052] FIG. 30 shows thermogravimetric analysis (TGA) of Compound I HC1 salt.

[0053] FIG. 31 shows an X-ray powder diffraction (XRPD) pattern of Compound I fumaric acid salt.

[0054] FIG. 32 shows a differential scanning calorimetry (DSC) curve of Compound I fumaric acid salt.

[0055] FIG. 33 shows a an X-ray powder diffraction (XRPD) pattern of Compound I phosphate salt Form I.

[0056] FIG. 34 shows a differential scanning calorimetry (DSC) curve of Compound I phosphate salt Form

I.

[0057] FIG. 35 shows thermogravimetric analysis (TGA) of Compound I phosphate salt Form I.

[0058] FIG. 36 shows a an X-ray powder diffraction (XRPD) pattern of Compound I phosphate salt Form H.

[0059] FIG. 37 shows a differential scanning calorimetry (DSC) curve of Compound I phosphate salt Form

II.

[0060] FIG. 38 shows thermogravimetric analysis (TGA) of Compound I phosphate salt Form II.

DETAILED DESCRIPTION

[0061] Etrumadenant (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl]-lH-l,2,3-triazol-

4-yl)pyrimidin-4-yl]-2-methylbenzonitrile), designated herein as Compound I, has the following formula:

[0062] Etrumadenant (also known as AB928) is a selective, dual antagonist of the adenosine 2A receptor (A2AR) and the adenosine 2B receptor (AZBR). Methods for making etrumadenant are known in the art. See, for example, WO 2018/136700, WO 2020/018680, and WO 2020/247789, the disclosures of which are incorporated herein by reference in their entirety.

[0063] Unless otherwise specified, reference to Compound I is intended to encompass the compound per se, or a salt, such as a pharmaceutically acceptable salt, solid form, solvate, and/or hydrate thereof.

Definitions

[0064] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0065] The term “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, reference to “the compound” includes a plurality of such compounds, and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0066] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 2.5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”.

[0067] Recitation of numeric ranges of values throughout the disclosure is intended to serve as a shorthand notation of referring individually to each separate value falling within the range inclusive of the values defining the range, and each separate value is incorporated in the specification as it were individually recited herein.

[0068] Forms of Compound I or salts, co-crystals, solvates, or hydrates thereof are provided herein. In one embodiment, reference to a form of Compound I or a salt, co-crystal, solvate, or hydrate thereof means that at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I or a salt, co-crystal, solvate, or hydrate thereof is present in a composition in the designated form. For instance, in one embodiment, reference to Compound I oxalic acid salt means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound I is present in a composition as Compound I oxalic acid salt.

[0069] The term “solid form” refers to a type of solid-state material that includes amorphous as well as crystalline forms. The term “crystalline form” refers to polymorphs as well as solvates, hydrates, etc. The term “polymorph” refers to a particular crystal structure having particular physical properties such as X-ray diffraction, melting point, and the like.

[0070] As used herein, the term “salt” refers to a compound formed by the reaction of an acid and a base, resulting in the formation of a positively charged cation and a negatively charged anion. In general, a salt is defined as a compound that is formed by the combination of positively and negatively charged ions, where the charges of the ions result in a neutral compound. Salts can be either inorganic or organic. As used herein, the term “salt” includes partially or fully ionized salt forms. In some embodiments, the salt is fully ionized.

[0071] The term “solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term “solvate” includes a “hydrate” (i.e., a complex formed by combination of water molecules with molecules or ions of the solute), hemi-hydrate, channel hydrate, etc. Some examples of solvents include, but are not limited to, acetonitrile, methanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.

[0072] The term “desolvated” refers to a Compound I form that is a solvate as described herein, and from which solvent molecules have been partially or completely removed. Desolvation techniques to produce desolvated forms include, without limitation, exposure of a Compound I form (solvate) to a vacuum, subjecting the solvate to elevated temperature, exposing the solvate to a stream of gas, such as air or nitrogen, or any combination thereof. Thus, a desolvated or “unsolvated” Compound I form can be anhydrous, i.e., completely without solvent molecules, or partially solvated wherein solvent molecules arc present in stoichiometric or non-stoichiometric amounts.

[0073] The term “amorphous” refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (glass transition).

[0074] Any formula or structure given herein, including Compound I, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. It is understood that for any given atom, the isotopes may be present essentially in ratios according to their natural occurrence, or one or more particular atoms may be enhanced with respect to one or more isotopes using synthetic methods known to one skilled in the art. Thus, hydrogen includes for example H, ²H, ³H; carbon includes for example ^HC, ¹²C, ¹³C, ¹⁴C; oxygen includes for example ¹⁶O, ¹⁷O, ¹⁸O; nitrogen includes for example ¹³N, ¹⁴N, N; sulfur includes for example ³²S, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁷S, ³⁸S; fluoro includes for example ¹⁷F, ¹⁸F, ¹⁹F; chloro includes for example ³⁵C1, ³⁶C1, ³⁷C1, ³⁸C1, ³⁹C1; and the like.

[0075] As used herein, the terms “treat,” “treating,” “therapy,” “therapies,” and like terms refer to the administration of material, e.g., any one or more solid, crystalline or polymorphs of Compound I as described herein in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated.

[0076] The term “administering” refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow -release device e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. [0077] As used herein, the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as adenosine 2A receptor (AZAR) and/or adenosine 2B receptor (A2BR) activity. For example, an agonist or antagonist of a particular biomolecule modulates the activity of the adenosine 2A receptor (A2AR) and/or adenosine 2B receptor (A2BR) by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity, of the biomolecule. Such activity is typically indicated in terms of an inhibitory concentration (IC50) or excitation concentration (EC50) of the compound for an inhibitor or activator, respectively. In some embodiments, the term “modulating” or “modulate” refers to inhibiting or inhibition of, for example, adenosine 2A receptor (AZAR) and/or adenosine 2B receptor (AZBR).

[0078] As used herein, the term “composition” refers to a pharmaceutical preparation suitable for administration to an intended subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof. The composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier or excipient.

[0079] As used herein, the term “subject” or “patient” refers to a living organism that is treated with compounds as described herein, including, but not limited to, any mammal, such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.

[0080] The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables. The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropyl amine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, diethanolamine, 2-dimethylamino ethanol, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0081] In the present context, the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated. For example, an effective amount is an amount sufficient to effectuate a beneficial or desired clinical result. The effective amounts can be provided all at once in a single administration or in fractional amounts that provide the effective amount in several administrations. The precise determination of what would be considered an effective amount may be based on factors individual to each subject, including their size, age, injury, and/or disease or injury being treated, and amount of time since the injury occurred or the disease began. One skilled in the art will be able to determine the effective amount for a given subject based on these considerations which are routine in the art.

[0082] In some embodiments, the phrase “substantially shown in Figure” or “substantially as shown in Figure” as applied to an X-ray powder diffractogram is meant to include a variation of ± 0.2 °29 or ± 0.1 °20, as applied to DSC thermograms is meant to include a variation of ± 3 “Celsius, and as applied to thermogravimetric analysis (TGA) is meant to include a variation of ± 2% in weight loss.

[0083] “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 99.9% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 99.5% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 99% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 98% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 97% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 96% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 95% of the material is the referenced polymorph.

Salts and Forms of Compound I

[0084] As described generally above, the present disclosure provides salts and solid forms, such as crystalline forms, of etrumadenant (also referred herein as Compound I), and salts, solvates, or hydrates thereof. Crystalline forms of Compound I and salts, solvates, or hydrates thereof, and other forms (e.g., amorphous forms) of Compound I and salts, solvates, or hydrates thereof are collectively referred to herein as “forms of Compound I.” [0085] In some embodiments, Compound I is in free form, e.g., a free base. In some embodiments, Compound I is a salt. In some embodiments, Compound I is a pharmaceutically acceptable salt. In some embodiments, Compound I is a solvate. In some embodiments, Compound I is a hydrate. In some embodiments, Compound I is unsolvated. In some embodiments, Compound I is an anhydrate. In some embodiments, provided is a substantially pure form of a solid form of Compound I as described herein. In some embodiments, provided is a substantially pure form of a crystalline form of Compound I as described herein.

Forms of Compound I

Compound 1 freebase Form IV

[0086] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) freebase Form IV (Compound I freebase Form IV), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.9, 21.0, and 21.2 °20 as determined on a diffractometer using Cu-Ka radiation.

[0087] In some embodiments, Compound I freebase Form IV is further characterized by: i) one or more additional peaks (±0.2°) at 7.9, 18.2, or 18.4 °20; ii) a diffractogram substantially as shown in FIG. 1; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 95 °C and an endothermic onset at about 192 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 2; v) thermogravimetric analysis (TGA) showing a weight loss of about 2.9% from about 25-150 °C; vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 3; or vii) a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a = 7.4312(2) A, b = 12.1841(4) A, c = 13.6454(9) A, a = 107.552(4)°, = 99.070(4)°, y = 100.500(2)°, V = 1128.07(9) A³.

[0088] In some embodiments, Compound I freebase Form IV is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (+0.2°) at 7.9, 18.2, or 18.4 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I freebase Form IV is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (+0.2°) at 14.9, 25.1, or 27.0 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I freebase Form IV is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 1.

[0089] In some embodiments, Compound I freebase Form IV is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 95 °C and an endothermic onset at about 192 °C. In some embodiments, Compound I freebase Form IV is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 111 °C and an endothermic peak at about 194 °C. In some embodiments, Compound I freebase Form IV is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 2.

[0090] In some embodiments, Compound I freebase Form IV is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 2.9% from about 25-150 °C. In some embodiments, Compound I freebase Form IV is further characterized by a thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 3.

[0091] In some embodiments, Compound I freebase Form IV is further characterized by a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a = 7.4312(2) A, b = 12.1841(4) A, c = 13.6454(9) A, a = 107.552(4)°, 0 = 99.070(4)°, y = 100.500(2)°, V = 1128.07(9) A³.

[0092] In some embodiments, Compound I freebase Form IV comprise about 1 mole equivalent of water.

Compound I oxalic acid salt

[0093] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl]-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) oxalic acid salt (Compound I oxalic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.7, 16.7, and 29.6 °20 as determined on a diffractometer using Cu-Ka radiation.

[0094] In some embodiments, Compound I oxalic acid salt is further characterized by: i) one or more additional peaks (±0.2°) at 6.1, 13.3, or 26.6 °20; ii) a diffractogram substantially as shown in FIG. 4; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 129 °C and an endothermic onset at about 145 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 5; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in

FIG. 6.

[0095] In some embodiments, Compound I oxalic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (+0.2°) at 6.1, 13.3, or 26.6 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I oxalic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 13.5, 13.6, or 20.3 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I oxalic acid salt is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 4.

[0096] In some embodiments, Compound I oxalic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 129 °C and an endothermic onset at about 145 °C. In some embodiments, Compound I oxalic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 137 °C and an endothermic peak at about 147 °C. In some embodiments, Compound I oxalic acid salt is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 5.

[0097] In some embodiments, Compound I oxalic acid salt is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 6. In some embodiments, Compound I oxalic acid salt is unsolvated.

Compound 1 benzenesulfonic acid salt

[0098] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) benzenesulfonic acid salt (Compound I benzenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.8, 17.7, and 22.1 °20 as determined on a diffractometer using Cu-Ka radiation.

[0099] In some embodiments, Compound I benzenesulfonic acid salt is further characterized by: i) one or more additional peaks (±0.2°) at 20.7, 23.8, or 25.5 °20; ii) a diffractogram substantially as shown in FIG. 7; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 209 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 8; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 9.

[0100] In some embodiments, Compound I benzenesulfonic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 20.7, 23.8, or 25.5 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I benzene sulfonic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 11.9, 13.5, or 31.1 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I benzenesulfonic acid salt is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 7.

[0101] In some embodiments, Compound I benzenesulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 209 °C. In some embodiments, Compound I benzenesulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 209 °C. In some embodiments, Compound I benzenesulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 8. [0102] In some embodiments, Compound I benzenesulfonic acid salt is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 9. In some embodiments, Compound I benzenesulfonic acid salt is unsolvated.

Compound I succinic acid salt

[0103] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) succinic acid salt (Compound I succinic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 15.0, 22.1, and 31 .6 °20 as determined on a diffractometer using Cu-Ka radiation.

[0104] In some embodiments, Compound I succinic acid salt is further characterized by: i) one or more additional peaks (±0.2°) at 18.3, 20.0, or 25.0 °20; ii) a diffractogram substantially as shown in FIG. 10; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 145 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 11; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in

FIG. 12.

[0105] In some embodiments, Compound I succinic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (+0.2°) at 18.3, 20.0, or 25.0 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I succinic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 7.9, 12.5, and 19.2 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I succinic acid salt is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 10.

[0106] In some embodiments, Compound I succinic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 145 °C. In some embodiments, Compound I succinic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 148 °C. In some embodiments, Compound I succinic acid salt is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 11.

[0107] In some embodiments, Compound I succinic acid salt is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 12. In some embodiments, Compound I succinic acid salt is unsolvatcd.

Compound 1 ethanedisulfonic acid salt

[0108] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) ethanedisulfonic acid salt (Compound I ethanedisulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.4, 14.3, and 21.5 °20 as determined on a diffractometer using Cu-Ka radiation.

[0109] In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by: i) one or more additional peaks (±0.2°) at 10.7, 20.8, or 21.1 °20; ii) a diffractogram substantially as shown in FIG. 13; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 53 °C and an endothermic onset at about 156 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 14; v) thermogravimetric analysis (TGA) showing a weight loss of about 10.8% from about 30- 150 °C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 15.

[0110] In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 10.7, 20.8, or 21.1 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 16.9, 23.1 , or 28.9 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 13.

[0111] In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 53 °C and an endothermic onset at about 156 °C. In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 85 °C and an endothermic peak at about 177 °C. In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 14.

[0112] In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 10.8% from about 30-150 °C. In some embodiments, Compound I ethanedisulfonic acid salt is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 15. In some embodiments, Compound I ethanedisulfonic acid salt is solvated.

Compound I p-toluenesulfonic acid salt

[0113] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl]-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) p-toluenesulfonic acid salt (Compound I p-toluenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.1, 8.7, and 17.9 °20 as determined on a diffractometer using Cu-Ka radiation.

[0114] In some embodiments, Compound I p-toluenesulfonic acid is further characterized by i) one or more additional peaks (±0.2°) at 7.6, 15.2, or 19.9 °20; ii) a diffractogram substantially as shown in FIG. 16; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 148 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 17; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 18.

[0115] In some embodiments, Compound I -toluenesul Ionic acid is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 7.6, 15.2, or 19.9 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I p- toluenesulfonic acid is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 16.9, 21.7, or 26.5 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I p-toluenesulfonic acid is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 16.

[0116] In some embodiments, Compound I / oluenesul Ionic acid is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 148 °C. In some embodiments, Compound I p-toluenesulfonic acid is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 152 °C. In some embodiments, Compound I p- toluenesulfonic acid is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 17.

[0117] In some embodiments, Compound I p-toluenesulfonic acid is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 18. In some embodiments, Compound I / oluenesul Ionic acid is unsolvated.

Compound 12,5-dihydroxybenzoic acid salt

[0118] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl } - 1 H- 1 ,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) 2,5-dihydroxybenzoic acid salt (Compound I 2,5-dihydroxybenzoic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.3, 10.5, and 15.7 °20 as determined on a diffractometer using Cu-Ka radiation.

[0119] In some embodiments, Compound 12,5-dihydroxybenzoic acid salt is further characterized by i) one or more additional peaks (±0.2°) at 14.5, 18.3, or 26.5 °20; ii) a diffractogram substantially as shown in FIG. 19; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 26 °C and an endothermic onset at about 141 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 20; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 21.

[0120] In some embodiments, Compound I 2,5-dihydroxybenzoic acid salt is further characterized by an X- ray powder diffractogram comprising one or more additional peaks (±0.2°) at 14.5, 18.3, or 26.5 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I 2,5- dihydroxybenzoic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 17.4, 19.4, or 27.8 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound 12,5-dihydroxybenzoic acid salt is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 19.

[0121] In some embodiments, Compound I 2,5-dihydroxybenzoic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 26 °C and an endothermic onset at about 141 °C. In some embodiments, Compound 12,5-dihydroxybenzoic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 35 °C and an endothermic peak at about 142 °C. In some embodiments, Compound I 2,5- dihydroxybenzoic acid salt is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 20.

[0122] In some embodiments, Compound I 2,5-dihydroxybenzoic acid salt is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 21. In some embodiments, Compound I 2,5-dihydroxybenzoic acid salt is unsolvated.

Compound 12-naphthalenesulfonic acid salt

[0123] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) 2-naphthalenesulfonic acid salt (Compound 12-naphthalenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.0, 18.3, and 18.7 °20 as determined on a diffractometer using Cu-Ka radiation.

[0124] In some embodiments, Compound I 2-naphthalenesulfonic acid salt is further characterized by i) one or more additional peaks (±0.2°) at 9.9, 17.9, or 27.1 °20; ii) a diffractogram substantially as shown in FIG. 22; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 25 °C, an endothermic onset at about 137 °C, and an endothermic onset at about 185 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 23; v) thermogravimetric analysis (TGA) showing a weight loss of about 2.7% from about 30-150

C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in

FIG. 24.

[0125] In some embodiments, Compound I 2-naphthalenesulfonic acid salt is further characterized by an X- ray powder diffractogram comprising one or more additional peaks (±0.2°) at 9.9, 17.9, or 27.1 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I 2- naphthalenesulfonic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 11.3, 13.0, or 21.4 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I 2-naphthalcncsulfonic acid salt is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 22.

[0126] In some embodiments, Compound I 2-naphthalenesulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 25 °C, an endothermic onset at about 137 °C, and an endothermic onset at about 185 °C. In some embodiments, Compound I 2-naphthalenesulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 39 °C, an endothermic peak at about 147 °C, and an endothermic peak at about 214 °C. In some embodiments, Compound I 2-naphthalenesulfonic acid salt is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 23.

[0127] In some embodiments, Compound I 2-naphthalenesulfonic acid salt is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 2.7% from about 30-150 °C. In some embodiments, Compound I 2-naphthalenesulfonic acid salt is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 24. In some embodiments, Compound I 2-naphthalenesulfonic acid salt is solvated.

Compound I gentisic acid salt

[0128] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) gentisic acid salt (Compound I gentisic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.5, 13.3, and 19.5 °20 as determined on a diffractometer using Cu-Ka radiation.

[0129] In some embodiments, Compound I gentisic acid salt is further characterized by i) one or more additional peaks (±0.2°) at 5.5, 15.2, or 16.5 °20; ii) a diffractogram substantially as shown in FIG. 25; iii) a differential scanning calorimetry (DSC) curve comprising a split endothermic onset at about 142 °C and at about 157 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 26; v) thermogravimetric analysis (TGA) showing a weight loss of about 4.2% from about 30-150 °C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in

FIG. 27.

[0130] In some embodiments, Compound I gentisic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 5.5, 15.2, or 16.5 °29 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I gentisic acid salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 23.0, 26.1, or 27.7 °29 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I gentisic acid salt is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 25.

[0131] In some embodiments, Compound I gentisic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising a split endothermic onset at about 142 °C and at about 157 °C. In some embodiments, Compound I gentisic acid salt is further characterized by a differential scanning calorimetry (DSC) curve comprising a split endothermic peak at about 150 °C and at about 160 °C. In some embodiments, Compound I gentisic acid salt is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 26.

[0132] In some embodiments, Compound I gentisic acid salt is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 4.2% from about 30-150 °C. In some embodiments, Compound I gentisic acid salt is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 27. In some embodiments, Compound I gentisic acid is solvated.

Compound I HCl salt

[0133] In one embodiment, provided is crystalline (3-[2-amino-6-(l-{[6-(2-hydroxypropan-2-yl)pyridin-2- yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) HCl salt (Compound I HCl salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 22.5, 24.4, and 26.7 °29 as determined on a diffractometer using Cu-Ka radiation.

[0134] In some embodiments, Compound I HCl salt is further characterized by i) one or more additional peaks (±0.2°) at 17.8, 18.8, or 31.2 °29; ii) a diffractogram substantially as shown in FIG. 28; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 45 °C, an endothermic onset at about 113 °C, and a split endothermic onset at about 175 °C and at about 194 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 29; v) thermogravimetric analysis (TGA) showing a weight loss of about 2.9% from about 25-50 °C and a weight loss of about 17.9% from about 50-175 °C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 30. [0135] In some embodiments, Compound I HC1 salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 17.8, 18.8, or 31.2 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I HC1 salt is further characterized by an X-ray powder diffractogram comprising one or more additional peaks (±0.2°) at 17.1, 20.3, or 21.1 °20 as determined on a diffractometer using Cu-Ka radiation. In some embodiments, Compound I HC1 salt is further characterized by an X-ray powder diffractogram substantially as shown in FIG. 28.

[0136] In some embodiments, Compound I HC1 salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 45 °C, an endothermic onset at about 113 °C, and a split endothermic onset at about 175 °C and at about 194 °C. In some embodiments, Compound I HC1 salt is further characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak at about 67 °C, an endothermic peak at about 118 °C, and a split endothermic peak at about 188 °C and at about 204 °C. In some embodiments, Compound I HC1 salt is further characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 29.

[0137] In some embodiments, Compound I HC1 salt is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 2.9% from about 25-50 °C and a weight loss of about 17.9% from about 50-175 °C. In some embodiments, Compound I HC1 salt is further characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 30. In some embodiments, Compound I HC1 salt is solvated.

Compositions

[0138] In some embodiments, provided is a composition comprising a salt or solid form of (3-[2-amino-6- ( 1 -{ [6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl } - 1H- 1 ,2,3-triazol-4-yl)pyrimidin-4-yl]-2- methylbenzonitrile) (Compound I), as described herein.

[0139] In one embodiment, provided is a composition comprising a salt or solid form of (3-[2-amino-6-(l- { [6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2- methylbenzonitrile) (Compound I), or salt or solvate thereof, wherein at least 50% to 99% (.e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in a composition is in the designated salt, solid form, crystalline form, or crystalline salt form.

[0140] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{[6-(2-hydroxypropan- 2-yl)pyridin-2-yl]methyl]-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) freebase (Compound I freebase Form IV), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound I freebase Form IV.

[0141] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{[6-(2-hydroxypropan- 2-yl)pyridin-2-yl]methyl ) - 1H- 1 ,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) oxalic acid salt (Compound I oxalic acid salt), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound I oxalic acid salt.

[0142] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{ [6-(2-hydroxypropan- 2-yl)pyridin-2-yl]methyl } - 1H- 1 ,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) benzenesulfonic acid salt (Compound I benzenesulfonic acid salt) or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound I benzenesulfonic acid salt.

[0143] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{ [6-(2-hydroxypropan-2- yl)pyridin-2-yl] methyl } - 1 H- 1 ,2, 3-triazol-4-y l)pyrimidin-4-yl] -2-methylbenzonitrile) succinic acid salt (Compound I succinic acid salt), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound I succinic acid salt.

[0144] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{ [6-(2-hydroxypropan-2- yl)pyridin-2-yl] methyl } - 1 H- 1 ,2, 3-triazol-4-y l)pyrimidin-4-yl] -2-methylbenzonitrile) ethanedisulfonic acid salt (Compound I ethanedisulfonic acid salt), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound I ethanedisulfonic acid salt.

[0145] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{ [6-(2-hydroxypropan-2- yl)pyridin-2-yl] methyl } - 1H- l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) p-toluenesu Ifonic acid salt (Compound I p-toluenesulfonic acid salt), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound I p- toluenesulfonic acid salt.

[0146] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{ [6-(2-hydroxypropan-2- yl)pyridin-2-yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) 2, 5-dihydroxy benzoic acid salt (Compound 12,5-dihydroxybenzoic acid salt), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound 12,5- dihydroxybenzoic acid salt.

[0147] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{ [6-(2-hydroxypropan-2- yl)pyridin-2-yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) 2-naphthalenesulfonic acid salt (Compound 12-naphthalenesulfonic acid salt), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound 12- naphthalenesulfonic acid salt.

[0148] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{ [6-(2-hydroxypropan-2- yl)pyridin-2-yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) gentisic acid salt (Compound I gentisic acid salt), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound I gentisic acid salt.

[0149] In one embodiment, provided is a composition comprising (3-[2-amino-6-(l-{ [6-(2-hydroxypropan-2- yl)pyridin-2-yl]methyl}-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile) HC1 salt (Compound I HC1 salt), or solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I present in the composition is Compound I HC1 salt.

[0150] In some embodiments, the composition is a pharmaceutical composition which further comprises a pharmaceutically acceptable excipient.

Pharmaceutical Compositions and Administration

[0151] In some embodiments, the chemical entity disclosed herein (e.g., a salt or solid form of Compound I, and salts, solvates, or hydrates thereof, as described herein) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. Some embodiments provide for a pharmaceutical composition comprising a crystalline form as described herein and a pharmaceutically acceptable carrier.

[0152] In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene -block polymers, and wool fat. Cyclodextrins such as a-, , and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- -cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of chemical entities described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art: for example, see Remington: The Science and Practice of Pharmacy, 22^nd Edition (Pharmaceutical Press, London, UK. 2012).

Routes of Administration and Composition Components

[0153] In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.

[0154] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0155] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In general, the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0156] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars or sodium chloride, may be included. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0157] Sterile injectable solutions are prepared by incorporating the active compounds (i.e. the chemical entities described herein) in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, exemplary methods of preparation arc vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0158] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[0159] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0160] In other embodiments, the chemical entities described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms).

[0161] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0162] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, poly vinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’S, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0163] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0164] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules, sterility is not required. The USP/NF standard is usually sufficient.

[0165] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0166] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

[0167] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

Dosages

[0168] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Proper dosage for a particular situation can be determined by one skilled in the medical arts. In some cases, the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0169] In some embodiments, the chemical entities described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0. 1 mg/Kg to about 200 mg/Kg; from about 0. 1 mg/Kg to about 150 mg/Kg; from about 0. 1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from about 0. 1 mg/Kg to about 10 mg/Kg; from about 0. 1 mg/Kg to about 5 mg/Kg; from about 0. 1 mg/Kg to about 1 mg/Kg; from about 0. 1 mg/Kg to about 0.5 mg/Kg), wherein the Kg refers to the body weight of the patient.

Regimens

[0170] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0171] In some embodiments, the period of administration of a chemical entity described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a chemical entity described herein is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a chemical entity described herein is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the chemical entity described herein is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a chemical entity described herein followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

Methods of Treatment

[0172] This disclosure provides methods of treating diseases, disorders, or conditions that would benefit from inhibition of AZAR, AZBR, or both AZAR and AZBR- While particular uses are described in detail hereafter, it is to be understood that the present disclosure is not so limited. Furthermore, although general categories of particular diseases, disorders, and conditions are set forth hereafter, some of the diseases, disorders, and conditions may be a member of more than one category, and others may not be a member of any of the disclosed categories.

[0173] In some embodiments, provided is a method of treating a disease, disorder, or condition, mediated at least in part by the adenosine AZA receptor (AZAR) and/or the adenosine AZB receptor (AZBR), comprising administering a therapeutically effective amount of a crystalline form or a pharmaceutical composition as disclosed herein.

[0174] In some embodiments, the diseases, disorders, or conditions described herein are mediated, at least in part, by AZAR. In some embodiments, the diseases, disorders, or conditions described herein are mediated, at least in part, by AZBR. In some embodiments, the diseases, disorders, or conditions described herein are mediated, at least in part, by both AZAR and AZBR receptors.

[0175] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein may be administered in an amount effective to treat or prevent cardiovascular diseases, CNS-related and neurological disorders, immune-related disorders, metabolic diseases, microbial-related disorders, or oncology and oncology-related diseases. Cardiovascular diseases, CNS-related and neurological disorders, immune-related disorders, metabolic diseases, microbial-related disorders, or oncology and oncology-related diseases for which treatment with an AZAR, AZBR, or both AZAR and AZBR inhibitor may be beneficial are described in W02018136700 and W02020018680A1, the disclosures of which are incorporated herein by reference. [0176] In accordance with the present disclosure, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent cancer (e.g., carcinomas, sarcomas, leukemias, lymphomas, myelomas, etc.).

[0177] Provided herein are methods of treating cancer comprising administering a salt, form, composition, or pharmaceutical composition as described herein to a subject in need thereof.

[0178] In certain embodiments, the cancer may be locally advanced and/or unresectable, metastatic, or at risk of becoming metastatic. Alternatively, or in addition, the cancer may be recurrent or no longer responding to a treatment, such as a standard of care treatment known to one of skill in the art. In various embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein may be used in an adjuvant setting or neoadjuvant setting. Alternatively or in addition, the salts, forms, compositions, or pharmaceutical compositions described herein may be used as a first line treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent cancer may be used as a second line, third line, or greater line of treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. When indicated as a second line or greater treatment, in some embodiments an earlier line of therapy included a checkpoint inhibitor.

[0179] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent hematological malignancies. Exemplary types of cancer affecting the hematopoietic system include leukemias, lymphomas and myelomas, including acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocyte leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute monocytic leukemia, Hodgkin’s and NonHodgkin’ s lymphoma, Diffuse large B Cell lymphoma, and multiple myeloma.

[0180] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent solid tumors. The solid tumor may be, for example, ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colon cancer, prostate cancer, cervical cancer, biliary cancer, pancreatic cancer, gastric cancer, esophageal cancer, liver cancer (hepatocellular carcinoma), kidney cancer (renal cell carcinoma), head-and-neck tumors, mesothelioma, melanoma, sarcomas, central nervous system (CNS) hemangioblastomas, and brain tumors (e.g., gliomas, such as astrocytoma, oligodendroglioma and glioblastomas). In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent lung cancer, genitourinary cancer, gastrointestinal cancer, or a combination thereof.

[0181] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, or gynecological cancer. In some embodiments, the cancer is bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is castrate resistant prostate cancer, esophageal adenocarcinoma, non-small cell lung carcinoma, pancreatic ductal adenocarcinoma, prostate adenocarcinoma, or urothelial cancer.

[0182] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent breast cancer. In further embodiments, the breast cancer is hormone receptor positive (e.g., ERa-positive breast cancer, PR-positive breast cancer, ERa-positive and PR-positive breast cancer), HER2 positive breast cancer, HER2 over-expressing breast cancer, or any combination thereof. In still further embodiments, the breast cancer is triple negative breast cancer. In still further embodiments, the breast cancer is locally advanced or metastatic triple negative breast cancer, optionally with disease progression on a prior treatment.

[0183] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions according to this disclosure are useful in the treatment of genitourinary cancer. In further embodiments, the genitourinary cancer is gynecologic cancer. In still further embodiments, the gynecologic cancer is endometrial cancer, cervical cancer, ovarian cancer or fallopian tube carcinoma. In still further embodiments, the gynecologic cancer is locally advanced or metastatic ovarian cancer, optionally with disease progression on a prior treatment. In still further embodiments, the genitourinary cancer is urothelial carcinoma, optionally advanced or metastatic urothelial carcinoma. In some embodiments, the genitourinary cancer is advanced or metastatic MTAP-deficient urothelial carcinoma. In still further embodiments, the genitourinary cancer is prostate cancer. In still further embodiments, the genitourinary cancer is adenocarcinoma of the prostate, optionally that is eligible for radical prostatectomy. In still further embodiments, the genitourinary cancer is castration-resistant prostate cancer, optionally metastatic castrate-resistant prostate cancer. In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent kidney cancer. In further embodiments, the kidney cancer is renal cell carcinoma. In still further embodiments, the renal cell carcinoma is clear cell renal carcinoma.

[0184] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions according to this disclosure arc useful in the treatment of kidney cancer. In further embodiments, the kidney cancer is renal cell carcinoma. In still further embodiments, the renal cell carcinoma is clear cell renal carcinoma.

[0185] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions according to this disclosure are useful in the treatment of liver cancer. In further embodiments, the liver cancer is hepatocellular carcinoma.

[0186] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions according to this disclosure are useful in the treatment of head and neck cancer. In further embodiments, the head and neck cancer is head and neck squamous cell carcinoma, optionally where the cancer has not been previously treated. [0187] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions according to this disclosure are useful in the treatment of skin cancer. In further embodiments, the skin cancer is melanoma.

[0188] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions according to this disclosure are useful in the treatment of lung cancer. In further embodiments, the lung cancer is mesothelioma, small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In still further embodiments, the NSCLC is lung squamous cell carcinoma or lung adenocarcinoma. In still further embodiments, the NSCLC is nonsquamous NSCLC that is metastatic, locally advanced, or recurrent with progression.

[0189] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent pancreatic cancer. In further embodiments, the pancreatic cancer is pancreatic neuroendocrine tumor or pancreatic adenocarcinoma.

[0190] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent a neuroendocrine tumor. In further embodiments, the neuroendocrine tumor is pancreatic neuroendocrine tumor, pheochromocytoma, paraganglioma, or a tumor of the adrenal gland.

[0191] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent brain cancer. In further embodiments, the brain cancer is a glioma. In still further embodiments, the glioma is an astrocytoma, an oligodendroglioma, or a glioblastoma.

[0192] In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein can be used to treat or prevent gastrointestinal (GI) cancer. In some embodiments, the GI cancer is a lower GI cancer, such as colon or rectal cancer. In some embodiments, the lower GI cancer is adenocarcinoma of the rectum, optionally non-metastatic adenocarcinoma of the rectum. In some embodiments, the lower GI cancer is colorectal adenocarcinoma that is metastatic, advanced, or recurrent with progression. In some embodiments, the GI cancer is an upper GI cancer, such as esophageal or gastric cancer. In further embodiments, the upper GI cancer is an adenocarcinoma, a squamous cell carcinoma, or any combination thereof. In still further embodiments, the upper GI cancer is esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJ), gastric adenocarcinoma (also referred to herein as “gastric cancer”) or any combination thereof, optionally wherein the upper GI cancer is metastatic, advanced, or recurrent with progression.

[0193] In some embodiments, provided is a method of treating cancer in a subject concomitantly receiving a CYP3A4 inhibitor or a P-gp inhibitor or in a subject that is a poor CYP3A4 metabolizer, said method comprising administering a therapeutically effective amount of a crystalline form or a pharmaceutical composition as disclosed herein to a subject in need thereof. [0194] In some embodiments, provided is a method of treating a disease, disorder, or condition, mediated at least in part by the adenosine AM receptor (AZAR) or the adenosine A2B receptor (AZBR) in a patient, wherein said patient is concomitantly receiving a CYP3A4 inhibitor or a P-gp inhibitor or the subject is a poor CYP3A4 metabolizer, the method comprising administering a therapeutically effective amount of a crystalline form or a pharmaceutical composition as disclosed herein.

[0195] The present disclosure also provides methods of treating or preventing other cancer-related diseases, disorders or conditions. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that arc associated, directly or indirectly, with cancer and non-canccrous proliferative disease, and includes, e.g., angiogenesis, precancerous conditions such as dysplasia, and non- cancerous proliferative diseases disorders or conditions, such as benign proliferative breast disease and papillomas. For clarity, the term(s) cancer-related disease, disorder and condition do not include cancer per se.

[0196] In general, the disclosed methods for treating or preventing cancer, or a cancer-related disease, disorder or condition, in a subject in need thereof comprise administering to the subject a salt, form, composition, or pharmaceutical composition described herein. In some embodiments, the present disclosure provides methods for treating or preventing cancer, or a cancer-related disease, disorder or condition with a salt, form, composition, or pharmaceutical composition described herein and at least one additional therapy, examples of which are set forth elsewhere herein.

Combination Therapy

[0197] This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0198] In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the chemical entities described herein.

[0199] In some embodiments, a chemical entity described herein can be administered in combination with one or more of additional therapeutic agents.

[0200] Exemplary therapies are described further below, as well as in WO2018/136700 and W02020/018680, the disclosures of which are incorporated herein by reference.

[0201] In some embodiments, provided is a method of treating cancer comprising administering a therapeutically effective amount of a crystalline form or a pharmaceutical composition as disclosed herein, and at least one additional therapeutic agent, to a subject in need thereof.

[0202] In some embodiments, one or more of the additional therapies is an additional treatment modality. Exemplary treatment modalities include but are not limited to surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy. [0203] In some embodiments, one or more of the additional therapies is a therapeutic agent. Exemplary therapeutic agents include chemotherapeutic agents, radiopharmaceuticals, hormone therapies, epigenetic modulators, ATP-adenosine axis-targeting agents, targeted therapies, signal transduction inhibitors, RAS signaling inhibitors, PI3K inhibitors, arginase inhibitors, HIF inhibitors, AXL inhibitors, PAK4 inhibitors, immunotherapeutic agents, cellular therapies, gene therapies, immune checkpoint inhibitors, and agonists of stimulatory or co-stimulatory immune checkpoints.

[0204] In some embodiments, one or more of the additional therapeutic agents is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but arc not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard: nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, pomalidomide, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pemetrexed, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2', 2"- trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel, nab paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin, carboplatin and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; anthracyclines and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises a chemotherapy regimen that includes one or more chemotherapeutic agents. In one embodiment, combination therapy comprises a chemotherapeutic regimen comprising one or more of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), platinum and platinum coordination complexes (e.g., cisplatin, carboplatin, oxaliplatin, etc.), a taxoid (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), and/or gemcitabine.

[0205] In some embodiments, one or more of the additional therapeutic agents is a radiopharmaceutical. A radiopharmaceutical is a form of internal radiation therapy in which a source of radiation (i.e., one or more radionuclide) is put inside a subject’s body. The radiation source can be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide 1-131, radium-223 dichloride, lobenguane iodine- 131, radioiodinated vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides comprise a radionuclide associated (e.g., by covalent or ionic interactions) with a molecule (“a targeting agent”) that specifically binds to a target on a cell, typically a cancer cell or an immune cell. The targeting agent may be a small molecule, a saccharide (inclusive of oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a saccharide (inclusive of oligosaccharides and polysaccharides), a lipid, a protein, or a peptide and the target is a tumor-associated antigen (enriched but not specific to a cancer cell), a tumorspecific antigen (minimal to no expression in normal tissue), or a neo-antigen (an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (i.e., an antigen enriched but not specific to a cancer cell), a tumor-specific antigen (i.e., an antigen with minimal to no expression in normal tissue), or a neo-antigen (i.e., an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). Non-limiting examples of targeted radionuclides include radionuclides attached to: somatostatin or peptide analogs thereof (e.g., 177Lu- Dotatate, etc.); prostate specific membrane antigen or peptide analogs thereof (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); a receptor’s cognate ligand, peptide derived from the ligand, or variants thereof (e.g., 188Re-labeled VEGF125-136 or variants thereof with higher affinity to VEGF receptor, etc.); and antibodies targeting tumor antigens (e.g., 1311-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), 1131-omburtamab, etc.).

[0206] In some embodiments, one or more of the additional therapeutic agents is a hormone therapy. Hormone therapies act to regulate or inhibit hormonal action on tumors. Examples of hormone therapies include, but are not limited to: selective estrogen receptor degraders such as fulvestrant, giredestrant, SAR439859, RG6171, AZD9833, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549; selective estrogen receptor modulators such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, toremifene; aromatase inhibitors such as anastrozole, exemestane, letrozole and other aromatase inhibiting 4(5)-imidazoles; gonadotropin-releasing hormone agonists such as nafareiin, triptorelin, goserelin; gonadotropin-releasing hormone antagonists such as degarelix; antiandrogens such as abiraterone, enzalutamide, apalutamide, darolutamide, llutamide, nilutamide, bicalutamide, leuprolide; 5a-reductase inhibitors such as finasteride, dutasteride; and the like. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent. In one embodiment, combination therapy comprises administration of enzalutamide.

[0207] In some embodiments, one or more of the additional therapeutic agents is an epigenetic modulator. An epigenetic modulator alters an epigenetic mechanism controlling gene expression, and may be, for example, an inhibitor or activator of an epigenetic enzyme. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HD AC) inhibitors. In one or more embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein are combined with DNA methyltransferase (DNMT) inhibitors or hypomethylating agents. Exemplary DNMT inhibitors include decitabine, zebularine and azacitadine. In one or more embodiments, combinations of the salts, forms, compositions, or pharmaceutical compositions described herein with a histone deacetylase (HD AC) inhibitor is also contemplated. Exemplary HD AC inhibitors include vorinostat, givinostat, abexinostat, panobinostat, belinostat and trichostatin A.

[0208] In some embodiments, one or more of the additional therapeutic agents is an ATP-adenosine axistargeting agent. ATP-adenosine axis-targeting agents alter signaling mediated by adenine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example by modulating the level of adenosine or targeting adenosine receptors. In certain embodiments, an ATP-adenosine axis-targeting agent is an inhibitor of an ectonucleotidase involved in the conversion of ATP to adenosine or an antagonist of adenosine receptor. Ectonucleotidases involved in the conversion of ATP to adenosine include the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, also known as CD39 or Cluster of Differentiation 39) and the ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or Cluster of Differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070 and quemliclustat (AB680). Exemplary anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleclumab (MEDI9447), NZV930, IPH5301, GS-1423, uliledlimab (TJD5, TJ004309), AB598, and BMS- 986179. In one embodiment, the present disclosure contemplates combination of the salts, forms, compositions, or pharmaceutical compositions described herein with a CD73 inhibitor such as those described in WO 2017/120508, WO 2018/067424, WO 2018/094148, and WO 2020/046813. In further embodiments, the CD73 inhibitor is quemliclustat.

[0209] In some embodiments, one or more of the additional therapeutic agents is a targeted therapy. In one aspect, a targeted therapy may comprise a chemotherapeutic agent, a radionuclide, a hormone therapy, or another small molecule drug attached to a targeting agent. The targeting agent may be a small molecule, a saccharide (inclusive of oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a saccharide (inclusive of oligosaccharides and polysaccharides), a lipid, a protein, or a peptide and the target is a tumor-associated antigen (enriched but not specific to a cancer cell), a tumor-specific antigen (minimal to no expression in normal tissue), or a neo-antigen (an antigen specific to the genome of a cancer cell generated by non- synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (enriched but not specific to a cancer cell), a tumor-specific antigen (minimal to no expression in normal tissue), or a neo-antigen (an antigen specific to the genome of a cancer cell generated by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody-drug conjugate comprising an antibody and a drug, wherein the antibody specifically binds to Trop-2, HER2, HER3, nectin-4, or Trop-2. Specific examples of a targeted therapy comprising an antibody and a small molecule drug include but are not limited to patritumab deruxtecan, sacituzumab govitecan-hziy, telisotuzumab vedotin, and trastuzumab deruxtecan. In other aspects, a targeted therapy may inhibit or interfere with a specific protein that helps a tumor grow and/or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, inhibitors of oncogenic transcription factors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, ATP-adenosine axis-targeting agents, AXL inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, HIF-2a inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. ATP-adenosine axis-targeting agents are described above, while other agents are described in further detail below.

[0210] In some embodiments, one or more of the additional therapeutic agents is a signal transduction inhibitor. Signal transduction inhibitors are agents that selectively inhibit one or more steps in a signaling pathway. Signal transduction inhibitors (STIs) contemplated by the present disclosure include but are not limited to: (i) BCR-ABL kinase inhibitors (e.g., imatinib); (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), including small molecule inhibitors (e.g., CLN-081, gefitinib, erlotinib, afatinib, icotinib, and osimertinib), and anti-EGFR antibodies: (iii) inhibitors of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, e.g., HER-2/neu receptor inhibitors (e.g., trastuzumab) and HER-3 receptor inhibitors; (iv) vascular endothelial growth factor receptor (VEGFR) inhibitors including small molecule inhibitors (e.g., axitinib, regorafenib, sunitinib and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib, XL092, etc.) and anti- VEGF antibodies (e.g., bevacizumab); (v) inhibitors of AKT family kinases or the AKT pathway (e.g., rapamycin); (vi) inhibitors of serine/threonine-protein kinase B-Raf (BRAF), such as, for example, vemurafenib, dabrafenib and encorafenib; (vii) inhibitors of rearranged during transfection (RET), including, for example, selpercatinib and pralsetinib; (viii) tyrosine-protein kinase Met (MET) inhibitors (e.g., tepotinib, tivantinib, cabozantinib and crizotinib); (ix) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib); (x) inhibitors of the RAS signaling pathway (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK) as described elsewhere herein; (xi) FLT-3 inhibitors (e.g., gilteritinib); (xii) inhibitors of Trop-2; (xiii) inhibitors of the JAK/STAT pathway, e.g., JAK inhibitors including tofacitinib and ruxolitinib, or STAT inhibitors such as napabucasin; (xiv) inhibitors of NF-kB; (xv) cell cycle kinase inhibitors (e.g., flavopiridol); (xvi) phosphatidyl inositol kinase (PI3K) inhibitors; (xix) protein kinase B (AKT) inhibitors (e.g., capivasertib, miransertib); (xx) platelet-derived growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, famitinib, ponatinib, axitinib, repretinib, etc.); and (xxi) insulin-like growth factor receptor (IGFR) inhibitors (e.g., erlotinib, afatinib, gefitinib, psimertinib, dacomitinib). In some embodiments, the additional therapeutic agent comprises an inhibitor of EGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-kB, PI3K, AKT, or any combination thereof. In some embodiments, the additional therapeutic agent comprises an inhibitor of EGFR and/or VEGFR.

[0211] In some embodiments, one or more of the additional therapeutic agents is a RAS signaling inhibitor. Oncogenic mutations in the RAS family of genes, e.g., HRAS, KRAS, and NRAS, are associated with a variety of cancers. For example, mutations of G12C, G12D, G12V, G12A, G13D, Q61H, GDC and G12S, among others, in the KRAS family of genes have been observed in multiple tumor types. Direct and indirect inhibition strategies have been investigated for the inhibition of mutant RAS signaling. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, and include, but are not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORCl, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, BI1701963. Direct inhibitors of RAS mutants have also been explored, and generally target the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib, adagrasib, mRNA-5671 and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, S0S1 inhibitors, mTORCl inhibitors, SHP2 inhibitors, and AKT inhibitors. In other embodiments the one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0212] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of a phosphatidylinositol 3-kinase (PI3K), particularly an inhibitor of the PI3Ky isoform. PI3Ky inhibitors can stimulate an anti-cancer immune response through the modulation of myeloid cells, such as by inhibiting suppressive myeloid cells, dampening immune-suppressive tumor-infiltrating macrophages or by stimulating macrophages and dendritic cells to make cytokines that contribute to effective T cell responses thereby decreasing cancer development and spread. Exemplary PI3Ky inhibitors include copanlisib, duvelisib, AT- 104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein are combined with one or more PI3Ky inhibitor described in WO 2020/0247496A1.

[0213] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of arginase. Arginase has been shown to be either responsible for or participate in inflammation-triggered immune dysfunction, tumor immune escape, immunosuppression and immunopathology of infectious disease. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein are combined with one or more arginase inhibitor described in WO/2019/173188 and WO 2020/102646.

[0214] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of an oncogenic transcription factor or an activator of an oncogenic transcription factor repressor. Suitable agents may act at the expression level (e.g., RNAi, siRNA, etc.), through physical degradation, at the protein/protein level, at the protein/DNA level, or by binding in an activation/inhibition pocket. Nonlimiting examples include inhibitors of one or more subunit of the MLL complex (e.g., HDAC, DOT1L, BRD4, Mcnin, LEDGF, WDR5, KDM4C (JMJD2C) and PRMT1), inhibitors of hypoxia-induciblc factor (HIF) transcription factor, and the like.

[0215] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of a hypoxiainducible factor (HIF) transcription factor, particularly HIF-2a. Exemplary HIF-2a inhibitors include belzutifan, ARO-HIF2, PT-2385, and those described in WO 2021113436 and WO 2021188769. In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein are combined with one or more HIF-2a inhibitors described in WO 2021188769.

[0216] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of anexelekto (AXL). The AXL signaling pathway is associated with tumor growth and metastasis, and is believed to mediate resistance to a variety of cancer therapies. There are a variety of AXL inhibitors under development that also inhibit other kinases in the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases including MET, FLT3, RON and AURORA, among others. Exemplary multikinase inhibitors include sitravatinib, rebastinib, glesatinib, gilteritinib, merestinib, cabozantinib, foretinib, BMS777607, LY2801653, S49076, and RXDX-106. AXL specific inhibitors have also been developed, e.g., small molecule inhibitors including DS-1205, SGI-7079, SLC-391, dubermatinib, bemcentinib and DP3975; anti- AXL antibodies such as ADCT-601; and antibody drug conjugates (ADCs) such as BA3011. Another strategy to inhibit AXL signaling involves targeting AXL’s ligand, GAS6. For example, batiraxcept is under development as is a Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein are combined with one or more AXL inhibitors described in PCT/US2022/030227 or PCT/US2022/030230.

[0217] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of p21- activated kinase 4 (PAK4). PAK4 overexpression has been shown across a variety of cancer types, notably including those resistant to PD-1 therapies. While no PAK4 inhibitors have been approved, some are in development, and exhibit dual PAK4/NAMPT inhibitor activity, e.g., ATG-019 and KPT-9274. In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein are combined with a PAK4 selective inhibitor. In some embodiments, the salts, forms, compositions, or pharmaceutical compositions described herein arc combined with a PAK4/NAMPT dual inhibitor, e.g., ATG-019 or KPT- 9274. [0218] In some embodiments, one or more of the additional therapeutic agents is (i) an agent that inhibits the enzyme poly (ADP-ribose) polymerase (e.g., olaparib, niraparib and rucaparib, etc.); (ii) an inhibitor of the Bcl-2 family of proteins (e.g., venetoclax, navitoclax, etc.); (iii) an inhibitor of MCL-1; (iv) an inhibitor of the CD47-SIRPa pathway (e.g., the anti-CD47 antibody, magrolimab, etc.); (v) an isocitrate dehydrogenase (IDH) inhibitor, e.g., IDH-1 or IDH-2 inhibitor (e.g., ivosidenib, enasidenib, etc.).

[0219] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutic agents treat a disease by stimulating or suppressing the immune system. Immunotherapeutic agents useful in the treatment of cancers typically elicit or amplify an immune response to cancer cells. Non-limiting examples of suitable immunotherapeutic agents include: immunomodulators; cellular immunotherapies; vaccines; gene therapies; ATP-adenosine axis-targeting agents; immune checkpoint modulators; and certain signal transduction inhibitors. ATP-adenosine axis-targeting agents and signal transduction inhibitors are described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulators are described further below.

[0220] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a cytokine or chemokine, such as, IL-1, IL-2, IL-12, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa/b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharides (LPS); an organic or inorganic adjuvant that activates antigen-presenting cells and promote the presentation of antigen epitopes on major histocompatibility complex molecules agonists including, but not limited to Toll-like receptor (TLR) agonists, antagonists of the mevalonate pathway, agonists of STING; indoleamine 2, 3 -dioxygenase 1 (IDO1) inhibitors and immune-stimulatory oligonucleotides, as well as other T-cell adjuvants.

[0221] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a cellular therapy. Cellular therapies are a form of treatment in which viable cells are administered to a subject. In certain embodiments, one or more of the additional therapeutic agents is a cellular immunotherapy that activates or suppresses the immune system. Cellular immunotherapies useful in the treatment of cancers typically elicit or amplify an immune response. The cells can be autologous or allogenic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T-cells, etc.) collected from one or more subject. Alternatively, the cells can be “(re)programmed” allogenic immune cells produced from immune precursor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell precursor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells may be an expanded subset of cells with distinct effector functions and/or maturation markers (e.g., adaptive memory NK cells, tumor infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), Ml macrophages, M2 macrophages, etc.), may be genetically modified to target the cells to a specific antigen and/or enhance the cells’ anti-tumor effects (e.g., engineered T cell receptor (TCR) cellular therapies, chimeric antigen receptor (CAR) cellular therapies, lymph node homing of antigen-loaded dendritic cells, etc.), may be engineered to express of have increased expression of a tumor-associated antigen, or may be any combination thereof. Non-limiting types of cellular therapies include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy, and dendritic cell vaccines. Exemplary cellular immunotherapies include sipuleucel-T, tisagenlecleucel, lisocabtagene maraleucel, idecabtagene vicleucel, brexucabtagene autoleucel, and axicabtagene ciloleucel, as well as CTX110, JCAR015, JCAR017, MB- CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK-92/5.28.Z.

[0222] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically a gene therapy. Gene therapies comprise recombinant nucleic acids administered to a subject or to a subject’s cells ex vivo in order to modify the expression of an endogenous gene or to result in heterologous expression of a protein (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, micro RNA (miRNA) agents, viral or bacterial gene delivery, etc.), as well as gene editing therapies that may or may not comprise a nucleic acid component (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR/Cas nucleases, etc.), oncolytic viruses, and the like. Non-limiting examples of gene therapies that may be useful in cancer treatment include Gendicine® (rAd-p53), Oncorine® (rAD5-H101), talimogene laherparepvec, Mx-dnGl, ARO-HIF2 (Arrowhead), quaratusugene ozeplasmid (Immunogene), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0223] In some embodiments, one or more of the additional therapeutic agent is an immunotherapeutic agent, more specifically an agent that modulates an immune checkpoint. Immune checkpoints are a set of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). Immune checkpoints engage when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present disclosure contemplates the use of the salts, forms, compositions, or pharmaceutical compositions described herein in combination with agonists of stimulatory or costimulatory pathways and/or antagonists of inhibitory pathways. Agonists of stimulatory or co-stimulatory pathways and antagonists of inhibitory pathways may have utility as agents to overcome distinct immune suppressive pathways within the tumor microenvironment, inhibit T regulatory cells, reverse/prevent T cell anergy or exhaustion, trigger innate immune activation and/or inflammation at tumor sites, or combinations thereof.

[0224] In some embodiments, one or more of the additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term “immune checkpoint inhibitor” refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms “immune checkpoint inhibitor”, “checkpoint inhibitor” and “CPI” may be used herein interchangeably. Immune checkpoint inhibitors may antagonize an inhibitory or co-inhibitory immune checkpoint by interfering with receptor -ligand binding and/or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of cancer cells, that can be antagonized include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T-lymphocyte associated antigen 4); TIM-3 (T cell immunoglobulin and mucin domain containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); CD276 (B7- H3), PD-L2, Galectin 9, CEACAM-1, CD69, Galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and Killer Inhibitory Receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Also contemplated are other less well- defined immune checkpoints that have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x and VCTN1)).

[0225] In some embodiments, an immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist can be an antagonistic CTLA-4 antibody. Suitable antagonistic CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, as well as bispecific antibodies such as MEDI5752 and KN046.

[0226] In some embodiments, an immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonistic PD-1 antibody, small molecule or peptide. Suitable antagonistic PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, cemiplimab, ezabenlimab (BI-754091), MEDL0680 (AMP-514; WO2012/145493), nivolumab, pembrolizumab, pidilizumab (CT-011), pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab; as well as bi-specific antibodies such as LY3434172. In still further embodiments, the PD-1 antagonist can be a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl (AMP-224). In certain embodiments, an immune checkpoint inhibitor is zimberelimab.

[0227] In some embodiments, an immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist can be an antagonistic PD-L1 antibody. Suitable antagonistic PD-L1 antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and envafolimab as well as bi-specific antibodies such as LY3434172 and KN046.

[0228] In some embodiments, an immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist can be an antagonistic TIGIT antibody. Suitable antagonistic anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, EOS-448, etigilimab, IBI-929, JS006, M6223, ociperlimab, SEA-TGT, tiragolumab, vibostolimab; as well as bi-specific antibodies such as AGEN1777 and AZD2936. In certain embodiments, an immune checkpoint inhibitor is an antagonistic anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, an immune checkpoint inhibitor is domvanalimab or AB308. [0229] In some embodiments, an immune checkpoint inhibitor is a LAG-3 antagonist. In further embodiments, the LAG-3 antagonist can be an antagonistic LAG-3 antibody. Suitable antagonistic LAG-3 antibodies include, for example, BMS-986016 (W010/19570, WO14/08218), or IMP-731 or IMP-321 (W008/132601, WO09/44273).

[0230] In certain embodiments, an immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonistic B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, enoblituzumab, omburtumab, enoblituzumab, DS-7300a, ABBV-155, and SHR-A1811.

[0231] In some embodiments, one or more of the additional therapeutic agents activates a stimulatory or costimulatory immune checkpoint. Examples of stimulatory or co-stimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2.

[0232] In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonistic CD137 antibody. Suitable CD 137 antibodies include, for example, urelumab and utomilumab. In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS- 986153, BMS-986156, TRX-518 (W006/105021, W009/009116) and MK-4166 (WO11/028683). In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is an 0X40 agonist. In further embodiments, the 0X40 agonist can be an agonistic 0X40 antibody. Suitable 0X40 antibodies include, for example, MEDL6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, an agent that activates a stimulatory or co- stimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonistic CD40 antibody. In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0233] In some embodiments, one or more of the additional therapeutic agents is an agent that inhibits or depletes immune-suppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes the agent may be CSF-1R antagonists such as CSF-1R antagonist antibodies including emactuzumab or cabiralizumab.

[0234] In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, a radiopharmaceutical, a hormone therapy, an epigenetic modulator, a targeted agent, an immunotherapeutic agent, a cellular therapy, or a gene therapy. For example, in one embodiment, the present disclosure contemplates the use of the salts, forms, compositions, or pharmaceutical compositions described herein in combination with one or more chemotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeted agent, an immunotherapeutic agent, a cellular therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of the salts, forms, compositions, or pharmaceutical compositions described herein in combination with one or more chemotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeted agent, an immunotherapeutic agent, or a cellular therapy. In another embodiment, the present disclosure contemplates the use of the salts, forms, compositions, or pharmaceutical compositions described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agent, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeted agent, a chemotherapeutic agent, a cellular therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of the salts, forms, compositions, or pharmaceutical compositions described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cellular therapy. In another embodiment, the present disclosure contemplates the use of the salts, forms, compositions, or pharmaceutical compositions described herein in combination with one or more immune checkpoint inhibitors and/or one or more ATP-adenosine axis-targeting agents, and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cellular therapy. In further embodiments of the above (a) the targeted agent is a PI3K inhibitor, an arginase inhibitor, a HIF2a inhibitor, an AXL inhibitor, a PAK4 inhibitor, a VEGFR inhibitor, a VEGF kinase inhibitor, an anti-VEGF antibody, or an antibody -drug conjugate; (b) the immunotherapeutic agent is an ATP-adenosine axis-targeting agent or an immune checkpoint inhibitor; (c) the ATP-adenosine axis-targeting agent is a CD73 inhibitor or a CD39 inhibitor; (d) the ATP-adenosine axis-targeting agent is qucmliclustat or AB598; (c) the immunotherapeutic agent is an anti-PD-1 antagonist antibody, an anti-PD-Ll antagonist antibody, or an anti-TIGIT antagonist antibody; (f) the immunotherapeutic agent is zimberelimab, domvanalimab, or AB3O8; or (g) any combination thereof. In still further embodiments of the above, the present disclosure contemplates the use of the salts, forms, compositions, or pharmaceutical compositions described herein in combination with domvanalimab, etrumadenant, quemliclustat, zimberelimab, AB308, AB521, AB598, AB610, or any combination thereof.

[0235] Selection of the additional therapeutic agent(s) may be informed by current standard of care for a particular cancer and/or mutational status of a subject’s cancer and/or stage of disease. Detailed standard of care guidelines are published, for example, by National Comprehensive Cancer Network (NCCN). See, for instance, NCCN Colon Cancer v3.2021, NCCN Hepatobiliary Cancer v5.2021, NCCN Kidney Cancer, v3.2022, NCCN NSCLC v7.2021, NCCN Pancreatic Adenocarcinoma v2.2021, NCCN Esophageal and Esophagogastric Junction Cancers v4.2021, NCCN Gastric Cancer v5.2021, Cervical Cancer vl.2022, Ovarian Cancer /Fallopian Tube Cancer /Primary Peritoneal Cancer v3.2021. EXAMPLES

[0236] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

Instruments and Methods

[0237] X-ray powder diffraction (XRPD) analysis was conducted on a diffractometer (Panalytical XPERT- PRO, Panalytical B. V., Almelo, Netherlands) or (Empyrean, Malvern Panalytical B. V., Almelo, Netherlands) using copper radiation (Cu Ka, A = 1.541874 A). Samples were spread evenly on a zerobackground sample plate. The generator was operated at a voltage of 45 kV and amperage of 40 mA. Slits were Soller 0.02 rad, antiscatter 1.0°, and divergence. Scans were performed from 2 to 40° 20 with a 0.0167 step size. Data analysis was performed using X’Pert Data Viewer VI.2d (PANalytical B.V., Almelo, Netherlands).

[0238] Differential Scanning Calorimetry (DSC) was run on a Q2000 (TA Instruments, New Castle, DE) by loading 1-10 mg of material into a crimped or open Tzero standard aluminum pan and heating the sample at 10 °C/min from 20 to 400 °C or above. The sample and reference pans were under a 50 mL/min nitrogen purge. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0239] Thermogravimetric analysis (TGA) was used to evaluate sample weight loss as a function of temperature on either a Q5000 or Q500 (TA Instruments, New Castle, DE), by loading 1-10 mg of material onto a weigh pan and heating the sample to 4000 °C at a rate of 10 °C/min. The sample and reference pans were under a 60 mL/min and 40 mL/min nitrogen purge, respectively. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0240] Hygroscopicity was studied using dynamic vapor sorption (ProUmid SPS, ProUmid GmbH & Co. KG, Ulm, Germany). A sample of about 0.1 to 2 grams is added to a tared sample pan. Temperature is fixed at 25 °C and the relative humidity (RH) is reduced to 0%, then increased in 10% increments up to 90%, then back down to 0% in the same way. This cycle is repeated once. Each RH level is maintained for 2-4 hours. Data analysis was performed using Microsoft Excel.

[0241] List of abbreviations and acronyms

Abbreviation Meaning

° C degrees Celsius

ACN/MeCN acetonitrile EtOH ethanol

HC1 hydrochloric acid

H3PO4 phosphoric acid

IPA isopropanol

MeOH methanol

THF tetrahydrofuran

Example 1. Compound I freebase Form IV

[0242] Compound I freebase Form IV is a monohydrated phase. It was isolated when a 20 mL glass vial was charged with about 65 mg of Compound 1 freebase Form I as described in WO 2020/018680 and 2 mL of THF, forming a solution. In a separate 20 mL glass vial about 34 mg of phosphoric acid was dissolved in about 2 mL of water. About 1 mL of the acid solution was added to the THF solution. Next about 2 mL of heptane was added to the vial, forming a biphasic solution. The vial was stored capped and at rest at ambient temperature overnight. Solids formed overnight and were isolated and determined to be Form IV of the free base via single crystal analysis.

[0243] Compound I freebase Form IV was also isolated when amorphous material was heat cycled separately in IPA, MeCN, MeOH, and water.

[0244] Compound I freebase Form IV XRPD pattern is shown in FIG. 1 and is characterized by reflections at 6.9, 21.0, and 21.2 °20; additional peaks at 7.9, 18.2 , and 18.4 °20; and further additional peaks at 14.9, 25.1, and 27.0 °20.

[0245] The DSC curve is shown in FIG. 2 and the curve shows a broad endothermic event at about 95 °C and another endothermic event at about 192 °C. The TGA curve is shown in FIG. 3 and shows an approximately 2.9% mass loss from about 25-150 °C. Single crystal data was collected on Compound I freebase Form IV and the data are summarized in Table 1. The crystal system is triclinic, and the space group is Pl . The cell parameters and calculated volume are a = 7.4312(2) A, b = 12.1841(4) A, c = 13.6454(9) A, a = 107.552(4)°, |3 = 99.070(4)°, y = 100.500(2)°, V = 1128.07(9) A³. The formula weight is 444.50 g mol^-1 with Z = 2, resulting in a calculated density of 1.309 g cm^-3. The asymmetric unit contains one molecule of Compound I freebase Form IV and one water molecule.

Table 1. Crystal Structure Data Compound I Freebase Form IV

Empirical formula C23H24N8O2 Formula weight (g mol^-1) 444.50 Temperature (K) 299.7(4) Wavelength (A) 1.54184 Crystal system triclinic Space group Pl

Unit cell parameters a = 7.4312(2) A a = 107.552(4)° b = 12.1841(4) A ^ = 99.070(4)° c = 13.6454(9) A y = 100.500(2)°

Unit cell volume (A³) 1128.07(9) Cell formula units, Z 2 Calculated density (g cm ) 1.309 Absorption coefficient (mm^-1) 0.723 F(000) 468

Crystal size (mm³) 0.29 x 0.15 x 0.06

Reflections used for cell measurement 5972 d range for cell measurement 3.9090°-75.4860° Total reflections collected 7893

Index ranges 15; -17 < / <

3 range for data collection 75.749° Completeness to ftnax

Completeness to (9f_uii = 67.684° Absorption correction multi-scan

Transmission coefficient range 0.939-1.000 Refinement method full matrix least-squares on F²

Independent reflections 7893 [Fi_m = 0.0348, R_a = 0.0152]

Reflections [ />2o(7) ] 6851

Reflections / restraints / parameters 7893 / 10 / 354 Goodness-of-fit on F² S = 1.06

Final residuals [ />2o(7) ] R = 0.0547, F_w = 0.1622

Final residuals [ all reflections ] R = 0.0600, F_w = 0.1681 Largest diff. peak and hole (e A^-3) 0.355, -0.499 Max/mean shift/standard uncertainty 4.620 / 0.063

Example 2. Compound I oxalic acid salt

[0246] Compound I oxalic acid salt is an unsolvated phase. It was isolated when a 4 ml glass vial was charged with about 55 mg of Compound I freebase Form I as described in WO 2020/018680, about 12 mg of oxalic acid and around 4 ml of acetone, creating a suspension that was allowed to sit at ambient conditions for about 18 days.

[0247] Alternatively Compound I oxalic acid salt was isolated when a 20 ml glass vial was charged with about 179 mg of Compound I freebase Form I as described in WO 2020/018680, about 53 mg of oxalic acid and around 4 mL of acetonitrile, creating a suspension that was filtered and isolated.

[0248] Compound I oxalic acid salt XRPD pattern is shown in FIG. 4 and is characterized by reflections at 6.7, 16.7, and 29.6 °20,; additional peaks at 6.1, 13.3, and 26.6 °20; and further additional peaks at 13.5, 13.6, and 20.3 °20. [0249] The DSC curve of Compound I oxalic acid salt is shown in FIG. 5 and shows an endothermic event with onset at about 129 °C and an endothermic event at about 145 °C. The TGA curve of Compound I oxalic acid salt is shown in FIG. 6 and indicates the phase is unsolvated.

Example 3. Compound I benzenesulfonic acid salt

[0250] Compound I benzenesulfonic acid salt is an unsolvated phase. It was isolated when a 20 mL glass vial was charged with about 200 mg of Compound I freebase Form I as described in WO 2020/018680, about 86 mg of benzenesulfonic acid, and about 3 mL of acetonitrile, forming a solution which became a suspension after refrigeration. The solids were then isolated and dried.

[0251] Compound I benzenesulfonic acid salt XRPD pattern is shown in FIG. 7 and is characterized by reflections at 8.8, 17.7, and 22.1 °20; additional peaks at 20.7, 23.8, and 25.5 °20; and further additional peaks at 11.9, 13.5, and 31.1 °20.

[0252] The DSC curve of Compound I benzenesulfonic acid salt is shown in FIG. 8 and shows an endothermic event around 209 °C. The TGA curve of Compound I benzenesulfonic acid salt is shown in FIG. 9 and indicated that the phase is unsolvated.

Example 4. Compound I succinic acid salt

[0253] Compound I succinic acid salt is an unsolvated phase. It was isolated when a 20 ml glass vial was charged with about 133 mg of Compound I freebase Form I as described in WO 2020/018680, about 41 mg of succinic acid, and about 1 mL of THF, creating a solution. The solution was evaporated to dryness at ambient conditions.

[0254] Compound I succinic acid salt XRPD pattern is shown in FIG. 10 and is characterized by reflections at 15.0, 22.1, and 31.6 °20; additional peaks at 18.3, 20.0, and 25.0 °20, ; and further additional peaks at 7.9, 12.5, and 19.2 °20.

[0255] The DSC curve of Compound I succinic acid salt is shown in FIG. 11 and shows an endothermic event around 145 °C. The TGA curve of Compound I succinic acid salt is shown in FIG. 12 and indicated that the form is unsolvated.

Example 5. Compound I ethanedisulfonic acid salt

[0256] Compound I ethanedisulfonic acid salt is a solvated phase. It was isolated when a 20 mL glass vial was charged with about 97 mg of Compound I freebase Form I as described in WO 2020/018680 and about 40 mg of ethanedisulfonic acid and about 4 mL of THF, forming a suspension. About 1 year later the vial contained a gel, to which was added about 0.2 mL of water, forming a solution which became a thick suspension after about 5 minutes. The suspension was sonicated for about 3 minutes after which solids were isolated and dried. [0257] Compound I ethanedisulfonic acid salt XRPD pattern is shown in FIG. 13 and is characterized by reflections at 5.4, 14.3, and 21.5 °20; additional peaks at 10.7, 20.8, and 21.1 °20, and further additional peaks at 16.9, 23.1, and 28.9 °20.

[0258] The DSC curve of Compound I ethanedisulfonic acid salt is shown in FIG. 14 and shows a broad endothermic event around 53 °C, followed by a an endothermic event around 156 °C. The TGA curve of Compound I ethanedisulfonic acid salt is shown in FIG. 15 and shows around a 10.8% weight loss from about 30-150 °C indicating a solvated phase.

Example 6. Compound I p-toluenesulfonic acid salt

[0259] Compound I -toluenesulfonic acid salt is an unsolvated phase. It was isolated when a 20 ml glass vial was charged with about 167 mg of Compound I freebase Form I as described in WO 2020/018680, about 86 mg of p-toluenesulfonic acid, and about 5 mL of water, creating a suspension. The suspension was stirred magnetically at ambient conditions and the solids were isolated and dried.

[0260] Compound I »-toluenesulfonic acid salt XRPD pattern is shown in FIG. 16 and is characterized by reflections at 5.1, 8.7, and 17.9 °20; additional peaks at 7.6, 15.2, and 19.9 °20, and further additional peaks at 16.9, 21.7, and 26.5 °20.

[0261] The DSC curve of Compound I />-toluenesul tonic acid salt is shown in FIG. 17 and shows an endothermic event around 148 °C. The TGA of Compound I p-toluenesulfonic acid salt curve is shown in FIG. 18 and indicated that the phase is unsolvated.

Example 7. Compound 12,5-dihydroxybenzoic acid salt

[0262] Compound 1 2,5-dihydroxybenzoic acid salt is an unsolvated phase. It was isolated when a 20 ml glass vial was charged with about 146 mg of Compound I freebase Form 1 as described in WO 2020/018680, about 70 mg of 2,5-dihydroxybenzoic acid, and about 5 mL of water, creating a suspension. The suspension was stirred magnetically at ambient conditions and the solids were isolated and dried.

[0263] Compound I 2,5-dihydroxybenzoic acid salt XRPD pattern is shown in FIG. 19 and is characterized by reflections at 5.3, 10.5, and 15.7 °20; additional peaks at 14.5, 18.3, and 26.5 °20, and further additional peaks at 17.4, 19.4, and 27.8 °20.

[0264] The DSC curve of Compound I 2,5-dihydroxybenzoic acid salt is found in FIG. 20 and shows an endothermic event around 26 °C, and an endothermic event around 141 °C. The TGA curve of Compound I 2,5-dihydroxybenzoic acid salt is found in FIG. 21 and indicated the phase is unsolvated.

Example 8. Compound 1 2-naphthalenesulfonic acid salt

[0265] Compound 1 2-naphthalenesulfonic acid salt is a solvated phase. It was isolated when a 20 ml glass vial was charged with about 139 mg of Compound I freebase Form I as described in WO 2020/018680, about 76 mg of 2-naphthalenesulfonic acid, and about 5 mL of water, creating a suspension. The suspension was stirred magnetically at ambient conditions and the solids isolated and dried. [0266] Compound I 2-naphthalenesulfonic acid salt XRPD pattern is shown in FIG. 22 and is characterized by reflections at 5.0, 18.3, and 18.7 °20; additional peaks at 9.9, 17.9, and 27.1 °20; further additional peaks at 11.3, 13.0, and 21.4 °20.

[0267] The DSC curve of Compound I 2-naphthalenesulfonic acid salt is shown in FIG. 23 and shows a broad endothermic event around 25 °C, an endothermic event around 137 °C, and an endothermic event around 185 °C. The TGA curve of Compound I 2-naphthalenesulfonic acid salt is shown in FIG. 24 and shows a mass loss of about 2.7% from about 30-150 °C indicating a solvated phase.

Example 9. Compound I gentisic acid salt

[0268] Compound I gentisic acid salt is a solvated phase. It was isolated when a 20 mL glass vial was charged with about 92 mg of Compound I freebase Form I as described in WO 2020/018680, about 38 mg of gentisic acid, and about 1 mL THF, forming a solution. The vial was allowed to partially evaporate at ambient conditions until solids formed at which point the vial was capped and a suspension was observed the following day when the solids were isolated and dried.

[0269] Compound I gentisic acid salt XRPD pattern is shown in FIG. 25 and is characterized by reflections at 6.5, 13.3, and 19.5 °20; additional peaks at 5.5, 15.2, and 16.5 °20; and further additional peaks at 23.0, 26.1, and 27.7 °20.

[0270] The DSC curve of Compound I gentisic acid salt is shown in FIG. 26 and shows a split endothermic event with onsets around 142 °C and around 157 °C. The TGA curve of Compound I gentisic acid salt is shown in FIG. 27 and shows a mass loss of about 4.2% from about 30-150 °C indicating a solvated phase.

Example 10. Compound I HC1 salt

[0271] Compound I HC1 salt is a solvated phase. It was isolated when a 4 mL glass vial was charged with about 50 mg of Compound I freebase Form I as described in WO 2020/018680, about 100 L of 6 M aqueous HO, and about 3 mL IP A, forming a suspension. The vial was sonicated for about one minute, then set to stir uncapped in a 50 °C bath. A suspension was observed the following day and solids were isolated and dried.

[0272] Compound I HC1 salt XRPD pattern is shown in FIG. 28 and is characterized by reflections at 22.5, 24.4, and 26.7 °20; additional peaks at 17.8, 18.8, and 31.2 °20; and further additional peaks at 17.1, 20.3, and 21.1 °20.

[0273] The DSC curve of Compound I HC1 salt is found in FIG. 29 and shows a broad endothermic event around 45 °C, an endothermic event at about 113 °C, and a split endothermic event around 175 °C and around 194 °C. The TGA curve of Compound I HC1 salt is shown in FIG. 30 and shows a mass loss of about 2.9% from about 25-50 °C and a mass loss of about 17.9% from about 50-175 °C indicating a solvated phase. Example 11. Compound I fumaric acid salt

[0274] Compound I fumaric acid salt was isolated when a 4 ml glass vial was charged with about 213 mg Compound I freebase Form I as described in WO 2020/018680, about 70 mg of fumaric acid, and a few mL of THF, forming a solution. The solution was allowed to evaporate at ambient and yielded an oil over night. About 1 mL of methanol was added to the oil, resulting in a suspension and solids were isolated and dried.

[0275] Compound I fumaric acid salt XRPD pattern is shown in FIG. 31 and is characterized by reflections at 5.9, 14.8, and 15.7 °20; additional peaks at 11.7, 18.8, and 24.9 °20; and further additional peaks at 13.9, 27.7, and 28.4 °20.

[0276] The DSC curve of Compound I fumaric acid salt is shown in FIG. 32 and shows an endothermic event around 95 °C, an exothermic event around 138 °C, and an endothermic event around 173°C.

Example 12. Compound I phosphate salt Form I

[0277] Compound I phosphate salt Form I is a solvated phase. It was isolated when around 176 mg of Compound I was suspended in around 4 mL of a water:acetone mixture and then around 140 microliters of 85% H3PO4 was added and sample left to sit at room temperature.

[0278] Compound I phosphate salt Form I was also isolated when around 5 g of Compound I Form I as described in WO 2020/018680 was suspended in about 20 mL of THF. Next, around 1.5 mL of 85% H3PO4 diluted in about 2 mL of water was added to the suspension. A solution was formed and the sample was seeded with Compound I phosphate salt seeds (made as described above) and a suspension formed and was stirred overnight. Sample was filtered and washed with around 10 mL of water and solids dried at room temperature under vacuum with nitrogen sweep.

[0279] Compound I phosphate salt Form I XRPD pattern is shown in FIG. 33 and is characterized by reflections at 5.6, 14.0, and 18.5 °20; additional peaks at 2.8, 16.3 and 21.2 °20; and further additional peaks at 12.0, 19.3, and 24.0 °20.

[0280] The DSC curve of Compound I phosphate salt Form I is shown in FIG. 34 and the curve shows endothermic events at about 30 °C, 64 °C, and 189 °C and an exothermic event at about 131 °C. The TGA curve of Compound I phosphate salt Form I is shown in FIG. 35 and shows an approximately 13.2% mass loss from about 25-150 °C indicating a solvated phase.

Example 13. Compound I phosphate salt Form II

[0281] Compound I phosphate salt Form II is a solvated phase. It was isolated when about 120 mL of EtOH:water (9:1 vol) was added to a 250 mL container. To this, around 2 molar equivalents of phosphoric acid was added along with a magnetic stirrer. Next, around 6 g of Compound I freebase Form I as described in WO 2020/018680 was added and the mixture stirred at room temperature. About 2 additional equivalents of phosphoric acid was added to the mixture and it was further stirred at room temperature. Resulting solids were filtered and washed twice with around 15 mL of EtOH:water (9: 1 vol) having excess phosphoric acid. Sample dried in funnel filter overnight.

[0282] Compound I phosphate salt Form II was also isolated when about 0.49 g of Compound I freebase Form I as described in WO 2020/018680 was added to 10 mL of EtOH: water (water activity of 0.5), followed by 1 mL of 85% H3PO4 and stirred at room temperature. After around 45 days, the solids were isolated and dried.

[0283] Compound I phosphate salt Form II XRPD pattern is shown in FIG. 36 and is characterized by reflections at 2.6, 5.1 , and 5.4 °20; additional peaks at 15.3, 20.6 and 26.2 °29; and further additional peaks at 7.6, 17.6, and 21.5 °20.

[0284] The DSC curve of Compound I phosphate salt Form II is shown in FIG. 37 and the curve shows endothermic events at about 47 °C, 130 °C, and 181 °C and an exothermic event at about 132 °C. The TGA curve of Compound I phosphate salt Form II is shown in FIG. 38 and shows an approximately 6.4% mass loss from about 25-150 °C indicating a solvated phase.

Claims

CLAIMS:

1. A crystalline form of Compound I:

(Compound I freebase Form IV), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.9, 21.0, and 21.2 °20 as determined on a diffractometer using Cu-Ka radiation.

2. The crystalline form of claim 1, further characterized by: i) one or more additional peaks (±0.2°) at 7.9, 18.2, or 18.4 °20; ii) a diffractogram substantially as shown in FIG. 1; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 95 °C and an endothermic onset at about 192 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 2; v) thcrmogravimctric analysis (TGA) showing a weight loss of about 2.9% from about 25-150 °C; vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 3; or vii) a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a = 7.4312(2) A, b = 12.1841(4) A, c = 13.6454(9) A, a = 107.552(4)°, = 99.070(4)°, = 100.500(2)°, V = 1128.07(9) A³.

3. The crystalline form of claim 1, comprising about 1 mole equivalent of water.

4. A crystalline form of an oxalic acid salt of Compound I:

(Compound I oxalic acid salt), characterized by an X-ray powder diffractogram comprising peaks

(±0.2°) at 6.7, 16.7, and 29.6 °20 as determined on a diffractometer using Cu-Ka radiation.

5. The crystalline form of claim 4, further characterized by: i) one or more additional peaks (+0.2°) at 6.1, 13.3, or 26.6 °20; ii) a diffractogram substantially as shown in FIG. 4; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 129 °C and an endothermic onset at about 145 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 5; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 6.

6. A crystalline form of a benzenesulfonic acid salt of Compound I:

(Compound I benzenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.8, 17.7, and 22.1 °20 as determined on a diffractometer using Cu-Ka radiation.

7. The crystalline form of claim 6, further characterized by: i) one or more additional peaks (±0.2°) at 20.7, 23.8, or 25.5 °20; ii) a diffractogram substantially as shown in FIG. 7; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 209 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 8; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 9.

8. A crystalline form of a succinic acid salt of Compound I:

(Compound I succinic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 15.0, 22.1, and 31.6 °20 as determined on a diffractometer using Cu-Ka radiation.

9. The crystalline form of claim 8, further characterized by: i) one or more additional peaks (±0.2°) at 18.3, 20.0, or 25.0 °20; ii) a diffractogram substantially as shown in FIG. 10; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 145 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 11; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in

FIG. 12.

10. A crystalline form of an ethanedisulfonic acid salt of Compound I:

(Compound I ethanedisulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.4, 14.3, and 21.5 °20 as determined on a diffractometer using Cu-Ka radiation.

11. The crystalline form of claim 10, further characterized by: i) one or more additional peaks (±0.2°) at 10.7, 20.8, or 21.1 °20; ii) a diffractogram substantially as shown in FIG. 13; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 53 °C and an endothermic onset at about 156 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 14; v) thermogravimetric analysis (TGA) showing a weight loss of about 10.8% from about 30-

150 °C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 15.

12. A crystalline form of a p-toluenesulfonic acid salt of Compound I:

(Compound I p-toluenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.1, 8.7, and 17.9 °20 as determined on a diffractometer using Cu-Ka radiation.

13. The crystalline form of claim 12, further characterized by: i) one or more additional peaks (±0.2°) at 7.6, 15.2, or 19.9 °20; ii) a diffractogram substantially as shown in FIG. 16; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 148 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 17; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in

FIG. 18.

14. A crystalline form of a 2,5-dihydroxybenzoic acid salt of Compound I:

(Compound 12,5-dihydroxybenzoic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.3, 10.5, and 15.7 °20 as determined on a diffractometer using Cu-Ka radiation.

15. The crystalline form of claim 14, further characterized by: i) one or more additional peaks (±0.2°) at 14.5, 18.3, or 26.5 °20; ii) a diffractogram substantially as shown in FIG. 19; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 26 °C and an endothermic onset at about 141 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 20; or v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 21.

16. A crystalline form of a 2-naphthalenesulfonic acid salt of Compound I:

(Compound I 2-naphthalenesulfonic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.0, 18.3, and 18.7 °20 as determined on a diffractometer using Cu-Ka radiation.

17. The crystalline form of claim 16, further characterized by: i) one or more additional peaks (±0.2°) at 9.9, 17.9, or 27.1 °20; ii) a diffractogram substantially as shown in FIG. 22; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 25 °C, an endothermic onset at about 137 °C, and an endothermic onset at about 185 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 23; v) thermogravimetric analysis (TGA) showing a weight loss of about 2.7% from about 30-150

°C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in

FIG. 24.

18. A crystalline form of a gentisic acid salt of Compound I:

(Compound I gentisic acid salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.5, 13.3, and 19.5 °20 as determined on a diffractometer using Cu-Ka radiation.

19. The crystalline form of claim 18, further characterized by: i) one or more additional peaks (±0.2°) at 5.5, 15.2, or 16.5 °20; ii) a diffractogram substantially as shown in FIG. 25; iii) a differential scanning calorimetry (DSC) curve comprising a split endothermic onset at about 142 °C and at about 157 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 26; v) thermogravimetric analysis (TGA) showing a weight loss of about 4.2% from about 30-150 °C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 27.

20. A crystalline form of a HC1 salt of Compound I:

(Compound I HC1 salt), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 22.5, 24.4, and 26.7 °20 as determined on a diffractometer using Cu-Ka radiation.

21. The crystalline form of claim 20, further characterized by: i) one or more additional peaks (±0.2°) at 17.8, 18.8, or 31.2 °29; ii) a diffractogram substantially as shown in FIG. 28; iii) a differential scanning calorimetry (DSC) curve comprising an endothermic onset at about 45 °C, an endothermic onset at about 113 °C, and a split endothermic onset at about 175 °C and at about 194 °C; iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 29; v) thermogravimetric analysis (TGA) showing a weight loss of about 2.9% from about 25-50 °C and a weight loss of about 17.9% from about 50-175 °C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 30.

22. A pharmaceutical composition comprising a crystalline form of any one of claims 1-21 and a pharmaceutically acceptable carrier.

23. A method of treating a disease, disorder, or condition, mediated at least in part by the adenosine AZA receptor (AZAR and/or the adenosine AZB receptor (AZBR), comprising administering a therapeutically effective amount of a crystalline form of any one of claims 1-21 or a pharmaceutical composition of claim 22 to a subject in need thereof.

24. The method of claim 23, wherein said disease, disorder, or condition is mediated at least in part by AZA .

25. The method of claim 23, wherein said disease, disorder, or condition is mediated at least in part by AZBR-

26. The method of claim 23, wherein said disease, disorder, or condition is mediated at least in part by both the AZAR and AZBR receptors.

27. A method of treating cancer comprising administering a therapeutically effective amount of a crystalline form of any one of claims 1-21 or a pharmaceutical composition of claim 22 to a subject in need thereof.

28. A method of treating cancer comprising administering a therapeutically effective amount of a crystalline form of any one of claims 1-21 or a pharmaceutical composition of claim 22, and at least one additional therapeutic agent, to a subject in need thereof.

29. The method of any one of claims 27-28, wherein the cancer is a solid tumor.

30. The method of any one of claims 27-28, wherein the cancer is breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, or gynecological cancer.

31. The method of any one of claims 27-28, wherein the cancer is bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

32. The method of any one of claims 27-28, wherein the cancer is castrate resistant prostate cancer, esophageal adenocarcinoma, non-small cell lung carcinoma, pancreatic ductal adenocarcinoma, prostate adenocarcinoma, or urothelial cancer.

33. A method of treating cancer in a subject concomitantly receiving a CYP3A4 inhibitor or a P-gp inhibitor or in a subject that is a poor CYP3A4 metabolizer, said method comprising administering a therapeutically effective amount of a crystalline form of any one of claims 1-21 or a pharmaceutical composition of claim 22 to a subject in need thereof.

34. A method of treating a disease, disorder, or condition, mediated at least in part by the adenosine AZA receptor (AZAR) or the adenosine AZB receptor ( AZBR) in a patient, wherein said patient is concomitantly receiving a CYP3A4 inhibitor or a P-gp inhibitor or the subject is a poor CYP3A4 metabolizer, the method comprising administering a therapeutically effective amount of a crystalline form of any one of claims 1-21 or a pharmaceutical composition of claim 22.