Polymorphic substance of JAK1 / TYK2 inhibitor and application thereof

Abstract

Provided herein are solid forms, e.g., polymorphs, of 2-(3-((7R, 8aS)-7-fluorohexahydropyrrolo [1, 2-a] pyrazine-2 (1H)-yl)-1-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) azetidin-3-yl) acetonitrile, which are useful in the treatment of kinase-related diseases or disorders. The solid forms and compositions thereof are useful for treating diseases in a subject, including but not limited to ocular diseases such as glaucoma, ocular hypertension, ocular wound repair, neurodegenerative ocular diseases, retinal detachment, and non-ocular diseases such as neuronal injury or skin wound repair, or inflammatory diseases, etc. (Compound 1). # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 465,091, filed May 9, 2023, and U.S. Provisional Patent Application No. 63 / 437,084, filed January 4, 2023, the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to solid forms, such as polymorphs, of 2-(3-((7R,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile, which can be used to treat kinase-related diseases or conditions (e.g., JAK1 or TYK2-related diseases or conditions). These include eye diseases or conditions (e.g., dry eye, corneal diseases, retinal diseases, and ocular hypertension), skin diseases, respiratory diseases or conditions, cardiovascular diseases, and diseases characterized by abnormal growth (e.g., cancer). Background Art

[0004] Dry eye disease (DED) is a multifactorial condition in which the eye experiences abnormal sensory reactions to minor stimuli, such as dryness, blurred vision, foreign body sensation, discomfort, irritation, and pain. The active pharmaceutical ingredient, 2-(3-((7R,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (Compound 1), is useful for treating DED.

[0005]

[0006] Compositions thereof and stable solid forms of Compound 1 having high purity have been discovered. The stability of the active agent can be used to withstand various manufacturing pressures so that the resulting administrable products contain the active agent at a pharmaceutically acceptable purity. The high purity of the active agent can be used, for example, to avoid administering to a subject byproducts of the active agent produced by the manufacturing process.

[0007] Thus, provided herein are polymorphic forms of Compound 1, methods for preparing them (including in high purity), compositions comprising such forms, and therapeutic uses thereof. Summary of the Invention

[0008] In some embodiments, provided herein are forms of Compound 1, including solid forms such as polymorphic forms.

[0009] Also disclosed herein are pharmaceutical compositions comprising the polymorphic forms, and methods of using the polymorphic forms to treat kinase-related diseases or disorders. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 The X-ray powder diffraction (XRPD) pattern of Compound 1 Form 1 is shown.

[0011] Figure 2 The XRPD pattern of the polymorph of Compound 1 prepared according to the Example is shown.

[0012] Figure 3 The XRPD pattern of the polymorph of Compound 1 prepared according to the Example is shown.

[0013] Figure 4 The XRPD pattern of Polymorph 1 of Compound 1 described in Table 13 is shown.

[0014] Figure 5 The XRPD pattern of Polymorph 2 of Compound 1 described in Table 14 is shown.

[0015] Figure 6 The XRPD pattern of Polymorph 3 of Compound 1 described in Table 15 is shown.

[0016] Figure 7 The XRPD pattern of Polymorph 4 of Compound 1 described in Table 16 is shown.

[0017] Figure 8 The XRPD pattern of Polymorph 5 of Compound 1 described in Table 17 is shown. DETAILED DESCRIPTION

[0018] Provided herein are polymorphic forms of Compound 1. Compound 1 can be prepared according to the synthesis described, for example, in WO2023279105A1 (the entire contents of which are incorporated herein by reference), including but not limited to Scheme 7.

[0019] The solid or polymorphic form of Compound 1 can be used to treat or prevent kinase-related diseases or conditions. In some embodiments, these include ocular diseases or conditions, such as dry eye, corneal damage, retinal inflammation and high intraocular pressure, respiratory diseases, cardiovascular diseases, and diseases characterized by abnormal growth, such as cancer, which may be referred to herein as JAK-related diseases. In some embodiments, the solid form or polymorphic form of the compound described herein can be used for: treating ocular diseases, including but not limited to non-infectious uveitis, non-infectious chorioretinitis, iritis, sterile conjunctivitis, keratitis, episcleritis, dry eye, meibomian gland dysfunction, allergic conjunctivitis, glaucoma or retinal diseases; as an anti-inflammatory agent; for treating skin diseases; for treating cardiovascular diseases; for treating autoimmune diseases, including but not limited to rheumatoid arthritis, Crohn's disease, ulcerative colitis; or for treating diseases characterized by abnormal growth, including but not limited to cancer, including but not limited to prostate cancer.

[0020] definition

[0021] Certain terms, whether used alone or as part of a phrase or another term, are defined below.

[0022] The articles "a" and "an" refer to one or more than one of the grammatical object of the article.

[0023] Numerical values associated with measurements are subject to measurement error, thereby limiting their accuracy. For this reason, all numerical values provided herein are understood to be modified by the term "about" unless otherwise stated. Therefore, the last decimal place of the numerical values provided herein represents its accuracy. If no other error range is given, when there are no decimals in a given numerical value, the maximum error range is applied by applying rounding rules to the last decimal place or the last significant figure.

[0024] The term "improvement" refers to a reduction in the severity of at least one indicator of a condition or disease, such as a delay or slowing of the progression of one or more indicators of a condition or disease. The severity of an indicator can be determined by subjective or objective measurements known to those skilled in the art.

[0025] The term "composition" refers to a mixture of at least two or more components.

[0026] The terms "effective amount" and "therapeutically effective amount" refer to an amount of a therapeutic compound, combination of compounds, or composition effective to produce the desired therapeutic effect, whether as a single dose or as part of a series of doses. Generally, a therapeutically effective amount can be initially assessed in cell culture assays or in mammalian animal models, such as non-human primates, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in non-human subjects and human subjects.

[0027] The term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, which is involved in transporting or transporting at least one compound described herein in or to a patient so that the compound can perform its intended function. A given carrier must be "acceptable", i.e., compatible with the other ingredients of a particular formulation (including the compounds described herein) and harmless to the patient. Other ingredients that may be included in the pharmaceutical compositions described herein are known in the art and are described, for example, in "Remington's Pharmaceutical Sciences" (Genaro (Ed.), Mack Publishing Co., 1985), the entire contents of which are incorporated herein by reference.

[0028] The term "pharmaceutical composition" refers to a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate administration of the compound or combination to a patient or subject. There are a variety of techniques for administering a compound, combination, or composition, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0029] The terms "treat" or "treating" refer to the application of one or more specific procedures for ameliorating a disease. "Prophylactic" treatment refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of the disease or condition, or reducing the severity of its onset.

[0030] The description of ranges of values herein is intended merely to serve as a shorthand method of individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. Thus, for the recitation of numerical ranges herein, each intervening number between them of equal precision is expressly contemplated. For example, for the range of 6-9, in addition to 6 and 9, the numbers 7 and 8 are also contemplated; and for the range of 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[0031] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended solely to better illustrate the described subject matter and does not limit the scope of the claimed subject matter. No language in this specification should be construed to indicate any non-claimed element essential to the practice of the described subject matter.

[0032] The grouping of the alternative elements or embodiments of the present disclosure should not be construed as limiting. Each group member can be cited and claimed individually or in any combination with other members of the group or other elements herein. In addition, for convenience or patentability reasons, the recorded members in a group can be included in or excluded from another group. When any such inclusion or exclusion occurs, the specification is deemed to include the modified group, thereby meeting the written description of all Markush groups used in the appended claims.

[0033] Throughout this specification, reference has been made to patents and printed publications, each of which is individually incorporated herein by reference in its entirety.

[0034] It should be understood that the embodiments of the present disclosure are illustrative. Therefore, the present disclosure is not limited to what has been shown and described.

[0035] Polymorphic forms

[0036] Provided herein are polymorphic forms of Compound 1. Also provided herein are amorphous forms of Compound 1.

[0037] Thus, in some embodiments, provided herein is a polymorphic form of Compound 1 comprising one or more XRPD signals about 2θ ± 0.2 selected from the group consisting of: 2.8, 4.5, 5.8, 6.4, 7.3, 7.7, 8, 8.9, 9.3, 9.7, 9.9, 10.6, 10.9, 11.5, 11.9, 12.4, 12.8, 13.5, 14.3, 14.6, 14.8, 15.2, 15.8, 17.4, 17.6, 18.5, 18.9, 19.8, 21.8, 22.4, 22.9, 23.3, 24.1, 25, 25.7, 26.1, 26.5, 27.1, 27.9, 28.5, 29.1, or 29.7.

[0038] Thus, in some embodiments, provided herein are polymorphic forms of Compound 1 comprising one or more XRPD signals about 2θ ± 0.2 selected from the group consisting of: 2.8, 4.5, 5.8, 7.3, 7.7, 9.3, 9.7, 9.9, 11.5, 14.6, 17.4, 22.9, 28.5, or 29.7.

[0039] In some embodiments, the polymorphic form of Compound 1 is Form 1, Form 2, Form 3, Form 4, or Form 5.

[0040] In some embodiments, the polymorphic form of Compound 1 is a crystalline form of Compound 1.

[0041] In some embodiments, the polymorphic form of Compound 1 is Form 1 and comprises one or more XRPD signals with respect to 2θ ± 0.2 selected from the group consisting of: 7.3, 11.5, 28.5, or 29.7.

[0042] In some embodiments, the polymorphic form of Compound 1 is Form 2 and comprises one or more XRPD signals with respect to 2θ ± 0.2 selected from the group consisting of: 2.8, 5.8, 9.9, or 22.9.

[0043] In some embodiments, the polymorphic form of Compound 1 is Form 3 and comprises one or more XRPD signals with respect to 2Θ ± 0.2 selected from the group consisting of: 7.7 or 17.4.

[0044] In some embodiments, the polymorphic form of Compound 1 is Form 4 and comprises one or more XRPD signals with respect to 2θ ± 0.2 selected from the group consisting of: 4.5, 9.3, or 9.7.

[0045] In some embodiments, the polymorphic form of Compound 1 is Form 5 and comprises an XRPD signal of 14.6 ± 0.2 2θ.

[0046] Composition

[0047] Provided herein are compositions comprising Compound 1 in one or more polymorphic forms. Thus, in some embodiments, provided herein are pharmaceutical compositions comprising one or more polymorphic forms of Compound 1 and at least one pharmaceutically acceptable carrier. In some embodiments, the composition is a solid composition. In some embodiments, the composition is an implantable composition. In some embodiments, the composition is an inhalable composition. In some embodiments, the composition is an orally ingestible composition. In some embodiments, the composition is an injectable composition. In some embodiments, the composition is a flowable powder composition. In some embodiments, the composition is a liquid composition, including but not limited to a suspension or emulsion of a form of Compound 1. In some embodiments, the composition is a gel, cream, or ointment comprising a form of Compound 1.

[0048] Craftsmanship

[0049] Also provided herein are processes for preparing the polymorphic forms of Compound 1 described herein.

[0050] Thus, in some embodiments, provided herein are methods of preparing a polymorphic form of Compound 1 comprising lyophilizing or crystallizing Compound 1 from a solvent or solvent system as described herein.

[0051] method

[0052] Provided herein are methods of using the polymorphic forms of Compound 1 described herein. In some embodiments, the method comprises administering a form of Compound 1 to a subject.

[0053] Thus, in some embodiments, the polymorphic forms of Compound 1 described herein can be used to treat kinase-related diseases, can be used to inhibit kinases, or can be used to prepare medicaments, including but not limited to on a commercially relevant scale.

[0054] Also provided herein are methods of treating an ocular disease or condition in a subject in need thereof, comprising administering to the subject Compound 1, wherein Compound 1 is in a form provided herein, including Compound 1 in an amorphous form, Form 1, Form 2, Form 3, Form 4, or Form 5 prepared herein, or a composition thereof, which can be a pharmaceutical composition, or any combination thereof, including but not limited to more than one form of Compound 1 provided herein. In some embodiments, Compound 1 can be provided in a purified form, including but not limited to purification by 1, 2, 3, or more repetitions of recrystallization, lyophilization, or a combination thereof.

[0055] In some embodiments, kinase-related diseases or conditions can include JAK1 or TYK2-related diseases or conditions. In some embodiments, diseases or conditions treated by administering the forms of Compound 1 provided herein include eye diseases or conditions (e.g., dry eye, corneal disease, retinal disease, and high intraocular pressure), skin diseases, respiratory diseases or conditions, cardiovascular diseases, and diseases characterized by abnormal growth (e.g., cancer).

[0056] In some embodiments, kinase-associated diseases or disorders may include, but are not limited to, ocular diseases such as glaucoma, ocular hypertension, ocular wound repair, neurodegenerative ocular diseases, retinal detachment, and non-ocular diseases such as neuronal damage or skin wound repair.

[0057] In some embodiments, provided herein are methods of treating dry eye, blurred vision, foreign body sensation, discomfort, irritation, or pain.

[0058] Reagent test kit

[0059] In some embodiments, provided herein are packaged forms, packaged compositions, or packaged pharmaceutical compositions of Compound 1 comprising a container holding a therapeutically effective amount of a form of Compound 1 described herein, and instructions for using the form of Compound 1 according to one or more methods provided herein.

[0060] Compound 1 and its related materials in the form of the present invention can be made into commercial products by the steps commonly performed in the art, such as by appropriate sterilization and packaging steps. For example, at a dose of 25-35 kGy, both electron beams and gamma radiation can effectively sterilize drugs. Alternatively, the material can be treated by UV / vis irradiation (200-500 nm), for example, using photoinitiators (e.g., Irgacure 184, 2959) with different absorption wavelengths, preferably using water-soluble initiators (e.g., Irgacure 2959). This irradiation is generally performed for an irradiation time of 1-60 minutes, but according to a specific method, longer irradiation times can also be applied. The material according to the present disclosure can ultimately be aseptically packaged to maintain sterility until use, and packaged (e.g., by adding a specific product information leaflet) into a suitable container (box, etc.).

[0061] According to further embodiments, the particles of the present invention can also be provided in the form of a kit in combination with other components required for administering the material to a patient. For example, the disclosed kits, such as kits for eye treatment or cancer treatment, can further comprise, for example, administration materials.

[0062] Kits can be designed in a variety of formats based on the specific defect they are designed to treat.

[0063] The form or composition of compound 1 provided herein can be prepared and placed in a container to store at ambient temperature or an elevated temperature. Compared to, for example, a polyvinyl chloride plastic container, when the form or composition of compound 1 is stored in a polyolefin plastic container, whether it is suspended in a liquid composition (for example, aqueous or organic liquid solution), or as a solid, the discoloration of the form (for example, the compound in the particle) or the composition can be reduced. Without being bound by theory, the container can reduce the exposure of the container contents to electromagnetic radiation, whether it is visible light (for example, a wavelength of about 380-780nm) or ultraviolet (UV) light (for example, a wavelength of about 190-320nm (UV B light) or about 320–380nm (UV A light)). Some containers also include the ability to reduce the exposure of the container contents to infrared light, or a second component with such ability. Some containers further have the ability to reduce the exposure of the container contents to heat or moisture. Useful containers include containers made of polyolefins, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutylene or a combination thereof, especially polyethylene, polypropylene or a combination thereof. In some embodiments, the container is a glass container, including but not limited to an amber glass container. The container can be further arranged in a second container, such as a paper container, a cardboard container, a paperboard container, a metal film container or a foil container or a combination thereof, to further reduce the exposure of the container contents to UV, visible light or infrared light. Products including dosage forms comprising compound 1 forms or compositions described herein benefit from reduced discoloration, decomposition or both during storage. Compound 1 forms or compositions provided herein may need to be stored for up to or more than three months; in some cases, may need to be stored for up to or more than one year. The container can be in any form suitable for containing the contents - for example, a bag, bottle or box, or any combination thereof.

[0064] The compounds and methods of the present invention will be better understood with reference to the following examples, which are intended to illustrate, but not to limit, the scope of the invention.

[0065] Example

[0066] Unless otherwise stated, the following instruments and methods were used in the following examples.

[0067] Instruments and methods

[0068] X-ray powder diffraction (XRPD): Bruker AXSD8 Advance. XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Kα irradiation (40 kV, 40 mA) in reflection geometry and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit with a 2.5° Soller slit followed by a Lynxeye detector. The software used for data collection was Diffrac Plus XRDCommander and for data analysis was HighScore Plus. The samples were run under ambient conditions as flat plate specimens using the received powder. The samples were prepared on polished zero-background (510) silicon wafers by gently pressing onto a flat surface or filling into a cut cavity. The sample was rotated in its own plane. Details of the standard data collection method are: angular range: 2-42° 2θ; step size: 0.05° 2θ; collection time: 0.5 s / step (total collection time: 6.40 min).

[0069] X-ray powder diffraction (XRPD): PANalytical Empyrean. XRPD diffractograms were collected in transmission geometry on a PANalytical Empyrean diffractometer using Cu Kα irradiation (45 kV, 40 mA). A 0.5° slit, a 4 mm mask, and a 0.04 rad Soller slit with a focusing mirror were used on the incident beam. A PIXcel placed on the diffracted beam 3D The detector is equipped with a receiving slit and a 0.04rad Soller slit. The software used for data collection is an X'Pert data collector using X'Pert Operator Interface. HighScore Plus is used to analyze and present the data. Samples are prepared and analyzed in metal or Millipore 96-well plates in transmission mode. X-ray transparent film is used between the metal sheets on the metal well plates, and powder (about 1-2 mg) is used as is. Millipore plates are used to separate and analyze solids from the suspension by adding a small amount of suspension directly to the plate before filtering under a light vacuum. The scanning mode of the metal plate uses an angular scanning axis, while the Millipore plate uses a 2θ scan. Details of the standard screening data collection method are: angle range: 2.5 to 32.0°2θ; step size: 0.0130°2θ; and collection time: 12.75s / step (total collection time is 2.07min).

[0070] The software used for data collection was X'Pert Data Collector, and the data were analyzed and presented using Highscore Plus.

[0071] Nuclear Magnetic Resonance (NMR): Solution-state NMR. 1 H NMR, 13 C NMR and / or 19 F NMR spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by an Avance NEO nanobay console. Unless otherwise stated, samples were prepared in DMSO-d6 solvent. The ICON-NMR configuration in Topspin software was used, using a standard Bruker-loaded experiment ( 1 H, 13 C{ 1 Automated experiments were obtained using the ACD Spectrus Processor.

[0072] Differential Scanning Calorimetry (DSC): TA Instruments Q2000. DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5-3 mg of each sample was placed in a pinhole aluminum pan and heated from 25°C to 300°C at 10°C / min. The sample was purged with 50 mL / min of dry nitrogen. Modulated temperature DSC (MDSC) was performed using a base heating rate of 2°C / min and a temperature modulation parameter of ±0.636°C (amplitude) per 60 seconds (cycle). The instrument control software was Advantage for Q Series and Thermal Advantage, and data analysis used Universal Analysis or TRIOS.

[0073] Differential Scanning Calorimetry (DSC): TA Instruments Discovery DSC. DSC data were collected using a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, 0.5-3 mg of each sample was placed in a pinhole aluminum pan and heated from 25°C to 300°C at 10°C / min. The sample was purged with dry nitrogen at 50 mL / min. The instrument was controlled by TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0074] Thermogravimetric analysis (TGA): TA Instruments Q500. TGA data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. Typically, 5-10 mg of each sample was placed in a pre-weighed aluminum DSC pan and heated from room temperature to 350°C at 10°C / min. A nitrogen purge was continuously applied to the sample at a flow rate of 60 mL / min. The instrument was controlled by Advantage for QSeries and Thermal Advantage software, and data were analyzed using Universal Analysis or TRIOS.

[0075] Thermogravimetric analysis (TGA): TA Instruments Discovery TGA. TGA data were collected using a TA Instruments Discovery TGA equipped with a 25-position autosampler. Typically, 5-10 mg of each sample was placed in a pre-weighed aluminum DSC pan and heated from room temperature to 350°C at 10°C / min. A nitrogen purge was continuously applied to the sample at a flow rate of 25 mL / min. The instrument was controlled by TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0076] Polarized Light Microscopy (PLM): Leica LM / DM polarizing microscope. Samples were analyzed using a Leica LM / DM polarizing microscope equipped with a digital video camera for image capture. A small amount of each sample was placed on a glass slide with or without immersion oil and covered with a glass cover. Samples were observed using appropriate magnification and partially polarized light with a λ false color filter. Images were captured using StudioCapture or Image ProPlus software.

[0077] Scanning electron microscopy (SEM). Data were collected using a Phenom Pro scanning electron microscope. A small sample was mounted on a short aluminum tube using conductive double-sided tape. A thin layer of gold was applied using a sputter coater (20 mA, 120 s).

[0078] Gravimetric Vapor Sorption (GVS): SMSDVS Intrinsic. The adsorption isotherm was obtained using a SMSDVS Intrinsic moisture sorption analyzer controlled by DVS IntrinsicControl software. The instrument control maintained the sample temperature at 25°C. Humidity was controlled by a mixed dry and wet nitrogen flow with a total flow rate of 200 mL / min. The relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0-100% RH) located near the sample. The weight change (mass relaxation) of the sample as a function of %RH was continuously monitored by a microbalance (accuracy ± 0.005 mg). Typically, 5-30 mg of sample was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25°C (typically room temperature conditions). The moisture sorption isotherm was performed as described below (2 scans per complete cycle). The standard isotherm was performed at 25°C, 0-90% RH at 10% RH intervals. Typically, a double cycle (4 scans) was performed. Data analysis was performed in Microsoft Excel using the DVS analysis suite. Typically, samples were recovered after completion of the isotherm and reanalyzed by XRPD.

[0079] Table 1. Method parameters for SMSDVS Intrinsic experiments.

[0080]

[0081]

[0082] Chemical purity was determined by high-performance liquid chromatography (HPLC). Purity analysis was performed on an Agilent HP1100 / Infinity II 1260 Series system equipped with a diode array detector using OpenLAB software. Full method details are provided in Table 2.

[0083] Table 2. HPLC method used for chemical purity determination.

[0084]

[0085] Liquid chromatography mass spectrometry (LC-MS). LC-MS data were collected using an Agilent 1260 equipped with a PDA and iQ mass spectrometer (single quadrupole, electrospray ionization (ESI)). Samples (approximately 1 mg) were dissolved in a 50:50 acetonitrile:water (1 mL) solution to give a final concentration of approximately 1 mg / mL. LC-MS method details are shown in Table 3. Data were processed using total ion count (TIC) chromatograms in positive and negative ion modes. Mass spectra were extracted for each peak at the peak apex, and the recorded ions were identified where possible.

[0086] Table 3. LC-MS method parameters.

[0087]

[0088]

[0089] Water was determined by Karl Fischer titration (KF). The water content of each sample was measured at 150°C using an 851 Titrano coulometer on a Metrohm 874 oven sample processor using a Hydranal Coulomat AG oven reagent and a nitrogen purge. Weighed solid samples were introduced into sealed sample vials. Approximately 10 mg of sample was used for each titration, and replicates were performed. Unless otherwise stated, the average values of the results are shown. Data collection and analysis were performed using Tiamo software.

[0090] Thermodynamic aqueous solubility. Aqueous solubility is determined by suspending enough compound in the relevant medium to obtain a maximum final concentration of ≥10 mg / mL of the parent compound free form. The suspension is equilibrated at 37°C for 24 hours on a Heidolph plate shaker set at 750 rpm. The pH of the saturated solution is then measured, and the suspension is centrifuged (13,400 rpm, 2 minutes), then filtered through a glass fiber C filter (particle retention 1.2 μm) and appropriately diluted. Quantification is performed by HPLC with reference to a standard solution of approximately 0.15 mg / mL in DMSO. Different volumes of standard diluted and undiluted sample solutions are injected. Solubility is calculated by integrating the peak area determined by the peak at the same retention time as the main peak in the standard injection. Analysis was performed using OpenLAB software on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector.

[0091] Table 4. HPLC method used for solubility measurements.

[0092]

[0093] Ion chromatography (IC) was performed using IC MagicNet software on a Metrohm 930 Compact IC Flex equipped with an 858 Professional autosampler and an 800 Dosino dosage unit monitor. Accurately weighed samples were prepared as stock solutions in appropriate solvents. Quantification was achieved by comparison with standard solutions of known concentrations of the ion being analyzed. Analyses were performed in duplicate, and unless otherwise stated, the average value is given.

[0094] Table 5. IC method for cation chromatography.

[0095]

[0096]

[0097] Table 6. IC method for anion chromatography.

[0098]

[0099] Fourier transform infrared spectroscopy (FTIR) was performed on a Perkin-Elmer Spectrum 3 equipped with a universal ATR sampling accessory using a 1 Bounce diamond / ZnSe crystal. 16 scans were collected from 4000 to 650 cm -1 Data were collected using Spectrum IR software and processed using an ACD Spectrus processor.

[0100] Static stability tests. Unless otherwise stated, solid materials were placed in open vials under elevated storage conditions. These conditions were achieved using saturated salt solutions at the specified temperature in sealed containers. The storage containers were pre-equilibrated prior to sample placement.

[0101] Table 7. Saline solutions used to generate static storage conditions.

[0102]

[0103] Freeze Dryer: Telstar Lyoquest. Samples were freeze-dried using a Telstar Lyoquest laboratory freeze dryer with a condenser temperature of -85°C, using a pressure of less than 10 mbar. The solution to be freeze-dried was first filtered through a 0.45 μm nylon filter and then flash-frozen using dry ice / acetone. The frozen sample was then connected to the freeze dryer and freeze-dried for approximately 20 hours. Direct contact between the sample container and the surrounding environment provided the thermal energy required for freeze-drying.

[0104] Example 1. Preparation of Form 1 of Compound 1

[0105] The solution solvent of compound 1 in dichloromethane is exchanged with isopropanol. Isopropanol and water are added to provide 15 volumes of isopropanol / water (80:20) mixture. The mixture is then heated to 80°C until completely dissolved. The mixture is then cooled to 65°C under stirring and 2.5% by weight of seed crystals are added. The mixture is then cooled to about 10°C over 4h and stirred for another 16h. The solid is filtered, the filter cake is washed with isopropanol (2 volumes), and then dried in a vacuum oven at 50°C. This gives compound 1 as a gray-white solid. The final drug substance is non-hygroscopic and is packaged at a temperature of ≤25°C. Melting point: 212°C. 1HNMR(600MHz,DMSO-d6)δ8.76(s,1H),7.76(s,1H),7.67(s,1H),7.44(s,1H),5.20(dtd,J=56.4,6.5,3.5 Hz,1H),4.10(dd,J=21.9,8.0Hz,4H),3.77(s,3H),3.48(ddd,J=16.5,10.4,6.3Hz,1H),3.04(d,J=2.1Hz, 2H),2.90(dt,J=10.1,5.0Hz,2H),2.69(d,J=10.7Hz,1H),2.33(dtd,J=12.9,9.8,8.5,3.9Hz,2H),2.29– 2.18(m,2H),2.03(s,3H),1.99(t,J=10.0Hz,1H),1.91(ddd,J=27.1,13.7,5.3Hz,1H),1.68–1.54(m,1H).

[0106] Example 2. Solubility of Form 1 of Compound 1

[0107] Compound 1 Form 1 was determined to be insoluble or poorly soluble in the following solvents or solvent systems: methanol; ethanol; 1-propanol; 2-propanol (IPA); acetonitrile; acetone; methyl ethyl ketone (MEK) (2-butanone); methyl isobutyl ketone (MIBK); 2-methylTHF; tetrahydrofuran (THF); toluene; ethyl acetate; isopropyl acetate; heptane; tert-butyl methyl ether (TBME); 2-methyl-1-propanol (isobutanol); 1-butanol; methanol / water (5% v / v); ethanol / water (5% v / v); IPA / water (5% v / v); acetone / water (10% v / v); ACN / water (1:2 v / v); THF / water (30% v / v); and water. Compound 1 Form 1 was determined to be slightly soluble in 1,4-dioxane or nitromethane, and more soluble in dichloromethane (DCM) and dimethyl sulfoxide (DMSO).

[0108] Surprisingly, when suspended in nitromethane at 50° C., cooled to 5° C., and then filtered, the purity of Form 1 of Compound 1, as assessed by HPLC, was found to increase from 98.8% with four impurities >0.1% to 99.3% with two impurities >0.1%. XRPD analysis confirmed that the solid form of Compound 1 remained in Form 1 before and after this purification process sequence.

[0109] Form 1 of Compound 1 can be rendered amorphous by dissolution in warm 1:1 acetonitrile:water followed by freeze drying.

[0110] Example 3. Characterization of Form 1 of Compound 1 from Example 1.

[0111] Table 8. Characterization data for Form 1 of Compound 1.

[0112]

[0113]

[0114] Example 4. Characterization of Amorphous Compound 1

[0115] Table 9. Characterization data of amorphous Compound 1.

[0116]

[0117] Regardless of the conditions (25°C / 97% RH or 40°C / 75% RH), the amorphous material is unstable under static storage conditions and will convert to a less crystalline material, i.e., XRPD shows pattern 1 (e.g., crystallized or rearranged to Form 1 of Compound 1) or pattern 5 of Compound 1 (Form 5).

[0118] Example 5. Preparation of Compound 1 Polymorph

[0119] Polymorph screening starting with amorphous Compound 1 resulted in material with four new XRPD patterns (Pattern 2, Pattern 3, Pattern 4, and Pattern 5). An overview of the polymorph screening results is provided in Table 10.

[0120] Isothermal slurry (cold slurry) at 5°C. A stirring bar was added to each HPLC vial, and an aliquot of one of the solvents or solvent systems was added as follows. Approximately 31-32 mg of amorphous compound 1 was combined with 5 vol (160 μL) or 10 vol (320 μL) of solvent and then stirred at 5°C, 500 rpm for approximately 24 hours. Due to the high melting point of the solvent, the samples in 1,4-dioxane and DMSO were stirred at 25°C. After the initial treatment period, all samples were suspensions. An aliquot of each suspension was pipetted onto an XRPD plate, the solvent evaporated, and the solid material was analyzed by XRPD. For XPRD analysis of samples containing THF or 2-MeTHF, an aliquot was pipetted onto a glass slide, the solvent evaporated, and the solid was then transferred to the XRPD plate.

[0121] Maturation. A stirring bar was added to each HPLC vial and an aliquot of one of the solvents or solvent systems was added as follows. Approximately 31-32 mg of amorphous compound 1 was combined with 5 vol (160 μL) or 10 vol (320 μL) of solvent and then shaken in a aging chamber, cycling between room temperature and 50°C every four hours for approximately 24 hours. After the initial treatment period, all samples were suspensions, except for the sample containing DMSO solvent, which became a clear solution after 1 day. The sample was matured for another 4 days, at which point the sample had formed a suspension. An aliquot of each suspension was pipetted onto an XRPD plate, the solvent evaporated, and the solid material analyzed by XRPD. For XPRD analysis of samples containing THF or 2-MeTHF, an aliquot was pipetted onto a glass slide, the solvent evaporated, and the solid was then transferred to the XRPD plate.

[0122] Isothermal slurry (hot slurry) at 50°C. A stirring bar was added to each HPLC vial and an aliquot of one of the solvents or solvent systems was added as follows. Approximately 31-32 mg of amorphous compound 1 was combined with 5 vol (160 μL) or 10 vol (320 μL) of solvent and then stirred at 50°C, 500 rpm for approximately 21 hours. After the initial treatment period, all samples were suspensions, except for the sample containing DMSO solvent, which became a clear solution after 1 day. The sample was continued to stir at 50°C for 5 days, at which time the sample had formed a suspension. An aliquot of each suspension was pipetted onto an XRPD plate, the solvent evaporated, and the solid material was analyzed by XRPD. For XPRD analysis of samples containing THF or 2-MeTHF, an aliquot was pipetted onto a glass slide, the solvent evaporated, and the solid was then transferred to the XRPD plate.

[0123] Table 10. Polymorph screening of amorphous Compound 1.

[0124]

[0125]

[0126]

[0127] The material represented by spectrum 2 was produced by cold slurry, hot slurry and aging technology. Surprisingly, the material found to be spectrum 3 by XRPD was prepared only by cold slurry technology. In the hot slurry and aging screening, samples containing materials with spectrum 4 were prepared only from heptane. Finally, materials represented by spectrum 5 based on XRPD were prepared by aging screening in methanol / water (5% v / v) and by hot slurry in methanol / water (5% v / v) or ethanol / water (5% v / v). There is also a sample that is a mixture of spectrum 5 and spectrum 1 obtained from water. Spectrum 5 was also observed after static storage of an amorphous sample of compound 1 at 25°C / 97%RH for 6 days.

[0128] As shown in Table 11, the purity of the Graph 1 samples under various conditions can be improved relative to the purity of the sample from Example 1.

[0129] Table 11. Comparison of the purity of samples of chromatogram 1 under different preparation conditions.

[0130]

[0131] This purity analysis showed that the process of preparing the amorphous material followed by treatment in a solvent to produce a material having pattern 1 by XRPD improved the purity of the material. In particular, the presence of ACN in the solvent appeared to produce the best improvement in purity.

[0132] Samples with each new pattern were selected for isolation and characterization by XRPD. Isolation was performed by air drying the samples on filter paper or by filtering the samples through a small glass frit under positive pressure and then drying under vacuum for approximately 1 hour.

[0133] After separation, the sample originally identified as having pattern 2 was found to have converted to material having pattern 1. A second sample was isolated, but again found to have converted to pattern 1. Therefore, pattern 2 was determined to be unstable and was not further characterized. Figure 3 shown.

[0134] use 1 The isolated stable Forms 1, 3, 4, and 5 of Compound 1 were characterized by H NMR spectroscopy, thermal analysis, purity analysis, and static storage at 40°C / 75% RH for 6 days. A comparison of the results and subsequent material assignments is shown in Table 12. The data can be found in Data Section 6 - Characterization of New Spectra.

[0135] Table 12.

[0136]

[0137]

[0138] Form 3-dry was prepared by dissolving amorphous Compound 1 in ACN:water 1:2 v / v and then stirring at 5° C. to obtain crystalline material. Form 3-dry (Pattern 3) was crystalline and had a high purity of 99.5% with only one major impurity present. 1 The H NMR spectrum was consistent with the starting material, with no traces of ACN solvent. DSC analysis showed a broad endotherm at 68.9°C, likely due to solvent loss, followed by a large endotherm at 147.9°C and a sharp endotherm at 215.9°C (consistent with a melt of Form 1). TGA showed an 11.4% weight loss before 105°C, consistent with the loss of approximately 3 equivalents of water. The solid form remained unchanged after storage at 40°C / 75% RH for 6 days and retained its chemical integrity at a high purity of 99.4%. Spectrum 3 appears to be a hydrated form, which potentially converts to anhydrous Form 1 material above 147.9°C.

[0139] Form 4-dry was prepared by suspension of amorphous Compound 1 in heptane followed by a maturation cycle between 5° C. and 50° C. to obtain crystalline material. Form 4-dry (Pattern 4) was a crystalline material and had good purity (98.8%). 1 The HNMR spectrum was consistent with the starting material, with a slight trace of heptane solvent. DSC analysis showed a small endotherm at 181.5°C and an exotherm at 184.8°C (possibly indicating recrystallization / form conversion), as well as a sharp endotherm at 216.5°C (consistent with a melt of Form 1). TGA showed no weight loss before the onset of degradation. The sample was stable under storage conditions, maintaining Mode 4 for 6 days at 40°C / 75% RH with a purity of 98.9%. Mode 4 appears to be the anhydrous form, which potentially converts to anhydrous Form 1 above 184.8°C.

[0140] Form 5-dry was prepared by suspension of amorphous Compound 1 in methanol:water 5% v / v, followed by a maturation cycle between 5° C. and 50° C. to obtain crystalline material. Form 5-dry (Pattern 5) was shown by XRPD to be crystalline and to have a high purity of 99.1%. 1 The H NMR spectrum was consistent with the starting material, with no traces of methanol solvent. DSC analysis showed a broad double endotherm at 61.4°C, followed by a large exotherm at 142.3°C and a sharp endotherm at 215.2°C (consistent with the melt of Form 1 material from Example 1). TGA showed a 9.6% weight loss before 103.1°C, consistent with the loss of approximately 2.5 equivalents of water. Upon storage at 40°C / 75% RH for 6 days, the sample partially converted to Form 1 and maintained a high purity of 99.0% under these accelerated storage conditions. Spectrum 5 appears to be a hydrated form that loses water before the exothermic event that may have led to Form 1, which then melts.

[0141] In summary, from the polymorph screening, materials with novel patterns by XRPD were obtained.

[0142] For example, Form 3 of Compound 1 obtained from a cold slurry in ACN:water 1:2 v / v (Pattern 3) is likely the trihydrate, with the highest purity and good stability of the new pattern.

[0143] For example, Form 4 of Compound 1 obtained from the maturation screening in heptane (Figure 4) is likely anhydrous and has good stability. However, some trace amounts of solvent remain, and the purity of this material is not significantly increased compared to Form 1 of Compound 1 from Example 1.

[0144] For example, Form 5 of Compound 1 (Pattern 5) obtained from the maturation screen in methanol:water 5% v / v is likely a hydrate with increased purity compared to Form 1 of Compound 1 from Example 1. However, Pattern 5 was unstable on storage at 40°C / 75% RH and partially converted to the same form as Form 1 of Compound 1 from Example 1.

[0145] Purity analysis was performed on samples selected from the polymorph screen by XRPD showing pattern 1. The lyophilization and screening conditions appeared to slightly improve the purity of these materials compared to Form 1 of Compound 1 from Example 1.

[0146] In particular, the solvent ACN appears to produce samples of increasing purity; this is observed both for the slightly increased purity of the sample of Spectrum 1 where the solvent contained ACN and for the high purity of Form 3-dried (Spectrum 3) obtained from ACN:water 1:2 v / v.

[0147] Amorphous Compound 1 was successfully prepared by lyophilization from ACN: water 1: 1 solvent and was found to have good purity (99.0%) and no significant traces of solvent. Therefore, this method was selected as being useful, for example, for producing large quantities of amorphous Compound 1 on a commercially relevant scale. However, melt-quench cooling mDSC analysis of crystalline Form 1 of Compound 1 showed that amorphous material could also be prepared by heating the sample to approximately 220°C and then rapidly cooling it in an ice bath.

[0148] A polymorphic screen was performed using amorphous Compound 1 and the original 28 process-acceptable solvent systems under three conditions: slurry at 5°C, aging cycles between 5°C and 50°C, and slurry at 50°C. While many materials resulting from the screen had patterns identical to Form 1 of Compound 1, materials with four new patterns by XRPD were obtained. After isolation, only three of the four materials retained their original new XRPD patterns, while one converted to having pattern 1 after isolation.

[0149] Table 13 includes a list of XRPD diffractogram signals for Form 1 of Compound 1; the corresponding XRPD diffractogram is shown in Figure 4 Table 14 includes a list of XRPD diffractogram signals for Form 2 of Compound 1; the corresponding XRPD diffractogram is shown in Figure 5 Table 15 includes a list of XRPD diffractogram signals for Form 3 of Compound 1; the corresponding XRPD diffractogram is shown in Figure 6 Table 16 includes a list of XRPD diffractogram signals for Form 4 of Compound 1; the corresponding XRPD diffractogram is shown in Figure 7 Table 17 includes a list of XRPD diffractogram signals for Form 5 of Compound 1; the corresponding XRPD diffractogram is shown in Figure 8 middle.

[0150] Table 13. Form 1 of Compound 1.

[0151]

[0152] Table 14. Form 2 of Compound 1.

[0153]

[0154]

[0155] Table 15. Form 3 of Compound 1.

[0156]

[0157] Table 16. Form 4 of Compound 1.

[0158]

[0159]

[0160] Table 17. Form 5 of Compound 1.

[0161]

[0162] Example 6: ROCK and JAK assays

[0163] ROCK kinase inhibition assay

[0164] All compounds were initially prepared as 10 mM stock solutions in anhydrous dimethyl sulfoxide (DMSO). A 20 μL aliquot of the 10 mM solution was transferred to each well in column 1 of a 96-well polypropylene microtiter plate (Corning #3363) and diluted with DMSO to a final compound concentration of 4 mM. Test compounds were then serially diluted 1:5 in DMSO to obtain an 11-point concentration response and further diluted in assay buffer to achieve a final range of 100 μM to 10 pM for all compounds in 2.5% DMSO. Assays were performed in a white 96-well, flat-bottom, half-area, non-binding assay plate (Corning #3642) in assay buffer consisting of 20 mM HEPES (pH 7.5), 10 mM MgCl2*6H2O, 100 μM sodium orthovanadate, 0.05% CHAPS, and 0.1% bovine serum albumin. To all wells, 10 μL of aliquoted compound from each well of the intermediate dilution plate and 20 μL of a 2X substrate / enzyme solution containing a receptor substrate (800 nM RSK2 peptide 10-mer with a MW of 1242.5, e.g., product number SRP0687 from Sigma-Aldrich), ROCK2 enzyme (10 nM) or ROCK1 enzyme, and 1,4-dithiothreitol (DTT, 2 μM) were added. The reaction was initiated by adding 10 μL of 4x stock solution ATP (2 μM). The reaction was mixed thoroughly by hand, capped, and incubated at room temperature for 75 minutes. Protein kinase activity was quantified using Promega's KINASE-GLOTM Luminescent Kinase Assay Kit according to the manufacturer's instructions. The ATP concentration remaining in the test well after termination of the enzymatic reaction was compared to a control well (CTRL) containing an equal amount of DMSO and no inhibitor. The ATP concentration in both the test and CTRL wells was normalized to the background (BKG) ATP concentration in wells containing a concentration of inhibitor that completely inhibited the protein kinase under investigation (i.e., a concentration that prevented any depletion of ATP during the incubation process). The percent control (POC) value for each concentration of test compound was determined according to the following equation:

[0165] POC=((test hole value-BKG) / (CTRL-BKG))*100

[0166] IC 50 Values are calculated using the following 4-parameter logistic curve fitting algorithm:

[0167] f(x)=(A+((BA) / (1+((x / C)^D))))

[0168] Use the following Cheng-Prusoff equation to convert IC 50 The value is converted to Ki value:

[0169] Ki =IC 50 / (1+([ATP] / Km ATP])).

[0170] The forms of Compound 1 described herein, such as the polymorph in Example 5, inhibit the assayed kinases at commercially or therapeutically relevant levels.

[0171] JAK kinase assay

[0172] In addition to the substrate and enzyme, the compound is prepared in exactly the same manner as described in the ROCK kinase assay. The JAK2X substrate / enzyme solution contains a receptor substrate (800 nM Abl peptide 12-mer with a MW of 1336.5, such as product number BML-P216-0001 from Enzo LifeSciences), a JAK1, TYK2, JAK2 or JAK3 enzyme (10 nM) and DTT (2 uM). All other steps and solutions remain the same as those in the above-mentioned ROCK kinase assay. Forms of compound 1 described herein, such as the polymorphs in Example 5, inhibit the kinases measured at commercial or therapeutically relevant levels.

[0173] Example 7. PTM-HTM Assay

[0174] Porcine trabecular meshwork cells (PTM) were isolated from freshly obtained, enucleated porcine eyes. Immortalized human trabecular meshwork cells (TM-1) were obtained through a donation from Donna Peters, Department of Ophthalmology and Visual Sciences, University of Wisconsin. Cells were seeded onto fibronectin-coated glass-bottom 96-well plates and allowed to attach overnight. The culture medium was removed and replaced with the test compound in culture medium containing 1% fetal bovine serum and incubated for various times. Following incubation, the cells were formaldehyde-fixed, Triton-solubilized, and stained. PTM cells were stained with Alexa Fluor. 488 phalloidin (F-actin) and Hoechst 33342 (nucleus) staining. TM-1 cells were stained with anti-paxillin and then stained with Alexa 488 goat anti-mouse IgG (focal adhesion) and Hoechst33342 (nucleus) staining. All staining reagents were provided by Invitrogen. Images were collected on an INCell 2200 imager with a 20X objective. The actin fiber length and total area of focal adhesions were analyzed using a custom algorithm developed in InCell Developer Toolbox v1.9.3. The collected data were converted to a percentage of the control (untreated cells). The curve was fitted to the data in GraphPad Prizm using a sigmoidal dose-response and limiting the top and bottom to 100% and 0%, respectively. The forms of compound 1 described herein, such as the polymorph in Example 5, improve actin fiber length or the total area of focal adhesions at commercial or therapeutically relevant levels.

[0175] Example 8. Treatment

[0176] A topical ophthalmic pharmaceutical composition comprising a form of Compound 1 described herein, such as the polymorph in Example 5, is prepared for the treatment of inflammation or dry eye. When this composition is topically applied once daily to one or both eyes of a subject, the composition reduces ocular inflammation in the eyes of a subject with meibomian gland dysfunction (MGD) or DED.

Claims

1. A solid form of a compound, wherein the compound is 2. The solid form of claim 1, which is a crystalline solid form 3. The solid form of claim 1, which is a solid form precipitated or crystallized from at least one solvent.

4. The solid form of claim 1 which is a lyophilized amorphous solid form.

5. The solid form of claim 1, which is purified.

6. The solid form of claim 1 , comprising one or more XRPD signals about 2θ ± 0.2 selected from the group consisting of: 2.8, 4.5, 5.8, 6.4, 7.3, 7.7, 8, 8.9, 9.3, 9.7, 9.9, 10.6, 10.9, 11.5, 11.9, 12.4, 12.8, 13.5, 14.3, 14.6, 14.8, 15.2, 15.8, 17.4, 17.6, 18.5, 18.9, 19.8, 21.8, 22.4, 22.9, 23.3, 24.1, 25, 25.7, 26.1, 26.5, 27.1, 27.9, 28.5, 29.1, or 29.

7.

7. The solid form of claim 1, comprising one or more XRPD signals about 2θ ± 0.2 selected from the group consisting of: 2.8, 4.5, 5.8, 7.3, 7.7, 9.3, 9.7, 9.9, 11.5, 14.6, 17.4, 22.9, 28.5, or 29.

7.

8. The solid form of claim 1, which is a polymorphic form selected from Form 1, Form 2, Form 3, Form 4, or Form 5.

9. The solid form of claim 1 which is Form 1 and comprises one or more XRPD signals about 2θ ± 0.2 selected from the group consisting of: 7.3, 11.5, 28.5, or 29.

7.

10. The solid form of claim 1 which is Form 2 and comprises one or more XRPD signals about 2θ ± 0.2 selected from the group consisting of: 2.8, 5.8, 9.9, or 22.

9.

11. The solid form of claim 1 which is Form 3 and comprises one or more XRPD signals about 2θ ± 0.2 selected from the group consisting of: 7.7 or 17.

4.

12. The solid form of claim 1 which is Form 4 and comprises one or more XRPD signals about 2θ ± 0.2 selected from the group consisting of: 4.5, 9.3, or 9.

7.

13. The solid form of claim 1 which is Form 5 and comprises an XRPD signal of 14.6 ± 0.2 2Θ.

14. The solid form of claim 1 having an XRPD pattern substantially as shown in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, or Figure 8.

15. The solid form of claim 1 , prepared by a process comprising lyophilizing or crystallizing from at least one solvent one or more of the following compounds:

16. A composition comprising the solid form of any one of claims 1 to 15 and at least one carrier.

17. The composition of claim 16, comprising the solid form of claim 1 having a purity of at least 99% EE.

18. The composition of claim 16 or 17, which is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier.

19. The composition of any one of claims 16-18, in the form of a solid (e.g., an implant or flowable powder, injectable, ingestible, or inhalable), liquid (e.g., a suspension, emulsion, injectable, ingestible, or inhalable), gel, cream, or ointment.

20. A method comprising administering to a subject the solid form of any one of claims 1-15 or the composition of any one of claims 16-19.

21. The method of claim 20, which is a therapeutic method in a subject in need thereof.

22. A method of inhibiting a kinase comprising contacting the kinase with the solid form of any one of claims 1-15 or the composition of any one of claims 16-19.

23. The method of claim 22, which is an in vivo method.

24. The method of claim 22, which is an in vitro method.

25. A method of treating a kinase-related disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the solid form of any one of claims 1-15 or the composition of any one of claims 16-19.

26. A method of treating dry eye in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the solid form of any one of claims 1-15 or the composition of any one of claims 16-19.

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