Solid state form of gusacitinib

Abstract

Gusacitinib and the crystalline solid form of compound (1):(I) are provided herein. The disclosure also provides pharmaceutical formulations comprising the crystalline solid form and uses thereof. [Formula 1] TIFF2026527514000040.tif36170

Description

Technical Field

[0001] Related Applications This application claims priority and benefit to the specification of International Patent Application No. PCT / CN2023 / 109559, filed on July 27, 2023, the entire content of which is incorporated herein by reference in its entirety.

Background Art

[0002] Inhibition of the JAK signaling pathway plays an important role in treating various diseases and disorders, including, for example, inflammatory diseases. See Schwartz, et al., Nat. Rev. Drug Discov. 17(1):78 (2017). Inhibition of spleen tyrosine kinase (SYK) is also regarded as promising as a treatment for immune-mediated diseases. Ibid. Inhibiting both JAK and SYK is theorized to increase efficacy by expanding the range of signaling pathways and target cytokines that are blocked. Ibid.; Pavel, et al., J. of Allergy and Clinical Immunology, 144(4):1011 - 1024 (2019).

Summary of the Invention

Means for Solving the Problems

[0003] Previous JAK / SYK inhibitors have been regarded as promising as therapeutic agents for specific autoimmune or inflammatory disorders, but have been troubled by excessive adverse events. See Schwartz, et al., Nat. Rev. Drug Discov. 17(1):78 (2017). There is still a need for a JAK / SYK inhibitor that can treat specific autoimmune or inflammatory disorders without being troubled by the side effects, and that has further storage stability and can be incorporated into an oral dosage form for easy administration.

[0004] One compound being evaluated for use in the treatment of JAK / SYK-mediated disorders is gusacitinib, also known as ASN-002, or 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazine-2-yl)piperidine-4-yl)acetonitrile, with the following structure: [ka] It has.

[0005] Gusacitinib is also represented by the following structure, referred to herein as "Compound 1": [ka] It is valued as a hydrochloride salt.

[0006] Gusacitinib is described in International Publication No. 2013 / 028818 (reported in Example 189), and specific formulations of gusacitinib and Compound 1 are described in International Publication No. 2018 / 201131, each of which is incorporated herein by reference in whole. However, there is still a need to identify crystalline, anhydrous, hydrated, and / or solvated forms of gusacitinib and / or Compound 1 that are useful for various therapeutic applications.

[0007] In particular, it is desirable to identify specific forms of gusacitinib and compound 1 that are stable under various conditions. Early attempts to formulate gusacitinib and compound 1 into forms more applicable for manufacturing and formulation yielded unstable or hygroscopic forms of compound 1. However, the applicant has discovered that specific forms of gusacitinib and compound 1 were exceptionally stable under various conditions. As illustrated in Example 1, identifying the crystalline forms of gusacitinib and compound 1 proved difficult, but polymorphic screening experiments identified only specific solid forms that showed stability suitable for further development.

[0008] However, the present disclosure resolves the problems identified above, and in some embodiments, provides a crystalline solid form exhibiting desirable properties such as improved stability, hygroscopicity, flow properties, compressibility, ease of processing, consistency in manufacturing, particle size distribution, bulk density, pharmacokinetics, bioavailability, and ease of formulation.

[0009] In some embodiments, this disclosure relates to compound 1: [ka] It provides a crystalline solid form.

[0010] In some embodiments, the crystalline solid form of compound 1 is an anhydrous. In some embodiments, the crystalline solid form of compound 1 is form A as described herein.

[0011] In some embodiments, the crystalline solid form of compound 1 is a hydrate. In some embodiments, the crystalline solid form of compound 1 is form B as described herein. In some embodiments, the crystalline solid form of compound 1 is form C as described herein. In some embodiments, the crystalline solid form of compound 1 is form D as described herein. In some embodiments, the crystalline solid form of compound 1 is form E as described herein.

[0012] In some embodiments, the crystalline solid form of compound 1 is a solvate. In some embodiments, the crystalline solid form of compound 1 is a solvate of DMF. In some embodiments, the crystalline solid form of compound 1 is form F as described herein.

[0013] In some embodiments, the present disclosure provides a crystalline solid form of dasatinib, i.e., 2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile, as the free base (Compound 2): [Chemical formula] is provided.

[0014] In some embodiments, the crystalline solid form of Compound 2 is Form G as described herein.

[0015] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising the crystalline solid form described herein. In some embodiments, the pharmaceutical formulation is in a unit dosage form. In some embodiments, the unit dosage form is in the form of a tablet.

[0016] In some embodiments, the present disclosure provides a method of treating a disease, disorder or condition of a subject in need thereof, comprising administering the crystalline form described herein to the subject.

[0017] In some embodiments, the present disclosure provides a method of treating a JAK / SYK-mediated disease, disorder or condition of a subject in need thereof, comprising administering the crystalline solid form described herein to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] [Figure 1A] X-ray powder diffraction (XRPD) pattern of Form A of Compound 1. [Figure 1B] Plots of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of Form A of Compound 1. [Figure 1C] 1H NMR spectrum of Form A of Compound 1. [Figure 2A]A series of X-ray powder diffraction (XRPD) patterns, from top to bottom: the SM of Compound 1 (i.e., Form 1); Form B of Compound 1; and Form B of Compound 1 after heating at 155 °C. [Figure 2B] Plots of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of Form B of Compound 1. [Figure 2C] 1H NMR spectrum of Form B of Compound 1. [Figure 3A] A series of X-ray powder diffraction (XRPD) patterns, from top to bottom: the SM of Compound 1 (i.e., Form 1); Form C of Compound 1; and Form C of Compound 1 after heating at 160 °C. [Figure 3B] Plots of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of Form C of Compound 1. [Figure 3C] 1H NMR spectrum of Form C of Compound 1. [Figure 4A] A series of X-ray powder diffraction (XRPD) patterns, from top to bottom: the SM of Compound 1 (i.e., Form 1); Form D of Compound 1; Form D of Compound 1 after heating at 140 °C; and Form D of Compound 1 after heating at 215 °C. [Figure 4B] Plots of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of Form D of Compound 1. [Figure 4C] 1H NMR spectrum of Form D of Compound 1. [Figure 5A] A series of X-ray powder diffraction (XRPD) patterns of Form E of Compound 1 (top), and Form E of Compound 1 after heating at 100 °C (bottom). [Figure 5B] Plots of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of Form E of Compound 1. [Figure 5C] 1H NMR spectrum of Form E of Compound 1. [Figure 6A] A series of X-ray powder diffraction (XRPD) patterns, from top to bottom: the SM of Compound 1 (i.e., Form 1); Form F of Compound 1; Form A of Compound 1; and Form F of Compound ı after heating at 230 °C. [Figure 6B] This is a plot of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) for form F of compound 1. [Figure 6C] This is the 1H NMR spectrum of compound 1 in form F. [Figure 7A] This is the X-ray powder diffraction (XRPD) pattern of compound 2, form G. [Figure 7B] This is a plot of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) for compound 2, form G. [Figure 7C] This is the 1H NMR spectrum of compound 2, form G. [Figure 8] These are a series of XRPD spectra of compound 1, form A, after exposure to specific stress conditions. [Figure 9] These are a series of XRPD spectra of compound 1, form B, after exposure to specific stress conditions. [Figure 10] This diagram illustrates different methods for transforming compound 1 and compound 2 into various solid forms. [Figure 11] These are the starting material (SM) and a series of XRPD spectra of compound 1 in forms A, B, C, D, E, and F. [Figure 12A] This is the XRPD spectrum of compound 1, form 1 (also referred to herein as the starting material (SM)). [Figure 12B] These are the DSC plot and TGA plot of compound 1, form 1. [Figure 12C] This is a dynamic vapor adsorption (DVS) plot of compound 1 in form 1. [Figure 12D] The images show a series of XRPD spectra of compound 1, form 1, before (top) and after (bottom) heating at 100°C. [Modes for carrying out the invention]

[0019] Gusacitinib, also known as 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimide[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile, is valued for the treatment of certain diseases, disorders, and conditions associated with the JAK / SYK pathway. This disclosure provides 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimide[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile in crystalline solid form, both in pharmaceutically acceptable salt form and in free base form. This disclosure recognizes, in particular, the remarkable discovery that gusacitinib and certain salts thereof can form crystalline solid forms, and furthermore, that these forms exhibit improved stability and other beneficial properties compared to the corresponding amorphous or other crystalline forms. Furthermore, this disclosure provides, in particular, specific pharmaceutical formulations (i.e., unit dosage forms) of gusacitinib suitable for oral administration.

[0020] In some embodiments, the present disclosure is represented by the following structure, which is referred to herein as "Compound 1": [ka] This provides a crystalline solid form of gusacitinib hydrochloride, which is referred to as [name of the product].

[0021] definition Approximately or about: As used herein, the terms “approximately” or “about” applied to one or more values ​​of interest refer to values ​​that are similar to the specified reference values. Generally, a person skilled in the art familiar with the context will understand the degree of variation that is encompassed by “approximately” or “about” in that context. For example, in some embodiments, the terms “approximately” or “about” may encompass a range of values ​​that are 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less (i.e., ±) of the value mentioned.

[0022] Administering: As used herein, the terms “administering” or “dosing” typically refer to administering a composition to a subject in order to deliver a drug, or a drug contained in a composition, to a target site or site to be treated. Those skilled in the art will recognize the various routes that may be used to administer to a subject, e.g., a human, in appropriate circumstances. For example, in some embodiments, administration may be intraocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., by bronchial infusion), buccal, percutaneous (e.g., one or more topical to the dermis, intradermal, interdermal, percutaneous, etc., or may include them), enteral, intra-arterial, intracutaneous, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, subarachnoid, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucosa, nasal, oral, rectal, subcutaneous, sublingual, topical, trachea (e.g., by intratracheal infusion), vagina, vitreous, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some specific embodiments, administration may be intravenous. In some specific embodiments, administration may be subcutaneous. In some embodiments, administration may consist of only a single dose. In some embodiments, administration may consist of applying a fixed number of doses. In some embodiments, administration may consist of medication that is intermittent (e.g., multiple doses separated by time) and / or periodic (e.g., individual doses separated by a common period). In some embodiments, administration may consist of continuous medication (e.g., perfusion) over at least a selected period. In some embodiments, administration may consist of a prime boost protocol. A prime boost protocol may consist of administering a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine), followed by administering a second or subsequent dose of the pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) after a certain period of time. In the case of an immunogenic composition, the prime boost protocol can result in an increased immune response in the patient.

[0023] Antagonist: As will be understood by those skilled in the art, the term “antagonist” generally refers to a drug whose presence or level correlates with a decrease in the level or activity of a target compared to what is observed in the absence of the drug (or at different levels of the drug). In some embodiments, an antagonist is one whose presence or level correlates with a target level or activity that is equivalent to or lower than a specific baseline level or activity (e.g., one observed under appropriate baseline conditions, such as the presence of a known antagonist, e.g., a positive control). In some embodiments, an antagonist may be a direct antagonist in that it directly affects the target (e.g., directly interacts with the target); in some embodiments, an antagonist may be an indirect antagonist in that it indirectly affects the target (e.g., acts on, e.g., interacts with, a modifier of the target or some other component or entity).

[0024] Biological Sample: As used herein, the term “biological sample” typically refers to a sample obtained from or derived from a biological source of interest (e.g., tissue, organism, or cell culture), as described herein. In some embodiments, the source of interest includes organisms such as animals or humans. In some embodiments, the biological sample is or includes biological tissue or bodily fluids. In some embodiments, the biological sample may be or include bone marrow; blood; blood cells; ascites; tissue or fine-needle biopsy specimens; cell-containing fluids; free suspended nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; lavage or irrigation fluids, e.g., mammary ductal irrigation or bronchoalveolar irrigation; aspirates; scrapes; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excrement; and / or cells derived therefrom. In some embodiments, the biological sample is or includes cells obtained from an individual. In some embodiments, the obtained cells are or include cells derived from the individual from which the sample was obtained. In some embodiments, the sample is a “primary sample” obtained directly from the source of interest by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine-needle aspiration or tissue biopsy), surgery, and collection of bodily fluids (e.g., blood, lymph, feces, etc.). In some embodiments, as is evident from the context, the term “sample” refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components and / or by adding one or more agents), such as filtration using a semipermeable membrane. Such a “processed sample” may include nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as mRNA amplification or reverse transcription, isolation and / or purification of specific components.

[0025] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle administered with the composition. In some exemplary embodiments, the carrier may include, for example, water and oils, such as petroleum, animal oils, vegetable oils, or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, or sesame oil, as sterile liquids. In some embodiments, the carrier is or comprises one or more solid components.

[0026] Combination Therapy: As used herein, the term “combination therapy” refers to a situation in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents or modalities). In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of the first regimen are administered before any dose of the second regimen is administered); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may include administering one or more agents or modalities in combination with a subject receiving other agents or modalities. For clarity, combination therapy does not require that individual agents be administered together (or more necessarily simultaneously) in a single composition; however, in some embodiments, two or more agents, or their active portions, may be administered together in a combination composition or further in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0027] Equivalent: As used herein, “equivalent” means two or more drugs, entities, situations, sets of conditions, etc., that may not be identical to each other but are similar enough to be comparable, so that a person skilled in the art can reasonably draw conclusions based on observed differences or similarities. In some embodiments, an equivalent set of conditions, situations, individuals, or groups are characterized by several substantially identical features and one or a few diverse features. A person skilled in the art will understand, in context, what degree of identity is required in any given situation for two or more such drugs, entities, situations, sets of conditions, etc., to be considered equivalent. For example, a person skilled in the art will understand that a set of situations, individuals, or groups are equivalent if they are characterized by a sufficient number and variety of substantially identical features to justify a reasonable conclusion that differences in results or observed phenomena under or by different sets of situations, individuals, or groups are caused by or exhibit variations of those diverse features.

[0028] Composition: Those skilled in the art will understand that the term “composition” may be used to refer to a distinct physical entity containing one or more specific components. Generally, unless otherwise specified, a composition may be in any form, such as a gas, gel, liquid, or solid.

[0029] Dosage Form or Unit Dosage Form: Those skilled in the art will understand that the term “dosage form” may be used to refer to individual physical units of an active agent (e.g., therapeutic or diagnostic agents). Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such an amount is an appropriate unit dose (or whole fraction thereof) for administration, following a dosing regimen that has been shown to correlate with desired or beneficial outcomes when administered to the population in question (i.e., by a therapeutic dosing regimen).

[0030] Dosing regimen or therapeutic regimen: Those skilled in the art will understand that the terms “dosing regimen” and “therapeutic regimen” can be used to refer to a series of unit doses (typically two or more) administered individually to a subject, typically spaced out over time. In some embodiments, a given therapeutic agent has a recommended dosing regimen which may comprise one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each spaced out over time from the others. In some embodiments, the individual doses are spaced out from each other by periods of equal length; in some embodiments, the dosing regimen comprises multiple doses and at least two distinct periods separating the individual doses. In some embodiments, all doses within the dosing regimen are the same unit dose. In some embodiments, the different doses within the dosing regimen are different amounts. In some embodiments, the dosing regimen comprises a first dose at a first dose, followed by one or more further doses at a second dose different from the first dose. In some embodiments, the dosing regimen comprises a first dose at a first dose, followed by one or more further doses at a second dose identical to the first dose. In some embodiments, the administration regimen correlates with the desired or beneficial outcome when administered to the relevant population (i.e., by the therapeutic administration regimen).

[0031] Excipients: As used herein, the term “excipient” refers to non-therapeutic agents that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired viscosity or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, and ethanol.

[0032] Modulator: As used herein, the term “modulator” refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can increase or decrease the magnitude of a particular activity of a certain molecule when compared to the magnitude of its activity in the absence of the modulator. For example, a modulator may be an agonist or antagonist of a particular target, as those terms are defined herein. For example, in some embodiments, the modulator is an agonist. In some embodiments, the modulator is an antagonist.

[0033] Oral administration: When used herein, the terms “oral administration” and “administered orally” have the meanings understood in the art, referring to the administration of a compound or composition by mouth.

[0034] Parenteral administration: When used herein, the terms “parenteral administration” and “administered parenterally” have the meanings understood in the art, but are not limited to, methods of administration other than enteral and local administration, usually by injection, including, but are not limited to, intravenous, intramuscular, intra-arterial, subarachnoid, intra-articular, intra-orbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0035] Patient or Subject: As used herein, the terms “patient” or “subject” refer to any organism to which the provided composition is administered, or may be administered, for example, for experimental, diagnostic, preventive, cosmetic, and / or therapeutic purposes. Typical patients or controls include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient or subject suffers from or is susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is or has been receiving a particular therapy to diagnose and / or treat a disease, disorder, or condition.

[0036] Pharmaceutical Composition: As used herein, the term “pharmaceutical composition” means an activator formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the activator is present in a unit dose appropriate for administration in a therapeutic or administration regimen that demonstrates a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including: oral administration, e.g., oral tablets (aqueous solutions, non-aqueous solutions, or suspensions), tablets, e.g., buccal, sublingual, and those targeting intracellular absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., sterile solutions or suspensions, or as sustained-release formulations, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection; topical application, e.g., creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or oral cavity; e.g., intravaginal or intrarectal, sublingual, intraocular, or transdermal, or transnasal, pulmonary, and other mucosal surfaces.

[0037] Pharmacologically acceptable: As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is within the bounds of sound medical judgment, commensurate with a reasonable benefit-risk ratio.

[0038] Pharmacopoeia-acceptable salts: As used herein, the term "pharmacopoeia-acceptable salt" refers to a salt of such a compound that is suitable for use in a medicinal context, i.e., a salt that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is within the bounds of sound medical judgment, corresponding to a reasonable benefit-risk ratio. Pharmacopoeia-acceptable salts are well known in the art. For example, pharmacopoeia-acceptable salts are described in detail by SMBerge et al. in J. Pharmaceutical Sciences, 66;1-19 (1977).

[0039] To prevent or prevent: As used herein, the terms “to prevent” or “prevent” mean, when used in relation to the occurrence of a disease, disorder, and / or condition, reducing the risk of the occurrence of the disease, disorder, and / or condition, and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention may be deemed complete if the onset of the disease, disorder, or condition is delayed over a predetermined period of time.

[0040] To treat: As used herein, the terms “to treat,” “treatment,” or “to treat” refer to any method used to partially or completely alleviate, remit, reduce, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to subjects who do not show signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects who show only the initial signs of a disease, disorder, and / or condition, for example, to reduce the risk of developing lesions associated with the disease, disorder, and / or condition.

[0041] Gusacitinib and crystalline solid form of compound 1 Gusacitinib has been evaluated for the treatment of certain autoimmune and inflammatory disorders. Gusacitinib is also known as ASN-002, or 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile, referred to herein as “Compound 2”, and has the following structure: [ka] It has.

[0042] Gusacitinib is also represented by the following structure, referred to herein as "Compound 1": [ka] It is valued as a hydrochloride salt.

[0043] Compound 2 is described in Example 189 of International Publication No. 2013 / 028818, and specific formulations of Compound 1 and Compound 2 are provided in International Publication No. 2018 / 201131, each of which is incorporated herein by reference in its entirety. Furthermore, the synthesis of Compound 2 is provided in International Publication No. 2013 / 028818.

[0044] The applicant has discovered that Compound 1 and Compound 2 can each exist in one or more polymorphic solid forms. As used herein, the term “polymorph” means that a compound can exist in one or more different crystalline structures. For example, in one or more polymorphs, pharmaceutically relevant physical properties, such as solubility, stability, and / or hygroscopicity, may change between one form and another. In some embodiments, the disclosure provides crystalline solid forms of Compound 1 or Compound 2.

[0045] Compound 1 or Compound 2 may be produced in amorphous solid form, crystalline solid form, or a mixture of these forms. The crystalline solid form of Compound 1 or Compound 2 may exist in one or more intrinsic solid forms, which may further contain one or more water or solvent molecules in the crystal lattice (i.e., hydrate or solvate, respectively). As described herein, the crystalline forms of Compound 1 and Compound 2 each have distinct and characteristic XRPD peaks not reported in previous disclosures of Compound 1 or Compound 2.

[0046] In some embodiments, the crystalline solid form of compound 1 exists as an anhydrous. A crystalline solid form in which no water is incorporated into the crystal structure is called an anhydrous. In some embodiments, the crystalline solid form of compound 1 is an anhydrous.

[0047] In some embodiments, the crystalline form of compound 1 exists as a solvate and / or hydrate. As used herein, the term “solvate” refers to a solid form in which one or more solvents, stoichiometric or nonstoichiometric in quantities, are incorporated into the crystal structure. For example, a solvated or heterosolvated polymorph may contain one or more solvents incorporated into the crystal lattice, independently in equivalent amounts such as 0.05, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, etc. As used herein, the term “hydrate” refers to a solvate in which the solvent incorporated into the crystal structure is water.

[0048] In some embodiments, the provided forms (e.g., forms of compound 1 and compound 2) are characterized in that their XRPD patterns have peaks that are optionally selected from "substantially all" of the provided list, with a 2θ within ±0.2 degrees of the specified value. An XRPD pattern having "substantially all" of the peaks in the provided list will be understood to mean an XRPD pattern that includes at least 80% (e.g., 80%, 85%, 90%, 95%, 99%, or 100%) of the listed peaks. In some embodiments, the XRPD pattern includes at least 90% of the listed peaks. In some embodiments, the XRPD pattern includes all of the listed peaks. In some embodiments, the XRPD pattern includes all but one of the listed peaks. In some embodiments, the XRPD pattern includes all but two of the listed peaks. In some embodiments, the XRPD pattern includes all but three of the listed peaks.

[0049] In some embodiments, the provided forms (e.g., forms of compound 1 and compound 2) are characterized by having a pattern or spectrum that is "substantially similar" to the figures provided herein. A pattern or spectrum having "substantially similar" to the figures provided herein will be understood to include one or more features of the figures provided (e.g., position (degrees of 2θ) values, temperature values, weight loss % values, intensity, curve shape, etc.) such that the forms characterized by the pattern or spectrum (e.g., solid form and / or salt form) can be identified as being the same as the forms characterized in the figures. For example, in some embodiments, an XRPD pattern having substantial similarity to the figures provided is a pattern with substantially all the same peaks and optionally including 2θ within ±0.2 degrees of the peaks in the reference figure. In some embodiments, an XRPD pattern having substantial similarity to the figures provided is a pattern with substantially all the same peaks and optionally including 2θ within ±0.2 degrees of the peaks in the reference figure and having approximately the same intensity.

[0050] Form A of Compound 1 In some embodiments, the crystalline solid form of compound 1 is an anhydrous form.

[0051] In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by one or more peaks selected from 2θ at 6.4, 12.8, 22.9, 25.8, 30.0, and 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by two or more peaks selected from 2θ at 6.4, 12.8, 22.9, 25.8, 30.0, and 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by three or more peaks selected from 2θ at 6.4, 12.8, 22.9, 25.8, 30.0, and 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by four or more peaks selected from 2θ degrees 6.4, 12.8, 22.9, 25.8, 30.0, and 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by five or more peaks selected from 2θ degrees 6.4, 12.8, 22.9, 25.8, 30.1, and 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by the following peaks: 6.4, 12.8, 22.9, 25.8, 30.1, and 2θ degrees 39.2 ± 0.2 degrees.

[0052] In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by one or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by two or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by three or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by four or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by five or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 39.2 ± 0.2 degrees of 2θ. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by six or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 39.2 ± 0.2 degrees of 2θ.In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by seven or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 39.2 ± 0.2 degrees of 2θ. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by eight or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 39.2 ± 0.2 degrees of 2θ. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by nine or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by ten or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by 11 or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees. In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by 12 or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees.In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by 13 or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 2θ at 39.2 ± 0.2 degrees.

[0053] In some embodiments, the anhydrous form of compound 1 is characterized in its X-ray powder diffraction pattern by one or more peaks selected from the following:

[0054] [Table 1]

[0055] In some embodiments, the anhydrous form of compound 1 is characterized by endothermic differential scanning calorimetry (DSC) with an onset minimum of approximately 254.63°C and / or a peak minimum of approximately 261.28°C.

[0056] In some embodiments, the anhydrous form of compound 1 is characterized by thermogravimetric analysis (TGA) with a weight loss of approximately 0.045% at 21–150°C.

[0057] In some embodiments, the anhydrous form of compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 1A. In some embodiments, the anhydrous form of compound 1 is characterized by a DSC pattern substantially similar to that of Figure 1B. In some embodiments, the anhydrous form of compound 1 is characterized by a TGA pattern substantially similar to that of Figure 1B. In some embodiments, the anhydrous form of compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to that of Figure 1A, (b) a DSC pattern substantially similar to that of Figure 1B, and (c) a TGA pattern substantially similar to that of Figure 1B.

[0058] In some embodiments, the crystalline solid form of compound 1 is form A.

[0059] Form B of compound 1 In some embodiments, the crystalline solid form of compound 1 is a hydrate.

[0060] In some embodiments, the hydrate form of compound 1 is characterized in its X-ray powder diffraction pattern by one or more peaks selected from 5.9, 9.5, 13.8, 16.1, and 23.8±0.2 degrees 2θ. In some embodiments, the hydrate form of compound 1 is characterized in its X-ray powder diffraction pattern by two or more peaks selected from 5.9, 9.5, 13.8, 16.1, and 23.8±0.2 degrees 2θ. In some embodiments, the hydrate form of compound 1 is characterized in its X-ray powder diffraction pattern by three or more peaks selected from 5.9, 9.5, 13.8, 16.1, and 23.8±0.2 degrees 2θ. In some embodiments, the hydrate form of compound 1 is characterized in its X-ray powder diffraction pattern by four or more peaks selected from 5.9, 9.5, 13.8, 16.1, and 23.8±0.2 degrees 2θ. In some embodiments, the hydrate form of compound 1 is characterized in its X-ray powder diffraction pattern by the following peaks: 5.9, 9.5, 13.8, 16.1, and 2θ at 23.8 ± 0.2 degrees.

[0061] In some embodiments, the hydrate form of compound 1 is characterized in its X-ray powder diffraction pattern by one or more peaks selected from the following:

[0062] [Table 2]

[0063] In some embodiments, the hydrate of compound 1 is characterized by endothermic differential scanning calorimetry (DSC) with an onset of approximately 259.22°C and / or a peak of approximately 260.66°C.

[0064] In some embodiments, the hydrate form of compound 1 is characterized by thermogravimetric analysis (TGA) with a weight loss of approximately 1.082% at 21–150°C.

[0065] In some embodiments, the hydrate form of compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 2A (center spectrum). In some embodiments, the hydrate of compound 1 is characterized by a DSC pattern substantially similar to that of Figure 2B. In some embodiments, the hydrate of compound 1 is characterized by a TGA pattern substantially similar to that of Figure 2B. In some embodiments, the hydrate of compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to that of Figure 2A (center spectrum); (b) a DSC pattern substantially similar to that of Figure 2B; and (c) a TGA pattern substantially similar to that of Figure 2B.

[0066] In some embodiments, the crystalline solid form of compound 1 is form B.

[0067] Form D of Compound 1 In some embodiments, the hydrate form of compound 1 is characterized by thermogravimetric analysis (TGA) with a weight loss of approximately 6.951% at 21–150°C.

[0068] In some embodiments, the hydrate form of compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4A (second spectrum from the top). In some embodiments, the hydrate of compound 1 is characterized by a DSC pattern substantially similar to that of Figure 4B. In some embodiments, the hydrate of compound 1 is characterized by a TGA pattern substantially similar to that of Figure 4B. In some embodiments, the hydrate of compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to that of Figure 4A (second spectrum from the top); (b) a DSC pattern substantially similar to that of Figure 4B; and (c) a TGA pattern substantially similar to that of Figure 4B.

[0069] In some embodiments, the crystalline solid form of compound 1 is form D.

[0070] Form E of compound 1 In some embodiments, the hydrate of compound 1 is characterized by endothermic reaction in differential scanning calorimetry (DSC) with a minimum value of approximately 258.69°C.

[0071] In some embodiments, the hydrate form of compound 1 is characterized by thermogravimetric analysis (TGA) with a weight loss of approximately 4.427% at 21–150°C.

[0072] In some embodiments, the hydrate form of compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 5A (spectrum above). In some embodiments, the hydrate of compound 1 is characterized by a DSC pattern substantially similar to that of Figure 5B. In some embodiments, the hydrate of compound 1 is characterized by a TGA pattern substantially similar to that of Figure 5B. In some embodiments, the hydrate of compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to that of Figure 5A (spectrum above); (b) a DSC pattern substantially similar to that of Figure 5B; and (c) a TGA pattern substantially similar to that of Figure 5B.

[0073] In some embodiments, the crystalline solid form of compound 1 is form E.

[0074] Form F of compound 1 In some embodiments, the crystalline solid form of compound 1 is a solvate. In some embodiments, the crystalline solid form of the compound is a solvate of DMF (i.e., DMF solvate).

[0075] In some embodiments, the DMF solvate of compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 6A (second spectrum from the top). In some embodiments, the DMF solvate of compound 1 is characterized by a DSC pattern substantially similar to that of Figure 6B. In some embodiments, the DMF solvate of compound 1 is characterized by a TGA pattern substantially similar to that of Figure 6B. In some embodiments, the DMF solvate of compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to that of Figure 6A (second spectrum from the top); (b) a DSC pattern substantially similar to that of Figure 6B; and (c) a TGA pattern substantially similar to that of Figure 6B.

[0076] In some embodiments, the DMF solvate of compound 1 is form F.

[0077] compound 2 In some embodiments, the disclosure provides a crystalline solid form of 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile (gusacitinib, hereafter referred to as Compound 2). [ka]

[0078] Form G of compound 2 In some embodiments, the crystalline solid form of compound 2 is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 7A. In some embodiments, the crystalline solid form of compound 2 is characterized by a DSC pattern substantially similar to that of Figure 7B. In some embodiments, the crystalline solid form of compound 2 is characterized by a TGA pattern substantially similar to that of Figure 7B. In some embodiments, the crystalline solid form of compound 2 is characterized by (a) an X-ray powder diffraction pattern substantially similar to that of Figure 7A; (b) a DSC pattern substantially similar to that of Figure 7B; and (c) a TGA pattern substantially similar to that of Figure 7B.

[0079] In some embodiments, the crystalline solid form of compound 2 is form G.

[0080] Method for preparing crystalline solid forms In some embodiments, the disclosure provides a method for preparing a crystalline solid form of a provided compound 1 or compound 2. In some embodiments, the crystalline solid form of compound 1 is prepared by slurring compound 1 (amorphous, partially crystalline, or crystalline) in a mixture containing one or more organic solvents. In some embodiments, a crystalline solid form of compound 1 in an anhydrous form is obtained by slurring form 1 of compound 1 in a mixture of one or more organic solvents. In some embodiments, the anhydrous form of compound 1 is form A. In some embodiments, one or more organic solvents are selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, ethyl acetate, isopropyl acetate, DMSO, dichloromethane, DMF, isobutanol, butanone, toluene, n-propanol, heptane, and combinations thereof. In some embodiments, form A of compound 1 is prepared by slurring compound 1 (in an amorphous, partially crystalline, or crystalline form) in a mixture containing one or more organic solvents. In some embodiments, one or more organic solvents are selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, ethyl acetate, isopropyl acetate, DMSO, dichloromethane, DMF, isobutanol, butanone, toluene, n-propanol, heptane, and combinations thereof.

[0081] In some embodiments, form A of compound 1 is prepared by heating form E of compound 1 to a temperature of about 100°C.

[0082] In some embodiments, the crystalline solid form of compound 1 is prepared by slurring compound 1 (amorphous, partially crystalline, or crystalline) in a mixture containing water. In some embodiments, the crystalline solid form of compound 1 in hydrate form is obtained by slurring compound 1 in a mixture containing water. In some embodiments, the mixture containing water further contains an organic solvent. In some embodiments, the organic solvent is ethanol. In some embodiments, form B of compound 1 is prepared by slurring compound 1 (amorphous, partially crystalline, or crystalline) in a mixture containing water. In some embodiments, form B of compound 1 is prepared by slurring compound 1 (amorphous, partially crystalline, or crystalline) in a mixture containing water at a suitable temperature. In some embodiments, form B of compound 1 is prepared by slurring compound 1 (amorphous, partially crystalline, or crystalline) in a mixture containing water at about 50°C. In some embodiments, the mixture containing water is a mixture of ethanol and water. In some embodiments, the mixture of ethanol and water is in a volume ratio of 1:3. In some embodiments, form B of compound 1 is prepared by slurring compound 1 (in amorphous, partially crystalline, or crystalline form) at about 50°C in an ethanol and water mixture in a volume ratio of 1:3.

[0083] In some embodiments, form D of compound 1 is prepared by gas-solid-phase diffusion of compound 1 (in amorphous, partially crystalline, or crystalline form) in water. In some embodiments, form D of compound 1 is prepared by gas-solid-phase diffusion of compound 1 (in amorphous, partially crystalline, or crystalline form) using, for example, a mixture of acetonitrile and water in a 1:1 ratio and a poor solvent selected from methyl tert-butyl ether and ethyl acetate.

[0084] In some embodiments, form F of compound 1 is prepared by poor solvent crystallization, in which compound 1 (in amorphous, partially crystalline, or crystalline form) is dissolved in a first solvent, the solution is filtered, and then an excess amount of the poor solvent is added to the solution to induce crystallization. In some embodiments, the first solvent is DMF or DMSO. In some embodiments, the first solvent is DMF. In some embodiments, the first solvent is DMSO. In some embodiments, the poor solvent is isopropyl alcohol or methyl tert-butyl ether. In some embodiments, the poor solvent is isopropyl alcohol. In some embodiments, the poor solvent is methyl tert-butyl ether.

[0085] In some embodiments, form G of compound 2 is prepared by slurring compound 1 (in amorphous, partially crystalline, or crystalline form) in water at a temperature of about 50°C or higher.

[0086] composition In some embodiments, the Disclosure provides compositions comprising a crystalline solid form of Compound 1 or Compound 2. In some embodiments, the provided compositions comprise a crystalline solid form of Compound 1 or Compound 2 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the composition does not contain significant amounts of foreign matter. Such foreign matter may include starting materials, other crystalline forms, residual solvents, or any other impurities that may arise from the preparation and / or isolation of the crystalline solid form. In some embodiments, the composition comprises at least about 90% by weight of a solid crystalline form of Compound 1 or Compound 2.

[0087] In some embodiments, the provided composition, comprising a crystalline solid form of compound 1 or compound 2, is substantially pure (for example, comprising at least about 95% by weight, 97% by weight, 97.5% by weight, 98% by weight, 98.5% by weight, 99% by weight, 99.5% by weight, or 99.8% by weight of the provided crystalline solid form, based on the total weight of the composition). In some embodiments, the composition comprising a crystalline solid form of compound 1 or compound 2 contains about 5.0 percent or less of total organic impurities. In some embodiments, the composition comprising a crystalline solid form of compound 1 or compound 2 contains about 3.0 percent or less of total organic impurities. In some embodiments, the composition comprising a crystalline solid form of compound 1 or compound 2 contains about 1.5 percent or less of total organic impurities. In some embodiments, the composition comprising a crystalline solid form of compound 1 or compound 2 contains about 1.0 percent or less of total organic impurities. In some embodiments, the composition comprising a crystalline solid form of compound 1 or compound 2 contains about 0.5 percent or less of total organic impurities. In some embodiments, the percentage of total organic impurities is measured by HPLC.

[0088] In some embodiments, the provided composition containing a crystalline solid form of compound 1 (e.g., form A, form B, form C, form D, form E, or form F) is substantially pure (e.g., containing at least about 95% by weight, 97% by weight, 97.5% by weight, 98% by weight, 98.5% by weight, 99% by weight, 99.5% by weight, or 99.8% by weight of the provided crystalline solid form, based on the total weight of the composition). In some embodiments, the composition containing a crystalline solid form of compound 1 contains about 5.0 percent or less of total organic impurities. In some embodiments, the composition containing a crystalline solid form of compound 1 contains about 3.0 percent or less of total organic impurities. In some embodiments, the composition containing a crystalline solid form of compound 1 contains about 1.5 percent or less of total organic impurities. In some embodiments, the composition containing a crystalline solid form of compound 1 contains about 1.0 percent or less of total organic impurities. In some embodiments, the composition containing a crystalline solid form of compound 1 contains about 0.5 percent or less of total organic impurities. In some embodiments, the percentage of total organic impurities is measured by HPLC.

[0089] In some embodiments, the provided composition containing the crystalline solid form of compound 2 (e.g., form G) is substantially pure (e.g., containing at least about 95% by weight, 97% by weight, 97.5% by weight, 98% by weight, 98.5% by weight, 99% by weight, 99.5% by weight, or 99.8% by weight of the provided crystalline solid form, based on the total weight of the composition). In some embodiments, the composition containing the crystalline solid form of compound 2 contains about 5.0 percent or less of total organic impurities. In some embodiments, the composition containing the crystalline solid form of compound 2 contains about 3.0 percent or less of total organic impurities. In some embodiments, the composition containing the crystalline solid form of compound 2 contains about 1.5 percent or less of total organic impurities. In some embodiments, the composition containing the crystalline solid form of compound 2 contains about 1.0 percent or less of total organic impurities. In some embodiments, the composition containing the crystalline solid form of compound 2 contains about 0.5 percent or less of total organic impurities. In some embodiments, the percentage of total organic impurities is measured by HPLC.

[0090] Pharmaceutical composition In some embodiments, the Disclosure provides a pharmaceutical composition comprising a crystalline solid form of compound 1 or compound 2 and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a crystalline solid form of compound 1 or compound 2 and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is the pharmaceutical composition described in whole in International Publication No. 2018 / 201131, which is incorporated herein by reference.

[0091] In some embodiments, the pharmaceutical composition comprises a crystalline solid form of compound 1 or compound 2, one or more binders, one or more fillers, one or more disintegrants, and / or one or more antioxidants. In some embodiments, the pharmaceutical composition comprises a crystalline solid form of compound 1 (e.g., form A, form B, form C, form D, form E, or form F). In some embodiments, the pharmaceutical composition comprises a crystalline solid form of compound 2 (e.g., form G).

[0092] In some embodiments, the pharmaceutical formulation contains about 10–30% by weight of compound 1 in its crystalline solid form, calculated as free base. As used herein, those skilled in the art will understand that reference to “free base weight” or to calculating weight “as free base” means using a weight equivalent to the molar equivalent of the free base of compound 1 (i.e., 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile) which is the agonist for any particular salt form. In some embodiments, the pharmaceutical formulation contains about 10–25% by weight of compound 1 in its crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 10–15% by weight of compound 1 in its crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, or about 15% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 10% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 10.5% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 11% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 11.5% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 12% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 12.5% ​​by weight of compound 1 in crystalline solid form, calculated as free base.

[0093] In some embodiments, the pharmaceutical formulation contains about 15–25% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, or about 25% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 20% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 21% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 22% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 23% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 24% by weight of compound 1 in crystalline solid form, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 25% by weight of compound 1 in crystalline solid form, calculated as free base.

[0094] In some embodiments, the pharmaceutical formulation contains about 1 to 10% by weight of a binder. In some embodiments, the pharmaceutical formulation contains about 1 to 5% by weight of a binder. In some embodiments, the pharmaceutical formulation contains about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of a binder. In some embodiments, the pharmaceutical formulation contains about 1% by weight of a binder. In some embodiments, the pharmaceutical formulation contains about 2% by weight of a binder. In some embodiments, the pharmaceutical formulation contains about 3% by weight of a binder. In some embodiments, the pharmaceutical formulation contains about 4% by weight of a binder. In some embodiments, the pharmaceutical formulation contains about 5% by weight of a binder.

[0095] In some embodiments, one or more binders are selected from polyvinylpyrrolidone or hydroxypropylcellulose. In some embodiments, the binder is polyvinylpyrrolidone. In some embodiments, the binder is hydroxypropylcellulose.

[0096] In some embodiments, the pharmaceutical formulation contains about 1 to 10% by weight of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 4 to 8% by weight of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 4% by weight of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 5% by weight of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 6% by weight of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 7% by weight of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 8% by weight of a disintegrant.

[0097] In some embodiments, one or more disintegrants are selected from crospovidone and croscarmellose sodium. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium.

[0098] In some embodiments, the pharmaceutical formulation contains about 0.05 to 1% by weight of antioxidants. In some embodiments, the pharmaceutical formulation contains about 0.05% to about 0.5% by weight of antioxidants. In some embodiments, the pharmaceutical formulation contains about 0.05% to about 0.1% by weight of antioxidants. In some embodiments, the pharmaceutical formulation contains about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1% of antioxidants.

[0099] In some embodiments, one or more antioxidants are selected from vitamin E and butylated hydroxytoluene. In some embodiments, the antioxidant is vitamin E. In some embodiments, the antioxidant is butylated hydroxytoluene.

[0100] In some embodiments, the crystalline solid form of compound 1 or compound 2 is micronized.

[0101] In some embodiments, the pharmaceutical composition comprises, calculated by weight of free base, about 10 to 30% by weight of compound 1 in crystalline solid form; about 1 to 10% by weight of a disintegrant; about 1 to 10% by weight of a binder; and about 0.1 to 1% by weight of an antioxidant. In some embodiments, the pharmaceutical composition comprises, calculated by weight of free base, about 10 to 30% by weight of compound 1 in crystalline solid form; about 1 to 10% by weight of croscarmellose sodium; about 1 to 10% by weight of hydroxypropyl cellulose; and about 0.05 to 1% by weight of vitamin E.

[0102] In some embodiments, the pharmaceutical composition comprises, calculated by weight of free base, about 10-15% by weight of compound 1 in crystalline solid form; about 3-8% by weight of a disintegrant; about 1-5% by weight of a binder; and about 0.05-1% by weight of an antioxidant. In some embodiments, the pharmaceutical composition comprises, calculated by weight of free base, about 10-15% by weight of compound 1 in crystalline solid form; about 3-8% by weight of croscarmellose sodium; about 1-5% by weight of hydroxypropyl cellulose; and about 0.05-1% by weight of vitamin E. In some embodiments, the pharmaceutical composition comprises about 10% by weight of compound 1 in crystalline form; about 3% by weight of a binder; about 6% by weight of a disintegrant; and about 0.1% by weight of an antioxidant. In some embodiments, the pharmaceutical composition comprises about 10% by weight of compound 1 in crystalline form; about 3% by weight of hydroxypropyl cellulose; about 6% by weight of croscarmellose sodium; and about 0.1% by weight of vitamin E. In some embodiments, the pharmaceutical composition comprises about 12% by weight of compound 1 in crystalline form; about 3% by weight of a binder; about 6% by weight of a disintegrant; and about 0.08% by weight of an antioxidant. In some embodiments, the pharmaceutical composition comprises about 12% by weight of compound 1 in crystalline form; about 3% by weight of hydroxypropyl cellulose; about 6% by weight of croscarmellose sodium; and about 0.08% by weight of vitamin E.

[0103] In some embodiments, the pharmaceutical composition comprises, calculated by weight of free base, about 20-25% by weight of compound 1 in crystalline solid form; about 3-8% by weight of a disintegrant; about 1-5% by weight of a binder; and about 0.05-1% by weight of an antioxidant. In some embodiments, the pharmaceutical composition comprises, calculated by weight of free base, about 20-25% by weight of compound 1 in crystalline solid form; about 3-8% by weight of croscarmellose sodium; about 1-5% by weight of hydroxypropyl cellulose; and about 0.05-1% by weight of vitamin E. In some embodiments, the pharmaceutical composition comprises about 20% by weight of compound 1 in crystalline form; about 3% by weight of a binder; about 6% by weight of a disintegrant; and about 0.1% by weight of an antioxidant. In some embodiments, the pharmaceutical composition comprises about 20% by weight of compound 1 in crystalline form; about 3% by weight of hydroxypropyl cellulose; about 6% by weight of croscarmellose sodium; and about 0.1% by weight of vitamin E. In some embodiments, the pharmaceutical composition comprises about 23% by weight of compound 1 in crystalline form; about 3% by weight of a binder; about 6% by weight of a disintegrant; and about 0.08% by weight of an antioxidant. In some embodiments, the pharmaceutical composition comprises about 23% by weight of compound 1 in crystalline form; about 3% by weight of hydroxypropyl cellulose; about 6% by weight of croscarmellose sodium; and about 0.08% by weight of vitamin E.

[0104] In some embodiments, the pharmaceutical formulation further comprises a filler. In some embodiments, the pharmaceutical composition comprises about 50 to 80% by weight of the filler. In some embodiments, the pharmaceutical composition comprises about 50 to about 75% by weight of the filler. In some embodiments, the pharmaceutical composition comprises about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of the filler. In some embodiments, the filler is lactose monohydrate.

[0105] In some embodiments, the pharmaceutical formulation further comprises about 5-10% by weight of microcrystalline cellulose. In some embodiments, the pharmaceutical formulation further comprises about 0.5-2% by weight of sodium lauryl sulfate. In some embodiments, the pharmaceutical formulation comprises about 1% by weight of magnesium stearate.

[0106] In some embodiments, the pharmaceutical formulation contains about 20 mg to about 120 mg of compound 1, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 40 mg to about 80 mg of compound 1, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 40 mg of compound 1, calculated as free base. In some embodiments, the pharmaceutical formulation contains about 80 mg of compound 1, calculated as free base.

[0107] In some embodiments, the pharmaceutical preparation is in the form of a unit dosage form. In some embodiments, the unit dosage form is in the form of a tablet.

[0108] In some embodiments, the provided pharmaceutical composition is administered once daily (QD). In some embodiments, the provided pharmaceutical composition is administered twice daily (BID). In some embodiments, the provided pharmaceutical composition is administered every other day (QOD). In some embodiments, the provided pharmaceutical composition is administered once weekly (QW). In some embodiments, the provided pharmaceutical composition is administered once every four weeks (Q4W).

[0109] use The crystalline solid forms provided, and compositions comprising such crystalline solid forms, are useful for treating a variety of diseases and disorders. For example, in some embodiments, the crystalline solid forms provided are useful for treating diseases, disorders, or conditions involving the JAK / SYK pathway.

[0110] In some embodiments, the Disclosure provides a method for treating a disease, disorder, or condition, comprising the step of administering a crystalline solid form of compound 1 or compound 2 to a subject who requires it. In some embodiments, the Disclosure provides a method for treating a disease, disorder, or condition, comprising the step of administering a crystalline solid form of compound 1 to a subject who requires it. In some embodiments, the Disclosure provides a method for treating a disease, disorder, or condition, comprising the step of administering a crystalline solid form of compound 2 to a subject who requires it.

[0111] In some embodiments, the disease, disorder, or condition is atopic dermatitis, alopecia areata, eczema of the hands and feet, chronic hand eczema, hidradenitis suppurativa, pemphigus vulgaris, psoriasis, cutaneous lupus, vitiligo, inflammatory bowel disease, rheumatoid arthritis, asthma, allergic rhinitis, systemic lupus erythematosus, psoriatic arthritis, multiple sclerosis, acute myeloid leukemia, graft-versus-host disease, myelofibrosis, warm hemolytic anemia, idiopathic thrombocytopenic purpura, immunoglobulin A nephropathy, scleroderma, idiopathic pulmonary fibrosis, uveitis, eosinophilic esophagitis, and lupus nephritis. In some embodiments, the disease, disorder, or condition is atopic dermatitis. In some embodiments, the disease, disorder, or condition is alopecia areata. In some embodiments, the disease, disorder, or condition is eczema of the hands and feet. In some embodiments, the disease, disorder, or condition is chronic hand eczema. In some embodiments, the disease, disorder, or condition is hidradenitis suppurativa. In some embodiments, the disease, disorder, or condition is pemphigus vulgaris. In some embodiments, the disease, disorder, or condition is psoriasis. In some embodiments, the disease, disorder, or condition is cutaneous lupus. In some embodiments, the disease, disorder, or condition is vitiligo. In some embodiments, the disease, disorder, or condition is inflammatory bowel disease. In some embodiments, the disease, disorder, or condition is rheumatoid arthritis. In some embodiments, the disease, disorder, or condition is asthma. In some embodiments, the disease, disorder, or condition is allergic rhinitis. In some embodiments, the disease, disorder, or condition is systemic lupus erythematosus. In some embodiments, the disease, disorder, or condition is psoriatic arthritis. In some embodiments, the disease, disorder, or condition is multiple sclerosis. In some embodiments, the disease, disorder, or condition is acute myeloid leukemia. In some embodiments, the disease, disorder, or condition is graft-versus-host disease. In some embodiments, the disease, disorder, or condition is myelofibrosis. In some embodiments, the disease, disorder, or condition is warm hemolytic anemia. In some embodiments, the disease, disorder, or condition is idiopathic thrombocytopenic purpura. In some embodiments, the disease, disorder, or condition is immunoglobulin A nephropathy.In some embodiments, the disease, disorder, or condition is scleroderma. In some embodiments, the disease, disorder, or condition is idiopathic pulmonary fibrosis. In some embodiments, the disease, disorder, or condition is uveitis. In some embodiments, the disease, disorder, or condition is eosinophilic esophagitis. In some embodiments, the disease, disorder, or condition is lupus nephritis.

[0112] In some embodiments, the disease, disorder, or condition is a JAK / SYK-mediated disease, disorder, or condition. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is atopic dermatitis, alopecia areata, eczema of the hands and feet, chronic eczema of the hands, hidradenitis suppurativa, pemphigus vulgaris, psoriasis, cutaneous lupus, vitiligo, inflammatory bowel disease, rheumatoid arthritis, asthma, allergic rhinitis, systemic lupus erythematosus, psoriatic arthritis, multiple sclerosis, acute myeloid leukemia, graft-versus-host disease, myelofibrosis, warm hemolytic anemia, idiopathic thrombocytopenic purpura, immunoglobulin A nephropathy, scleroderma, idiopathic pulmonary fibrosis, uveitis, eosinophilic esophagitis, and lupus nephritis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is atopic dermatitis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is alopecia areata. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is eczema of the hands and feet. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is chronic hand eczema. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is hidradenitis suppurativa. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is pemphigus vulgaris. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is psoriasis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is cutaneous lupus. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is vitiligo. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is inflammatory bowel disease. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is rheumatoid arthritis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is asthma. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is allergic rhinitis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is systemic lupus erythematosus. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is psoriatic arthritis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is multiple sclerosis.In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is acute myeloid leukemia. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is graft-versus-host disease. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is myelofibrosis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is warm hemolytic anemia. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is idiopathic thrombocytopenic purpura. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is immunoglobulin A nephropathy. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is scleroderma. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is idiopathic pulmonary fibrosis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is uveitis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is eosinophilic esophagitis. In some embodiments, the JAK / SYK-mediated disease, disorder, or condition is lupus nephritis. [Examples]

[0113] As described in the following examples, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. While the synthesis of specific compounds of this disclosure is shown by general methods, it will be understood that the following general methods and other methods known to those skilled in the art may be applied to all compounds, as well as each of their subclasses and species, as described herein.

[0114] In the following examples, the following abbreviations may be used: ACN (acetonitrile); DCM (dichloromethane); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); EA (ethyl acetate); EtOH (ethanol); h (hour); HPLC (high-performance liquid chromatography); IPA (isopropyl alcohol); IPAC (isopropyl acetate); LCMS (liquid chromatography-mass spectrometry); methanol (MeOH); MTBE (methyl tert-butyl ether); min (minute); NMR (nuclear magnetic resonance); RH (relative humidity); rt or RT (room temperature); s (second); SM (starting material); THF (tetrahydrofuran); and UV (ultraviolet light).

[0115] Materials and methods X-ray powder diffraction (XRPD) Solid samples were examined using an X-ray diffractometer (Bruker D8 Focus). The samples were scanned from 3° to 42° (2θ) with a step width of 0.02° (2θ). The tube voltage and tube current were 40kV and 40mA, respectively. The samples were transferred from the sample container to a zero-background XRPD holder and flattened to ensure a smooth surface.

[0116] Thermogravimetric analysis (TGA) TGA analysis was performed on a TA Instruments TGA Discovery 550. Samples were placed in tare-weighted platinum or aluminum pans, weighed automatically, and inserted into the TGA furnace. The samples were heated at a rate of 10°C / min until the final temperature was reached. The purge gases used were nitrogen at a rate of 40 mL / min for balance and 60 mL / min for sample, respectively.

[0117] Differential Scanning Calorimetry (DSC) DSC analysis was performed on a TA Instruments Discovery DSC 25. The calibration standard was indium. The sample was placed in a TA DSC pan by weight and its weight was accurately recorded. A crimp pan was used for analysis, and the sample was heated under nitrogen (50 mL / min) at a rate of 10°C / min until the final temperature was reached.

[0118] Dynamic vapor adsorption (DVS) Dynamic vapor adsorption and desorption were tested using Intrinsic DVS (System Measurement System UK). Approximately 20-30 mg of the prepared sample was placed in a sample basket and suspended in the measurement chamber. For isothermal testing, the chamber temperature was maintained at a constant 25 ± 1°C using a water bath. The sample was tested at target RH from 0 to 90% for the entire step mode cycle. Analysis was performed by increasing the RH by 10% increments. The duration at each RH was set to 60 minutes to allow the sample to reach equilibrium with the chamber environment. Data was collected in 20-second intervals.

[0119] Scanning electron microscope (SEM) Solid samples were examined using Phenom pure+. The samples were sprayed in an ion sputtering apparatus for 60 seconds. The resulting solid was placed in a scanning electron microscope, and the electron scanning mode was turned on. The crystal morphology and microstructure were obtained by adjusting the magnification in various ways.

[0120] Example 1: Polymorphic Screening By applying various crystallization methods, specific crystalline solid forms of 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile hydrochloride (compound 1) were discovered. The methods used in this example and the resulting crystalline forms are summarized in Table 1. From these experiments, a total of six new forms were discovered.

[0121] [Table 3]

[0122] solubility analysis In this example, the solubility of compound 1 was evaluated in various solvents. Specifically, form 1 of compound 1 (referred to as "SM" in the table below) was added to an 8 mL glass vial, followed by the addition of the corresponding solvent at room temperature. The solvent was added in stages until the solution became visually clear or the total volume reached 3 mL. The parameters and results are summarized in Table 2.

[0123] [Table 4]

[0124] Evaporation of mixed solvent The first 13 solvents listed in Table 2 were further tested in the following analysis. Two mL of each solution from Table 2 was filtered through a 0.22 μm filter membrane. Approximately 1.4 mL of the filtrate was distributed into a 96-well plate according to the solvent matrix shown in Table 3. The numbers indicate solvent mixtures selected from solvents 1-13 in Table 2. For example, "1 / 2" means a MeOH / EtOH mixture.

[0125] [Table 5]

[0126] The plate was covered and allowed to evaporate slowly at room temperature to induce precipitation. The solid was isolated for XRPD analysis. The results are summarized in Table 4.

[0127] [Table 6]

[0128] Single solvent slurry The remaining suspension / solution of this example was stirred at room temperature, and samples were taken at different times for XRPD measurement. Results from this slurry confirmed that SM is converted to form A in many solvents, including methanol (MeoH), tetrahydrofuran (THF), acetonitrile (ACN), acetone, ethyl acetate (EA), isopropyl acetate (IPAC), isobutanol, butanone, toluene, n-propanol, and heptane. The results are summarized in Table 5.

[0129] [Table 7]

[0130] Single solvent evaporation Approximately 600 μL of the residual filtrate was prepared in a 96-well plate and then evaporated at room temperature in a test tube in a working laboratory fume hood. All obtained solids were analyzed by XRPD. While solid separation was not observed in most single-solvent recrystallizations, the solid evaporated from DMF was a mixture of A and B. The results are summarized in Table 6.

[0131] [Table 8]

[0132] Crushing The grinding experiment was performed by placing approximately 20 mg of SM in a mortar, then adding different solvents (water, MeOH, MTBE, ACN) to form a paste, which was then gently ground at room temperature for 5 minutes. The morphology of the starting material remained unchanged. The parameters and results are summarized in Table 7.

[0133] [Table 9]

[0134] Gas-solid phase diffusion Gas-solid diffusion experiments were conducted under the following eight conditions. SM solids were placed in a 1.5 mL centrifuge tube and then in a 10 mL glass vial containing 3 mL of solvent. The vial was then sealed, and the solvent vapor was allowed to come into full contact with the solid to induce crystallization. After one week, the remaining solids were collected for XRPD analysis. Solids obtained from MeOH, THF, ACN, and acetone were morphology A, solids obtained from water were morphology D, and solids obtained from EA were a mixture of SM and morphology A. However, there was no change in the crystalline morphology of solids obtained from MTBE or toluene. The results are summarized in Table 8.

[0135] [Table 10]

[0136] Poor solvent crystallization Poor solvent crystallization experiments were performed under 21 conditions. Excess SM solid was dissolved in the solvent. After filtration, the filtrate was evenly packed into vials. Then, three times the volume of the poor solvent was added to the vials to induce crystallization. The resulting solids were isolated for XRPD analysis. In this experiment, no solids were observed when water was used as the solvent. When DMSO and DMF were used as solvents, the resulting solids were morphology A and its solvate, morphology F. The parameters and results are shown in Table 9.

[0137] [Table 11]

[0138] Water-active slurry Water activity slurry experiments were conducted under eight conditions by suspending the starting material in 1 mL of solvent in a 4 mL glass vial. The resulting suspensions were stirred at room temperature for 3 days. All obtained solids were mixtures of morphology A and morphology B. Morphology A was obtained with one solvent. Parameters and results are summarized in Table 10.

[0139] [Table 12]

[0140] Gas-liquid phase diffusion Gas-liquid phase diffusion experiments were conducted under eight conditions. The starting material solution was placed in a 1.5 mL centrifuge tube, and this tube was transferred to a 10 mL glass vial containing 3 mL of poor solvent. The vial was then sealed with film, and crystallization was induced by allowing sufficient contact between the solvent vapor and the starting material solution. After one week, the solid was collected for XRPD analysis. Morphology D was observed in the MTBE and EA systems of ACN:water (1:1). Parameters and results are summarized in Table 11.

[0141] [Table 13]

[0142] Mixed solvent slurry Mixed solvent slurry experiments were conducted under eight conditions by suspending the starting materials in a mixed solvent in a 4 mL glass vial. The resulting solutions were stirred at room temperature and 50°C. All observed solids were morphology A, morphology B, or mixtures thereof. The parameters and results are summarized in Table 12.

[0143] [Table 14]

[0144] Slow cooling Slow cooling experiments were performed under four conditions. The starting materials were placed in 1 mL of solvent in an 8 mL glass vial. The resulting suspension was heated to 65°C until clear, then cooled to 5°C at a rate of 0.2°C / min and held overnight at 5°C. Slow cooling resulted in the following solids: ACN:water (3:1), acetone:water (15:4), and 1,4-dioxane:water (15:2) yielded morphology A, while the solid obtained from MeOH:water (15:2) was morphology B. The parameters and results are summarized in Table 13.

[0145] [Table 15]

[0146] Example 2: Crystal morphology transformation In this example, the transformation of compound 1 in crystalline solid form from one form to another was investigated. In this example, the sample was weighed into a vial, 1 mL of the selected solvent was added, and the resulting mixture was stirred at room temperature. Parameters and results are summarized in Table 14:

[0147] [Table 16]

[0148] Example 3: Stability evaluation of Forms 1, A, and B of Compound 1 The stability of compound 1 in its starting material form (i.e., form 1), form A, and form B was evaluated under controlled temperature / humidity conditions. In this example, approximately 10 mg of the solid was placed in a 2 mL glass vial. Unsealed vials were stored under stress conditions of 25°C / 60%RH, 40°C / 75%RH, and 60°C / 75%RH, while sealed vials were stored under stress conditions of 80°C and light. The resulting solids were then analyzed by XRPD and HPLC.

[0149] The results of the starting material stability test are summarized in Table 15. The starting material for compound 1 showed some degree of stability after 4 weeks at 25°C / 60%RH and 40°C / 75%RH, as well as after 1 day at 80°C and 1 week at 60°C / 75%RH.

[0150] [Table 17]

[0151] Similarly, the stability of morphology A and morphology B was evaluated. The results of the stability test for morphology A are shown in Table 16 below. The results of the stability test for morphology B are shown in Table 17 below.

[0152] [Table 18]

[0153] [Table 19]

[0154] As can be seen from Table 17, form B forms a mixture of form A and form B under specific test conditions.

[0155] Example 4: Solubility evaluation of Form 1 and Form A of Compound 1 The solubility of compound 1's starting material (i.e., form 1) and form A was evaluated in buffer systems at various pH levels, particularly at 37°C. Approximately 10 mg of the indicated solid was stirred in 1 mL of solvent at 37°C for 2 hours and 24 hours. The suspension was then filtered, the residual solid was analyzed by XRPD, and the filtrate was measured by HPLC. The results are shown in Table 18.

[0156] [Table 20]

[0157] Example 5. Preparation of starting materials for Compound 1 (also known as Form 1 of Compound 1) The starting material ("SM") of Compound 1, also referred to herein as "Form 1 of Compound 1," used in the polymorphic screening experiment described above, was prepared as follows: [ka]

[0158] Step 1: Compound 5.1 (27.7 kg), compound 5.2 (19.5 kg), and DMSO (184 kg) were added to a 1000 L reactor under a nitrogen atmosphere. Then triethylamine (28.5 kg) was added. The mixture was stirred at 25-35°C until the area percentage of 5.1 was 1.0% or less as determined by HPLC. Then water (507.8 kg) was added to the reaction mixture, and the mixture was filtered. The recovered solid was dried at 40-55°C to obtain compound 5.3 (35.2 kg, yield 93%).

[0159] Step 2: SeO2 (23.3 kg) and DMSO (387.6 kg) were added to a 1000 L reactor under a nitrogen atmosphere. Compound 5.3 (35.2 kg) was then added, and nitrogen was bubbling over the resulting mixture for 2-5 minutes. The mixture was heated to 90-98°C until the area percentage of 5.3, as determined by HPLC, was 1.0% or less. The mixture was then cooled to ambient temperature. The mixture was filtered, and the filtrate was transferred to a 3000 L reactor containing water (776.1 kg). The mixture was stirred at 25-35°C for 1 hour, and then filtered. The recovered solid was added to a reactor containing water (352.2 kg), and the mixture was stirred at 25-35°C for 1 hour. The mixture was then filtered. The recovered solid was added to a reactor containing isopropanol (140.4 kg), and the mixture was stirred at 25-35°C for 1 hour. Next, the mixture was heated to 65-75°C and hydrazine hydrate (6.8 kg) was added. The mixture was stirred at 65-75°C until more than 99.7% conversion was confirmed by HPLC. The mixture was then cooled to ambient temperature, stirred for 1 hour, filtered, rinsed twice with isopropyl alcohol and twice with water, and then dried at a temperature below 55°C to obtain compound 5.4 (23.5 kg, yield 68.5%).

[0160] Step 3: Compound 5.4 (23.3 kg) and DMF (178.5 kg) were added to a 2000 L reactor under a nitrogen atmosphere. The mixture was cooled to 0-10°C, and mCPBA (21.2 kg) was added in five portions. The mixture was stirred at 0-10°C until the area percentage of 5.4 was 1.0% or less as determined by HPLC. Next, compound 5.5 (15.6 kg) was added to the mixture in five portions. The mixture was left to stand and warmed to 25-35°C, and stirred at this temperature until a conversion of 99.0 or higher was confirmed by HPLC. Next, the mixture was warmed to 50-60°C and filtered. Next, the filtrate was warmed to 40-50°C, water (631.9 kg) was added, and the mixture was stirred at 40-50°C for 1 hour. The mixture was filtered again, washed twice with water, and the recovered solid was added to a reactor containing water (234.8 kg) and sodium bicarbonate (6.1 kg) at 25-35°C. After stirring at 25-35°C for 1 hour, the mixture was filtered and washed twice with water, and the recovered solid was dried at 40-60°C to obtain crude compound 2 (27.8 kg, yield 84.0%).

[0161] Crude compound 2 (32.2 kg) was added to a 3000 L reactor containing DMF (346.4 kg), and the mixture was stirred at 25-35°C until a clear solution was obtained. This solution was filtered through an activated carbon cartridge into another 3000 L reactor and heated to 40-50°C and stirred for 2-4 hours. Water (260.0 kg) was added, and the mixture was stirred at 40-50°C for 2-4 hours, then cooled to 10-15°C and stirred for 2-4 hours. The solid was recovered by filtration, washed with water and methanol, and then dried at 50-65°C to obtain compound 2 (30.3 kg, yield 94%). The isolated compound 2 (30.2 kg) was added to a 3000 L reactor containing DCM (803.7 kg) and methanol (108.0 kg), and heated to 30-40°C for 1-2 hours with stirring. The mixture was cooled to 15-25°C, and MTBE (224.5 kg) was added. The mixture was stirred for 4-6 hours and then filtered. The recovered solid was dried at a temperature below 50°C to obtain compound 2 (27.0 kg, yield 89%).

[0162] Step 4: Compound 2 (22.5 kg) was added to a 3000 L reactor containing methanol (340.2 kg) under a nitrogen atmosphere. Hydrochloric acid (5.4 kg) in isopropanol (36.9 kg) was added at 15-25°C. The mixture was stirred at 18-23°C for 20.5 hours, at which point crystallization occurred. The crystals were recovered by filtration and rinsed with methanol and MTBE. The recovered solid was dried at a temperature below 40°C to obtain Compound 1 (21.5 kg, yield 89%).

[0163] Compound 1, prepared from this process, was designated as Form 1 of Compound 1. The XRPD spectrum of Form 1 of Compound 1 is shown in Figure 12A.

[0164] As shown in Figure 12B, the TGA curve shows a weight loss of approximately 1.386% up to 150°C, which is attributed to the loss of residual solvent or water. The DSC curve (Figure 12B) shows one major endothermic peak with an onset temperature of 257.25°C and a peak temperature of 260.24°C.

[0165] Figure 12C shows the DVS analysis of compound 1, form 1, indicating a 3.258% weight increase at 80% RH. DVS demonstrated that compound 1, form 1, is hygroscopic. XRPD analysis of the material was the same before and after DVS.

[0166] When form 1 of compound 1 was heated to 100°C, the XRPD pattern remained the same (Figure 12D). Therefore, since no change in morphology was observed after the removal of the solvent, form 1 of compound 1 can be a channel-type hydrate.

[0167] Example 6. Characterization of a specific provided solid form Form A of Compound 1 Form A of compound 1 was prepared as described in the above examples. In addition, the preparation of form A of compound 1 was scaled up as follows: Approximately 500 mg of SM (i.e., form 1) of compound 1 was added to a 50 mL flask, and 6 mL of DMSO was added. After filtering the solution, 18 mL of acetone was added to the filtrate. The mixture was allowed to stand overnight, the suspension was filtered, and the residue was washed with acetone to obtain form A of compound 1.

[0168] Furthermore, form A of compound 1 was prepared as follows: Approximately 200 mg of SM (i.e., form 1) of compound 1 was added to 4 mL of acetone in an 8 mL vial and stirred at room temperature. After 2 days, the suspension was filtered to obtain form A of compound 1.

[0169] The XRPD spectrum of compound 1, form A is shown in Figure 1A. The TGA / DSC analysis of compound 1, form A is shown in Figure 1B, and the 1H NMR analysis of compound 1, form A is shown in Figure 1C. Based on the TGA results, compound 1, form A was identified as the anhydrous form.

[0170] Form B of compound 1 Form B of compound 1 was prepared as described in the above examples. In addition, the preparation of form B of compound 1 was scaled up as follows: approximately 99 mg of SM of compound 1 (i.e., form 1) was added to an 8 mL vial, and 2 mL of EtOH:water (1:3) was added. The resulting mixture was stirred at 50°C for 6 hours and then filtered to obtain form B of compound 1.

[0171] The XRPD spectrum of compound 1, form B is shown in Figure 2A (center spectrum). The TGA / DSC analysis of compound 1, form B is shown in Figure 2B. 1 The 1H NMR analysis is shown in Figure 2C. Based on the TGA results, form B of compound 1 was identified as the hydrate.

[0172] Form C of compound 1 Form C of compound 1 was prepared as described in the above examples. For example, form C of compound 1 was obtained by slurring SM (i.e., form 1) of compound 1 in water at room temperature for 3 days.

[0173] The XRPD spectrum of compound 1, form C is shown in Figure 3A (center spectrum). The TGA / DSC analysis of compound 1, form C is shown in Figure 3B, and the 1H NMR analysis of compound 1, form C is shown in Figure 3C. Based on the TGA results, compound 1, form C was identified as a hydrate with low crystallinity.

[0174] Form D of Compound 1 Form D of compound 1 was prepared as described in the above examples. For example, form D of compound 1 was obtained by gas-solid phase diffusion in water.

[0175] The XRPD spectrum of compound 1, form D, is shown in Figure 4A (second spectrum from the top). The TGA / DSC analysis of compound 1, form D, is shown in Figure 4B, and the 1H NMR analysis of compound 1, form D, is shown in Figure 4C. Based on the TGA results, compound 1, form D, was identified as the hydrate.

[0176] Form E of compound 1 Form E of compound 1 was prepared as described in the above examples. For example, form E of compound 1 was obtained by slurring form A of compound 1 in water at room temperature for 3 days.

[0177] The XRPD spectrum of compound 1, form E is shown in Figure 5A (upper spectrum). The TGA / DSC analysis of compound 1, form E is shown in Figure 5B, and the 1H NMR analysis of compound 1, form E is shown in Figure 5C. Based on the TGA results, compound 1, form E was identified as the hydrate.

[0178] Form F of compound 1 Form F of compound 1 was prepared as described in the above examples. For example, form F of compound 1 was obtained by poor solvent crystallization in DMF / IPA or DMF / MTBE.

[0179] The XRPD spectrum of compound 1, form F, is shown in Figure 6A (second spectrum from the top). The TGA / DSC analysis of compound 1, form F, is shown in Figure 6B. 1 The 1H NMR analysis is shown in Figure 6C. Based on the TGA results, form F of compound 1 was identified as the DMF solvate.

[0180] Form G of compound 2 Form G of compound 2 was prepared as described in the above examples. For example, form G of compound 2 was prepared by slurring SM (i.e., form 1) of compound 1 in water at 50°C for 30 minutes.

[0181] The XRPD spectrum of compound 2, form G, is shown in Figure 7A. The TGA / DSC analysis of compound 2, form G, is shown in Figure 7B. 1 The 1H NMR analysis is shown in Figure 7C.

[0182] Example 7. Pharmaceutical preparations of Compound 1 and Compound 2 Exemplary formulations in solid form provided were generally prepared as follows: Compound 1, lactose monohydrate, and croscarmellose sodium were combined with an isopropyl alcohol solution of hydroxypropyl cellulose and vitamin E to obtain wet granules, which were then dried and ground. The resulting ground granules were then blended with croscarmellose sodium, microcrystalline cellulose, magnesium stearate, and sodium lauryl sulfate to obtain the final blend. The final blend was then compressed into tablets. The tablets were film-coated with a suspension of an aesthetic coating in a 1:1 alcohol:water mixture.

[0183] Example formulation #1 An exemplary formulation without coating is shown in the table below:

[0184] [Table 21]

[0185] Example formulation #2 An exemplary formulation without coating is shown in the table below:

[0186] [Table 22]

[0187] The embodiments of the present disclosure described above are intended to be merely illustrative, and numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention, as defined in the appended claims.

Claims

1. Compound 1: 【Chemistry 1】 It is a crystalline solid form, The crystalline solid form is anhydrous, and its X-ray powder diffraction pattern is characterized by one or more peaks selected from 6.4, 12.8, 15.6, 17.8, 18.1, 19.3, 20.7, 22.9, 25.1, 25.8, 26.5, 27.6, 30.0, and 39.2 ± 0.2 degrees of 2θ.

2. The crystalline solid form, in its X-ray powder diffraction pattern, Table 1 A crystalline solid form according to claim 1, characterized by one or more peaks selected from the above.

3. The crystalline solid morphology according to claim 1 or claim 2, wherein the crystalline solid morphology is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 1A.

4. The crystalline solid according to any one of claims 1 to 3, wherein the crystalline solid form is form A.

5. Compound 1: 【Chemistry 2】 It is a crystalline solid form, The crystalline solid form is a hydrate, characterized in its X-ray powder diffraction pattern by one or more peaks selected from 2θ of 5.9, 9.5, 13.8, 16.1, and 23.8 ± 0.2 degrees.

6. The crystalline solid form, in its X-ray powder diffraction pattern, Table 2 The crystalline solid form according to claim 5, characterized by one or more peaks selected from the above.

7. The crystalline solid morphology according to claim 5 or claim 6, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 2A (center spectrum).

8. The crystalline solid form according to any one of claims 5 to 7, wherein the crystalline solid form is form B.

9. Compound 1: 【Transformation 3】 It is a crystalline solid form, The crystalline solid form is a hydrate, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 4A (second spectrum from the top).

10. The crystalline solid form according to claim 9, wherein the crystalline solid form is form D.

11. Compound 1: 【Chemistry 4】 It is a crystalline solid form, The crystalline solid form is a hydrate, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 5A (spectrum above).

12. The crystalline solid form according to claim 11, wherein the crystalline solid form is form E.

13. Compound 1: 【Transformation 5】 It is a crystalline solid form, The crystalline solid form is a DMF solvate, characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 6A (second spectrum from the top).

14. The crystalline solid form according to claim 13, wherein the crystalline solid form is form F.

15. The crystalline solid form of the compound 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile.

16. The crystalline solid morphology according to claim 15, wherein the crystalline solid morphology is characterized by an X-ray powder diffraction pattern substantially similar to that of Figure 7.

17. The crystalline solid form according to claim 16, wherein the crystalline solid form is form G.

18. A sample comprising the crystalline solid form described in any one of claims 1 to 17, wherein the sample is substantially free of impurities.

19. A pharmaceutical preparation comprising a crystalline solid form according to any one of claims 1 to 17 and one or more pharmaceutically acceptable excipients.

20. The aforementioned pharmaceutical preparation The crystalline solid form of compound 1 in an amount of approximately 10-30% by weight, calculated by the weight of the free base; Approximately 1-10% by weight of a disintegrant; Approximately 1 to 10% by weight of a binder; and Approximately 0.05 to 0.5% by weight of antioxidant A pharmaceutical preparation according to claim 19, including the above.

21. The pharmaceutical preparation according to claim 20, further comprising a lubricant.

22. The pharmaceutical formulation according to claim 20 or 21, wherein the binder is hydroxypropyl cellulose.

23. The pharmaceutical preparation according to any one of claims 20 to 22, wherein the disintegrant is croscarmellose sodium.

24. The pharmaceutical preparation according to any one of claims 20 to 23, wherein the antioxidant is vitamin E.

25. The pharmaceutical formulation according to any one of claims 20 to 24, wherein the pharmaceutical formulation contains the crystalline solid form of compound 1 in an amount of approximately 20 mg to approximately 120 mg, calculated by weight of free base.

26. The pharmaceutical formulation according to claim 25, wherein the pharmaceutical formulation contains approximately 40 mg to approximately 80 mg of compound 1 in its crystalline solid form, calculated by weight of free base.

27. The pharmaceutical preparation according to any one of claims 19 to 26, wherein the pharmaceutical preparation is in a unit dosage form.

28. The pharmaceutical preparation according to claim 27, wherein the unit dosage form is in the form of a tablet.

29. A method for treating a disease, disorder, or condition requiring the crystalline form described in any one of claims 1 to 17, or a pharmaceutical preparation described in any one of claims 19 to 28, comprising the step of administering the said preparation.

30. The method according to claim 29, wherein the disease, disorder, or condition is selected from atopic dermatitis, alopecia areata, eczema of the hands and feet, chronic hand eczema, hidradenitis suppurativa, pemphigus vulgaris, psoriasis, lupus cutaneously, vitiligo, inflammatory bowel disease, rheumatoid arthritis, asthma, allergic rhinitis, systemic lupus erythematosus, psoriatic arthritis, multiple sclerosis, acute myeloid leukemia, graft-versus-host disease, myelofibrosis, warm hemolytic anemia, idiopathic thrombocytopenic purpura, immunoglobulin A nephropathy, scleroderma, idiopathic pulmonary fibrosis, uveitis, eosinophilic esophagitis, and lupus nephritis.

31. A method for treating a JAK / SYK-mediated disease, disorder, or condition requiring the crystalline form described in any one of claims 1 to 17, or a pharmaceutical preparation described in any one of claims 19 to 28, comprising the step of administering the crystalline form described in any one of claims 19 to 28.

32. Use of the crystalline form according to any one of claims 1 to 17, or the pharmaceutical preparation according to any one of claims 19 to 28, in the treatment of the aforementioned disease, disorder, or condition.

33. The use according to claim 32, wherein the disease, disorder, or condition is selected from atopic dermatitis, alopecia areata, eczema of the hands and feet, chronic eczema of the hands, hidradenitis suppurativa, pemphigus vulgaris, psoriasis, lupus cutaneously, vitiligo, inflammatory bowel disease, rheumatoid arthritis, asthma, allergic rhinitis, systemic lupus erythematosus, psoriatic arthritis, multiple sclerosis, acute myeloid leukemia, graft-versus-host disease, myelofibrosis, warm hemolytic anemia, idiopathic thrombocytopenic purpura, immunoglobulin A nephropathy, scleroderma, idiopathic pulmonary fibrosis, uveitis, eosinophilic esophagitis, and lupus nephritis.

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