Solid state forms of gusacitinib

Abstract

Provided herein are crystalline solid forms of gusacitinib and Compound (1): (1). The present disclosure also provides pharmaceutical formulations comprising said crystalline solid forms, as well as uses thereof.

Description

SOLID STATE FORMS OF GUSACITINIBRELATED APPLICATIONS

[0001] This application claims priority to and benefit of International Patent Application No. PCT / CN2023 / 109559, filed July 27, 2023, the entire contents of which are hereby incorporated by reference in its entirety.BACKGROUND

[0002] Inhibition of the JAK signaling pathway plays an important role in the treatment of a variety of 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) has also shown promise as treatment for immune-mediated diseases. Id. Inhibiting both JAK and SYK has been theorized to enhance efficacy by broadening the signaling pathways that are blocked, and cytokines that are targeted. Id. ; Pavel, et al. , J. of Allergy and Clinical Immunology, 144(4): 1011- 1024 (2019).SUMMARY

[0003] Previous JAK / SYK inhibitors have shown promise as treatment of certain autoimmune or inflammatory disorders, but have suffered from exaggerated adverse events. See Schwartz, et al., Nat. Rev. Drug Discov. 17( 1):78 (2017). There remains a need for JAK / SYK inhibitors that can treat certain autoimmune or inflammatory disorders that do not suffer from said side effects, and further are shelf stable and capable of being incorporated into oral dosage forms for ease of administration.

[0004] One compound that is being evaluated for use in treating JAK / SYK mediated disorders is gusacitinib, otherwise known as ASN-002, or 2-(l-(4-((4-(4-hydroxypiperidin-l- yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile, and having a structure:Gusacitinib is also being evaluated as a hydrochloride salt, represented by the structure below, and referred to herein as “Compound 1”:Compound 1

[0005] Gusacitinib is described in WO2013 / 028818, reported at example 189, and certain formulations of gusacitinib and Compound 1 are described in W02018 / 201131, each of which is incorporated herein by reference in its entirety. There remains, however, a need for identifying crystalline, anhydrate, hydrate and / or solvate forms of gusacitinib and / or Compound 1 useful for various therapeutic applications.

[0006] In particular, it is also desirable to identify particular forms of gusacitinib and Compound 1 that are stable in a variety of conditions. Initial attempts to formulate gusacitinib and Compound 1 into a form more amenable for manufacturing and formulation, resulted in a form of Compound 1 that was unstable or hygroscopic. Applicant discovered, however, that particular forms of gusacitinib and Compound 1 were exceptionally stable in a variety of conditions. Identifying a crystalline form of gusacitinib and Compound 1 proved challenging, as illustrated in Example 1, where polymorph screening experiments identified only certain solid forms that exhibited suitable stability for further development.

[0007] The present disclosure, however, solves the problems identified above and provides crystalline solid forms that, in some embodiments, exhibit desirable characteristics such asimproved stability, hygroscopicity, flow properties, compressibility, ease of processing, consistency in manufacturing, particle size distribution, bulk density, pharmacokinetics, bioavailability, and ease of formulation.

[0008] In some embodiments, the present disclosure provides a crystalline solid form of Compound 1:Compound 1

[0009] In some embodiments, a crystalline solid form of Compound 1 is an anhydrate. In some embodiments, a crystalline solid form of Compound 1 is Form A, as described herein.

[0010] In some embodiments, a crystalline solid form of Compound 1 is a hydrate. In some embodiments, a crystalline solid form of Compound 1 is Form B, as described herein. In some embodiments, a crystalline solid form of Compound 1 is Form C, as described herein. In some embodiments, a crystalline solid form of Compound 1 is Form D, as described herein. In some embodiments, a crystalline solid form of Compound 1 is Form E, as described herein.

[0011] In some embodiments, a crystalline solid form of Compound 1 is a solvate. In some embodiments, a crystalline solid form of Compound 1 is a solvate of DMF. In some embodiments, a crystalline solid form of Compound 1 is Form F, as described herein.

[0012] In some embodiments, the present disclosure provides a crystalline solid form of gusacitinib, i.e., 2-(l-(4-((4-(4-hydroxypiperidin-l-yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile as a free base (“Compound “2):Compound 2

[0013] In some embodiments, a crystalline solid form of Compound 2 is Form G, as described herein.

[0014] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a crystalline solid form described herein. In some embodiments, a pharmaceutical formulation is a unit dosage form. In some embodiments, a unit dosage form is in the form of a tablet.

[0015] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition, in a subject in need thereof, comprising a step of administering to the subject a crystalline form described herein.

[0016] In some embodiments, the present disclosure provides a method of treating a J AK / SYK- mediated disease, disorder, or condition, in a subject in need thereof, comprising a step of administering to the subject a crystalline solid form described herein.BRIEF DESCRIPTION OF THE DRAWING

[0017] FIG. 1A is an X-ray powder diffraction (XRPD) pattern of Compound 1 Form A.

[0018] FIG. IB is a differential scanning calorimetric (DSC) and thermal gravimetric analysis (TGA) plot of Compound 1 Form A.

[0019] FIG. 1C is a 1H NMR spectrum of Compound 1 Form A.

[0020] FIG. 2A is a series of X-ray powder diffraction (XRPD) patterns, from top to bottom: Compound 1 SM (i.e., Form 1); Compound 1 Form B; and Compound 1 Form B after heating at 155 °C.

[0021] FIG. 2B is a differential scanning calorimetric (DSC) and thermal gravimetric analysis (TGA) plot of Compound 1 Form B.

[0022] FIG. 2C is a 1H NMR spectrum of Compound 1 Form B.

[0023] FIG. 3A is a series of X-ray powder diffraction (XRPD) patterns, from top to bottom: Compound 1 SM (i.e., Form 1); Compound 1 Form C; and Compound 1 Form C after heating at 160 °C.

[0024] FIG. 3B is a differential scanning calorimetric (DSC) and thermal gravimetric analysis (TGA) plot of Compound 1 Form C.

[0025] FIG. 3C is a 1H NMR spectrum of Compound 1 Form C.

[0026] FIG. 4A is a series of X-ray powder diffraction (XRPD) patterns, from top to bottom: Compound 1 SM (i.e., Form 1); Compound 1 Form D; Compound 1 Form D after heating at 140 °C; and Compound 1 Form D after heating at 215 °C.

[0027] FIG. 4B is a differential scanning calorimetric (DSC) and thermal gravimetric analysis (TGA) plot of Compound 1 Form D.

[0028] FIG. 4C is a 1H NMR spectrum of Compound 1 Form D.

[0029] FIG. 5A is a series of X-ray powder diffraction (XRPD) patterns of Compound 1 FormE (top) and Compound 1 Form E after heating to 100 °C (bottom).

[0030] FIG. 5B is a differential scanning calorimetric (DSC) and thermal gravimetric analysis (TGA) plot of Compound 1 Form E.

[0031] FIG. 5C is a 1H NMR spectrum of Compound 1 Form E.

[0032] FIG. 6A is a series of X-ray powder diffraction (XRPD) patterns, from top to bottom: Compound 1 SM (i.e., Form 1); Compound 1 Form F; Compound 1 Form A; and Compound 1 Form F after heating at 230 °C.

[0033] FIG. 6B is a differential scanning calorimetric (DSC) and thermal gravimetric analysis (TGA) plot of Compound 1 Form F.

[0034] FIG. 6C is a 1H NMR spectrum of Compound 1 Form F.

[0035] FIG. 7A is an X-ray powder diffraction (XRPD) pattern of Compound 2 Form G.

[0036] FIG. 7B is a differential scanning calorimetric (DSC) and thermal gravimetric analysis (TGA) plot of Compound 2 Form G.

[0037] FIG. 7C is a 1H NMR spectrum of Compound 2 Form G.

[0038] FIG. 8 is a series of XRPD spectra of Compound 1 Form A after being subjected to certain stress conditions.

[0039] FIG. 9 is a series of XRPD spectra of Compound 1 Form B after being subjected to certain stress conditions.

[0040] FIG. 10 is a diagram illustrating different methods of converting various solid forms of Compound 1 and Compound 2.

[0041] FIG. 11 is a series of XRPD spectra of Compound 1 starting material (SM) and Forms A, B, C, D, E, and F.

[0042] FIG. 12A is an XRPD spectrum of Compound 1 Form 1 (also referred to herein as starting material (SM)).

[0043] FIG. 12B is a DSC and TGA plot of Compound 1 Form 1.

[0044] FIG. 12C is a dynamic vapor sorption (DVS) plot of Compound 1 Form 1.

[0045] FIG. 12D provides a series of XRPD spectra of Compound 1 Form 1 before (top) and after (bottom) heating at 100 °C.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0046] Gusacitinib, otherwise known as 2-(l-(4-((4-(4-hydroxypiperidin-l-yl)phenyl)amino)- 5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile is being evaluated in the treatment of certain diseases, disorders, and conditions associated with the JAK / SYK pathway. The present disclosure provides crystalline solid forms of 2-(l-(4-((4-(4-hydroxypiperidin-l- yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile, both in the form of a pharmaceutically acceptable salt as well as in the free base form. The present disclosure, among other things, recognizes the surprising discovery that gusacitinib, and certain salts thereof, are capable of forming crystalline solid forms, and further, that those forms exhibit improved stability and other beneficial properties relative to a corresponding amorphous form or other crystalline forms. Further, the present disclosure, among other things, provides particular pharmaceutical formulations (i.e., unit dosage forms) of gusacitinib that are suitable for oral administration.

[0047] In some embodiments, the present disclosure provides crystalline solid forms of a hydrochloride salt form of gusacitinib, represented by the structure below, and referred to herein as “Compound 1”:Compound 1Definitions

[0048] About or approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "approximately" or "about" may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0049] Administering: As used herein, the term "administering" or "administration" typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In someembodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (c.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime- and-boost protocol. A prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine). In the case of an immunogenic composition, a prime-and-boost protocol can result in an increased immune response in a patient.

[0050] Antagonist: As will be understood by those skilled in the art, the term “antagonist” generally refers to an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an antagonist is one whose presence or level correlates with a target level or activity that is comparable to or less than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known antagonist, e.g., a positive control). In some embodiments, an antagonist may be a direct antagonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an antagonist may be an indirect antagonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.

[0051] Biological sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or includecells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0052] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0053] Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality(ies)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0054] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that aresufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0055] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc.

[0056] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).

[0057] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two differenttime periods separating individual doses. In some embodiments, all doses within a dosing regimen arc of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0058] Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0059] Modulator: The term “modulator,” as used herein, 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 cause an increase or decrease in the magnitude of a certain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator. For example, a modulator can be an agonist or an antagonist of a particular' target, as those terms are defined herein. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist.

[0060] Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

[0061] Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0062] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental,diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (c.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0063] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0064] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0065] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that arc appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and arc commensurate with a reasonable bcncfit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0066] Prevent or prevention: As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0067] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.Crystalline Solid Forms of Gusacitinib and Compound 1

[0068] Gusacitinib, is being evaluated in the treatment of a certain autoimmune and inflammatory disorders. Gusacitinib is otherwise known as ASN-002, or 2-(l-(4-((4-(4- hydroxypiperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile, is referred herein as “Compound 2,” and has a structure:Compound 2Gusacitinib is also being evaluated as a hydrochloride salt, represented by the structure, and referred to herein as “Compound 1”:Compound 1

[0069] Compound 2 is reported in WO2013 / 028818, in example 189, and certain formulations of Compound 1 and Compound 2 arc provided in WO2018 / 201131, each of which is incorporated herein by reference in its entirety. A synthesis of Compound 2 is also provided in WO2013 / 028818.

[0070] Applicant discovered that Compound 1 and Compound 2 can each exist in one or more polymorphic solid forms. As used herein, the term “polymorph” refers to the ability of a compound to exist in one or more different crystal structures. For example, one or more polymorphs may vary in pharmaceutically relevant physical properties between one form and another, e.g., solubility, stability, and / or hygroscopicity. In some embodiments, the present disclosure provides a crystalline solid form of Compound 1 or Compound 2.

[0071] Compound 1 or Compound 2 can occur in an amorphous solid form, in a crystalline solid form, or in mixtures of forms. Crystalline solid forms of Compound 1 or Compound 2 can exist in one or more unique solid forms, which can additionally comprise one or more molecules of water or solvent (i.e., hydrates or solvates, respectively) in the crystal lattice. As described herein, crystalline forms of Compound 1 and Compound 2 each have distinct characteristic XRPD peaks that are not reported in previous disclosures of Compound 1 or Compound 2.

[0072] In some embodiments, a crystalline solid form of Compound 1 exists as an anhydrate. A crystalline solid form that does not have any water incorporated into the crystalline structure is an “anhydrate.” In some embodiments, a crystalline solid form of Compound 1 is an anhydrate.

[0073] In some embodiments, a crystalline form of Compound 1 exists as a solvate and / or hydrate. As used herein, the term “solvate” refers to a solid form with a stoichiometric or non- stoichiometric amount of one or more solvents incorporated into the crystal structure. For example,a solvated or heterosolvated polymorph can comprise 0.05, 0.1 , 0.2, 0.5, 1.0, 1.5, 2.0, etc. equivalents independently of one or more solvents incorporated into the crystal lattice. As used herein, the term “hydrate” refers to a solvate, wherein the solvent incorporated into the crystal structure is water.

[0074] In some embodiments, provided forms (e.g., forms of Compound 1 and Compound 2) are characterized by having peaks in its XRPD pattern selected from “substantially all” of a provided list, optionally within ± 0.2 degrees 2-theta of the stated value. It will be appreciated that an XRPD pattern having “substantially all” of a provided list of peaks refers to an XRPD pattern that comprises at least 80% (e.g., 80%, 85%, 90%, 95%, 99% or 100%) of the listed peaks. In some embodiments, an XRPD pattern comprises at least 90% of the listed peaks. In some embodiments, an XRPD pattern comprises all of the listed peaks. In some embodiments, an XRPD pattern comprises all but one of the listed peaks. In some embodiments, an XRPD pattern comprises all but two of the listed peaks. In some embodiments, an XRPD pattern comprises all but three of the listed peaks.

[0075] In some embodiments, provided forms (e.g., forms of Compound 1 and Compound 2) are characterized by having a pattern or spectrum that is “substantially similar” to a Figure provided herein. It will be appreciated that a pattern or spectrum having “substantial similarity” to a Figure provided herein is one that comprises one or more features (e.g., position (degrees 2- theta) values, temperature values, % weight loss values, intensity, shape of curve, etc.) of the provided Figure so as to enable identification of the form (e.g., solid and / or salt form) characterized by the pattern or spectrum as being the same as the form characterized in the Figure. For example, in some embodiments, an XRPD pattern having substantial similarity to a provided Figure is one that comprises substantially all of the same peaks, optionally within ± 0.2 degrees 2-theta of peaks in the reference Figure. In some embodiments, an XRPD pattern having substantial similarity to a provided Figure is one that comprises substantially all of the same peaks, optionally within ± 0.2 degrees 2-theta of peaks in the reference Figure, with about the same intensities.Compound 1 Form A

[0076] In some embodiments, a crystalline solid form of Compound 1 is an anhydrate.

[0077] In some embodiments, an anhydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.4, 12.8, 22.9, 25.8, 30.0, and39.2 ± 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 6.4, 12.8, 22.9, 25.8, 30.0, and 39.2 ± 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 6.4, 12.8, 22.9, 25.8, 30.0, and 39.2 ± 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 6.4, 12.8, 22.9, 25.8, 30.0, and 39.2 ± 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 6.4, 12.8, 22.9, 25.8, 30.1, and 39.2 ± 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern: 6.4, 12.8, 22.9, 25.8, 30.1, and 39.2 ± 0.2 degrees 2-theta.

[0078] In some embodiments, an anhydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by five or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by six or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by seven or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 ischaracterized by eight or more peaks in its X-ray powder diffraction pattern 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 2-thcta. In some embodiments, an anhydrate form of Compound 1 is characterized by nine or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by ten or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by eleven or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by twelve or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by thirteen or more peaks in its X-ray powder diffraction pattern 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 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern: 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 2-theta.

[0079] In some embodiments, an anhydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from:

[0080] In some embodiments, an anhydrate form of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm having a minima with an onset at about 254.63 and / or a peak at about 261.28 °C.

[0081] In some embodiments, an anhydrate form of Compound 1 is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 0.045% between 21-150 °C.

[0082] In some embodiments, an anhydrate form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1A. In some embodiments, an anhydrate of Compound 1 is characterized by a DSC pattern substantially similar to FIG. IB. In some embodiments, an anhydrate of Compound 1 is characterized by a TGA pattern substantially similar to FIG. IB. In some embodiments, an anhydrate of Compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 1 A (b) a DSC pattern substantially similar to FIG. IB; and (c) a TGA pattern substantially similar to FIG. IB.

[0083] In some embodiments, a crystalline solid form of Compound 1 is Form A.Compound 1 Form B

[0084] In some embodiments, a crystalline solid form of Compound 1 is a hydrate.

[0085] In some embodiments, a hydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.9, 9.5, 13.8, 16.1, and 23.8 ± 0.2 degrees 2-theta. In some embodiments, a hydrate form of Compound 1 is characterized by two ormore peaks in its X-ray powder diffraction pattern selected from 5.9, 9.5, 13.8, 16.1 , and 23.8 ± 0.2 degrees 2-thcta. In some embodiments, a hydrate form of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 5.9, 9.5, 13.8, 16.1, and 23.8 ± 0.2 degrees 2-theta. In some embodiments, a hydrate form of Compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 5.9, 9.5, 13.8, 16.1, and 23.8 ± 0.2 degrees 2-theta. In some embodiments, a hydrate form of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern: 5.9, 9.5, 13.8, 16.1, and 23.8 ± 0.2 degrees 2-theta.

[0086] In some embodiments, a hydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from:

[0087] In some embodiments, a hydrate of Compound 1 is characterized by a differential scanning calorimctcry (DSC) endotherm having a minima with an onset at about 259.22 °C and / or a peak at about 260.66 °C.

[0088] In some embodiments, a hydrate form of Compound 1 is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 1.082% between 21-150 °C.

[0089] In some embodiments, a hydrate form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 2 A (middle spectrum). In some embodiments, a hydrate of Compound 1 is characterized by a DSC pattern substantially similar to FIG. 2B. In some embodiments, a hydrate of Compound 1 is characterized by a TGA patternsubstantially similar to FIG. 2B. In some embodiments, a hydrate of Compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 2A (middle spectrum); (b) a DSC pattern substantially similar to FIG. 2B; and (c) a TGA pattern substantially similar to FIG. 2B.

[0090] In some embodiments, a crystalline solid form of Compound 1 is Form B.Compound 1 Form D

[0091] In some embodiments, a hydrate form of Compound 1 is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 6.951% between 21-150 °C.

[0092] In some embodiments, a hydrate form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 4A (second spectrum from top). In some embodiments, a hydrate of Compound 1 is characterized by a DSC pattern substantially similar to FIG. 4B. In some embodiments, a hydrate of Compound 1 is characterized by a TGA pattern substantially similar to FIG. 4B. In some embodiments, a hydrate of Compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 4A (second spectrum from top); (b) a DSC pattern substantially similar to FIG. 4B; and (c) a TGA pattern substantially similar to FIG. 4B.

[0093] In some embodiments, a crystalline solid form of Compound 1 is Form D.Compound 1 Form E

[0094] In some embodiments, a hydrate of Compound 1 is characterized by a differential scanning calorimetery (DSC) endotherm having a minima at about 258.69 °C.

[0095] In some embodiments, a hydrate form of Compound 1 is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 4.427% between 21-150 °C.

[0096] In some embodiments, a hydrate form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 5A (top spectrum). In some embodiments, a hydrate of Compound 1 is characterized by a DSC pattern substantially similar’ to FIG. 5B. In some embodiments, a hydrate of Compound 1 is characterized by a TGA pattern substantially similar to FIG. 5B. In some embodiments, a hydrate of Compound 1 is characterized by (a) an X- ray powder diffraction pattern substantially similar to FIG. 5A (top spectrum); (b) a DSC pattern substantially similar to FIG. 5B; and (c) a TGA pattern substantially similar to FIG. 5B.

[0097] In some embodiments, a crystalline solid form of Compound 1 is Form E.Compound 1 Form F

[0098] In some embodiments, a crystalline solid form of Compound 1 is a solvate. In some embodiments, a crystalline solid form of Compound is a solvate of DMF (i.e., is a DMF solvate).

[0099] In some embodiments, a DMF solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 6A (second spectrum from top). In some embodiments, a DMF solvate of Compound 1 is characterized by a DSC pattern substantially similar to FIG. 6B. In some embodiments, a DMF solvate of Compound 1 is characterized by a TGA pattern substantially similar to FIG. 6B. In some embodiments, a DMF solvate of Compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 6A (second spectrum from top); (b) a DSC pattern substantially similar to FIG. 6B and (c) a TGA pattern substantially similar to FIG. 6B.

[0100] In some embodiments, a DMF solvate of Compound 1 is Form F.Compound 2

[0101] In some embodiments, the present disclosure provides a crystalline solid form of 2-( 1- (4-((4-(4-hydroxypiperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile (gusacitinib, otherwise referred to herein as Compound 2):Compound 2Compound 2 Form G

[0102] In some embodiments, a crystalline solid form of Compound 2 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 7 A. In some embodiments, a crystalline solid form of Compound 2 is characterized by a DSC pattern substantially similar toFIG. 7B. In some embodiments, a crystalline solid form of Compound 2 is characterized by a TGA pattern substantially similar to FIG. 7B. In some embodiments, a crystalline solid form of Compound 2 is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 7 A; (b) a DSC pattern substantially similar to FIG. 7B; and (c) a TGA pattern substantially similar to FIG. 7B.

[0103] In some embodiments, a crystalline solid form of Compound 2 is Form G.Methods of Preparing Crystalline Solid Forms

[0104] In some embodiments, the present disclosure provides methods of preparing provided crystalline solid forms of Compound 1 or Compound 2. In some embodiments, a crystalline solid form of Compound 1 is prepared by slurrying Compound 1 (amorphous, partially crystalline or crystalline) in a mixture comprising one or more organic solvents. In some embodiments, slurrying Compound 1 Form 1 in a mixture of one or more organic solvents yields a crystalline solid form of Compound 1 in the form of an anhydrate. In some embodiments, an anhydrate form of Compound 1 is Form A. In some embodiments, one or more organic solvents is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, methyl tertbutyl ether, acetone, ethyl acetate, isopropyl acetate, DMSO, dichloromethane, DMF, iso-butanol, butanone, toluene, n-propanol, heptane, and combinations thereof. In some embodiments, Form A of Compound 1 is prepared by slurrying Compound 1 (in an amorphous, partially crystalline, or crystalline form) in a mixture comprising one or more organic solvents. In some embodiments, one or more organic solvents is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, ethyl acetate, isopropyl acetate, DMSO, dichloromethane, DMF, iso-butanol, butanone, toluene, n-propanol, heptane, and combinations thereof.

[0105] In some embodiments, Form A of Compound 1 is prepared by heating Form E of Compound 1 to a temperature of about 100 °C.

[0106] In some embodiments, a crystalline solid form of Compound 1 is prepared by slurrying Compound 1 (amorphous, partially crystalline, or crystalline) in a mixture comprising water. In some embodiments, slurrying Compound 1 in a mixture comprising water yields a crystalline solid form of Compound 1 in the form of a hydrate. In some embodiments, a mixture comprising water further comprises an organic solvent. In some embodiments, an organic solvent is ethanol. Insome embodiments, Form B of Compound 1 is prepared by slurrying Compound 1 (in an amorphous, partially crystalline, or crystalline form) in a mixture comprising water. In some embodiments, Form B of Compound 1 is prepared by slurrying Compound 1 (in an amorphous, partially crystalline, or crystalline form) in a mixture comprising water and at a suitable temperature. In some embodiments, Form B of Compound 1 is prepared by slurrying Compound 1 (in an amorphous, partially crystalline, or crystalline form) in a mixture comprising water at about 50 °C. In some embodiments, a mixture comprising water is a mixture of ethanol and water. In some embodiments, a mixture of ethanol and water is at a volume ratio of 1:3 of ethanol to water. In some embodiments, Form B of Compound 1 is prepared by slurrying Compound 1 (in an amorphous, partially crystalline, or crystalline form) in a mixture of ethanol and water at a volume ratio of 1:3 of ethanol to water and at about 50 °C.

[0107] In some embodiments, Form D of Compound 1 is prepared by vapor-solid diffusion of Compound 1 (in an amorphous, partially crystalline, or crystalline form) in water. In some embodiments, Form D of Compound 1 is prepared by vapor-liquid diffusion of Compound 1 (in an amorphous, partially crystalline, or crystalline form) using a mixture of acetonitrile and water, e.g., in a 1:1 ratio, and an anti-solvent selected from methyl tert-butyl ether and ethyl acetate.

[0108] In some embodiments, Form F of Compound 1 is prepared by anti-solvent crystallization wherein Compound 1 (in an amorphous, partially crystalline, or crystalline form) is dissolved in a first solvent, the solution filtered, and then anti-solvent added to the solution in excess to induce crystallization. In some embodiments, a first solvent is DMF or DMSO. In some embodiments, a first solvent is DMF. In some embodiments, a first solvent is DMSO. In some embodiments, an anti-solvent is isopropyl alcohol or methyl tert-butyl ether. In some embodiments, an anti-solvent is isopropyl alcohol. In some embodiments, an anti-solvent is methyl tert-butyl ether.

[0109] In some embodiments, Form G of Compound 2 is prepared by slurrying Compound 1 (in an amorphous, partially crystalline, or crystalline form) in water at a temperature of about 50 °C or greater.Compositions

[0110] In some embodiments, the present disclosure provides compositions comprising a crystalline solid form of Compound 1 or Compound 2. In some embodiments, a providedcomposition comprises 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 contains no significant amount of extraneous matter. Such extraneous matter may include starting materials, alternative crystalline forms, residual solvents, or any other impurities that may result from the preparation of and / or isolation of a 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.

[0111] In some embodiments, a provided composition comprising a crystalline solid form of Compound 1 or Compound 2 is substantially pure (e.g., comprises at least about 95%, 97%, 97.5%, 98,% 98.5%, 99%, 99.5%, or 99.8% by weight of the provided crystalline solid form based on the total weight of the composition). In some embodiments, a composition comprising a crystalline solid form of Compound 1 or Compound 2 comprises no more than about 5.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 or Compound 2 comprises no more than about 3.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 or Compound 2 comprises no more than about 1.5 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 or Compound 2 comprises no more than about 1.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 or Compound 2 comprises no more than about 0.5 percent of total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.

[0112] In some embodiments, a provided composition comprising 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., comprises at least about 95%, 97%, 97.5%, 98,% 98.5%, 99%, 99.5%, or 99.8% by weight of the provided crystalline solid form based on the total weight of the composition). In some embodiments, a composition comprising a crystalline solid form of Compound 1 comprises no more than about 5.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 comprises no more than about 3.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 comprises no more than about 1.5 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 comprises nomore than about 1 .0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 comprises no more than about 0.5 percent of total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.

[0113] In some embodiments, a provided composition comprising a crystalline solid form of Compound 2 (e.g., Form G) is substantially pure (e.g., comprises at least about 95%, 97%, 97.5%, 98,% 98.5%, 99%, 99.5%, or 99.8% by weight of the provided crystalline solid form based on the total weight of the composition). In some embodiments, a composition comprising a crystalline solid form of Compound 2 comprises no more than about 5.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 2 comprises no more than about 3.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 2 comprises no more than about 1.5 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 2 comprises no more than about 1.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 2 comprises no more than about 0.5 percent of total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.Pharmaceutical Compositions

[0114] In some embodiments, the present 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, a pharmaceutical composition comprises a crystalline solid form of Compound 1 or Compound 2 and one or more pharmaceutically acceptable excipients. In some embodiments, a pharmaceutical composition is one described in W02018 / 201131, which is incorporated herein by reference in its entirety.

[0115] In some embodiments, a 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, a 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, a pharmaceutical composition comprises a crystalline solid form of Compound 2 (e.g., Form G).

[0116] In some embodiments, a pharmaceutical formulation comprises about 10-30% by weight of a crystalline solid form of Compound 1, calculated as a free base. As used herein, a person of skill in the art will understand that reference to a “free base weight” or reference to calculating a weight “as a free base” refers to using the weight corresponding to a molar equivalent of a free base of Compound 1 (i.e., 2-(l-(4-((4-(4-hydroxypiperidin-l-yl)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile), which is agnostic to any particular salt form. In some embodiments, a pharmaceutical formulation comprises about 10- 25% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 10-15% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 10% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 10.5% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 11% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 11.5% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 12% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 12.5% by weight of a crystalline solid form of Compound 1, calculated as a free base.

[0117] In some embodiments, a pharmaceutical formulation comprises about 15-25% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 20% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 21% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 22% by weight of acrystalline solid form of Compound 1 , calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 23% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 24% by weight of a crystalline solid form of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 25% by weight of a crystalline solid form of Compound 1, calculated as a free base.

[0118] In some embodiments, a pharmaceutical formulation comprises about 1-10% by weight of a binder. In some embodiments, a pharmaceutical formulation comprises about 1-5% by weight of a binder. In some embodiments, a pharmaceutical formulation comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of a binder. In some embodiments, a pharmaceutical formulation comprises about 1% by weight of a binder. In some embodiments, a pharmaceutical formulation comprises about 2% by weight of a binder. In some embodiments, a pharmaceutical formulation comprises about 3% by weight of a binder. In some embodiments, a pharmaceutical formulation comprises about 4% by weight of a binder. In some embodiments, a pharmaceutical formulation comprises about 5% by weight of a binder.

[0119] In some embodiments, one or more binders are selected from polyvinylpyrollidone or hydroxylpropyl cellulose. In some embodiments, a binder is polyvinylprollidone. In some embodiments, a binder is hydroxypropyl cellulose.

[0120] In some embodiments, a pharmaceutical formulation comprises about 1-10% by weight of a disintegrant. In some embodiments, a pharmaceutical formulation comprises about 4-8% by weight of a disintegrant. In some embodiments, a pharmaceutical formulation comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of a disintegrant. In some embodiments, a pharmaceutical formulation comprises about 4% by weight of a disintegrant. In some embodiments, a pharmaceutical formulation comprises about 5% by weight of a disintegrant. In some embodiments, a pharmaceutical formulation comprises about 6% by weight of a disintegrant. In some embodiments, a pharmaceutical formulation comprises about 7% by weight of a disintegrant. In some embodiments, a pharmaceutical formulation comprises about 8% by weight of a disintegrant.

[0121] In some embodiments, one or more disintegrants are selected from crospovidone and croscarmcllosc sodium. In some embodiments, a disintcgrant is crospovidone. In some embodiments, a disintegrant is croscarmellose sodium.

[0122] In some embodiments, a pharmaceutical formulation comprises about 0.05-1% by weight of an antioxidant. In some embodiments, a pharmaceutical formulation comprises about 0.05% to about 0.5% by weight of an antioxidant. In some embodiments, a pharmaceutical formulation comprises about 0.05% to about 0.1% by weight of an antioxidant. In some embodiments, a pharmaceutical formulation comprises about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09% or about 0.1% of an antioxidant.

[0123] In some embodiments, one or more antioxidants are selected from vitamin E and butylated hydroxytoluene. In some embodiments, an antioxidant is vitamin E. In some embodiments, an antioxidant is butylated hydroxy toluene.

[0124] In some embodiments, a crystalline solid form of Compound 1 or Compound 2 is micronized.

[0125] In some embodiments, a pharmaceutical composition comprises: about 10-30% by weight of a crystalline solid form of Compound 1, calculated by free base weight; about 1-10% by weight of a disintegrant; about 1-10% by weight of a binder; and about 0.1-1% by weight of an antioxidant. In some embodiments, a pharmaceutical composition comprises: about 10-30% by weight of a crystalline solid form of Compound 1, calculated by free base weight; about 1-10% by weight of croscarmellose sodium; about 1-10% by weight of hydroxypropyl cellulose; and about 0.05-1% by weight of vitamin E.

[0126] In some embodiments, a pharmaceutical composition comprises about 10-15% by weight of a crystalline solid form of Compound 1, calculated by free base weight; 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, a pharmaceutical composition comprises about 10-15% by weight of a crystalline solid form of Compound 1, calculated by free base weight; 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, a pharmaceutical composition comprises about 10% by weight of a crystalline form of Compound 1; 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, a pharmaceutical composition comprises about 10% by weight of a crystalline formof Compound 1 ; about 3% by weight of hydroxypropyl cellulose; about 6% by weight of a croscarmcllosc sodium; and about 0.1% by weight of vitamin E. In some embodiments, a pharmaceutical composition comprises about 12% by weight of a crystalline form of Compound 1; 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, a pharmaceutical composition comprises about 12% by weight of a crystalline form of Compound 1; about 3% by weight of hydroxypropyl cellulose; about 6% by weight of a croscarmellose sodium; and about 0.08% by weight of vitamin E.

[0127] In some embodiments, a pharmaceutical composition comprises about 20-25% by weight of a crystalline solid form of Compound 1, calculated by free base weight; 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, a pharmaceutical composition comprises about 20-25% by weight of a crystalline solid form of Compound 1, calculated by free base weight; 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, a pharmaceutical composition comprises about 20% by weight of a crystalline form of Compound 1; 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, a pharmaceutical composition comprises about 20% by weight of a crystalline form of Compound 1; about 3% by weight of hydroxypropyl cellulose; about 6% by weight of a croscarmellose sodium; and about 0.1% by weight of vitamin E. In some embodiments, a pharmaceutical composition comprises about 23% by weight of a crystalline form of Compound 1; 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, a pharmaceutical composition comprises about 23% by weight of a crystalline form of Compound 1; about 3% by weight of hydroxypropyl cellulose; about 6% by weight of a croscarmellose sodium; and about 0.08% by weight of vitamin E.

[0128] In some embodiments, a pharmaceutical formulation further comprises a filler. In some embodiments, a pharmaceutical composition comprises about 50-80% by weight of a filler. In some embodiments, a pharmaceutical composition comprises about 50% to about 75% by weight of a filler. In some embodiments, a pharmaceutical composition comprises about 50%, about 55%,about 60%, about 65%, about 70%, or about 75% by weight a filler. In some embodiments, a filler is lactose monohydratc.

[0129] In some embodiments, a pharmaceutical formulation further comprises about 5-10% by weight of microcrystalline cellulose. In some embodiments, a pharmaceutical formulation further comprises about 0.5-2% by weight of sodium lauryl sulfate. In some embodiments, a pharmaceutical formulation comprises about 1% by weight of magnesium stearate.

[0130] In some embodiments, a pharmaceutical formulation comprises about 20 mg to about 120 mg of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 40 mg to about 80 mg of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 40 mg of Compound 1, calculated as a free base. In some embodiments, a pharmaceutical formulation comprises about 80 mg of Compound 1, calculated as a free base.

[0131] In some embodiments, a pharmaceutical formulation is a unit dosage form. In some embodiments, a unit dosage form in the form of a tablet.

[0132] In some embodiments, a provided pharmaceutical composition is administered once daily (QD). In some embodiments, a provided pharmaceutical composition is administered twice daily (BID). In some embodiments, a provided pharmaceutical composition is administered every other day (QOD). In some embodiments, a provided pharmaceutical composition is administered once weekly (QW). In some embodiments, a provided pharmaceutical composition is administered once every four weeks (Q4W).Uses

[0133] Provided crystalline solid forms and compositions comprising said crystalline solid forms are useful in the treatment of a variety of diseases and disorders. For example, in some embodiments, a provided crystalline solid form is useful for treating a disease, disorder, or condition that is mediated by the JAK / SYK pathway.

[0134] In some embodiments, the present disclosure provides a method of treating a disease, disorder or condition, comprising administering to a subject in need there of a crystalline solid form of Compound 1 or Compound 2. In some embodiments, the present disclosure provides a method of treating a disease, disorder or condition, comprising administering to a subject in need there of a crystalline solid form of Compound 1. In some embodiments, the present disclosureprovides a method of treating a disease, disorder or condition, comprising administering to a subject in need there of a crystalline solid form of Compound 2.

[0135] In some embodiments, a disease, disorder, or condition is atopic dermatitis, alopecia areata, hand and foot eczema, 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, a disease, disorder, or condition is atopic dermatitis. In some embodiments, a disease, disorder, or condition is alopecia areata. In some embodiments, a disease, disorder, or condition is hand and foot eczema. In some embodiments, a disease, disorder, or condition is chronic hand eczema. In some embodiments, a disease, disorder, or condition is hidradenitis suppurativa. In some embodiments, a disease, disorder, or condition is pemphigus vulgaris. In some embodiments, a disease, disorder, or condition is psoriasis. In some embodiments, a disease, disorder, or condition is cutaneous lupus. In some embodiments, a disease, disorder, or condition is vitiligo. In some embodiments, a disease, disorder, or condition is inflammatory bowel disease. In some embodiments, a disease, disorder, or condition is rheumatoid arthritis. In some embodiments, a disease, disorder, or condition is asthma. In some embodiments, a disease, disorder, or condition is allergic rhinitis. In some embodiments, a disease, disorder, or condition is systemic lupus erythematosus. In some embodiments, a disease, disorder, or condition is psoriatic arthritis. In some embodiments, a disease, disorder, or condition is multiple sclerosis. In some embodiments, a disease, disorder, or condition is acute myeloid leukemia. In some embodiments, a disease, disorder, or condition is graft versus host disease. In some embodiments, a disease, disorder, or condition is myelofibrosis. In some embodiments, a disease, disorder, or condition is warm hemolytic anemia. In some embodiments, a disease, disorder, or condition is idiopathic thrombocytopenic purpura. In some embodiments, a disease, disorder, or condition is immunoglobulin A nephropathy. In some embodiments, a disease, disorder, or condition is scleroderma. In some embodiments, a disease, disorder, or condition is idiopathic pulmonary fibrosis. In some embodiments, a disease, disorder, or condition is uveitis. In some embodiments, a disease, disorder, or condition is eosinophilic esophagitis. In some embodiments, a disease, disorder, or condition is lupus nephritis.

[0136] In some embodiments, a disease, disorder, or condition is a JAK / SYK-mediated disease, disorder, or condition. In some embodiments, a JAK / SYK-mcdiatcd disease, disorder, or condition is atopic dermatitis, alopecia areata, hand and foot eczema, 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, a JAK / SYK-mediated disease, disorder, or condition is atopic dermatitis. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is alopecia areata. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is hand and foot eczema. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is chronic hand eczema. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is hidradenitis suppurativa. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is pemphigus vulgaris. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is psoriasis. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is cutaneous lupus. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is vitiligo. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is inflammatory bowel disease. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is rheumatoid arthritis. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is asthma. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is allergic rhinitis. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is systemic lupus erythematosus. In some embodiments, a JAK / SYK- mediated disease, disorder, or condition is psoriatic arthritis. In some embodiments, a JAK / SYK- mediated disease, disorder, or condition is multiple sclerosis. In some embodiments, a JAK / SYK- mediated disease, disorder, or condition is acute myeloid leukemia. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is graft versus host disease. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is myelofibrosis. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is warm hemolytic anemia. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is idiopathic thrombocytopenic purpura. In some embodiments, a JAK / SYK-mediated disease, disorder, orcondition is immunoglobulin A nephropathy. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is scleroderma. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is idiopathic pulmonary fibrosis. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is uveitis. In some embodiments, a JAK / SYK- mediated disease, disorder, or condition is eosinophilic esophagitis. In some embodiments, a JAK / SYK-mediated disease, disorder, or condition is lupus nephritis.EXAMPLES

[0137] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0138] The following abbreviations may be used in the Examples below: ACN (acetonitrile); DCM (dichloromethane); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); EA (ethyl acetate); EtOH (ethanol); h (hour or hours); HPLC (high-performance liquid chromatography) IPA (isopropyl alcohol); IP AC (isopropyl acetate); LCMS (liquid chromatography-mass spectrometry); methanol (MeOH); MTBE (methyl tert-butyl ether); min (minute or minutes); NMR (nuclear' magnetic resonance); RH (relative humidity); it or RT (room temperature); s (second or seconds); SM (starting material); THF (tetrahydrofuran); and UV (ultraviolet).Materials and MethodsX-Ray Powder Diffraction (XRPD)

[0139] The solid samples were examined using an X-ray diffractometer (Bruker D8 Focus). The samples were scanned from 3° to 42° (20), at a step size 0.02° (20). The tube voltage and current were 40 kV and 40 mA, respectively. The sample was transferred from the sample container onto a zero background XRPD-holder and planished to make the surface smooth.Thermal Gravimetric Analysis (TGA)

[0140] TGA analysis was carried out on a TA Instruments TGA Discovery 550. Samples were placed in a tared platinum or aluminum pan, automatically weighed, and inserted into the TGA furnace. The samples were heated at a rate of 10 °C / min to the final temperature. The purge gas was nitrogen for balance at 40 mL / min and for the sample at 60 mL / min, respectively.Differential Scanning Calorimetric Analysis (DSC)

[0141] DSC analysis was conducted on a TA Instruments Discovery DSC 25. The calibration standard was indium. A sample in weight was placed into a TA DSC pan, and weight accurately recorded. Crimped pans were used for analysis and the samples were heated under nitrogen (50 mL / min) at a rate of 10 °C / min to the final temperature.Dynamic Vapor Sorption (DVS)

[0142] Dynamic vapor sorption and desorption were studied using an Intrinsic DVS (System Measurement System UK). About 20-30 mg of prepared sample was placed in a sample basket and hung in the measuring chamber. For an isotherm test, the chamber temperature is maintained by a water bath at constant 25 + 1 °C. The sample was tested at a targeted RH of 0 to 90% full cycle in step mode. The analysis was performed in 10% RH increments. Time duration at each RH was set as 60 min so that the sample could reach equilibrium with the chamber environment. Data were collected in 20 second increments.Scanning Electron Microscope (SEM)

[0143] The solid samples were examined using Phenom pure+. The samples were sprayed in an ion sputtering apparatus for 60 s. The resulting solid was put into a scanning electron microscope and the electron scanning mode was turned on. The crystal morphology and microstructure were obtained by adjusting the different magnification times.Example 1: Polymorph Screening

[0144] Various crystallization methods were applied to discover certain crystalline solid forms of 2-(l-(4-((4-(4-hydroxypiperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4-yl)acetonitrile hydrochloride (Compound 1). The methods utilized in the present example and the crystal forms obtained are summarized in Table 1. Overall, six new forms were discovered from these experiments.Table 1* starting material (i.e., Compound 1 Form 1)Solubility Analysis

[0145] In the present example, the solubility of Compound 1 was assessed in a variety of solvents. In particular, Compound 1 Form 1 (referred to as “SM” in the table below) was added into an 8-mL glass vial followed by the addition of corresponding solvent at room temperature. The solvent was added step wise until the solution was visually clear or a total volume of 3 mL was reached. The parameters and results are summarized in Table 2.Table 2Mixed Solvent Evaporation

[0146] The first 13 solvents listed in Table 2 were further studied in the next analysis. Two mL of from Table 2 solution was filtered through a 0.22 pm filter membrane. About 1.4 mL of the filtrates were distributed in 96-well plates according to the solvent matrix that is shown in Table 3. The numbers refer to the solvent mixtures selected from the solvents 1-13 in Table 2. E.g., “1 / 2” refers to a MeOH / EtOH mix.Table 3

[0147] The plates were covered and subjected to slow evaporation at room temperature to induce precipitation. The solids were isolated for XRPD analysis. The results are summarized in Table 4.Table 4AM: amorphous; N / A: not tested; A-G: Forms A-G.Single Solvent Slurry

[0148] The remaining suspensions / solutions in in the present example were stirred at room temperature, and the samples were taken at different times for determination of XRPD. It was determined from the slurry results that SM converted to Form A in many solvents including methanol (MeoH), tetrahydrofuran (THF), acetonitrile (ACN), acetone, ethyl acetate (EA), isopropyl acetate (IP AC), iso-butanol, butanone, toluene, n-propanol, and heptane. The results are summarized in Table 5.Table 5SM = starting material; A-G = Forms A-GSingle Solvent Evaporation

[0149] About 600 pL of residual filtrates, after 96-well plate preparation, were allowed to evaporate at RT in test tubes in an operated laboratory fume hood. Any obtained solid would be analyzed by XRPD. Most of the single solvent recrystallizations had no solid separated out, while the solid evaporated from DMF was the mixture of A and B. The results are summarized in Table 6.Table 6A-G = Forms A-GGrinding

[0150] Grinding experiments were performed by placing ~20 mg of SM in a mortar followed by addition of different solvents (water, MeOH, MTBE, ACN) to make a paste, which was gently ground at RT for 5 minutes. The form of the starting material did not change. The parameters and results are summarized in Table 7.Table 7SM = starting materialVapor-Solid Diffusion

[0151] Vapor-solid diffusion experiments were conducted under 8 conditions provided below.The SM solid was placed in a 1.5 mL centrifuge tube which was put into a 10 mL glass vial with3 mL solvent. Then the vial was sealed and the solvent vapor was allowed to be fully in contact with the solid to induce crystallization. After one week, the remaining solids were collected for XRPD analysis. The solids obtained from MeOH, THF, ACN and acetone were Form A, the solid obtained from water was Form D and the solid obtained from EA was a mixture of SM and Form A, while the crystal form of the solid obtained from MTBE or toluene did not change. The results are summarized in Table 8.Table 8A-G = Forms A-G; SM = starting materialAnti-Solvent Crystallization

[0152] Anti-solvent crystallization experiments were performed in 21 conditions. The excess SM solid was dissolved in a solvent. After filtration, the filtrate was packed into vials equally. Then the anti- solvent, for which the volume is 3 times that of the solvent, was added to the vial to induce crystallization. The resulting solid was isolated for XRPD analysis. In this experiment, there was no solid observed when using water as a solvent. When DMSO and DMF were used as a solvent, the resulting solid was Form A and its solvate, Form F. The parameters and results are shown in Table 9.Table 9A-G = Forms A-G.Water Activity Slurry

[0153] Water activity slurry experiments were conducted in 8 conditions by suspending starting material with 1 mL solvent in a 4 mL glass vial. The resulting suspension was stirred at RT for 3 days. All of the resulting solids were the mixture of Form A and Form B. One solvent provided Form A. The parameters and results are summarized in Table 10.Table 10*Aw = Water activity; A-G = Forms A-GVapor-Liquid Diffusion

[0154] Vapor- liquid diffusion experiments were conducted in 8 conditions. The starting material solution was placed in a 1.5 mL centrifuge tube, and the tube was transferred into a 10 mL glass vial with 3 mL anti-solvent. Then the vial was sealed with film and the solvent vapor was allowed to be fully in contact with the starting material solution to induce crystallization. After one week, the solids were collected for XRPD analysis. Form D was observed in ACN:water (1:1), MTBE and EA systems. The parameters and results are summarized in Table 11.Table 11A-G = Forms A-G; SM = starting materiaMixed Solvent Slurry

[0155] Mixed solvent slurry experiments were carried out in 8 conditions by suspending starting material with mixed solvents in a 4-mL glass vial. The resulting solution was stirred at room temperature and at 50 °C. All of the solids observed were Form A, Form B, or a mixture thereof. The parameters and results arc summarized in Table 12.Table 12A-G = Forms A-G.Slow Cooling

[0156] Slow cooling experiments were performed in 4 conditions. The starting material was placed into 1 mL of solvent in an 8-mL glass vial. The resulting suspension was heated to 65 °C until it was clear, then cooled down at a rate of 0.2 °C / min to 5 °C and kept at 5 °C overnight. By slow cooling, solids were observed in the following mixtures: ACN:water (3:1), acetone: water (15:4), and 1,4-dioxane: water (15:2) provided Form A, and the solid obtained from MeOH:water (15:2) was Form B. The parameters and results are summarized in Table 13.Table 13A-G = Forms A-GExample 2: Crystal Form Conversion

[0157] The present example examines the conversion of one form of a crystalline solid form Compound 1 to another form. For this example, samples were weighed into a vial, and 1 mL of selected solvents were added, and the resulting mixtures were stirred at room temperature. The parameters and results are summarized in Table 14:Table 14A-G = Forms A-G; SM = starting materialsExample 3: Stability Evaluation of Compound 1 Form 1, Form A, and Form B

[0158] Stability of Compound 1 starting material (i.e., Form 1), Form A, and Form B was assessed under controlled temperature / humidity conditions. In the present example, about 10 mg solid was put into a 2-mL glass vial. Uncapped vials were stored under stress conditions of 25 °C / 60% RH, 40 °C / 75% RH and 60 °C / 75% RH and capped vials were stored under stress test conditions of 80 °C and light. Then the resulting solid was analyzed by XRPD and HPLC.

[0159] The stability result of the starting material is summarized in Table 15. Compound 1 starting material demonstrated some stability after four weeks at 25 °C / 60% RH and 40 °C / 75% RH, as well as at 80 °C for 1 day and 60 °C / 75% RH for one week.Table 15

[0160] The stability of Form A and Form B was similarly assessed. The results for the stability tests of Form A are provided in Table 16, below. The results for the stability tests of Form B are provided in Table 17, below.Table 16Table 17

[0161] As can be seen in Table 17, Form B forms a mixture of Forms A and B under certain test conditions.Example 4: Solubility Evaluation of Compound Form 1 and Form A

[0162] Solubility of Compound 1 starting material (i.c., Form 1) and Form A was assessed at various pHs and in particular buffer systems at 37 °C. About 10 mg of the indicated solid was stirred in 1 mL solvent at 37 °C for 2 hours and 24 hours. The suspension was then filtered, and the residual solid was analyzed by XRPD and the filtrate measured by HPLC. The results are shown in Table 18.Table 18FaSSIF = Fasted State Simulated Intestinal Fluid; FeSSIF = Fed State Simulated Intestinal Fluid;SGF = Simulated Gastric Fluid; SM = Starting Material; A-G = Forms A-GExample 5. Preparation of Compound 1 Starting Material (aka Compound 1 Form 1)

[0163] Compound 1 starting material (“SM”), also referred to herein as “Compound 1 Form 1,” used in the above polymorph screening experiments was prepared as follows:

[0164] 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 nitrogen atmosphere. Triethylamine (28.5 kg) was then added. The mixture was stirred at 25-35 °C until area% of 5.1 was < 1.0 % as judged by HPLC. Water (507.8 kg) was then added to the reaction mixture, and the mixture was filtered. The collected solids were dried at 40-55 °C to give compound 5.3 (35.2 kg, 93% yield).

[0165] Step 2: SeO2 (23.3 kg) and DMSO (387.6 kg) were added to a 1000 L reactor under nitrogen atmosphere. Compound 5.3 (35.2 kg) was then added, and nitrogen was bubbled through the resulting mixture for 2-5 min. The mixture was heated to 90-98 °C until area% of 5.3 was < 1.0 % as judged by HPLC. The mixture was then cooled to ambient temperature. The mixture was filtered and the filtrate transferred into a 3000 L reactor containing water (776.1 kg). The mixture was stirred for 1 hour at 25-35 °C and then filtered. The collected solids were added to a a reactor containing water (352.2 kg) and the mixture stirred for 1 hour at 25-35 °C. The mixture was then filtered. The collected solids were added to a reactor containing isopropanol (140.4 kg) and stirred for 1 hour at 25-35 °C. The mixture was then heated to 65-75 °C, and hydrazine hydrate (6.8 kg) was added. The mixture was stirred at 65-75 °C until >99.7%conversion was confirmed by HPLC. The mixture was then cooled to ambient temperature and stirred for 1 hour, filtered, rinsed twice with isopropyl alcohol and twice with water, and then dried at < 55 °C to give compound 5.4 (23.5 kg, 68.5% yield).

[0166] Step 3: Compound 5.4 (23.3 kg) and DMF (178.5 kg) were added to 2000 L reactor under 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 area% of 5.4 was < 1.0 % as judged byHPLC. Then, compound 5.5 (15.6 kg) was added to the mixture in five portions. The mixture was allowed to warm to 25-35 °C and stirred at that temperature until >99.0convcrsion was confirmed by HPLC. The mixture was then warmed to 50-60 °C and filtered. The filtrate was then warmed to 40-50 °C, water (631.9 kg) was added, and the mixture stirred for 1 h at 40-50 °C. The mixture was filtered again, washed twice with water, and the collected solids were added to a reactor containing water (234.8 kg) and sodium bicarbonate (6.1 kg) at 25-35 °C. After stirring for 1 h at 25-35 °C, the mixture was filtered, washed twice with water, and the collected solids were dried at 40-60 °C to give crude Compound 2 (27.8 kg, 84.0% yield).

[0167] 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. The solution was filtered through an activated carbon cartridge into another 3000 L reactor, 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 was cooled to 10-15 °C and stirred for 2-4 hours. The solid was collected by filtration, washed with water and methanol, then dried at 50-65 °C to give Compound 2 (30.3 kg, 94% yield). 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 h with stirring. The mixture was cooled to 15-25 °C, and MTBE (224.5 kg) was added. The mixture was stirred for 4-6 h and then filtered. The collected solids were dried at < 50 °C to give Compound 2 (27.0 kg, 89% yield).

[0168] Step 4: Compound 2 (22.5 kg) was added to a 3000 L reactor containing methanol (340.2 kg) under nitrogen atmosphere. At 15-25 °C, hydrochloric acid (5.4 kg) in isopropanol (36.9 kg) was added. The mixture was stirred at 18-23 °C for 20.5 h, resulting in crystallization. Crystals were collected by filtration, rinsing with methanol and MTBE. The collected solids were dried at < 40 °C to give Compound 1 (21.5 kg, 89% yield).

[0169] Compound 1 prepared from this process was assigned as Compound 1 Form 1. An XRPD spectrum of Compound 1 Form 1 is provided in FIG. 12A.

[0170] As shown in FIG. 12B, about 1.386% of weight loss was observed up to 150 °C in the TGA curve and was attributed to loss of residual solvent or water. The DSC curve (FIG. 12B) shows one main endothermic peak with an onset temperature of 257.25 °C and a peak temperature of 260.24 °C.

[0171] FIG. 12C provides a DVS analysis of Compound 1 Form 1, showing a 3.258% weight increase at 80% RH. DVS indicated that Compound 1 Form 1 is hygroscopic. XRPD analysis of the material before and after DVS was the same.

[0172] When Compound 1 Form 1 was heated to 100 °C, the XRPD pattern remained the same (FIG. 12D). Compound 1 Form 1 may therefore be a channel hydrate, since no change in form was observed after removal of solvent.Example 6. Characterization of Certain Provided Solid FormsCompound 1 Form A

[0173] Compound 1 Form A was prepared as described in the examples above. Additionally, preparation of Compound 1 Form A was scaled up as follows: About 500 mg of Compound 1 SM (i.e., Form 1) was added to a 50 mL flask and 6 mL DMSO was added. After filtering the solution, 18 mL acetone was added to the filtrate. The mixture was allowed to stand overnight, the suspension was filtered, and the filter cake was washed with acetone to give Compound 1 Form A.

[0174] Compound 1 Form A was also prepared as follows: About 200 mg of Compound 1 SM (i.e., Form 1) was added to 4 mL acetone in a 8 mL vial and stirred at room temperature. After 2 days, the suspension was filtered to give Compound 1 Form A.

[0175] An XRPD spectrum of Compound 1 Form A is provided in FIG. 1A. TGA / DSC analysis of Compound 1 Form A is provided in FIG. IB, and 1H NMR analysis of Compound 1 Form A is provided in FIG. 1C. Based on the TGA results, Compound 1 Form A was assigned as an anhydrate.Compound 1 Form B

[0176] Compound 1 Form B was prepared as described in the examples above. Additionally, preparation of Compound 1 Form B was scaled up as follows: About 99 mg Compound 1 SM (i.e., Form 1) was added to a 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 give Compound 1 Form B.

[0177] An XRPD spectrum of Compound 1 Form B is provided in FIG. 2A (middle spectrum). TGA / DSC analysis of Compound 1 Form B is provided in FIG. 2B, and ’H NMR analysis ofCompound 1 Form B is provided in FIG. 2C. Based on the TGA results, Compound 1 Form B was assigned as a hydrate.Compound 1 Form C

[0178] Compound 1 Form C was prepared as described in the examples above. For example, Compound 1 Form C was obtained by slurrying Compound 1 SM (i.e., Form 1) in water for 3 days at RT.

[0179] An XRPD spectrum of Compound 1 Form C is provided in FIG. 3A (middle spectrum). TGA / DSC analysis of Compound 1 Form C is provided in FIG. 3B, and 1H NMR analysis of Compound 1 Form C is provided in FIG. 3C. Based on the TGA results, Compound 1 Form C was assigned as a hydrate with low crystallinity.Compound 1 Form D

[0180] Compound 1 Form D was prepared as described in the examples above. For example, Compound 1 Form D was obtained by vapor-solid diffusion in water.

[0181] An XRPD spectrum of Compound 1 Form D is provided in FIG. 4A (second spectrum from top). TGA / DSC analysis of Compound 1 Form D is provided in FIG. 4B, and 1H NMR analysis of Compound 1 Form D is provided in FIG. 4C. Based on the TGA results, Compound 1 Form D was assigned as a hydrate.Compound 1 Form E

[0182] Compound 1 Form E was prepared as described in the examples above. For example, Compound 1 Form E was prepared by slurrying Compound 1 Form A in water at room temperature for 3 days.

[0183] An XRPD spectrum of Compound 1 Form E is provided in FIG. 5A (top spectrum). TGA / DSC analysis of Compound 1 Form E is provided in FIG. 5B, and 1H NMR analysis of Compound 1 Form E is provided in FIG. 5C. Based on the TGA results, Compound 1 Form E was assigned as a hydrate.Compound 1 Form F

[0184] Compound 1 Form F was prepared as described in the examples above. For example, Compound 1 Form F was obtained by anti-solvent crystallization in DMF / IPA or DMF / MTBE.

[0185] An XRPD spectrum of Compound 1 Form F is provided in FIG. 6A (second spectrum from top). TGA / DSC analysis of Compound 1 Form F is provided in FIG. 6B, and!H NMR analysis of Compound 1 Form F is provided in FIG. 6C. Based on the TGA results, Compound 1 Form F was assigned as a DMF solvate.Compound 2 Form G

[0186] Compound 2 Form G was prepared as described in the examples above. For example, Compound 2 Form G was prepared by slurrying Compound 1 SM (i.e., Form 1) in water at 50 °C for 30 min.

[0187] An XRPD spectrum of Compound 2 Form G is provided in FIG. 7 A. TGA / DSC analysis of Compound 2 Form G is provided in FIG. 7B, andNMR analysis of Compound 2 Form G is provided in FIG. 7C.Example 7. Pharmaceutical Formulations of Compound 1 and Compound 2

[0188] Exemplary formulations of provided solid forms were prepared generally as follows: Compound 1, lactose monohydrate, and croscarmellose sodium were combined with a solution of hydroxypropyl cellulose and vitamin E in isopropyl alcohol to provide wet granules, which were then dried and milled. The resulting milled granules were then blended with croscarmellose sodium, microcrystalline cellulose, magnesium stearate, and sodium lauryl sulfate to provide the final blend. The final blend was then compressed into a tablet. The tablets were film-coated with a suspension of aesthetic coating in 1:1 alcohol: water.Exemplary Formulation #1

[0189] An exemplary formulation, without coating, is provided in the following table:■^Corresponding to 80 mg free base weight of Compound 1Exemplary Formulation #2

[0190] An exemplary formulation, without coating, is provided in the following table:^Corresponding to 40 mg free base weight of Compound 1

[0191] The embodiments of the disclosure described above are intended to be merely exemplary, 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 any appended claims.

Claims

CLAIMS1. A crystalline solid form of Compound 1 :Compound 1, wherein the crystalline solid form is an anhydrate and is characterized by one or more peaks in its X-ray powder diffraction pattern 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 2-theta.

2. The crystalline solid form of claim 1, wherein the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from:

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

4. The crystalline solid of any one of claims 1-3, wherein the crystalline solid form is Form5. A crystalline solid form of Compound 1:Compound 1 , wherein the crystalline solid form is a hydrate and is characterized by one or more peaks in its X- ray powder diffraction pattern selected from 5.9, 9.5, 13.8, 16.1, and 23.8 ± 0.2 degrees 2-theta.

6. The crystalline solid form of claim 5, wherein the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from:

7. The crystalline solid form of claim 5 or 6, wherein the crystalline solid form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 2A (middle spectrum).

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

9. A crystalline solid form of Compound 1 :Compound 1, wherein the crystalline solid form is a hydrate and is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 4A (second spectrum from top).

10. The crystalline solid form of claim 9, wherein the crystalline solid form is Form D.

11. A crystalline solid form of Compound 1 :Compound 1, wherein the crystalline solid form is a hydrate and is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 5A (top spectrum).

12. The crystalline solid form of claim 11, wherein the crystalline solid form is Form E.

13. A crystalline solid form of Compound 1 :Compound 1, wherein the crystalline solid form is a DMF solvate and is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 6A (second spectrum from top).

14. The crystalline solid form of claim 13, wherein the crystalline solid form is Form F.

15. A crystalline solid form of a compound that is 2-(l-(4-((4-(4-hydroxypiperidin-l- yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.

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

17. The crystalline solid form of claim 16, wherein the crystalline solid form is Form G.

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

19. A pharmaceutical formulation comprising the crystalline solid form of any one of claims 1-17, and one or more pharmaceutically acceptable excipients.

20. The pharmaceutical formulation of claim 19, wherein the pharmaceutical formulation comprises: about 10-30% by weight of the crystalline solid form of Compound 1, calculated by free base weight; about 1-10% by weight of a disintegrant; about 1-10% by weight of a binder; and about 0.05-0.5% by weight of an antioxidant.

21. The pharmaceutical formulation of claim 20, further comprising a lubricant.

22. The pharmaceutical formulation of claims 20 or 21, wherein the binder is hydroxypropyl cellulose.

23. The pharmaceutical formulation of any one of claims 20-22, wherein the disintegrant is croscarmellose sodium.

24. The pharmaceutical formulation of any one of claims 20-23, wherein the antioxidant is vitamin E.

25. The pharmaceutical formulation of any one of claims 20-24, wherein the pharmaceutical formulation comprises about 20 mg to about 120 mg of the crystalline solid form of Compound 1, calculated by free base weight.

26. The pharmaceutical formulation of claim 25, wherein the pharmaceutical formulation comprises about 40 mg to about 80 mg of the crystalline solid form of Compound 1, calculated by free base weight.

27. The pharmaceutical formulation of any one of claims 19-26, wherein the pharmaceutical formulation is a unit dosage form.

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

29. A method of treating a disease, disorder, or condition, in a subject in need thereof, comprising a step of administering to the subject the crystalline form of any one of claims 1-17 or the pharmaceutical formulation of any one of claims 19-28.

30. The method of claim 29, wherein the disease, disorder, or condition is selected from atopic dermatitis, alopecia areata, hand and foot eczema, 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.

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

32. Use of the crystalline form of any one of claims 1-17, or the pharmaceutical formulation of any one of claims 19-28 in the treatment of a disease, disorder, or condition.

33. The use of claim 32, wherein the disease, disorder, or condition is selected from atopic dermatitis, alopecia areata, hand and foot eczema, 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.

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