Solid forms comprising (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrimidine-3-carboxamide and oxalic acid, compositions thereof, and methods of use thereof

Abstract

Provided herein are formulations, processes, solid forms, and methods of use related to (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrimidine-3-carboxamide.

Description

1. Technical Field

[0001] Provided herein are solid forms comprising (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and oxalic acid. Also provided herein are pharmaceutical compositions comprising such solid forms, and methods for treating, preventing and managing various conditions. 2. Background technology

[0002] In view of the fact that the change of solid form may affect a variety of physical and chemical properties, the identification and selection of solid forms of pharmaceutical compounds are very complex, and these properties may provide benefits or disadvantages in processing, formulation, stability and bioavailability and other important pharmaceutical properties. Potential pharmaceutical solids include crystalline solids and amorphous solids. Amorphous solids are characterized by lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired category of pharmaceutical solids depends on the specific application; sometimes amorphous solids are selected according to, for example, enhanced dissolution characteristics, while crystalline solids may be desired due to their characteristics such as, for example, physical or chemical stability (see, for example, SR Vippagunta et al., Adv. Drug. Deliv. Rev., (2001) 48: 3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48: 27-42).

[0003] Whether crystalline or amorphous, potential solid forms of drug compounds include single-component solids and multi-component solids. Single-component solids are composed primarily of the drug compound and do not contain other compounds. The diversity of single-component crystalline materials may arise from the phenomenon of polymorphism, in which a particular drug compound exists in multiple three-dimensional arrangements (see, for example, SR Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The example of ritonavir (an HIV protease inhibitor formulated as a soft gelatin capsule) emphasizes the importance of discovering polymorphs. About two years after the product was released, the unexpected precipitation of a new, less soluble polymorph in the formulation made it inevitable that the product would be withdrawn from the market until a more consistent formulation was developed (see SR Chemburkar et al., Org. Process Res. Dev., (2000) 4: 413-417).

[0004] Additional diversity in the potential solid forms of pharmaceutical compounds may be caused by the possibility of multi-component solids. Crystalline solids containing two or more ionic species are called salts (see, for example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P.H. Stahl and C.G. Wermuth, (2002), Wiley, Weinheim). Other types of multi-component solids that may provide other property improvements for pharmaceutical compounds or their salts include, for example, hydrates, solvates, co-crystals and inclusion compounds, etc. (see, for example, S.R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). In addition, multi-component crystalline forms may be susceptible to polymorphism, in which a given multi-component composition may exist in more than one three-dimensional crystalline arrangement. The discovery of solid forms is very important for developing safe, effective, stable and marketable pharmaceutical compounds.

[0005] It is noteworthy that it is impossible to predict in advance whether crystalline forms of a compound will exist, let alone how to successfully prepare them (see, e.g., Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem. Commun.: 3635-3645 (with regard to crystal engineering, if the instructions are not very precise and / or if other external factors influence the process, the results can be unpredictable); Jones et al., 2006, "Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31: 875-879 (at present, it is generally impossible to predict computationally the number of observable polymorphs of even the simplest molecules); Price, 2004, "The computational prediction of pharmaceutical crystal structures and polymorphism," Advanced Drug Delivery Reviews 56: 301-319 ("Price"); and Bernstein, 2004, "Crystal Structure Prediction and Polymorphism," ACA Transactions 39:14–23 (There is still much to learn and accomplish before crystal structures (let alone polymorphic forms) can be predicted with confidence).

[0006] A cocrystal is a crystalline molecular complex of two or more non-volatile compounds bound together in a crystal lattice by non-ionic interactions. Pharmaceutical cocrystals are cocrystals (referred to herein as coformers) of a therapeutic compound (e.g., an active pharmaceutical ingredient (API)) with one or more non-volatile compounds. The coformers in a pharmaceutical cocrystal are typically selected from non-toxic pharmaceutically acceptable molecules such as, for example, food additives, preservatives, pharmaceutical excipients, or other APIs. In recent years, pharmaceutical cocrystals have emerged as a possible alternative approach to enhance the physicochemical properties of drug products. The diversity of possible solid forms leads to a potential diversity in the physical and chemical properties of a given drug compound.

[0007] The compound with the chemical name (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and its tautomers (collectively referred to herein as "Compound 1") are disclosed in U.S. Patent No. 9,447,106 issued on September 20, 2016 and International Publication No. WO2014 / 173289, the entire contents of each of which are incorporated herein by reference.

[0008] Crystalline Form A of Compound 1 is disclosed in U.S. Patent No. 10,927,117 issued on February 23, 2021 and International Publication No. WO2018 / 033853, the entire contents of each of which are incorporated herein by reference.

[0009] Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that such reference is prior art to the present application. 3. Summary of the invention

[0010] Provided herein is a compound comprising:

[0011]

[0012] The invention discloses a solid form of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, including its tautomers and oxalic acid. The invention also provides methods for preparing, isolating and characterizing the solid form.

[0013] Further provided herein are crystalline forms comprising Compound 1. One crystalline form provided herein has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks at 2θ angles of approximately 8.17, 11.65 or 21.61 degrees. In one embodiment, the X-ray powder diffraction pattern may also comprise characteristic X-ray powder diffraction peaks at 2θ angles of approximately 8.56, 18.54 or 19.56 degrees.

[0014] In one embodiment, the solid form is a co-crystal. In one embodiment, the solid form is a salt.

[0015] In one embodiment, the crystalline form has a thermogravimetric analysis thermogram comprising a total mass loss of about 0.7% of the total mass of the crystalline form when heated from about 17.6 to about 130° C. In one embodiment, the crystalline form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 160.4° C. when heated from about 50° C. to about 200° C. In one embodiment, the crystalline form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at about 159.1° C. when heated from about 50° C. to about 200° C.

[0016] In one embodiment, the molar ratio of oxalic acid to Compound 1 in the crystalline form is about 0.5. The crystalline form may be substantially pure.

[0017] All solid forms and pharmaceutical compositions provided herein can be used as medicines. In certain embodiments, the solid form of compound 1 can be used to treat or prevent cancer and diseases that can be treated or prevented by inhibiting kinase pathways (such as BTK pathways). All solid forms and pharmaceutical compositions can be used in methods for treating or preventing cancer, allergic diseases, autoimmune diseases, inflammatory diseases, combinations of two or more thereof, or diseases that can be treated or prevented by inhibiting kinase pathways. The method includes applying an effective amount of a solid form or pharmaceutical composition to a subject in need. The kinase pathway is a BTK kinase pathway. In one embodiment, provided herein is a method for treating a subject's B cell proliferative disease by administering a solid form disclosed herein to a subject, the B cell proliferative disease being selected from chronic lymphocytic, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, or a combination of two or more thereof.

[0018] All solid forms and pharmaceutical compositions provided herein can be used in the method for achieving complete response, partial response or stable disease of solid tumor response evaluation criteria (RECIST 1.1) of the subject. The method includes administering an effective amount of solid form or pharmaceutical composition to the subject suffering from solid tumor.

[0019] All solid forms and pharmaceutical compositions provided herein can be used in methods for improving NHL International Workshop Criteria (International Workshop Criteria, IWC) or Eastern Cooperative Oncology Group Performance Statu (Eastern Cooperative Oncology Group Performance Statu, ECOG). The method includes administering an effective amount of a solid form or pharmaceutical composition to a subject in need thereof.

[0020] A more complete understanding of the embodiments of the present invention may be obtained by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments. 4. Description of the drawings

[0021] Figure 1 The X-ray powder diffraction pattern of Form 1 is depicted.

[0022] Figure 2 Thermogravimetric analysis of Form 1 is depicted.

[0023] Figure 3 Differential scanning calorimetry analysis of Form 1 is depicted.

[0024] Figure 4 Depicts form 1 1 H NMR.

[0025] Figure 5 DVS results are plotted, showing that Form 1 has a water uptake of less than 0.2% at 25°C / 80%RH, indicating that it is not hygroscopic.

[0026] Figure 6 Depicted are solubility curves of Form 1, Form A of Compound 1, and an amorphous form of Compound 1 at room temperature.

[0027] Figure 7 Depicted are solubility curves of Form 1, Form A of Compound 1, and an amorphous form of Compound 1 at 37°C. 5. Specific implementation methods

[0028] 5.1 Definitions

[0029] As used herein and unless otherwise indicated, the terms "oxalic acid" and "oxalate" refer to both non-ionized / unassociated oxalic acid and ionized / associated oxalic acid.

[0030] As used herein and in the specification and claims that follow, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents, unless the context clearly dictates otherwise.

[0031] As used herein and unless otherwise indicated, the terms "about" and "approximately" when used in conjunction with the dose, amount or weight percentage of an ingredient of a composition or dosage form means a dose, amount or weight percentage that one of ordinary skill in the art considers to provide a pharmacological effect equivalent to that obtained from a specified dose, amount or weight percentage. In certain embodiments, the terms "about" and "approximately" when used herein encompass doses, amounts or weight percentages within 30%, within 20%, within 15%, within 10% or within 5% of a specified dose, amount or weight percentage.

[0032] As used herein and unless otherwise indicated, the terms "about" and "approximately" when used in conjunction with a numerical value or range of values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range, such as, for example, describing melting, dehydration, desolvation, or glass transition temperature; a change in mass, such as, for example, a change in mass as a function of temperature or humidity; solvent or water content, such as, for example, mass or percentage; or peak position, such as, for example, in an analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values ​​may deviate to an extent that is considered reasonable by a person of ordinary skill in the art, while still describing the solid form. Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and solubility studies. In certain embodiments, the terms "about" and "approximately" when used in this context indicate that a numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, the values ​​of XRPD peak positions may vary by up to ±0.2 degrees 2θ while still describing a specific XRPD peak.

[0033] As used herein and unless otherwise indicated, "pure," i.e., crystalline that is substantially free of other crystalline or amorphous forms, contains less than about 10% by weight of one or more other crystalline or amorphous forms, less than about 5% by weight of one or more other crystalline or amorphous forms, less than about 3% by weight of one or more other crystalline or amorphous forms, or less than about 1% by weight of one or more other crystalline or amorphous forms.

[0034] As used herein and unless otherwise indicated, the term "substantially pure" when used to describe a polymorph of a compound (i.e., a crystalline form or amorphous form of a compound) refers to a crystalline form or amorphous form of a compound that contains the crystalline form or amorphous form and is substantially free of other polymorphs of the compound. A substantially pure crystalline form is not less than about 95% pure, not less than about 96% pure, not less than about 97% pure, not less than about 98% pure, not less than about 98.5% pure, not less than about 99% pure, not less than about 99.5% pure, or not less than about 99.8% pure. In certain embodiments, a substantially pure form contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% of one or more other polymorphs by weight.

[0035] As used herein and unless otherwise indicated, a "substantially physically pure" solid form is substantially free of other solid forms. In certain embodiments, a substantially physically pure crystalline form contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% by weight of one or more other solid forms. Detection of other solid forms can be accomplished by any method apparent to one of ordinary skill in the art, including but not limited to diffraction analysis, thermal analysis, elemental combustion analysis and / or spectral analysis.

[0036] As used herein and unless otherwise indicated, a "substantially chemically pure" solid form is substantially free of other chemical compounds (i.e., chemical impurities). In certain embodiments, a substantially chemically pure solid form contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of one or more other chemical compounds. Detection of other chemical compounds can be accomplished by any method apparent to one of ordinary skill in the art, including, but not limited to, chemical analysis methods, such as mass spectrometry, spectral analysis, thermal analysis, elemental combustion analysis, and / or chromatographic analysis.

[0037] As used herein and unless otherwise indicated, a chemical compound, solid form, or composition that is "substantially free" of another chemical compound, solid form, or composition means that, in certain embodiments, the compound, solid form, or composition contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of another compound, solid form, or composition.

[0038] Unless otherwise indicated, the terms "solvate" and "solvated" as used herein refer to a solid form of a substance containing a solvent. The terms "hydrate" and "hydrated" refer to a solvate in which the solvent is water. "Polymorphs of a solvate" refers to the presence of more than one solid form of a particular solvate composition. Similarly, "polymorphs of a hydrate" refers to the presence of more than one solid form of a particular hydrate composition. The term "desolvated solvate" as used herein refers to a solid form of a substance that can be made by removing a solvent from a solvate. The terms "solvate" and "solvated" as used herein may also refer to a solvate of a salt, co-crystal, or molecular complex. The terms "hydrate" and "hydrated" as used herein may also refer to a hydrate of a salt, co-crystal, or molecular complex.

[0039] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is located, and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0040]

[0041] It is readily understood by those skilled in the art that various functional groups and other structures may exhibit tautomerism, and all tautomers of Compound 1 are within the scope of the present invention.

[0042] Unless otherwise indicated, the term "composition" as used herein is intended to encompass a product comprising one or more specified ingredients (and, if indicated, in one or more specified amounts), as well as any product consisting directly or indirectly of one or more specified ingredients combined in one or more specified amounts. "Pharmaceutically acceptable" means that the diluent, excipient or carrier in the formulation must be compatible with one or more other ingredients of the formulation and not deleterious to the recipient thereof.

[0043] The term "solid form" refers to a physical form that is not predominantly liquid or gaseous. As used herein and unless otherwise indicated, the term "solid form" when used herein to refer to Compound 1 refers to a physical form comprising Compound 1 that is not predominantly liquid or gaseous. The solid form may be a crystalline form or a mixture thereof. In certain embodiments, the solid form may be a liquid crystal. In certain embodiments, the term "solid form comprising Compound 1" includes a crystalline form comprising Compound 1. In one embodiment, the solid form of Compound 1 is Form 1.

[0044] As used herein and unless otherwise indicated, the term "crystalline" when used to describe a compound, substance, modification, material, component or product, means that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction, unless otherwise indicated. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rd Edition, 1843-1844 (1995).

[0045] The term "crystalline form" or "crystalline form" refers to a solid form of crystallization. In certain embodiments, the crystalline form includes salts. In certain embodiments, the crystalline form of a substance may be substantially free of amorphous forms and / or other crystalline forms. In certain embodiments, the crystalline form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45% or less than about 50% of one or more amorphous forms and / or other crystalline forms by weight. In certain embodiments, the crystalline form of a substance can be physically and / or chemically pure. In certain embodiments, a crystalline form of a substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and / or chemically pure.

[0046] Unless otherwise indicated, the terms "polymorph", "polymorphic form" and related terms herein refer to two or more crystalline forms consisting of substantially the same molecule, molecules or ions. Due to different arrangements or conformations of molecules or ions in the crystal lattice, different polymorphs may have different physical properties, such as, for example, melting temperature, heat of fusion, solubility, dissolution rate and / or vibrational spectrum. The differences in physical properties exhibited by polymorphs may affect drug parameters such as storage stability, compressibility and density (important in formulation and product manufacturing) and dissolution rate (an important factor in bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, so that when a dosage form is composed of one polymorph, its color change rate is faster than when it is composed of another polymorph) or mechanical changes (e.g., tablets will break during storage as a kinetically favorable polymorph is converted to a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more easily decomposed under high humidity). Due to differences in solubility / dissolution, some polymorphic transitions may result in a lack of potency at one extreme, or toxicity at the other extreme. Additionally, the physical properties of the crystals may be important during processing; for example, one polymorph may form solvates more easily or may be difficult to filter and wash free of impurities (e.g., particle shape and size distribution may differ between polymorphs).

[0047] Unless otherwise indicated, the term "co-crystal" as used herein refers to a crystalline material composed of Compound 1 (including tautomers thereof) and one or more non-volatile compounds held together in a crystal lattice by non-covalent interactions.

[0048] Unless otherwise indicated, the term "amorphous" or "amorphous form" means that the substance, component or product in question is substantially non-crystalline as determined by X-ray diffraction. Specifically, the term "amorphous form" describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In certain embodiments, the amorphous form of a substance may be substantially free of other amorphous forms and / or crystalline forms. In certain embodiments, the amorphous form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45% or less than about 50% (by weight) of one or more other amorphous forms and / or crystalline forms. In certain embodiments, the amorphous form of a substance may be physically and / or chemically pure. In certain embodiments, an amorphous form of a substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and / or chemically pure.

[0049] As used herein, "treating" means completely or partially alleviating a disease or condition, or symptoms associated with a disease or condition, or slowing or stopping further progression or worsening of a disease or condition, or symptoms associated with a disease or condition.

[0050] As used herein, "preventing" or "preventing" means preventing the onset, recurrence, or spread of a disease or disorder, or symptoms associated with the disorder or disease, in a patient at risk of developing the disease or disorder.

[0051] The term "effective amount" associated with the solid form of compound 1 means in one embodiment an amount that can fully or partially alleviate the symptoms associated with a disorder or disease, or slow down or stop the further development or worsening of these symptoms, or in another embodiment means an amount that can prevent or provide prevention of the disease or disorder in a subject at risk of developing a disease or disorder disclosed herein (such as cancer). In one embodiment, the effective amount of the solid form of compound 1 is such as, for example, an amount that inhibits kinases in cells in vitro or in vivo. In one embodiment, the kinase is BTK. In some embodiments, the effective amount of the solid form of compound 1 inhibits the kinases in cells by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99% compared to the activity of the kinases in untreated cells. For example, in a pharmaceutical composition, the effective amount of the solid form of compound 1 can be a level that exerts the desired effect; for example, a unit dose of about 0.005 mg / kg subject weight to about 100 mg / kg patient weight for oral and parenteral administration. It will be apparent to one skilled in the art that it is contemplated that an effective amount of a solid form of Compound 1 disclosed herein may vary depending on the indication being treated, e.g., an effective amount of a solid form of Compound 1 for treating a patient having or at risk of having an inflammatory disorder may be different than an effective amount of a solid form of Compound 1 for treating a patient having or at risk of having a different disorder (e.g., cancer or a metabolic disorder).

[0052] "Patient" or "subject" is defined herein to include animals, such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quail, or guinea pigs, etc. In specific embodiments, the patient or subject is a human.

[0053] The term "cancer" refers to a B-cell proliferative disorder selected from chronic lymphocytic, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia (CLL), or a combination of two or more thereof.

[0054] In certain embodiments, treatment of lymphoma can be assessed by the International Workshop Criteria (IWC) for Non-Hodgkin Lymphoma (NHL) using the response and endpoints shown below (see Cheson BD, Pfistner B, Juweid, ME et al. Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-586):

[0055]

[0056]

[0057] Abbreviations: CR, complete remission; FDG, [ 18 F] fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial response; SPD, sum of product diameters; SD, stable disease; PD, progressive disease.

[0058]

[0059] Abbreviations: CR: complete response; PR: partial response.

[0060] In one embodiment, the endpoint of lymphoma is evidence of clinical benefit. Clinical benefit may reflect an improvement in quality of life, or a reduction in patient symptoms, infusion requirements, frequent infections, or other parameters. The time from the reappearance or progression of lymphoma-related symptoms may also be used for this endpoint.

[0061] In certain embodiments, treatment of CLL can be assessed by the International Workshop Guidelines for CLL using the response and endpoint definitions set forth therein (see Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 2008; (111) 12: 5446-5456) using the response and endpoint definitions set forth therein, particularly the following:

[0062]

[0063] Group A criteria define tumor burden; Group B criteria define the function of the hematopoietic system (or bone marrow). CR (complete remission): all criteria must be met and the patient must have no disease-related systemic symptoms; PR (partial remission): at least two of the criteria in Group A plus one of the criteria in Group B must be met; SD is the absence of progressive disease (PD) and failure to achieve at least PR; PD: at least one of the above criteria in Group A or Group B must be met. The sum of the products of multiple lymph nodes (as assessed by CT scans in clinical trials or physical examinations in general practice). These parameters are irrelevant for certain response categories.

[0064] In certain embodiments, treatment of cancer can be evaluated by the solid tumor response evaluation criteria (RECIST 1.1) (see Thereasse P. et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer EA, Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European J. Cancer; 2009; (45) 228-247). The overall response for all possible combinations of tumor responses in target lesions and non-target lesions with or without the appearance of new lesions is as follows:

[0065] Target lesions Non-target lesions New lesions Overall Response CR CR no CR CR Incomplete response / SD no PR PR Non-PD no PR SD Non-PD no SD PD any Yes or No PD any PD Yes or No PD any any yes PD

[0066] CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.

[0067] For the evaluation of target lesions, complete response (CR) is the disappearance of all target lesions, partial response (PR) is a reduction of at least 30% in the sum of the longest diameters of target lesions based on the baseline sum of the longest diameters, progressive disease (PD) is an increase of at least 20% in the sum of the longest diameters of target lesions based on the smallest sum of the longest diameters recorded since the start of treatment, or the appearance of one or more new lesions, and stable disease (SD) is a reduction that is not sufficient to meet the characterization of a partial response, nor an increase that is sufficient to meet the criteria for progressive disease, based on the smallest sum of the longest diameters recorded since the start of treatment.

[0068] For the evaluation of non-target lesions, complete response (CR) means the disappearance of all non-target lesions and the normalization of tumor marker levels; incomplete response / stable disease (SD) means the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limit; progressive disease (PD) means the appearance of one or more new lesions and / or clear progression of existing non-target lesions.

[0069] The following procedures, practices and definitions provide guidance for implementing the recommendations of the response criteria of the RANO working group on high-grade gliomas (Wen P., Macdonald, DR., Reardon, DA. et al., Updated response assessment criteria for highgrade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 2010; 28: 1963-1972). The main modifications to the time point response (TPR) criteria in the RANO criteria may include adding operational practices for defining changes in glucocorticoid doses, and removing the clinical deterioration component of the subject to focus on objective radiological assessment. The baseline MRI scan is defined as an assessment performed at the end of the postoperative rest period and before restarting the combined treatment. The baseline MRI serves as a reference for assessing complete response (CR) and partial response (PR). The minimum SPD (sum of perpendicular diameter products) obtained at baseline or subsequent assessments will be designated as the lowest point assessment and used as a reference for determining progression. Five days before any protocol-defined MRI scan, the subject did not receive any glucocorticoids or took a stable dose of glucocorticoids. Stable dose was defined as the same daily dose prior to the MRI scan for 5 consecutive days. If the dose of prescribed glucocorticoids was changed within 5 days prior to the baseline scan, a new baseline scan was required in which the glucocorticoid use met the above criteria. The following definitions will be used.

[0070] Measurable Lesions: Measurable lesions are contrast-enhancing lesions that can be measured in 2D. Measure the largest enhancing tumor diameter (also called the longest diameter, LD). Measure the largest perpendicular diameter on the same image. The crosshairs of the 2D measurements should cross, and then calculate the product of these diameters.

[0071] Minimum diameter: T1-weighted images with 5mm slices and 1mm skips. The minimum LD for a measurable lesion is set at 5mm x 5mm. A larger diameter may be required to be included and / or designated as a target lesion. After baseline, if a target lesion becomes smaller than the minimum requirement for measurement or no longer fits in 2D, it will be recorded with a default value of 5mm for each 5mm smaller diameter. Disappeared lesions will be recorded as 0mm x 0mm.

[0072] Multicentric Lesions: Lesions considered multicentric (as opposed to continuous) are those in which there is normal intervening brain tissue between two (or more) lesions. For multicentric lesions, i.e. discrete lesions that enhance, the approach is to measure each enhancing lesion that meets the inclusion criteria separately. If there is no normal brain tissue between two (or more) lesions, they will be considered the same lesion.

[0073] Nonmeasurable lesions: All lesions that do not meet the criteria for measurable disease as defined above are considered nonmeasurable lesions, as well as all nonenhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include enhancing lesions smaller than a specified minimum diameter (i.e., less than 5 mm x 5 mm), nonenhancing lesions (e.g., seen on T1-weighted postcontrast, T2-weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal tumors. Hemorrhagic lesions often have intrinsic T1-weighted high signal intensity that can be misinterpreted as enhancing tumors, therefore, precontrast T1-weighted images may be reviewed to exclude baseline or interval subacute hemorrhage.

[0074] At baseline, lesions will be categorized as follows: Target lesions: Up to 5 measurable lesions will be selected as target lesions, each at least 10 mm x 5 mm, representative of the subject's disease; Non-target lesions: All other lesions, including all non-measurable lesions (including mass effect and T2 / FLAIR findings) and any measurable lesions not selected as target lesions. At baseline, target lesions should be measured as described in the definition of measurable lesions, and the SPD of all target lesions should be determined. The presence of all other lesions should be recorded. The baseline classification of lesions as target and non-target lesions will be maintained at all post-treatment evaluations, and lesions will be recorded and described in a consistent manner over time (e.g., recorded in the same order on the source document and on the eCRF). For the duration of the study, all measurable and non-measurable lesions must be assessed using the same technique as at baseline (e.g., subjects should be imaged on the same MRI scanner or at least using the same magnetic intensity) to reduce difficulties in interpreting changes. At each evaluation, target lesions will be measured and the SPD calculated. Non-target lesions will be qualitatively assessed, and new lesions, if present, will be recorded separately. At each evaluation, the time point response for target lesions, non-target lesions, and new lesions will be determined. Tumor progression can be determined even if only a subset of lesions are evaluated. However, unless progression is observed, objective status (stable disease, PR, or CR) can only be determined after all lesions have been evaluated.

[0075] Confirmation of overall time point response for CR and PR will be assessed at the next scheduled assessment, but may not be performed if scans are spaced less than 28 days apart. The best response combined with confirmation requirements will be derived from a range of time points.

[0076] In extreme cases, complete inhibition is referred to herein as prevention or chemoprevention. In this context, the term "prevention" includes completely preventing the occurrence of clinically apparent cancer, or preventing the occurrence of preclinically apparent stages of cancer. The definition is also intended to encompass preventing transformation into malignant cells or arresting or reversing the progression of premalignant cells into malignant cells. This includes prophylactic treatment of those at risk of developing cancer.

[0077] Unless otherwise indicated, if there is a discrepancy between the depicted chemical structure of a compound provided herein and the chemical name of the compound provided herein, the chemical structure controls.

[0078] 5.2 Compound 1

[0079] The solid forms, formulations, and methods of use provided herein relate to Compound 1:

[0080]

[0081] Its name is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, including its tautomers.

[0082] Compound 1 is disclosed in U.S. Patent No. 9,447,106 issued on September 20, 2016 and International Publication No. WO 2014 / 173289, the entire contents of each of which are incorporated herein by reference.

[0083] Crystalline Form A of Compound 1 is disclosed in U.S. Patent No. 10,927,117 issued on February 23, 2021 and International Publication No. WO2018 / 033853, the entire contents of each of which are incorporated herein by reference.

[0084] It should be noted that if there is an inconsistency between the depicted structure and the name given to the structure, the depicted structure should have higher weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated, for example, by bold or dashed lines, the structure or portion of the structure should be interpreted as encompassing all stereoisomers thereof.

[0085] 5.3 Solid Form of Compound 1

[0086] Although not intending to be bound by any particular theory, certain solid forms (e.g., salts or co-crystals) are characterized by physical properties (e.g., stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. In addition, although not intending to be bound by any particular theory, certain solid forms (e.g., salts or co-crystals) are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, viscosity, solubility, water absorption, electrical properties, thermal behavior, solid state reactivity, physical stability, and chemical stability) that affect specific processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization), which make certain solid forms (e.g., salts or co-crystals) suitable for manufacturing solid dosage forms. Such properties can be determined using specific analytical chemistry techniques, including solid-state analytical techniques described herein and known in the art (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0087] In one embodiment, provided herein is a solid form comprising (a) Compound 1; and (b) oxalic acid (e.g., a crystalline form, an amorphous form, a salt form, or a mixture thereof). In one embodiment, provided herein is a solid form comprising (a) a free base of Compound 1; and (b) oxalic acid (e.g., a crystalline form, an amorphous form, or a mixture thereof). Compound 1 can be synthesized or obtained according to methods known in the literature or based on the teachings herein, including methods described in detail in the Examples herein. In certain embodiments, the coformer is oxalic acid.

[0088] In one embodiment, the solid form provided herein may be a crystalline form, a salt form, or an amorphous form or a mixture thereof (e.g., a mixture of crystalline forms, or a mixture of crystalline forms and amorphous forms), comprising (a) Compound 1; and (b) oxalic acid. In one embodiment, provided herein is a crystalline form comprising (a) Compound 1; and (b) oxalic acid. In one embodiment, provided herein is a co-crystal form comprising (a) Compound 1; and (b) oxalic acid. In one embodiment, provided herein is a salt form comprising (a) Compound 1; and (b) oxalic acid. In one embodiment, provided herein is an amorphous form comprising (a) Compound 1; and (b) oxalic acid. In one embodiment, provided herein is a mixture comprising (i) a co-crystal comprising (a) Compound 1; and (b) oxalic acid; and (ii) a crystalline form of Compound 1. In one embodiment, provided herein is a mixture comprising (i) a salt comprising (a) Compound 1; and (b) oxalic acid; and (ii) a crystalline form of Compound 1. In one embodiment, provided herein is a mixture comprising (i) a co-crystal comprising (a) Compound 1; and (b) oxalic acid; and (ii) an amorphous form of Compound 1. In one embodiment, provided herein is a mixture comprising (i) a co-crystal comprising (a) Compound 1; and (b) a salt of oxalic acid; and (ii) an amorphous form of Compound 1.

[0089] In one embodiment, provided herein is a solid form comprising (a) Compound 1 and (b) substantially crystalline oxalic acid. In one embodiment, provided herein is a salt form comprising (a) Compound 1; and (b) substantially crystalline oxalic acid. In one embodiment, provided herein is a solid form comprising a co-crystal containing (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein is a solid form comprising a salt containing (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein is a solid form comprising (i) a co-crystal comprising (a) Compound 1 and (b) oxalic acid and (ii) an amorphous form of Compound 1. In one embodiment, provided herein is a solid form comprising (i) a salt comprising (a) Compound 1 and (b) oxalic acid and (ii) an amorphous form of Compound 1. In one embodiment, provided herein is a solid form comprising (i) a co-crystal comprising (a) Compound 1 and (b) oxalic acid and (ii) one or more additional crystalline forms of Compound 1. In one embodiment, provided herein is a solid form comprising (i) a salt comprising (a) Compound 1 and (b) oxalic acid and (ii) one or more additional crystalline forms of Compound 1.

[0090] In one embodiment, provided herein is a non-solvated solid form comprising (a) compound 1 and (b) oxalic acid. In one embodiment, provided herein is an anhydrous solid form comprising (a) compound 1 and (b) oxalic acid. In one embodiment, provided herein is a non-solvated crystalline form comprising (a) compound 1 and (b) oxalic acid. In one embodiment, provided herein is an anhydrous crystalline form comprising (a) compound 1 and (b) oxalic acid. In one embodiment, provided herein is a non-solvated amorphous form comprising (a) compound 1 and (b) oxalic acid. In one embodiment, provided herein is an anhydrous amorphous form comprising (a) compound 1 and (b) oxalic acid. In one embodiment, provided herein is a solvated solid form comprising (a) compound 1 and (b) oxalic acid. In one embodiment, provided herein is a hydrated solid form (e.g., a hydrate with stoichiometric or non-stoichiometric water) comprising (a) compound 1 and (b) oxalic acid. In one embodiment, provided herein is a hydrated form of (a) compound 1 and (b) oxalic acid, including but not limited to hemihydrates, monohydrates, dihydrates, trihydrates, etc. In some embodiments, the hydrated form is substantially crystalline. In one embodiment, the hydrated form is substantially amorphous. In some embodiments, the anhydrous form is substantially crystalline. In one embodiment, the anhydrous form is substantially amorphous. In one embodiment, provided herein are non-solvated co-crystals comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein are anhydrous co-crystals comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein are hydrated co-crystals comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein are solvated co-crystals comprising (a) Compound 1 and (b) oxalic acid.

[0091] In one embodiment, provided herein is a non-solvated salt comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein is an anhydrous salt comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein is a hydrated salt comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein is a solvated salt comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, the salt is substantially crystalline.

[0092] The solid forms provided herein can be prepared by the methods described herein or by the following techniques, including but not limited to heating, cooling, freeze drying, spray drying, freeze drying, quenching cooling melt, fast solvent evaporation, slow solvent evaporation, solvent recrystallization, anti-solvent addition, slurry recrystallization, crystallization from the melt, desolvation, recrystallization in a confined space (e.g., in a nanopore or capillary), recrystallization on a surface or template (e.g., on a polymer), recrystallization in the presence of additives (such as, for example, salt anti-molecules, eutectic anti-molecules), desolvation, dehydration, rapid cooling, slow cooling, exposure to solvents and / or water, drying (including, for example, vacuum drying, vapor diffusion, sublimation), grinding (including, for example, low-temperature grinding and solvent drop grinding), microwave-induced precipitation, ultrasound-induced precipitation, laser-induced precipitation, and precipitation from supercritical fluids. The particle size of the resulting solid form can vary (e.g., from nanometer size to millimeter size), can be controlled by changing crystallization conditions (such as, for example, crystallization rate and / or crystallization solvent system) or by particle size reduction techniques (e.g., grinding, milling, micronization, or ultrasound treatment).

[0093] In some embodiments, a solid form comprising (a) Compound 1 and (b) oxalic acid can be obtained by crystallization from certain solvent systems, such as a solvent system comprising one or more of the following solvents: ACN; EtOH; IPA; 1-BuOH; butyl acetate; 1-propanol; THF / H2O, 1:1; MeOAc; MeOH / MTBE, 1:2; 1,4-dioxane / H2O, 2:1; CHCl3 / n-heptane, 1:1; DCM / toluene, 1:2; EtOAc; anisole; CPME; DMSO / H2O, 1:4; ACN / H2O, 989:11, a w About 0.2; ACN / H2O, 978:22, a w About 0.4; ACN / H2O, 959:41, a w About 0.6; ACN / H2O, 925:75, a w About 0.8; water-saturated EtOAc; isopropyl acetate; 2-methyltetrahydrofuran; or a combination thereof. In certain embodiments, the solid form provided herein (e.g., a co-crystal comprising (a) Compound 1 and (b) oxalic acid) can be obtained by cooling evaporation crystallization, powder crystallization in a saturated solution, slurry crystallization, and grinding crystallization.

[0094] In some embodiments, co-crystals comprising (a) Compound 1 and (b) oxalic acid can be obtained by crystallization from certain solvent systems, such as solvent systems comprising one or more of the following solvents: ACN; EtOH; IPA; 1-BuOH; butyl acetate; 1-propanol; THF / H2O, 1:1; MeOAc; MeOH / MTBE, 1:2; CHCl3 / n-heptane, 1:1; DCM / toluene, 1:2; EtOAc; anisole; CPME; DMSO / H2O, 1:4; ACN / H2O, 989:11, a w About 0.2; ACN / H2O, 978:22, a w About 0.4; ACN / H2O, 959:41, a w About 0.6; ACN / H2O, 925:75, a w About 0.8; water-saturated EtOAc; isopropyl acetate; 2-methyltetrahydrofuran; or a combination thereof. In certain embodiments, the solid form provided herein (e.g., a co-crystal comprising (a) Compound 1 and (b) oxalic acid) can be obtained by cooling evaporation crystallization, powder crystallization in a saturated solution, slurry crystallization, and grinding crystallization.

[0095] In certain embodiments, the non-covalent force is one or more hydrogen bonds (H bonds). The co-former can form H bonds directly with compound 1, or can form H bonds with another molecule bonded to compound 1. The other molecule can form H bonds with compound 1, or can be bonded to compound 1 in an ionic or covalent manner. The other molecule can also be a different active or inactive ingredient. In certain embodiments, the co-crystal can include one or more solvate molecules in the crystal lattice, i.e., a solvate of the co-crystal, or also includes a co-crystal of a solvent or compound that is liquid at room temperature. In certain embodiments, the co-crystal can be a co-crystal between a co-former and a salt of compound 1. In certain embodiments, the non-covalent force is pi stacking, guest-host complexation and / or van der Waals interactions. Hydrogen bonds can lead to several different intermolecular configurations. For example, hydrogen bonds can lead to the formation of dimers, linear or cyclic structures. These configurations can also include extended (two-dimensional) hydrogen bond networks and isolated triads. In certain embodiments, when the co-former is in its purified form, it is solid under ambient temperature conditions. In one embodiment, the coformer is oxalic acid.

[0096] In certain embodiments, the formation of a co-crystal can result in an enhancement of the physical properties of the resulting solid form, such as solubility, dissolution rate, bioavailability, physical stability, chemical stability, flowability, fractability, or compressibility. In certain embodiments, the formation of a salt can result in an enhancement of the physical properties of the resulting solid form, such as solubility, dissolution rate, bioavailability, physical stability, chemical stability, flowability, fractability, or compressibility.

[0097] In certain embodiments, provided herein is a cooling evaporation method for preparing a solid form of Compound 1, comprising 1) obtaining a near saturated solution of Compound 1 and oxalic acid at a certain ratio (e.g., about 1:0.2 to about 1:3, about 1:0.5, about 1:0.55, about 1:0.9, about 1:1, about 1:1.2, and about 1:2.2) in a solvent; 2) heating the solution to a first temperature (e.g., about 30°C to about 50°C); 3) cooling the solution to a second temperature (e.g., about -5°C to about 15°C); 4) maintaining the solution at the second temperature for a period of time (e.g., 72 hours); 5) filtering the solution to obtain a solid if there is precipitation; and 6) evaporating the solvent to collect the solid if there is no precipitation after step 4. In one embodiment, seed crystals may be added to the solution. In certain embodiments, provided herein is a cooling evaporation method for preparing a solid form of Compound 1, comprising 1) obtaining a near saturated solution of Compound 1 and oxalic acid in a solvent; 2) heating the solution to about 40°C); 3) cooling the solution to about 2°C); 4) maintaining the solution at about 2°C for about 48 hours; 5) filtering the solution to obtain a solid if there is a precipitate; and 6) evaporating the solvent to collect the solid if there is no precipitate after step 4. In certain embodiments, the solvent is ACN; EtOH; IPA; 1-BuOH; butyl acetate; 1-propanol; THF / H2O, 1:1; MeOAc; MeOH / MTBE, 1:2; 1,4-dioxane / H2O, 2:1; CHCl3 / n-heptane, 1:1; DCM / toluene, 1:2; EtOAc; anisole; CPME; DMSO / H2O, 1:4; ACN / H2O, 989:11, a w About 0.2; ACN / H2O, 978:22, a w About 0.4; ACN / H2O, 959:41, a w About 0.6; ACN / H2O, 925:75, a w about 0.8; water-saturated EtOAc; isopropyl acetate; 2-methyltetrahydrofuran; or a combination thereof. In one embodiment, the molar ratio of compound 1 to oxalic acid in step 1 is about 1:0.5. In one embodiment, the solid form is a co-crystal. In one embodiment, the solid form is a salt.

[0098] In certain embodiments, provided herein is a method for preparing a powder in a saturated solution of a solid form of Compound 1, comprising 1) obtaining a saturated solution of Compound 1 in a solvent; 2) adding oxalic acid to the solution; 3) stirring the solution at ambient temperature for a period of time; 4) filtering the solution to obtain a first solid and 5) evaporating the solvent to collect a second solid. In one embodiment, seed crystals may be added to the solution. In certain embodiments, the solvent is ACN; EtOH; IPA; 1-BuOH; butyl acetate; 1-propanol; THF / H2O, 1:1; MeOAc; MeOH / MTBE, 1:2; 1,4-dioxane / H2O, 2:1; CHCl3 / n-heptane, 1:1; DCM / toluene, 1:2; EtOAc; anisole; CPME; DMSO / H2O, 1:4; ACN / H2O, 989:11, a w About 0.2; ACN / H2O, 978:22, a w About 0.4; ACN / H2O, 959:41, a w About 0.6; ACN / H2O, 925:75, a w about 0.8; water-saturated EtOAc; isopropyl acetate; 2-methyltetrahydrofuran; or a combination thereof. In one embodiment, the molar ratio of Compound 1 to oxalic acid is about 1:0.5. In one embodiment, the time period is about 72 hours. In one embodiment, the solid form is a co-crystal. In one embodiment, the solid form is a salt.

[0099] In certain embodiments, provided herein is a slurry method for preparing a solid form of Compound 1, comprising 1) obtaining a slurry of Compound 1 and oxalic acid at a certain ratio in a solvent; 2) stirring the slurry for a period of time; 3) collecting solids from the slurry by filtration (e.g., centrifugal filtration). In one embodiment, seeds may be added to the solution. In certain embodiments, the solvent is ACN; EtOH; IPA; 1-BuOH; butyl acetate; 1-propanol; THF / H2O, 1:1; MeOAc; MeOH / MTBE, 1:2; 1,4-dioxane / H2O, 2:1; CHCl3 / n-heptane, 1:1; DCM / toluene, 1:2; EtOAc; anisole; CPME; DMSO / H2O, 1:4; ACN / H2O, 989:11, a w About 0.2; ACN / H2O, 978:22, a w About 0.4; ACN / H2O, 959:41, a w About 0.6; ACN / H2O, 925:75, a wabout 0.8; water-saturated EtOAc; isopropyl acetate; 2-methyltetrahydrofuran; or a combination thereof. In one embodiment, the molar ratio of Compound 1 to oxalic acid is about 1:0.5. In one embodiment, the time period is about 3 days. In one embodiment, the solid form is a co-crystal. In one embodiment, the solid form is a salt.

[0100] In certain embodiments, provided herein is a grinding method for preparing a solid form of Compound 1, comprising 1) adding Compound 1, oxalic acid, and a solvent to a grinder; 2) vibrating the container at a specific frequency for a period of time; 3) collecting the resulting solid by filtration (e.g., centrifugal filtration). In certain embodiments, the solvent is ACN; EtOH; IPA; 1-BuOH; butyl acetate; 1-propanol; THF / H2O, 1:1; MeOAc; MeOH / MTBE, 1:2; 1,4-dioxane / H2O, 2:1; CHCl3 / n-heptane, 1:1; DCM / toluene, 1:2; EtOAc; anisole; CPME; DMSO / H2O, 1:4; ACN / H2O, 989:11, a w About 0.2; ACN / H2O, 978:22, a w About 0.4; ACN / H2O, 959:41, a w About 0.6; ACN / H2O, 925:75, a w about 0.8; water-saturated EtOAc; isopropyl acetate; 2-methyltetrahydrofuran; or a combination thereof. In one embodiment, the molar ratio of compound 1 to oxalic acid is about 1:0.5. In one embodiment, the time period is about 72 hours. In one embodiment, the frequency is about 30 Hz. In one embodiment, the solid form is a cocrystal. In one embodiment, the solid form is a salt.

[0101] A variety of methods known to those of ordinary skill in the art can be used to characterize the solid form co-crystals provided herein (e.g., Form 1), including, but not limited to, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), single differential thermal analysis (SDTA), high performance liquid chromatography coupled to mass spectrometry (HPLC-MS), thermogravimetric analysis coupled to single differential thermal analysis (TGA-SDTA), and thermogravimetric analysis coupled to mass spectrometry (TGA-MS). The particle size and size distribution of the solid forms provided herein can be determined by conventional methods, such as laser scattering techniques.

[0102] The purity of the solid forms provided herein can be determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS).

[0103] It should be understood that the values ​​of the peaks of the X-ray powder diffraction pattern may vary slightly between different machines or different samples, so the quoted values ​​should not be regarded as absolute values, but should have allowable variations, such as ±0.2 degrees 2θ (°2θ) (see United State Pharmacopoeia, page 2228 (2003)).

[0104] 5.3.1 Solid form 1 comprising compound 1 and oxalic acid

[0105] Provided herein is a solid form 1 comprising compound 1 and oxalic acid. In one embodiment, form 1 is a co-crystal. In one embodiment, form 1 is a salt. In one embodiment, form 1 is substantially crystalline. In one embodiment, provided herein is a solid form comprising (i) a co-crystal comprising compound 1 and oxalic acid and (ii) an amorphous form of compound 1. In one embodiment, provided herein is a solid form comprising (i) a salt comprising compound 1 and oxalic acid and (ii) an amorphous form of compound 1. In one embodiment, provided herein is a solid form comprising (i) a co-crystal comprising compound 1 and oxalic acid and (ii) one or more additional crystalline forms of compound 1. In one embodiment, provided herein is a solid form comprising (i) a salt comprising compound 1 and oxalic acid and (ii) one or more additional crystalline forms of compound 1. Provided herein are various embodiments, preparations or variations of form 1 comprising compound 1 and oxalic acid.

[0106] In one embodiment, Form 1 is an anhydrous form comprising Compound 1 and oxalic acid. In one embodiment, Form 1 is a solvated form comprising Compound 1 and oxalic acid. In one embodiment, Form 1 is an ACN solvated form comprising Compound 1 and oxalic acid. In another embodiment, Form 1 is crystalline.

[0107] In one embodiment, the molar ratio of oxalic acid to Form 1 of Compound 1 is 0.5±0.1, 0.5±0.05, 0.5±0.01, or about 0.5. In one embodiment, Form 1 is an oxalic acid cocrystal form. In one embodiment, Form 1 is an oxalate salt of Compound 1.

[0108] In certain embodiments, provided herein is a slurry method for preparing Form 1, comprising 1) obtaining a slurry of Compound 1 and oxalic acid at a certain ratio in a solvent; 2) stirring the slurry for a period of time; 3) collecting solids from the slurry by filtration (e.g., centrifugal filtration). In one embodiment, seeds may be added to the solution. In certain embodiments, the solvent is ACN; EtOH; IPA; 1-BuOH; butyl acetate; 1-propanol; THF / H2O, 1:1; MeOAc; MeOH / MTBE, 1:2; 1,4-dioxane / H2O, 2:1; CHCl3 / n-heptane, 1:1; DCM / toluene, 1:2; EtOAc; anisole; CPME; DMSO / H2O, 1:4; ACN / H2O, 989:11, a w About 0.2; ACN / H2O, 978:22, a w About 0.4; ACN / H2O, 959:41, a w About 0.6; ACN / H2O, 925:75, a w about 0.8; water-saturated EtOAc; isopropyl acetate; 2-methyltetrahydrofuran; or a combination thereof. In one embodiment, the molar ratio of Compound 1 to oxalic acid is about 1:0.3 to 1:3. In one embodiment, the molar ratio of Compound 1 to oxalic acid is about 1:0.5, about 1:1.2, about 1:0.55, about 1:2.2, or about 1:1. In one embodiment, the time period is about 3 days. In one embodiment, the solid form is a cocrystal. In one embodiment, the solid form is a salt.

[0109] In certain embodiments, the solid forms provided herein (e.g., Form 1) are substantially crystalline as indicated by, for example, X-ray powder diffraction measurements. In one embodiment, Form 1 of Compound 1 has substantially Figure 1 In one embodiment, Form 1 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at 2θ angles of approximately 8.17, 11.65 or 21.61 degrees, such as Figure 1In another embodiment, Form 1 of Compound 1 has one, two, three, four or five characteristic X-ray powder diffraction peaks at 2θ angles of approximately 8.17, 11.65, 18.54, 19.56 or 21.61 degrees. In another embodiment, Form 1 of Compound 1 has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at 2θ angles of approximately 8.17, 8.56, 11.65, 18.54, 19.56 or 21.61 degrees. In another embodiment, Form 1 of Compound 1 has one, two, three, four, five, six, seven, eight or nine characteristic X-ray powder diffraction peaks at 2θ angles of approximately 8.17, 8.56, 11.65, 16.52, 16.84, 18.54, 19.56, 19.92 or 21.61 degrees. In another embodiment, Form 1 of Compound 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks as shown in Table 9.

[0110] In one embodiment, Form 1 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at 2θ angles of approximately 8.17, 11.65 or 21.61 degrees, such as Figure 1 In another embodiment, Form 1 of Compound 1 has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at 2θ angles of approximately 8.17, 11.65, 18.54, 19.56, 20.69 or 21.61 degrees.

[0111] In one embodiment, provided herein is a method having a structure substantially corresponding to Figure 2 1. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of about 0.7% of the total mass of the sample between about 17.6° C. and about 130.0° C. when heated from about 17.6° C. to about 300° C. Thus, in certain embodiments, the crystalline form loses about 0.7% of the total mass of the crystalline form when heated from about 17.6° C. to about 130° C.

[0112] In one embodiment, provided herein is a Figure 3 The depicted differential scanning calorimetry (DSC) thermogram of Form 1 comprises an endothermic event with a maximum at about 160.4° C. when heated from about 25° C. to about 300° C. In one embodiment, the crystalline form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at about 159.1° C. when heated from about 50° C. to about 200° C.

[0113] In yet another embodiment, Form 1 of Compound 1 is substantially pure. In certain embodiments, the substantially pure Form 1 of Compound 1 is substantially free of other solid forms, such as amorphous forms. In certain embodiments, the purity of the substantially pure Form 1 of Compound 1 is not less than about 95% pure, not less than about 96% pure, not less than about 97% pure, not less than about 98% pure, not less than about 98.5% pure, not less than about 99% pure, not less than about 99.5% pure, or not less than about 99.8% pure.

[0114] 5.4 Usage

[0115] The solid forms and pharmaceutical compositions provided herein can be used in all methods provided herein. The solid forms and pharmaceutical compositions provided herein can be used to treat all diseases, disorders or conditions provided herein.

[0116] Provided herein are methods for treating or preventing cancer, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to a patient suffering from cancer.

[0117] In some embodiments, cancer is a B cell proliferative disease. For example, B cell proliferative disease is chronic lymphocytic, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or a combination of two or more thereof. In some such embodiments, cancer has progressed under standard anticancer therapy, or the patient cannot tolerate standard anticancer therapy. In other embodiments, cancer is a cancer for which there is no approved therapy. In some embodiments, cancer is resistant to standard therapy. In another embodiment, the patient relapses after standard treatment.

[0118] In certain embodiments, the cancer is chronic lymphocytic leukemia (CLL).

[0119] In certain embodiments, the cancer is marginal zone lymphoma (MZL).

[0120] In certain embodiments, the cancer is Waldenstrom's macroglobulinemia (WM).

[0121] In certain embodiments, the cancer is mantle cell lymphoma (MCL).

[0122] In certain embodiments, the cancer is follicular lymphoma (FL).

[0123] The B-cell proliferative disorder is chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0124] In certain embodiments, the cancer is of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testicle or other reproductive organ, skin, thyroid, blood, lymph node, kidney, liver, pancreas, and brain or central nervous system.

[0125] In other embodiments, the cancer is a solid tumor.In certain embodiments, the solid tumor is a relapsed or refractory solid tumor.

[0126] In other embodiments, the solid tumor may be an advanced solid tumor.

[0127] In other embodiments, the cancer is a cancer associated with a pathway involving BTK.

[0128] In certain embodiments, provided herein are methods for achieving complete response, partial response or stable disease in patients with solid tumors. Methods of solid tumor response evaluation criteria (e.g., RECIST 1.1) are included, comprising administering to the patient a solid form of compound 1 provided herein or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods for achieving complete response, partial response or stable disease in patients with leukemia. Methods of the National Cancer Institute-sponsored working group on chronic lymphocytic leukemia (NCI-WG CLL) include administering to the patient a solid form of compound 1 provided herein or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods for achieving complete response, partial response or stable disease in patients with prostate cancer. Methods of the Prostate Cancer Working Group 2 (PCWG2) standards, including administering to the patient a solid form of compound 1 provided herein or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods for achieving complete response, partial response or stable disease in patients with non-Hodgkin's lymphoma. Methods of the International Workshop Standards (IWC) for non-Hodgkin's lymphoma, including administering to the patient a solid form of compound 1 provided herein or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods for achieving a complete response, partial response, or stable disease according to the International Uniform Response Criteria for Multiple Myeloma (IURC) in a patient with multiple myeloma, comprising administering to the patient a solid form of Compound 1 provided herein, or a pharmaceutical composition thereof.

[0129] In certain embodiments, provided herein are methods for increasing disease progression-free survival in a patient suffering from cancer, comprising administering to the patient a solid form of Compound 1 provided herein, or a pharmaceutical composition thereof.

[0130] In certain embodiments, provided herein are methods for treating cancer, comprising administering a solid form of Compound 1 provided herein, or a pharmaceutical composition thereof, to a patient suffering from cancer, wherein the treatment results in the prevention or delay of clinical progression, such as cancer-related cachexia or increased pain.

[0131] In some embodiments, provided herein are methods for treating cancer, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to a patient suffering from cancer, wherein the treatment results in one or more of inhibition of disease progression, increase in time to progression (TTP), increase in progression-free survival (PFS), and / or increase in overall survival (OS), etc.

[0132] 5.5 Pharmaceutical Compositions

[0133] The solid form of Compound 1 provided herein can be used to prepare a pharmaceutical composition comprising an effective amount of a solid form of Compound 1 and a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutical composition described herein is suitable for oral, parenteral, mucosal, transdermal or topical administration.

[0134] In certain embodiments, provided herein are compositions comprising one or more solid forms of Compound 1. Also provided herein are compositions comprising: (i) one or more solid forms of Compound 1 provided herein (e.g., one or more co-crystal forms or mixtures thereof), and (ii) other active or inactive ingredients.

[0135] In one embodiment, the pharmaceutical compositions provided herein comprise a solid form of Compound 1 and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise Form 1 of Compound 1 and one or more pharmaceutically acceptable excipients or carriers.

[0136] In one embodiment, the pharmaceutically acceptable excipients and carriers are selected from binders, diluents, disintegrants and lubricants. In another embodiment, the pharmaceutically acceptable excipients and carriers further include one or more antioxidants (eg, EDTA or BHT).

[0137] In certain embodiments, binders include, but are not limited to, cellulose (e.g., microcrystalline cellulose, such as PH 101, PH112 and PH 102) and starch (e.g., pregelatinized starch (STARC )). In one embodiment, the binder is cellulose. In another embodiment, the binder is microcrystalline cellulose. In yet another embodiment, the binder is PH 101. In yet another embodiment, the binder is PH 102. In yet another embodiment, the binder is starch. In yet another embodiment, the binder is pregelatinized starch. In yet another embodiment, the binder is STARCH

[0138] In certain embodiments, diluents include, but are not limited to, lactose (e.g., lactose monohydrate (FAST 316) and anhydrous lactose), cellulose (e.g., microcrystalline cellulose, such as PH 101 and PH102). In one embodiment, the diluent is lactose. In another embodiment, the diluent is lactose monohydrate. In yet another embodiment, the diluent is 316. In another embodiment, the diluent is anhydrous lactose. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is PH 101. In yet another embodiment, the diluent is PH102).

[0139] In certain embodiments, disintegrants include, but are not limited to, starches (e.g., corn starch) and carboxymethylcellulose (e.g., croscarmellose sodium, such as ). In one embodiment, the disintegrant is starch. In another embodiment, the disintegrant is corn starch. In yet another embodiment, the disintegrant is carboxymethyl cellulose. In yet another embodiment, the disintegrant is cross-linked sodium carboxymethyl cellulose. In another embodiment, the disintegrant is

[0140] In certain embodiments, lubricants include, but are not limited to, starch (e.g., corn starch), magnesium stearate, and stearic acid. In one embodiment, the lubricant is starch. In another embodiment, the lubricant is corn starch. In another embodiment, the lubricant is magnesium stearate. In yet another embodiment, the lubricant is stearic acid.

[0141] In another embodiment, the pharmaceutical compositions provided herein comprise a solid form of Compound 1 and one or more pharmaceutically acceptable excipients or carriers, each independently selected from carboxymethyl cellulose, cellulose, lactose, magnesium stearate, starch, and stearic acid.

[0142] In certain embodiments, provided herein are pharmaceutical compositions in which the amounts of the listed components may vary independently by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25%.

[0143] The pharmaceutical compositions provided herein can be provided in unit dosage form or multiple dosage form. As used herein, unit dosage form refers to physically discrete units suitable for administration to human and animal subjects and individually packaged as known in the art. Each unit dose contains a predetermined amount of active ingredient combined with a desired pharmaceutical carrier or excipient sufficient to produce the desired therapeutic effect. Examples of unit dosage forms include individually packaged tablets or capsules. Unit dosage forms can be administered in parts or multiples thereof. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, administered in isolated unit dosage forms. Unless the context otherwise requires, the dosage herein is expressed as free base equivalents.

[0144] In another embodiment, provided herein is a unit dose formulation comprising about 0.1 mg to about 2000 mg, about 1 mg to about 200 mg, about 35 mg to about 1400 mg, about 125 mg to about 1000 mg, about 250 mg to about 1000 mg, or about 500 mg to about 1000 mg of a solid form of Compound 1 or a pharmaceutically acceptable salt, isotopomer, or solid form thereof.

[0145] In certain embodiments, provided herein are unit dose formulations comprising about 0.1 mg, about 0.25 mg, about 0.5 mg, about 1 mg, about 2 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 100 mg, about 125 mg, about 140 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 560 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 1000 mg, or about 1400 mg of a solid form of Compound 1. In certain embodiments, provided herein is a unit dose formulation comprising about 2.5 mg, about 5 mg, about 7.5 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, or about 100 mg of a solid form of Compound 1, or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof.

[0146] In some embodiments, a unit dosage form comprising Compound 1, or a pharmaceutically acceptable salt, isotopologue, or solid form thereof, can be administered once a day (QD), twice a day (BID), three times a day, four times a day, or more frequently.

[0147] In certain embodiments, provided herein are methods for preparing the compositions provided herein, comprising: (i) weighing out a desired amount of a solid form of Compound 1 (e.g., Form 1) and a desired amount of an excipient (such as lactose monohydrate, cross-linked sodium carboxymethyl cellulose and / or microcrystalline cellulose); (ii) mixing or blending the solid form of Compound 1 and the excipient; (iii) sieving the mixture of the solid form of Compound 1 and the excipient (such as a 25 mesh sieve); (iv) mixing or blending the solid form of Compound 1 and the excipient after sieving. (v) weighing out the desired amount of lubricant (e.g., stearic acid and magnesium stearate); (vi) sieving the lubricant (such as a 35 mesh screen); (vii) mixing or blending the solid form of Compound 1, excipients, and lubricants; (viii) compressing the mixture of the solid form of Compound 1, excipients, and lubricants (such as compressed into tablet form); and optionally (ix) coating the compressed mixture of the solid form of Compound 1, excipients, and lubricants with a coating agent (such as Opadry pink, yellow, or beige). In certain embodiments, the methods for preparing the compositions provided herein are performed in the dark, under yellow light, or in the absence of ultraviolet light.

[0148] In certain embodiments, pharmaceutical compositions provided herein contain Form 1 of Compound 1, including substantially pure Form 1.

[0149] 6. Examples

[0150] The following examples are presented for illustration only and not limitation. The following abbreviations are used in the description and examples:

[0151] 2MXETOH: 2-methoxyethanol

[0152] AAC: Accelerated aging conditions (48 hours at 40°C and 75% RH)

[0153] ACN: Acetonitrile

[0154] Am: Amorphous

[0155] AmPhos: p-dimethylaminophenyl dibutylphosphine

[0156] API: Active Pharmaceutical Ingredient

[0157] AS: ID of antisolvent crystallization experiment

[0158] Boc: tert-Butyloxycarbonyl

[0159] dba: dibenzylideneacetone

[0160] DCM: dichloromethane

[0161] DIPEA: N,N-diisopropylethylamine

[0162] DMF: N,N-dimethylformamide

[0163] DMSO: dimethyl sulfoxide

[0164] DSC: Differential Scanning Calorimetry

[0165] ECP: Evaporation Experiment ID

[0166] EDTA: Ethylenediaminetetraacetate

[0167] ESI: Electrospray ionization

[0168] EtOH: ethanol

[0169] FTIR: Fourier Transform Infrared Spectroscopy

[0170] GRP: Grinding Experiment

[0171] HF: ID of hot filtration crystallization experiment

[0172] HPLC: High Performance Liquid Chromatography

[0173] IPA:2-Propanol

[0174] LCMS: Liquid Chromatography and Mass Spectrometry

[0175] MeOH: Methanol

[0176] mp: melting point

[0177] MS: Mass spectrometry

[0178] Ms: Methanesulfonate or mesyl

[0179] MTBE: tert-butyl methyl ether

[0180] MTBE: Methyl tert-butyl ether

[0181] NBS: N-bromosuccinimide

[0182] NMP: N-methyl-2-pyrrolidone

[0183] NMP: N-methylpyrrolidone

[0184] NMR: Nuclear Magnetic Resonance

[0185] PSU: ID of cooling evaporation crystallization experiment

[0186] QSA: ID of Phase 1 experiment

[0187] RH:Relative humidity

[0188] RT: Room temperature

[0189] S:Solvent

[0190] SDTA: Single Differential Thermal Analysis

[0191] SLP: ID of serum experiment

[0192] SM: Starting material

[0193] TA: Thermal Analysis

[0194] TCP: ID for thermal cycling and reflow experiments

[0195] Tf: triflate or trifluoromethanesulfonyl

[0196] TFA: Trifluoroacetic acid

[0197] TFE:2,2,2-Trifluoroethanol

[0198] TGA: Thermogravimetric analysis

[0199] TGA-MS / TG-MS: Thermogravimetric analysis coupled with mass spectrometry

[0200] THF:Tetrahydrofuran

[0201] TLC: Thin layer chromatography

[0202] VDL: Vapor Diffusion into Solution Experiment ID

[0203] VDS: Vapor Diffusion into Solids Experiment ID

[0204] XRPD: X-ray powder diffraction

[0205] 6.1 Analytical methods

[0206] XRPD

[0207] For XRPD analysis, a PANalytical Empyrean X-ray powder diffractometer was used. The XRPD parameters used are listed in Table 1.

[0208] Table 1: XRPD test parameters

[0209]

[0210] TGA and DSC

[0211] TGA data were collected using TA Q5000 / Discovery TGA 5500 from TA Instruments. DSC was performed using Discovery DSC 2500 from TA Instruments. The standard deviations for TGA and DSC were approximately ±0.3° C. The detailed parameters used are listed in Table 2.

[0212] Table 2: Parameters of TGA and DSC tests

[0213]

[0214]

[0215] HPLC

[0216] Waters H-Class was used and the detailed chromatographic conditions are listed in Table 3.

[0217] Table 3: Chromatographic conditions and parameters for purity and solubility testing

[0218]

[0219] IC

[0220] Thermo Scientific TM Dionex TM Aquion TM Ion chromatography (IC) system 1100, detailed chromatographic conditions are listed in Table 4.

[0221] Table 4: Chromatographic conditions and parameters for ion content test

[0222]

[0223] 6.2 Experimental methods

[0224] Table 5 provides a summary of the solvents and methods for each batch.

[0225] Table 5: Summary of solvents and methods for each batch

[0226]

[0227] Preparation procedure of oxalate form A

[0228] Test 1

[0229] 800.0 mg of free base Form A was weighed and suspended in a HPLC vial with 4 mL of ACN.

[0230] 106.9 mg of dehydrated oxalic acid (0.5 equivalent) was dissolved in 2.5 mL of acetonitrile (ACN).

[0231] The acid solution was added to the free base suspension. During the addition, the mixture formed a clear solution and solids precipitated rapidly within seconds after the acid addition.

[0232] Incubate under magnetic stirring at RT for 1 day.

[0233] The solid was separated from the suspension by centrifugation. The solid was dried under vacuum at RT overnight before characterization.

[0234] Test 2

[0235] 403.2 mg of free base Form A and 125.1 mg of dehydrated oxalic acid (approximately 1.2 equivalents) were weighed into an HPLC vial.

[0236] 5 mL of ACN was added to the vial. During the addition, the mixture formed a clear solution to which a small amount of oxalate Form A seed crystals were added. A thick suspension formed immediately upon addition of the seed crystals.

[0237] Incubate under magnetic stirring at RT for 3 days.

[0238] The solid was separated from the suspension by centrifugation. The wet sample showed a clear oxalic acid diffraction peak. The wet sample was slurry washed with ACN (1 mL, 5 min, 3 times) to remove the residual acid.

[0239] The solid was dried under vacuum at RT overnight before characterization.

[0240] Test 3

[0241] 40.1 mg of free base Form A and 6.0 mg of dehydrated oxalic acid (0.55 equivalents) were weighed into a HPLC vial.

[0242] Add 0.5 mL ACN to the vial. Stir magnetically at RT for 3 days.

[0243] The solid was separated from the suspension by centrifugation and corresponded to Form A oxalate.

[0244] IC / HPLC analysis indicated that the molar ratio of ion to free base was 0.5.

[0245] Test 4

[0246] 40.1 mg of free base Form A and 23.6 mg of dehydrated oxalic acid (2.2 equivalents) were weighed into an HPLC vial.

[0247] Add 0.5 mL ACN to the vial. Stir magnetically at RT for 3 days.

[0248] The solid was separated from the suspension by centrifugation. The wet sample showed a clear oxalic acid diffraction peak. The wet sample was slurry washed with ACN (1 mL, 5 min, 3 times) to remove the residual acid.

[0249] IC / HPLC analysis indicated that the molar ratio of ion to free base was 0.5.

[0250] Test 5

[0251] 40.1 mg of free base Form A and 10.7 mg of dehydrated oxalic acid (1 equivalent) were weighed into a HPLC vial.

[0252] 0.5 mL of ACN was added to the vial. During the addition, the mixture formed a clear solution and turned into a suspension within a few seconds.

[0253] Incubate under magnetic stirring at RT for 3 days.

[0254] The solid was separated from the suspension by centrifugation and dried under vacuum at RT overnight before characterization.

[0255] Test 6

[0256] 40.1 mg of free base Form A and 10.9 mg of dehydrated oxalic acid (1 equivalent) were weighed into a HPLC vial.

[0257] 0.5 mL of isopropyl acetate (IPAc) was added to the vial to form a suspension.

[0258] Incubate under magnetic stirring at RT for 3 days.

[0259] The solid was separated from the suspension by centrifugation and dried under vacuum at RT overnight before characterization.

[0260] Test 7

[0261] 1. Weigh 39.9 mg of free base Form A and 10.7 mg of dehydrated oxalic acid (1 equivalent) into a HPLC vial.

[0262] 2. Add 0.5 mL of 2-methyltetrahydrofuran (2-MeTHF) to the vial. During the addition, the mixture formed a clear solution and turned into a suspension within a few seconds.

[0263] 3. Incubate under magnetic stirring at RT for 3 days.

[0264] 4. The solid was separated from the suspension by centrifugation and dried under vacuum at RT overnight before characterization.

[0265] Test 8

[0266] 15.3 mg of the amorphous oxalate salt (obtained by triturating 99.8 mg of the free base Form A and 26.6 mg (approximately 1 equivalent) of oxalic acid dihydrate in 3.75 mL of IPAc) was weighed into a HPLC vial.

[0267] 0.2 mL of ACN was added to the vial.

[0268] One week of temperature cycling was allowed to proceed (one cycle was heating to 50°C at a rate of 4.5°C / min, holding the temperature for about 2 hours, cooling to 5°C at a rate of 0.1°C / min, holding the temperature for about 2 hours).

[0269] The solid was separated from the suspension by centrifugation and dried under vacuum at RT overnight before characterization.

[0270] Test 9

[0271] 14.7 mg of the amorphous oxalate salt (obtained by triturating 99.8 mg of the free base Form A and 26.6 mg (approximately 1 equivalent) of oxalic acid dihydrate in 3.75 mL of IPAc) was weighed into a HPLC vial.

[0272] Add 0.2 mL IPAc to the vial.

[0273] One week of temperature cycling was allowed to proceed (one cycle was heating to 50°C at a rate of 4.5°C / min, holding the temperature for about 2 hours, cooling to 5°C at a rate of 0.1°C / min, holding the temperature for about 2 hours).

[0274] The solid was separated from the suspension by centrifugation and dried under vacuum at RT overnight before characterization.

[0275] Test 10

[0276] 16.7 mg of the amorphous oxalate salt (obtained by triturating 99.8 mg of the free base Form A and 26.6 mg (approximately 1 equivalent) of oxalic acid dihydrate in 3.75 mL of IPAc) was weighed into a HPLC vial.

[0277] 0.2 mL of 2-MeTHF was added to the vial.

[0278] One week of temperature cycling was allowed to proceed (one cycle was heating to 50°C at a rate of 4.5°C / min, holding the temperature for about 2 hours, cooling to 5°C at a rate of 0.1°C / min, holding the temperature for about 2 hours).

[0279] The solid was separated from the suspension by centrifugation and dried under vacuum at RT overnight before characterization.

[0280] Polymorph Screening of Oxalate Form A

[0281] Table 6: Summary of Oxalate Form A Polymorph Screening

[0282]

[0283]

[0284] 6.2.1 Solubility

[0285] Tables 7 and 8 provide summaries of solubility experiments in water at 37°C and 25°C, respectively.

[0286] Table 7: Summary of solubility experiments in water (37°C)

[0287]

[0288]

[0289] S: solubility, mg / mL; FC: solid form change. Solid loading: 2 mg / mL.

[0290] Table 8: Summary of solubility experiments in water (25°C)

[0291]

[0292] S: solubility, mg / mL; FC: solid form change. Solid loading: 2 mg / mL.

[0293] 6.2.2 Eutectic Solid Form 1

[0294] Form 1 was prepared using the method used in Experiment 2 when dehydrated oxalic acid was used and ACN was used as the solvent. Form 1 is a crystalline solid form of Compound 1 and oxalic acid.

[0295] Figure 1 An XRPD pattern is provided for Form 1. A list of X-ray diffraction peaks for Form 1 is provided in Table 9 below.

[0296] Table 9. X-ray diffraction peaks of Form 1

[0297]

[0298]

[0299] Figure 2 and Figure 3 TGA data and DSC data of Form 1 are provided separately. Figure 2 A mass loss of 0.70% was observed between about 17.6°C and about 130°C. Figure 3From the DSC signal data, an endothermic melting event was observed with an onset temperature of 159.1 °C and a peak temperature of 160.4 °C.

[0300] Figure 4 Provided in Form 1 1 H NMR.

[0301] Figure 5 DVS results are provided, showing that the water uptake of Form 1 is less than 0.2% at 25°C / 80%RH, indicating that it is not hygroscopic.

[0302] Figure 6 Provided are solubility profiles of Form A of Compound 1 and an amorphous form of Compound 1 at room temperature.

[0303] Figure 7 Solubility curves of Form A of Compound 1 and the amorphous form of Compound 1 at 37°C are provided.

[0304] Two samples were prepared for stoichiometric testing. Each sample was tested for compound 1 concentration by HPLC and oxalic acid concentration by IC. HPLC and IC results showed that the molar ratio of oxalic acid to compound 1 was 0.5.

[0305] At least the following methods can be used to determine whether Form 1 of Compound 1 is a cocrystal and whether Form 1 of Compound 1 is a salt:

[0306] (1) Single crystal X-ray diffraction, which is the most commonly used method to distinguish cocrystals from salts. Standard experimental methods, procedures and parameters can be found in Cullity, BD, & Stock, SR (2001). Elements of X-Ray Diffraction (3rd edition). Pearson; and Pecharsky, V., & Zavalij, P. (2008). Fundamentals of Powder Diffraction and Structural Characterization of Materials, 2nd edition (2nd edition 2009 edition). Springer.

[0307] (2) Solid-state NMR. Standard experimental methods, procedures, and parameters can be found in Apperley, DC, Harris, RK, & Hodgkinson, P. (2012c). Solid-state NMR. Amsterdam University Press.

[0308] (3) X-ray Photoelectron Spectroscopy. Standard experimental methods, procedures and parameters can be found in der Heide, VP (2011). X-ray Photoelectron Spectroscopy: An introduction to Principles and Practices (1st edition). Wiley.

[0309] Solid-state NMR and X-ray photoelectron spectroscopy do not require single crystals.

[0310] The scope of the embodiments disclosed herein is not limited by the specific embodiments disclosed in the examples, which are intended to illustrate several aspects of the disclosed embodiments, and any functionally equivalent embodiments are encompassed in the present disclosure. Indeed, various modifications and embodiments disclosed herein, in addition to those shown and described herein, will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0311] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. A solid form comprising (a) (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide; and (b) oxalic acid.

2. The solid form of claim 1 which is substantially crystalline.

3. The solid form of claim 2 which is substantially a co-crystal.

4. The solid form of claim 2 which is substantially a salt.

5. The solid form of claim 2, which is a crystalline form comprising Compound 1: It has an X-ray powder diffraction pattern comprising peaks at approximately 8.2, 11.7 and 21.6° 2θ.

6. The crystalline form of claim 5, having an X-ray powder diffraction pattern further comprising peaks at approximately 8.6, 18.5 and 19.6° 2θ.

7. The crystalline form of claim 5, having a thermogravimetric analysis thermogram comprising a total mass loss of about 0.7% of the total mass of the crystalline form when heated from about 17.6°C to about 130°C.

8. The crystalline form of claim 5, having a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature of approximately 159.1°C when heated from about 50°C to about 200°C.

9. The crystalline form of claim 5, which is an oxalic acid cocrystal form.

10. The crystalline form of claim 5, which is an oxalate salt.

11. The crystalline form of claim 5, wherein the molar ratio of oxalic acid to Compound 1 is about 0.

5.

12. The crystalline form of claim 5 which is substantially pure.

13. A method for treating or preventing a B-cell proliferative disorder or a condition treatable or preventable by inhibiting a kinase pathway, comprising administering to a subject in need thereof an effective amount of the solid form of any one of claims 1-12.

14. The method of claim 13, wherein the kinase pathway is the BTK pathway.

15. A method for achieving a complete response, partial response, or stable disease in a subject according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), comprising administering to a subject having a solid tumor an effective amount of the solid form of any one of claims 1-12.

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