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

Abstract

Provided herein are formulations, processes, solid forms, and methods of use for (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide. Also 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 approximately 8.17, 11.65, or 21.61 degrees 2-theta. In one embodiment, the X-ray powder diffraction pattern may further comprise characteristic X-ray powder diffraction peaks at approximately 8.56, 18.54, or 19.56 degrees 2-theta.

Description

[Technical Field]

[0001] 1.Technical Field 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 using them to treat, prevent, and manage various disorders. [Background technology]

[0002] 2.Background technology Identifying and selecting a solid form for a pharmaceutical compound is complex, considering that changes in solid form can affect various physical and chemical properties, which can provide advantages or disadvantages in processing, formulation, stability, and bioavailability, among other important pharmaceutical properties. Potential pharmaceutical solids include crystalline solids and amorphous solids. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired pharmaceutical solid class depends on the specific application; amorphous solids may be selected, for example, based on an enhanced dissolution profile, while crystalline solids may be desirable for properties such as physical or chemical stability (see, e.g., S.R. Vippagunta et al., Adv. Drug. Deliv. Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48:27-42).

[0003] Potential solid forms of pharmaceutical compounds, whether crystalline or amorphous, include single-component and multi-component solids. Single-component solids consist essentially of the pharmaceutical compound in the absence of other compounds. Variation among single-component crystalline materials can potentially result from polymorphism, where multiple three-dimensional configurations exist for a particular pharmaceutical compound (see, e.g., SR Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The importance of identifying polymorphs was highlighted by the case of ritonavir, an HIV protease inhibitor formulated as a soft gelatin capsule. Approximately two years after the product was launched, unexpected precipitation of a new, less soluble polymorph in the formulation forced the product to be withdrawn from the market until a more consistent formulation could be developed (see SR Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417).

[0004] Further diversity among potential solid forms of pharmaceutical compounds can result from the possibility of multi-component solids. Crystalline solids containing two or more ionic species are called salts (see, e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl and C.G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types of multi-component solids that can potentially provide improved properties to pharmaceutical compounds or their salts include, among others, hydrates, solvates, cocrystals, and clathrates (see, e.g., S.R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Furthermore, multi-component crystalline forms can potentially be subject to polymorphism, meaning that a given multi-component composition may exist in more than one three-dimensional crystal configuration. Solid form discovery is crucial for the development of safe, effective, stable, and marketable pharmaceutical compounds.

[0005] In particular, it is impossible to predict in advance whether crystalline forms of a compound will exist, let alone how to successfully prepare them (e.g., Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem. Commun.: 3635-3645 (with respect to crystal engineering, the results can be unpredictable if the instructions are not very precise and / or other external factors affect the process); Jones et al., 2006, “Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 31: 875-879 (currently, it is generally not possible to computationally predict 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 (much still needs to be learned and done before the ability to predict the crystal structures of much less polymorphic forms can be stated with any degree of confidence).

[0006] Cocrystals are crystalline molecular complexes of two or more nonvolatile compounds bound together in a crystal lattice by nonionic interactions. Pharmaceutical cocrystals are cocrystals of a therapeutic compound, e.g., an active pharmaceutical ingredient (API), with one or more nonvolatile compounds (referred to herein as coformers). The coformers in pharmaceutical cocrystals are typically selected from nontoxic, pharmaceutically acceptable molecules, such as food additives, preservatives, pharmaceutical excipients, or other APIs. In recent years, pharmaceutical cocrystals have emerged as a potential alternative approach to improving the physicochemical properties of pharmaceuticals. The variety of possible solid forms provides a potential diversity of physical and chemical properties for a given pharmaceutical compound.

[0007] The compound having 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 September 20, 2016, and International Publication No. WO2014 / 173289, each of which is incorporated herein by reference in its entirety. Crystalline Form A of Compound 1 is disclosed in U.S. Patent No. 10,927,117, issued February 23, 2021, and International Publication No. WO2018 / 033853, the entire contents of each of which are incorporated herein by reference. Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that the reference is prior art to the present application. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent No. 10,927,117 [Patent Document 2] International Publication No. 2018 / 033853 [Non-patent literature]

[0009] [Non-Patent Document 1] SRVippagunta et al.,Adv.Drug. Deliv. Rev.,(2001)48:3-26;L.Yu,Adv.Drug. Deliv. Rev.,(2001)48:27-42 [Non-patent document 2] SRByrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette [Non-patent document 3] SR Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417 [Non-patent document 4] Handbook of Pharmaceutical Salts: Properties, Selection and Use, PH Stahl and CGWermuth, Eds., (2002), Wiley, Weinheim. [Non-Patent Document 5] Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 31:875-879 [Non-patent document 6] Price, 2004, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56:301-319 (“Price”) Summary of the Invention [Means for solving the problem]

[0010] 3. Summary of the Invention Provided herein is a solid form comprising Compound 1, having the name (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: [ka] Also provided are methods for preparing, isolating, and characterizing the solid forms.

[0011] Further provided herein is a crystalline form comprising Compound 1. One crystalline form provided herein has an X-ray powder diffraction pattern comprising characteristic X-ray powder diffraction peaks at approximately 8.17, 11.65, or 21.61 degrees 2-theta angle. In one embodiment, the X-ray powder diffraction pattern may further comprise characteristic X-ray powder diffraction peaks at approximately 8.56, 18.54, or 19.56 degrees 2-theta angle.

[0012] In one embodiment, the solid form is a co-crystal. In one embodiment, the solid form is a salt.

[0013] In one embodiment, the crystalline form has a thermogravimetric analysis thermogram that includes a total mass loss of approximately 0.7% of the crystalline form's total mass when heated from about 17.6° C. to about 130° C. In one embodiment, the crystalline form has a differential scanning calorimetry thermogram that includes an endothermic event with a maximum at approximately 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 that includes an endothermic event with an onset temperature of approximately 159.1° C. when heated from about 50° C. to about 200° C.

[0014] In one embodiment, the molar ratio of oxalic acid to the crystalline form of Compound 1 is about 0.5. The crystalline form can be substantially pure.

[0015] All of the solid forms and pharmaceutical compositions provided herein can be used as pharmaceuticals. In certain embodiments, solid forms of Compound 1 are useful for treating or preventing cancer and conditions treatable or preventable by inhibition of a kinase pathway, such as the BTK pathway. All of the 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 conditions treatable or preventable by inhibition of a kinase pathway. The methods include administering an effective amount of the solid form or pharmaceutical composition to a subject in need thereof. The kinase pathway is the BTK kinase pathway. In one embodiment, a method is provided for treating 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, or a combination of two or more thereof in a subject by administering a solid form disclosed herein to the subject.

[0016] All solid forms and pharmaceutical compositions provided herein can be used in methods for achieving a complete response, partial response, or stable disease in a subject with a solid tumor (RECIST 1.1). The methods include administering an effective amount of the solid form or pharmaceutical composition to a subject with a solid tumor.

[0017] All solid forms and pharmaceutical compositions provided herein can be used in methods for improving International Workshop Criteria (IWC) or Eastern Cooperative Oncology Group Performance Status (ECOG) for NHL. The method comprises administering an effective amount of the solid form or pharmaceutical composition to a subject in need thereof.

[0018] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments. 4. Brief description of the drawings [Brief explanation of the drawings]

[0019] [Figure 1] 1 shows the X-ray powder diffraction pattern of Form 1. [Figure 2] 1 shows a thermogravimetric analysis of Form 1. [Figure 3] 1 shows a differential scanning calorimetry analysis of Form 1. [Figure 4] 1H NMR of Form 1 is shown. [Figure 5] Figure 1 shows DVS results showing that the water uptake of Form 1 at 25°C / 80% RH was lower than 0.2%, indicating that it was non-hygroscopic. [Figure 6] 1 shows the solubility profiles of Form 1, Form A of Compound 1, and the amorphous form of Compound 1 at room temperature. [Figure 7] 1 shows the solubility profiles of Form 1, Form A of Compound 1, and the amorphous form of Compound 1 at 37° C. DETAILED DESCRIPTION OF THE INVENTION

[0020] 5. MODE FOR CARRYING OUT THE INVENTION 5.1 Definition As used herein, and unless otherwise specified, the terms "oxalic acid" and "oxalate" refer to both non-ionized / unassociated oxalic acid and ionized / associated oxalic acid.

[0021] As used herein, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents unless the context clearly indicates otherwise.

[0022] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percent.

[0023] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or range of values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range (e.g., those describing melting, dehydration, desolvation, or glass transition temperatures), mass change (e.g., mass change as a function of temperature or humidity), solvent or water content (e.g., in mass or percentage), or peak position (e.g., in analysis by IR or Raman spectroscopy or XRPD), indicate that the value or range of values ​​may deviate to an extent considered reasonable by one of ordinary skill in the art and still describe 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 diffractometry (XRPD), single crystal X-ray diffractometry, and solubility studies. In certain embodiments, the terms "about" and "approximately," as 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 stated value or range of values. For example, in some embodiments, XRPD peak position values ​​may vary by up to ±0.2 degrees two-theta while describing a particular XRPD peak.

[0024] As used herein, and unless otherwise specified, a crystal that is "pure," i.e., 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.

[0025] As used herein, and unless otherwise specified, the term "substantially pure" when used to describe a polymorph of a compound, i.e., a crystalline or amorphous form of a compound, refers to a crystalline or amorphous form of a compound that is inclusive of the crystalline or amorphous form and is substantially free of other polymorphs of the compound. A substantially pure crystalline form is at least about 95% pure, at least about 96% pure, at least about 97% pure, at least about 98% pure, at least about 98.5% pure, at least about 99% pure, at least about 99.5% pure, or at least 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% by weight of one or more other polymorphs.

[0026] As used herein, and unless otherwise specified, a solid form that is "substantially physically pure" 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 may be achieved by any method apparent to one of skill in the art, including, but not limited to, diffraction analysis, thermal analysis, elemental combustion analysis, and / or spectroscopy.

[0027] As used herein, and unless otherwise specified, a solid form that is "substantially chemically pure" 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 performed by any method apparent to one of skill in the art, including, but not limited to, chemical analysis methods such as mass spectrometry, spectroscopic analysis, thermal analysis, elemental combustion analysis, and / or chromatographic analysis.

[0028] As used herein, and unless otherwise specified, 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 other compounds, solid forms, or compositions.

[0029] Unless otherwise specified, the terms "solvate" and "solvate," as used herein, refer to a crystalline form of a substance that includes a solvent. The terms "hydrate" and "hydrate" refer to a solvate in which the solvent is water. A "polymorph of a solvate" refers to the existence of more than one solid form of a particular solvate composition. Similarly, a "polymorph of a hydrate" refers to the existence 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 produced by removing the solvent from a solvate. The terms "solvate" and "solvate," as used herein, may also refer to a solvate of a salt, co-crystal, or molecular complex. The terms "hydrate" and "hydrate," as used herein, may also refer to a hydrate of a salt, co-crystal, or molecular complex.

[0030] "Tautomer" refers to isomers of a compound that are in equilibrium with each other. The concentration of isomers may vary depending on the environment in which the compound is found, 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 called tautomers of each other: [ka]

[0031] As will be readily appreciated by those skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of Compound 1 are within the scope of the present invention.

[0032] Unless otherwise specified, as used herein, the term "composition" is intended to encompass a product containing the specified ingredient(s) (where indicated, in the specified amount(s)), as well as any product resulting directly or indirectly from combining the specified amounts of the specified ingredient(s). "Pharmaceutically acceptable" means that a diluent, excipient, or carrier in a formulation must be compatible with the other ingredient(s) of the formulation and not deleterious to the recipient thereof.

[0033] The term "solid form" refers to a physical form that is not predominantly in a liquid or gaseous state. As used herein, and unless otherwise specified, the term "solid form" used herein to refer to Compound 1 refers to a physical form comprising Compound 1 that is not predominantly in a liquid or gaseous state. A solid form may be a crystalline form or a mixture thereof. In certain embodiments, a solid form may be 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.

[0034] As used herein, and unless otherwise specified, the term "crystalline" when describing 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 specified. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23 rd ed., 1843-1844 (1995).

[0035] The term "crystalline form" or "crystalline form" refers to a solid form that is crystalline. In certain embodiments, crystalline forms include salts. In certain embodiments, a crystalline form of a substance may be substantially free of amorphous forms and / or other crystalline forms. In certain embodiments, a 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% by weight of one or more amorphous forms and / or other crystalline forms. In certain embodiments, a crystalline form of a substance may be physically and / or chemically pure. In certain embodiments, the crystalline form of the 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.

[0036] Unless otherwise specified, the terms "polymorph(s)," "polymorph(s)," and related terms herein refer to two or more crystalline forms consisting of essentially the same molecule(s) or ions. Different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution characteristics, and / or vibrational spectra, as a result of different arrangements or conformations of the molecules or ions within the crystalline lattice. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (a key factor in bioavailability). Differences in stability can be due to changes in chemical reactivity (e.g., differential oxidation, such that a dosage form consisting of one polymorph discolors more rapidly than one consisting of another polymorph), or mechanical changes (e.g., a tablet disintegrates during storage to a thermodynamically more stable polymorph as a kinetically favored polymorphic transformation), or both (e.g., tablets of one polymorph are more susceptible to degradation under high humidity). As a result of differences in solubility / disintegration, in extreme cases, some polymorphic transitions may result in a lack of efficacy or, in other extreme cases, toxicity. Additionally, the physical properties of the crystals may be important in processing; for example, some polymorphs may be more likely to form solvates or may be difficult to filter and wash free of impurities (e.g., particle shape and size distribution may differ between polymorphs).

[0037] Unless otherwise specified, as used herein, the term "cocrystal" refers to a crystalline material composed of Compound 1 (including its tautomers) and one or more non-volatile compounds bound within a crystal lattice by non-covalent interactions.

[0038] Unless otherwise specified, the terms "amorphous" or "amorphous form" mean that the substance, component, or product in question is substantially not crystalline as determined by X-ray diffraction. Specifically, the term "amorphous form" describes an irregular solid form, i.e., a solid form lacking long-range crystalline order. In certain embodiments, an amorphous form of a substance is substantially free of other amorphous and / or crystalline forms. In certain embodiments, an amorphous form of a substance may contain, on a weight basis, less than about 1 wt%, less than about 2 wt%, less than about 3 wt%, less than about 4 wt%, less than about 5 wt%, less than about 10 wt%, less than about 15 wt%, less than about 20 wt%, less than about 25 wt%, less than about 30 wt%, less than about 35 wt%, less than about 40 wt%, less than about 45 wt%, or less than about 50 wt% of one or more other amorphous and / or crystalline forms. In certain embodiments, the amorphous form of the substance can be physically and / or chemically pure, ie, 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.

[0039] As used herein, "treating" means the total or partial alleviation of a disease or disorder, or symptoms associated with a disease or disorder, or the slowing or halting of further progression or worsening of a disease or disorder, or symptoms associated with a disease or disorder.

[0040] As used herein, "preventing" means preventing the onset, recurrence, or spread of a disease or disorder, or symptoms associated with a disease or disorder, in a patient at risk of developing the disease or disorder.

[0041] The term "effective amount" with respect to a solid form of Compound 1 refers, in one embodiment, to an amount capable of alleviating, in whole or in part, symptoms associated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or, in another embodiment, an amount capable of preventing or providing prophylaxis for a disease or disorder in a subject at risk of developing a disease or disorder, such as a cancer, disclosed herein. In one embodiment, an effective amount of a solid form of Compound 1 is an amount that inhibits a kinase in a cell, e.g., in vitro or in vivo. In one embodiment, the kinase is BTK. In some embodiments, an effective amount of a solid form of Compound 1 inhibits a kinase in a cell by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99% compared to the activity of the kinase in untreated cells. For example, an effective amount of a solid form of Compound 1 in a pharmaceutical composition can be at a level that exerts a desired effect, e.g., from about 0.005 mg / kg of subject body weight to about 100 mg / kg of patient body weight, for both oral and parenteral unit dosages. As will be apparent to one of skill in the art, it is expected that the effective amount of the solid forms of Compound 1 disclosed herein may vary depending on the indication being treated; for example, an effective amount of a solid form of Compound 1 when treating a patient suffering from or at risk of an inflammatory disease may be different from an effective amount of a solid form of Compound 1 when treating a patient suffering from or at risk of a different disease, such as cancer or a metabolic disorder.

[0042] A "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, birds, turkeys, quail, or guinea pigs, etc. In specific embodiments, the patient or subject is a human.

[0043] 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.

[0044] In certain embodiments, treatment of lymphoma may be evaluated by the International Workshop criteria (IWC) for Non-Hodgkin's Lymphoma (NHL) (see Cheson BD, Pfistner B, Juweid, ME, et. al. Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-586), using the response and endpoint definitions set forth below: [Table 11]

[0045] Abbreviations: CR, complete remission; FDG, [ 18 [F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial response; SPD, sum of diameters; SD, stable disease; PD, progressive disease. [Table 12]

[0046] In one embodiment, the endpoint for lymphoma is evidence of clinical benefit. Clinical benefit may be reflected in improved quality of life or a reduction in patient symptoms, transfusion requirements, frequent infections, or other parameters. Time to reappearance or progression of lymphoma-related symptoms can also be used for this endpoint.

[0047] In certain embodiments, treatment of CLL may be evaluated according to the International Workshop Guidelines for CLL (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 1996 guidelines of the National Cancer Institute Working Group. Blood, 2008;(111) 12:5446-5456), using the definitions of response and endpoints set forth therein, in particular: [Table 13]

[0048] Group A criteria define tumor burden; Group B criteria define hematopoietic system (or marrow) function. CR (complete response): all criteria must be met and the patient must be free of disease-related constitutional symptoms; PR (partial response): at least two of the Group A criteria + one of the Group B criteria must be met; SD is the absence of progressive disease (PD) and failure to achieve at least PR; PD: at least one of the Group A or Group B criteria must be met. Sum of the products of multiple lymph nodes (when assessed by CT scan in clinical trials or by physical examination in general practice). These parameters may be irrelevant depending on the response classification.

[0049] In certain embodiments, cancer treatments can be evaluated by Response Evaluation Criteria in Solid Tumors (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 tumors: Revised RECIST guideline (version 1.1). European J. Cancer; 2009; (45) 228-247). The overall response for all possible combinations of tumor response in target and non-target lesions, with or without the appearance of new lesions, is as follows: [Table 14]

[0050] Regarding the evaluation of target lesions, a complete response (CR) was the disappearance of all target lesions, a partial response (PR) was 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) was an increase of at least 20% in the sum of the longest diameters of target lesions based on the minimum sum of the longest diameters recorded since the start of treatment, or the appearance of one or more new lesions, and stable disease (SD) was neither sufficient shrinkage to qualify as a partial response nor sufficient increase to qualify as progression based on the minimum sum of the longest diameters since the start of treatment.

[0051] Regarding the evaluation of non-target lesions, a complete response (CR) is the disappearance of all non-target lesions and normalization of tumor marker levels; an incomplete response / stable disease (SD) is the persistence of one or more non-target lesion(s) and / or tumor marker levels remaining above the upper limit of normal, and progressive disease (PD) is the appearance of one or more new lesions and / or clear worsening of existing non-target lesions.

[0052] The procedures, rules, and definitions described below provide guidance for implementing the recommendations of the Neuro-Oncology Response Assessment (RANO) Working Group on response criteria for high-grade gliomas (Wen P., Macdonald, DR., Reardon, DA., et al. Updated response assessment criteria for high-grade gliomas: Response assessment in neuro-oncology working group. 01J Clin Oncol 2010;28:1963-1972). Key modifications to the RANO criteria for time-point response (TPR) may include the addition of operational rules for defining changes in glucocorticoid dose and the elimination of the subject's clinical deterioration component to focus on objective radiological assessment. A baseline MRI scan is defined as an assessment performed at the end of the postoperative rest period before resuming compound treatment. The baseline MRI is used as the reference point for assessing complete response (CR) and partial response (PR). Meanwhile, the smallest SPD (sum of products of perpendicular diameters) obtained at either baseline or subsequent assessments is designated the nadir assessment and used as the criterion for determining progression. For 5 days prior to any protocol-defined MRI scan, subjects must be glucocorticoid-free or receive a stable dose of glucocorticoid. A stable dose is defined as the same daily dose for 5 consecutive days prior to the MRI scan. If the prescribed glucocorticoid dose is changed 5 days prior to the baseline scan, a new baseline scan is required in which glucocorticoid use meets the above criteria. The following definitions are used:

[0053] Measurable Lesions: Measurable lesions are contrast-enhancing lesions that can be measured two-dimensionally. Measurements are taken of the maximum enhancing tumor diameter (also known as the longest diameter, LD). On the same image, the maximum perpendicular diameter is measured. The crosshairs of the two-dimensional measurement are intersected, and the product of these diameters is calculated.

[0054] Minimum diameter: T1-weighted images with 5 mm cross sections and 1 mm skip. The minimum LD for a measurable lesion is set at 5 mm x 5 mm. Larger diameters may be required for inclusion and / or designation as a target lesion. After baseline, target lesions that become smaller than the minimum measurement requirement or are no longer suitable for two-dimensional measurement are recorded with a default value of 5 mm for each diameter less than 5 mm. Lesions that disappear are recorded as 0 mm x 0 mm.

[0055] Multicentric Lesions: Lesions considered multicentric (as opposed to contiguous) are those with intervening normal brain tissue between two (or more) lesions. For multicentric lesions that are separate foci of enhancement, 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 are considered the same lesion.

[0056] Nonmeasurable Lesions: All lesions that do not meet the criteria for measurable disease defined above are considered nonmeasurable lesions, as well as all nonenhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include foci of enhancement of a specified minimum diameter (i.e., less than 5 mm × 5 mm), nonenhancing lesions (e.g., those seen on postcontrast T1-weighted, T2-weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or primarily cystic or necrotic lesions, and leptomeninges. Hemorrhagic lesions often have an inherent T1-weighted hyperintensity that may be misinterpreted as an enhancing tumor; therefore, precontrast T1-weighted images may be examined to rule out baseline or interval subacute hemorrhage.

[0057] At baseline, lesions are classified as follows: Target Lesions: Up to five measurable lesions, each at least 10mm x 5mm in size, representative of the target disease may be selected as target lesions; Non-Target Lesions: All other lesions, all non-measurable lesions (including mass effect and T2 / FLAIR findings), and any measurable lesions not selected as target lesions. At baseline, target lesions are measured according to the definition of measurable lesions, and the SPD of all target lesions is determined. The presence of all other lesions must be documented. At all post-treatment assessments, the baseline classification of lesions into target and non-target lesions is maintained, and lesions are documented and described in a consistent manner over time (e.g., recorded in the same order on source documents and eCRFs). To reduce the difficulty of interpreting changes, throughout the study, all measurable and non-measurable lesions should be assessed using the same technique as at baseline (e.g., subjects should be imaged on the same MRI scanner, or at least with the same magnet strength). At each assessment, target lesions are measured, and SPD is calculated. Non-target lesions are assessed qualitatively, and any new lesions are recorded separately. At each assessment, a time-point response is determined for target, non-target, and new lesions. Tumor progression can be established even if only a subset of lesions is assessed. However, unless progression is observed, an objective status (stable disease, PR, or CR) can only be determined if all lesions are assessed.

[0058] Confirmatory assessment of overall time-point response for CR and PR will be performed at the next scheduled assessment, but confirmation may not occur if scans are spaced less than 28 days apart. Best response incorporating confirmation requirements will be derived from a series of time points.

[0059] In extreme cases, complete inhibition is referred to herein as prevention or chemoprevention. In this context, the term "prevention" includes either completely preventing the onset of clinically evident cancer or preventing the development of an evident preclinical stage of cancer. Also intended to be encompassed by this definition is the prevention of transformation to malignant cells, or the arrest or reversal of the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing cancer.

[0060] Unless otherwise specified, if there is a discrepancy between the depicted chemical structure of a compound provided herein and the chemical name of a compound provided herein, the chemical structure shall control.

[0061] 5.2 Compound 1 The solid forms, formulations and methods of use provided herein relate to Compound 1, which has the name (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (including its tautomers): [ka]

[0062] Compound 1 is disclosed in U.S. Patent No. 9,447,106, issued September 20, 2016, and International Publication No. WO2014 / 173289, each of which is incorporated herein by reference in its entirety.

[0063] Crystalline Form A of Compound 1 is disclosed in U.S. Patent No. 10,927,117, issued February 23, 2021, and International Publication No. WO2018 / 033853, the entire contents of each of which are incorporated herein by reference.

[0064] It should be noted that in the event of a discrepancy between a depicted structure and a name given to that structure, the depicted structure is given more weight. Additionally, if the stereochemistry of a structure or portion of a structure is not shown, e.g., with bold or dashed lines, the structure or portion of a structure is to be interpreted as encompassing all stereoisomers thereof.

[0065] 5.3 Solid Forms of Compound 1 Without intending to be bound by any particular theory, certain solid forms (e.g., salts or co-crystals) are characterized by physical properties, such as stability, solubility, and dissolution rate, that are suitable for pharmaceutical and therapeutic dosage forms. Furthermore, without wishing 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, splitting, viscosity, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that affect certain processes (e.g., production, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make certain solid forms (e.g., salts or co-crystals) suitable for manufacturing solid dosage forms. Such properties can be determined using certain analytical and chemical techniques, such as solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), described herein and known in the art.

[0066] In one embodiment, provided herein is a solid form (e.g., a crystalline form, an amorphous form, a salt form, or a mixture thereof) comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein is a solid form (e.g., a crystalline form, an amorphous form, or a mixture thereof) comprising (a) the free base of Compound 1 and (b) oxalic acid. Compound 1 can be synthesized or obtained according to methods known in the literature, including those described in detail in the Examples herein, or based on the teachings herein. In certain embodiments, the coformer is oxalic acid.

[0067] In one embodiment, the solid form provided herein can 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 and amorphous forms), which comprises (a) Compound 1 and (b) oxalic acid. In one embodiment, a crystalline form comprising (a) Compound 1 and (b) oxalic acid is provided. In one embodiment, a co-crystal comprising (a) Compound 1 and (b) oxalic acid is provided. In one embodiment, a salt form comprising (a) Compound 1 and (b) oxalic acid is provided. In one embodiment, an amorphous form comprising (a) Compound 1 and (b) oxalic acid is provided. 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 salt comprising (a) Compound 1 and (b) oxalic acid, and (ii) an amorphous form of Compound 1.

[0068] 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 comprising (a) Compound 1 and (b) oxalic acid. In one embodiment, provided herein is a solid form comprising a salt comprising (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) Compound 1 and (b) a salt comprising oxalic acid; and (ii) one or more additional crystalline forms of Compound 1.

[0069] 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 comprising (a) Compound 1 and (b) oxalic acid (e.g., a hydrate containing stoichiometric or non-stoichiometric amounts of water). In one embodiment, provided herein are hydrated forms of (a) Compound 1 and (b) oxalic acid, including, but not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, etc. In one embodiment, the hydrated form is substantially crystalline. In one embodiment, the hydrated form is substantially amorphous. In one embodiment, the non-hydrated form is substantially crystalline. In one embodiment, the non-hydrated 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.

[0070] In one embodiment, provided herein is a nonsolvated 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.

[0071] The solid forms provided herein may be prepared by methods described herein or techniques including, but not limited to, heating, cooling, freeze-drying, spray-drying, lyophilization, quench cooling of the melt, fast solvent evaporation, slow solvent evaporation, solvent recrystallization, anti-solvent addition, slurry recrystallization, crystallization from the melt, desolvation, recrystallization in confined spaces such as nanopores or capillaries, recrystallization on a surface or template such as a polymer, recrystallization in the presence of an additive such as a salt counter molecule, a co-crystal counter molecule, etc., desolvation, dehydration, rapid cooling, slow cooling, exposure to solvents and / or water, drying (including, for example, vacuum drying), vapor diffusion, sublimation, milling (including, for example, cryogenic milling and solvent drop milling), microwave-induced precipitation, sonication-induced precipitation, laser-induced precipitation, and precipitation from supercritical fluids. The particle size of the resulting solid form, which may vary (e.g., from nanometer dimensions to millimeter dimensions), can be controlled, for example, by varying crystallization conditions, such as the rate of crystallization and / or the crystallization solvent system, or by comminution techniques, such as grinding, milling, micronization, or sonication.

[0072] 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 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; 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 Approximately 0.2; ACN / H2O, 978:22, a w Approximately 0.4; ACN / H2O, 959:41, a w Approximately 0.6; ACN / H2O, 925:75, a w about 0.8; EtOAc saturated with water; isopropyl acetate; 2-methyltetrahydrofuran; or combinations thereof. In certain embodiments, the solid forms provided herein (e.g., co-crystals comprising (a) Compound 1 and (b) oxalic acid) can be obtained by cooling evaporation crystallization, powder crystallization in saturated solution, slurry crystallization, and grinding crystallization.

[0073] In some embodiments, a co-crystal 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 Approximately 0.2; ACN / H2O, 978:22, a w Approximately 0.4; ACN / H2O, 959:41, a w Approximately 0.6; ACN / H2O, 925:75, a wabout 0.8; EtOAc saturated with water; isopropyl acetate; 2-methyltetrahydrofuran; or combinations thereof. In certain embodiments, the solid forms provided herein (e.g., co-crystals comprising (a) Compound 1 and (b) oxalic acid) can be obtained by cooling evaporation crystallization, powder crystallization in saturated solution, slurry crystallization, and grinding crystallization.

[0074] In certain embodiments, the non-covalent force is one or more hydrogen bonds (H-bonds). The coformer may be H-bonded directly to Compound 1 or to an additional molecule bound to Compound 1. The additional molecule may be H-bonded to Compound 1 or ionically or covalently bound to Compound 1. The additional molecule may be a different active or inactive component. In certain embodiments, the cocrystal may include one or more solvated molecules within the crystal lattice, i.e., a solvate of the cocrystal, or a cocrystal further comprising a solvent or compound that is liquid at room temperature. In certain embodiments, the cocrystal may be a cocrystal between the coformer and a salt of Compound 1. In certain embodiments, the non-covalent force is π-stacking, guest-host complexation, and / or van der Waals interactions. Hydrogen bonding can result in several different intermolecular configurations. For example, hydrogen bonding can form dimers, linear chains, or cyclic structures. These configurations may further include extended (two-dimensional) hydrogen-bonded networks and isolated triads. In certain embodiments, the coformer is a solid in its pure form under ambient conditions, hi one embodiment, the conformer is oxalic acid.

[0075] In certain embodiments, the formation of a co-crystal may lead to enhanced 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 may lead to enhanced physical properties of the resulting solid form, such as solubility, dissolution rate, bioavailability, physical stability, chemical stability, flowability, fractability, or compressibility.

[0076] In certain embodiments, provided herein is a cryo-evaporation method for producing a solid form of Compound 1, the method including: 1) obtaining a near-saturated solution of Compound 1 and oxalic acid in a solvent at a 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); 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) if a precipitate is present, filtering the solution to obtain a solid; and 6) if no precipitate is present after step 4, evaporating the solvent to recover the solid. In one embodiment, the solution may be seeded. In certain embodiments, provided herein is a cryo-evaporation method for producing a solid form of Compound 1, the method 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 a precipitate is present; and 6) evaporating the solvent to recover the solid if no precipitate is present after step 4. In certain embodiments, the solvent may be selected from the group consisting of 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 Approximately 0.2; ACN / H2O, 978:22, a w Approximately 0.4; ACN / H2O, 959:41, a w Approximately 0.6; ACN / H2O, 925:75, a w In one embodiment, the molar ratio of compound 1 to oxalic acid in step 1 is about 1:0.8; EtOAc saturated with water; 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 cocrystal. In one embodiment, the solid form is a salt.

[0077] In certain embodiments, provided herein is a powder-in-saturated solution method for producing a solid form of Compound 1, the method 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 recover a second solid. In one embodiment, the solution can be seeded. In certain embodiments, the solvent can be selected from the group consisting of 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 Approximately 0.2; ACN / H2O, 978:22, a w Approximately 0.4; ACN / H2O, 959:41, a w Approximately 0.6; ACN / H2O, 925:75, a w In one embodiment, the molar ratio of Compound 1 to oxalic acid is about 1:0.5; EtOAc saturated with water; 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 period is about 72 hours. In one embodiment, the solid form is a cocrystal. In one embodiment, the solid form is a salt.

[0078] In certain embodiments, provided herein is a slurry method for producing a solid form of Compound 1, the method comprising: 1) obtaining a slurry of Compound 1 and oxalic acid in a solvent at a predetermined ratio; 2) stirring the slurry for a period of time; and 3) recovering the solid from the slurry by filtration (e.g., centrifugal filtration). In one embodiment, the solution may be seeded. In certain embodiments, the solvent may be selected from the group consisting of 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, and the like. w Approximately 0.2; ACN / H2O, 978:22, a w Approximately 0.4; ACN / H2O, 959:41, a w Approximately 0.6; ACN / H2O, 925:75, a w In one embodiment, the molar ratio of Compound 1 to oxalic acid is about 1:0.5; EtOAc saturated with water; 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 period is 3 days. In one embodiment, the solid form is a cocrystal. In one embodiment, the solid form is a salt.

[0079] In certain embodiments, provided herein are milling methods for producing a solid form of Compound 1, the methods comprising: 1) adding Compound 1, oxalic acid, and a solvent to a mill; 2) shaking the container at a specific frequency for a period of time; and 3) collecting the resulting solid by filtration (e.g., centrifugal filtration). In certain embodiments, the solvents are selected from the group consisting of 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; and w Approximately 0.2, ACN / H2O, 978:22, a wApproximately 0.4; ACN / H2O, 959:41, a w Approximately 0.6; ACN / H2O, 925:75, a w In one embodiment, the molar ratio of Compound 1 to oxalic acid is about 1:0.5; about 0.8; EtOAc saturated with water; 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 duration 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.

[0080] The solid form cocrystals provided herein (e.g., Form 1) can be characterized using several methods known to those skilled in the art, 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 phase microscopy), spectroscopy (e.g., infrared, Raman, and solid state nuclear magnetic resonance), single differential thermal analysis (SDTA), high performance liquid chromatography-mass spectrometry (HPLC-MS), thermogravimetric analysis-single differential thermal analysis (TGA-SDTA), and thermogravimetric analysis-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 light scattering techniques.

[0081] 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).

[0082] It is understood that the numerical values ​​of peaks in X-ray powder diffraction patterns may vary slightly depending on the instrument or sample, and therefore quoted values ​​should not be interpreted as absolute but as having an allowable variation such as ±0.2 degrees two-theta (°2θ) (see United States Pharmacopoeia, page 2228 (2003)).

[0083] 5.3.1 Solid Form 1 Comprising Compound 1 and Oxalic Acid Provided herein is 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 modifications of Form 1 comprising Compound 1 and oxalic acid.

[0084] 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.

[0085] 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 co-crystal form. In one embodiment, Form 1 is the oxalate salt of Compound 1.

[0086] In certain embodiments, provided herein is a slurry method for preparing Form 1, which includes: 1) obtaining a slurry of Compound 1 and oxalic acid in a solvent at a predetermined ratio; 2) stirring the slurry for a period of time; and 3) recovering the solid from the slurry by filtration (e.g., centrifugal filtration). In one embodiment, the solution can be seeded. In certain embodiments, the solvent can be selected from the group consisting of 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; and w Approximately 0.2, ACN / H2O, 978:22, a w Approximately 0.4; ACN / H2O, 959:41, a w Approximately 0.6; ACN / H2O, 925:75, a w The molar ratio of compound 1 to oxalic acid is about 1:0.8; EtOAc saturated with water; 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 period is about 3 days. In one embodiment, the solid form is a cocrystal. In one embodiment, the solid form is a salt.

[0087] In certain embodiments, the solid forms provided herein, e.g., Form 1, are substantially crystalline, as shown, for example, by X-ray powder diffraction measurement. In one embodiment, Form 1 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in Figure 1. In one embodiment, Form 1 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at approximately 8.17 degrees, 11.65 degrees, or 21.61 degrees 2-theta angle, as shown in Figure 1. In another embodiment, Form 1 of Compound 1 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 8.17, 11.65, 18.54, 19.56, or 21.61 degrees 2-theta angle. In another embodiment, Form 1 of Compound 1 has one, two, three, four, five, or six characteristic X-ray powder diffraction peaks at approximately 8.17, 8.56, 11.65, 18.54, 19.56, or 21.61 degrees 2-theta angle. In another embodiment, Form 1 of Compound 1 has 1, 2, 3, 4, 5, 6, 7, 8, or 9 characteristic X-ray powder diffraction peaks at approximately 8.17, 8.56, 11.65, 16.52, 16.84, 18.54, 19.56, 19.92, or 21.61 degrees 2-theta. In another embodiment, Form 1 of Compound 1 has 1, 2, 3, 4, 5, 6, 7, or 8 characteristic X-ray powder diffraction peaks as shown in Table 9.

[0088] In one embodiment, Form 1 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at approximately 8.17, 11.65, or 21.61 degrees 2-theta, as shown in 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 approximately 8.17, 11.65, 18.54, 19.56, 20.69, or 21.61 degrees 2-theta.

[0089] In one embodiment, provided herein is Form 1 having a thermogravimetry (TGA) thermogram substantially corresponding to the representative TGA thermogram shown in Figure 2. In certain embodiments, the crystalline form exhibits a TGA thermogram when heated from approximately 17.6°C to approximately 300°C that includes a total mass loss of approximately 0.7% of the total mass of the sample between approximately 17.6°C and approximately 130.0°C. Thus, in certain embodiments, the crystalline form loses approximately 0.7% of its total mass when heated from about 17.6°C to about 130°C.

[0090] In one embodiment, provided herein is Form 1 having a differential scanning calorimetry (DSC) thermogram when heated from about 25° C. to about 300° C. that includes an endothermic event with a maximum at about 160.4° C., as shown in Figure 3. In one embodiment, the crystalline form has a differential scanning calorimetry thermogram when heated from about 50° C. to about 200° C. that includes an endothermic event with an onset temperature of approximately 159.1° C.

[0091] In yet another embodiment, Form 1 of Compound 1 is substantially pure. In certain embodiments, substantially pure Form 1 of Compound 1 is substantially free of other solid forms, e.g., amorphous forms. In certain embodiments, substantially pure Form 1 of Compound 1 is about 95% or more pure, about 96% or more pure, about 97% or more pure, about 98% or more pure, about 98.5% or more pure, about 99% or more pure, about 99.5% or more pure, or about 99.8% or more pure.

[0092] 5.4 How to use The solid forms and pharmaceutical compositions provided herein can be used in any of the methods provided herein.The solid forms and pharmaceutical compositions provided herein can be used to treat any of the diseases, disorders, or conditions provided herein.

[0093] 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 with cancer.

[0094] In some embodiments, the cancer is a B-cell proliferative disorder. For example, the B-cell proliferative disorder 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, the cancer has progressed with standard anti-cancer therapy or the patient is unable to tolerate standard anti-cancer therapy. In still other cases, the cancer is a cancer for which no approved treatment exists. In some embodiments, the cancer is resistant to standard therapy. In other cases, the patient has relapsed after standard therapy.

[0095] In certain embodiments, the cancer is chronic lymphocytic leukemia (CLL).

[0096] In certain embodiments, the cancer is marginal zone lymphoma (MZL).

[0097] In certain embodiments, the cancer is Waldenstrom's Macroglobulinemia (WM).

[0098] In certain embodiments, the cancer is mantle cell lymphoma (MCL).

[0099] In certain embodiments, the cancer is follicular lymphoma (FL).

[0100] The B-cell proliferative disorder is chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0101] In certain embodiments, the cancer is a cancer 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 organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system.

[0102] In other embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is a recurrent or refractory solid tumor.

[0103] In other embodiments, the solid tumor can be an advanced solid tumor.

[0104] In other embodiments, the cancer is a cancer associated with a pathway involving BTK.

[0105] In certain embodiments, provided herein are methods for achieving a complete response, partial response, or stable disease according to Response Evaluation Criteria for Solid Tumors (e.g., RECIST 1.1) in a patient with a solid tumor, the method 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 a National Cancer Institute-Sponsored Chronic Lymphocytic Leukemia Working Group (NCI-WG CLL) complete response, partial response, or stable disease in a patient with leukemia, the method 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 a complete response, partial response, or stable disease according to Prostate Cancer Working Group 2 (PCWG2) criteria in a patient with prostate cancer, the method 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 an International Workshop Criteria (IWC) complete response, partial response, or stable disease in a patient with non-Hodgkin's lymphoma, 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 an International Uniform Response Criteria (IURC) complete response, partial response, or stable disease in a patient with multiple myeloma, comprising administering to the patient a solid form of Compound 1 provided herein, or a pharmaceutical composition thereof.

[0106] In certain embodiments, provided herein is a method for increasing survival without disease progression in a patient with cancer, the method comprising administering to the patient a solid form of Compound 1 provided herein or a pharmaceutical composition thereof.

[0107] In certain embodiments, provided herein are methods of treating cancer, the methods comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to a patient with cancer, wherein the treatment prevents or delays clinical progression, such as cancer-associated cachexia or increased pain.

[0108] In some embodiments, provided herein are methods for treating cancer, the methods comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to a patient with cancer, wherein the treatment results in one or more of: inhibiting disease progression, increasing time to progression (TTP), increasing progression-free survival (PFS), and / or increasing overall survival (OS), etc.

[0109] 5.5 Pharmaceutical Compositions The solid forms of Compound 1 provided herein are useful for preparing pharmaceutical compositions comprising an effective amount of a solid form of Compound 1 and a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutical compositions described herein are suitable for oral, parenteral, mucosal, transdermal, or topical administration.

[0110] 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-crystalline forms or mixtures thereof), and (ii) other active ingredient(s) or inactive ingredient(s).

[0111] In one embodiment, a pharmaceutical composition provided herein comprises a solid form of Compound 1 and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, a pharmaceutical composition provided herein comprises Form 1 of Compound 1 and one or more pharmaceutically acceptable excipients or carriers.

[0112] In one embodiment, the pharmaceutically acceptable excipients and carriers are selected from binders, diluents, disintegrants, and lubricants, hi another embodiment, the pharmaceutically acceptable excipients and carriers further comprise one or more antioxidants (e.g., EDTA or BHT).

[0113] In certain embodiments, binders include, but are not limited to, cellulose (e.g., microcrystalline cellulose such as AVICEL® PH101, AVICEL® PH112, and AVICEL® PH102) and starch (e.g., pregelatinized starch (STARCH 1500®)). In one embodiment, the binder is cellulose. In another embodiment, the binder is microcrystalline cellulose. In yet another embodiment, the binder is AVICEL® PH101. In yet another embodiment, the binder is AVICEL® PH102. In yet another embodiment, the binder is starch. In yet another embodiment, the binder is pregelatinized starch. In yet another embodiment, the binder is STACHR 1500®.

[0114] In certain embodiments, diluents include, but are not limited to, lactose (e.g., lactose monohydrate (FAST FLO® 316) and anhydrous lactose), cellulose (e.g., microcrystalline cellulose such as AVICEL® PH101 and AVICEL® PH102). In one embodiment, the diluent is lactose. In another embodiment, the diluent is lactose monohydrate. In yet another embodiment, the diluent is FAST FLO® 316. In yet 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 AVICEL® PH101. In yet another embodiment, the diluent is AVICEL® PH102.

[0115] In certain embodiments, disintegrants include, but are not limited to, starch (e.g., cornstarch) and carboxymethylcellulose (e.g., croscarmellose sodium, such as AC-DI-SOL®). In one embodiment, the disintegrant is starch. In another embodiment, the disintegrant is cornstarch. In yet another embodiment, the disintegrant is carboxymethylcellulose. In yet another embodiment, the disintegrant is croscarmellose sodium. In yet another embodiment, the disintegrant is AC-DI-SOL®.

[0116] In certain embodiments, lubricants include, but are not limited to, starch (e.g., cornstarch), magnesium stearate, and stearic acid. In one embodiment, the lubricant is starch. In another embodiment, the lubricant is cornstarch. In one embodiment, the lubricant is magnesium stearate. In yet another embodiment, the lubricant is stearic acid.

[0117] In another embodiment, the pharmaceutical compositions provided herein comprise a solid form of Compound 1 and one or more pharmaceutically acceptable excipients or carriers independently selected from carboxymethylcellulose, cellulose, lactose, magnesium stearate, starch, and stearic acid.

[0118] In certain embodiments, provided herein are pharmaceutical compositions in which the amounts of the listed ingredients may independently vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25%.

[0119] The pharmaceutical compositions provided herein may 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(s) sufficient to produce the desired therapeutic effect, together with the necessary pharmaceutical carriers or excipients. Examples of unit-dosage forms include individually packaged tablets or capsules. Unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Doses are expressed herein as free base equivalents unless the context requires otherwise.

[0120] 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, isotopically substituted derivative, or solid form thereof.

[0121] 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 are unit dose formulations 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, isotopic substitution, or stereoisomer thereof.

[0122] In some embodiments, a unit dosage form comprising Compound 1, or a pharmaceutically acceptable salt, isotopic substitution, or solid form thereof, may be administered once daily (QD), twice daily (BID), three times daily, four times daily, or more frequently.

[0123] In certain embodiments, provided herein are methods for preparing the compositions provided herein, the methods comprising: (i) weighing 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, croscarmellose sodium, and / or microcrystalline cellulose); (ii) mixing or blending the solid form of Compound 1 and the excipient; (iii) passing the mixture of the solid form of Compound 1 and the excipient through a screen (such as a 25 mesh screen); and (iv) mixing or blending the solid form of Compound 1 and the excipient after passing through the screen. (v) weighing the desired amount of lubricant (such as stearic acid and magnesium stearate); (vi) passing the lubricant through a screen (such as a 35 mesh screen); (vii) mixing or blending the solid form of Compound 1, excipients, and lubricant; (viii) compressing (e.g., forming a tablet) the mixture of solid form of Compound 1, excipients, and lubricant; and optionally (ix) coating the compressed mixture of solid form of Compound 1, excipients, and lubricant with a coating (such as Opadry pink, yellow, or beige). In certain embodiments, the methods of preparing the compositions provided herein are carried out in the dark, under yellow light, or in the absence of ultraviolet light.

[0124] In certain embodiments, the pharmaceutical compositions provided herein comprise Form 1 of Compound 1, including substantially pure Form 1. [Example]

[0125] 6. Working Example The following examples are offered by way of illustration and not by way of limitation. The following abbreviations are used in the description and examples: [Table 15-1] [Table 15-2]

[0126] 6.1 Analysis method XRPD

[0127] For XRPD analysis, a PANalytical Empyrean X-ray powder diffractometer was used, and the XRPD parameters used are listed in Table 1.

[0128] [Table 1]

[0129] TGA and DSC

[0130] TGA data were collected using a TA Instruments TA Q5000 / Discovery TGA 5500. DSC was performed using a TA Instruments Discovery DSC 2500. TGA and DSC have a standard deviation of approximately ±0.3°C. Detailed parameters used are shown in Table 2.

[0131] [Table 2]

[0132] HPLC

[0133] A Waters H-Class was used, and the detailed chromatographic conditions are listed in Table 3.

[0134] [Table 3]

[0135] I C

[0136] A Thermo Scientific™ Dionex™ Aquion™ ion chromatography (IC) system 1100 equipped with a conductivity detector was used, and the detailed chromatographic conditions are listed in Table 4.

[0137] [Table 4]

[0138] 6.2 Experimental Method Table 5 outlines the solvents and methods for each batch.

[0139] [Table 5]

[0140] Preparation procedure for oxalate form A

[0141] Test 1

[0142] 800.0 mg of free base Form A is suspended in 4 mL of ACN and weighed into an HPLC vial.

[0143] Dissolve 106.9 mg of oxalic acid dehydrate (0.5 equivalents) in 2.5 mL of acetonitrile (ACN).

[0144] The acid solution was added to the free base suspension. During the addition, the mixture formed a clear solution and the solid broke down within a few seconds of adding the acid.

[0145] Stir magnetically at room temperature for 1 day.

[0146] The solid was separated from the suspension by centrifugation and dried under vacuum at room temperature overnight before characterization.

[0147] Test 2

[0148] 403.2 mg of free base Form A and 125.1 mg of oxalic acid dehydrate (approximately 1.2 equivalents) are weighed into an HPLC vial.

[0149] 5 mL of ACN was added to the vial. During the addition, the mixture formed a clear solution, and the solution was seeded with a small amount of oxalate Form A. Immediately upon seeding, a thick suspension formed.

[0150] Stir magnetically at room temperature for 3 days.

[0151] The solid was separated from the suspension by centrifugation. A clear diffraction peak of oxalic acid was observed in the wet sample. The wet sample was slurry washed with ACN (1 mL, 5 min, 3 times) to remove residual acid.

[0152] The solid was dried under vacuum at room temperature overnight before characterization.

[0153] Test 3

[0154] 40.1 mg of free base Form A and 6.0 mg of oxalic acid dehydrate (0.55 equivalents) are weighed into an HPLC vial.

[0155] Add 0.5 mL of ACN to the vial. Stir magnetically at room temperature for 3 days.

[0156] The solid was separated from the suspension by centrifugation and was designated as oxalate form A.

[0157] IC / HPLC testing revealed a molar ratio of ion to free base of 0.5.

[0158] Test 4

[0159] 40.1 mg of free base Form A and 23.6 mg of oxalic acid dehydrate (2.2 equivalents) are weighed into an HPLC vial.

[0160] Add 0.5 mL of ACN to the vial. Stir magnetically at room temperature for 3 days.

[0161] The solid was separated from the suspension by centrifugation. A clear diffraction peak of oxalic acid was observed in the wet sample. The wet sample was slurry washed with ACN (1 mL, 5 min, 3 times) to remove residual acid.

[0162] IC / HPLC testing revealed a molar ratio of ion to free base of 0.5.

[0163] Test 5

[0164] 40.1 mg of free base Form A and 10.7 mg of oxalic acid dehydrate (1 equivalent) are weighed into an HPLC vial.

[0165] 0.5 mL of ACN was added to the vial. During the addition, the mixture formed a clear solution which turned into a suspension within a few seconds.

[0166] Stir magnetically at room temperature for 3 days.

[0167] The solid is separated from the suspension by centrifugation and dried in vacuo at room temperature overnight before characterization.

[0168] Test 6

[0169] 40.1 mg of free base Form A and 10.9 mg of oxalic acid dehydrate (1 equivalent) are weighed into an HPLC vial.

[0170] Add 0.5 mL of isopropyl acetate (IPAc) to the vial to form a suspension.

[0171] Stir magnetically at room temperature for 3 days.

[0172] The solid is separated from the suspension by centrifugation and dried in vacuo at room temperature overnight before characterization.

[0173] Test 7

[0174] Weigh 1.39.9 mg of free base Form A and 10.7 mg of oxalic acid dehydrate (1 equivalent) into an HPLC vial.

[0175] 2. Add 0.5 mL of 2-methyltetrahydrofuran (2-MeTHF) to the vial. During the addition, the mixture formed a clear solution, which turned into a suspension within a few seconds.

[0176] 3. Magnetically stir at room temperature for 3 days.

[0177] 4. Separate the solid from the suspension by centrifugation and vacuum dry at room temperature overnight before characterization.

[0178] Test 8

[0179] 15.3 mg of amorphous oxalate salt (obtained by triturating 99.8 mg of free base form A and 26.6 mg (approximately 1 equivalent) of oxalic acid dihydrate in 3.75 mL of IPAc) is weighed into an HPLC vial.

[0180] Add 0.2 mL of ACN to the vial.

[0181] Temperature cycling was allowed for one week (one cycle consisted of heating to 50°C at a rate of 4.5°C / min, isothermal for approximately 2 hours, cooling to 5°C at a rate of 0.1°C / min, and isothermal for approximately 2 hours).

[0182] The solid is separated from the suspension by centrifugation and dried in vacuo at room temperature overnight before characterization.

[0183] Test 9

[0184] 14.7 mg of amorphous oxalate salt (obtained by triturating 99.8 mg of free base form A and 26.6 mg (approximately 1 equivalent) of oxalic acid dihydrate in 3.75 mL of IPAc) is weighed into an HPLC vial.

[0185] Add 0.2 mL of IPAc to the vial.

[0186] Temperature cycling was allowed for one week (one cycle consisted of heating to 50°C at a rate of 4.5°C / min, isothermal for approximately 2 hours, cooling to 5°C at a rate of 0.1°C / min, and isothermal for approximately 2 hours).

[0187] The solid is separated from the suspension by centrifugation and dried under vacuum at room temperature overnight before characterization.

[0188] Test 10

[0189] 16.7 mg of amorphous oxalate salt (obtained by triturating 99.8 mg of free base form A and 26.6 mg (approximately 1 equivalent) of oxalic acid dihydrate in 3.75 mL of IPAc) is weighed into an HPLC vial.

[0190] Add 0.2 mL of 2-MeTHF to the vial.

[0191] Temperature cycling was allowed for one week (one cycle consisted of heating to 50°C at a rate of 4.5°C / min, isothermal for approximately 2 hours, cooling to 5°C at a rate of 0.1°C / min, and isothermal for approximately 2 hours).

[0192] The solid is separated from the suspension by centrifugation and dried under vacuum at room temperature overnight before characterization.

[0193] Oxalate Form A Polymorph Screening

[0194] [Table 6]

[0195] 6.2.1 Solubility Tables 7 and 8 summarize the solubility experiments in water at 37°C and 25°C, respectively.

[0196] [Table 7]

[0197] S: solubility, mg / mL, FC: solid form change. Solid loading: 2 mg / mL.

[0198] [Table 8]

[0199] S: solubility, mg / mL, FC: solid form change. Solid loading: 2 mg / mL.

[0200] 6.2.2 Cocrystal solid form 1 Form 1 was prepared using oxalic acid dehydrate and the method used in Study 2 using ACN as the solvent. Form 1 is a crystalline solid form of Compound 1 and oxalic acid.

[0201] Figure 1 provides the XRPD pattern of Form 1. A list of the X-ray diffraction peaks for Form 1 is provided in Table 9 below.

[0202] [Table 9-1] [Table 9-2]

[0203] Figures 2 and 3 provide TGA and DSC data, respectively, for Form 1. In Figure 2, a mass loss of 0.70% was observed between about 17.6°C and about 130°C. According to the DSC signal data in Figure 3, an endothermic melting event was observed with an onset temperature of 159.1°C and a peak temperature at 160.4°C.

[0204] Figure 4 shows the configuration of Form 1. 1 H NMR is provided.

[0205] FIG. 5 provides the DVS results showing that the water uptake of Form 1 at 25° C. / 80% RH was less than 0.2%, indicating that it was non-hygroscopic.

[0206] FIG. 6 provides the solubility profiles of Compound 1 Form A and the amorphous form of Compound 1 at room temperature.

[0207] FIG. 7 provides the solubility profiles of Compound 1 Form A and the amorphous form of Compound 1 at 37° C.

[0208] Two samples were prepared for stoichiometry testing. Each sample was tested by HPLC for the concentration of Compound 1 and by IC for the concentration of oxalic acid. The HPLC and IC results indicated that the molar ratio of oxalic acid to Compound 1 was 0.5.

[0209] To determine whether Form 1 of Compound 1 is a co-crystal and whether Form 1 of Compound 1 is a salt, at least the following methods can be used: (1) Single-crystal X-ray diffraction is the most common method for distinguishing cocrystals from salts. Standard experimental methods, procedures, and parameters can be found in Cullity, B.D., & Stock, S.R. (2001). Elements of X-Ray Diffraction (3rd ed.). Pearson; and Pecharsky, V., & Zavalij, P. (2008). Fundamentals of Powder Diffraction and Structural Characterization of Materials, Second Edition (2nd ed. 2009 ed.). Springer. (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. (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 ed.). Wiley. Solid-state NMR and X-ray photoelectron spectroscopy do not require single crystals.

[0210] The embodiments disclosed herein are not limited in scope by the specific embodiments disclosed in the examples, which are intended as illustrations of some aspects of the disclosed embodiments, but any embodiments that are functionally equivalent are encompassed by the present disclosure. Indeed, various modifications of the embodiments disclosed herein in addition to those shown and described herein will be apparent to those skilled in the art and are intended to be within the scope of the appended claims.

[0211] 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. 10. The solid form of claim 1, which is substantially crystalline.

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

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

5. 3. The solid form of claim 2, which is a crystalline form comprising Compound 1 having an X-ray powder diffraction pattern comprising peaks at approximately 8.2, 11.7, and 21.6 degrees 2θ. 【Chemistry 4】

6. 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 degrees 2θ.

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

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

9. 6. The crystalline form of claim 5, which is an oxalic acid co-crystalline form.

10. 6. The crystalline form of claim 5 which is the oxalate salt.

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

5.

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

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

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

15. 13. A method for achieving a complete response, partial response or stable disease in a subject having a solid tumor, comprising administering to the subject an effective amount of the solid form of any one of claims 1 to 12.

Images