Polymorphisms of JAK1 / TYK2 inhibitors and uses thereof

Abstract

Provided herein are solid forms, e.g., 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 are useful for treating 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 nerve injury, or skin wound repair, or inflammatory diseases, among others. (Compound 1) TIFF2026501674000028.tif4839

Description

[Technical Field]

[0001] Related Applications 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.

[0002] Technical Field The present disclosure relates to solid forms, e.g., 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 are useful for treating kinase-associated diseases or disorders, such as JAK1 or TYK2-associated diseases or disorders. These include ophthalmic diseases or disorders (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, such as cancer. [Background technology]

[0003] background Dry eye disease (DED) is a multifactorial disorder in which the eye responds to minor irritation with abnormal sensations 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) can be used to treat DED. [ka]

[0004] Stable solid forms of Compound 1 and compositions thereof having high purity Compound 1 have been discovered. The stability of the active agent is useful for withstanding the various stresses of manufacturing so that the resulting administrable article of manufacture contains the active agent of pharmaceutically acceptable purity. A high purity active agent is useful, for example, to avoid administering to a subject by-products of the active agent resulting from the manufacturing process.

[0005] Thus, provided herein are polymorphic forms of Compound 1, methods useful for their preparation, including preparation in high purity, compositions comprising such forms, and therapeutic uses thereof. Summary of the Invention [Means for solving the problem]

[0006] overview In some embodiments, provided herein are forms of Compound 1, including solid forms such as polymorphic forms.

[0007] Also disclosed are pharmaceutical compositions comprising the polymorphic form and methods of using the polymorphic form for the treatment of kinase-related diseases or disorders. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of Form 1 of Compound 1.

[0009] [Figure 2] FIG. 2 shows the XRPD patterns of polymorphs of Compound 1 prepared in the same manner as in the Examples.

[0010] [Figure 3] FIG. 3 shows the XRPD patterns of polymorphs of Compound 1 prepared similarly to the Examples.

[0011] [Figure 4] FIG. 4 shows the XRPD pattern of polymorphic Form 1 of Compound 1 listed in Table 13.

[0012] [Figure 5] FIG. 5 shows the XRPD pattern of polymorphic Form 2 of Compound 1 listed in Table 14.

[0013] [Figure 6] FIG. 6 shows the XRPD pattern of polymorphic Form 3 of Compound 1 listed in Table 15.

[0014] [Figure 7] FIG. 7 shows the XRPD pattern of polymorphic Form 4 of Compound 1 listed in Table 16.

[0015] [Figure 8] FIG. 8 shows the XRPD pattern of polymorphic Form 5 of Compound 1 listed in Table 17. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description Provided herein are polymorphic forms of Compound 1. Compound 1 can be prepared, for example, by the synthesis described in WO2023279105A1, including but not limited to Scheme 7, the entire contents of which are incorporated herein by reference.

[0017] Solid or polymorphic forms of Compound 1 can be used to treat or prevent kinase-related diseases or disorders. In some embodiments, this includes ophthalmic diseases or disorders such as dry eye, corneal injury, retinitis, and ocular hypertension, 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, solid or polymorphic forms of the compounds described herein are useful for treating ophthalmic diseases, including but not limited to, non-infectious uveitis, non-infectious chorioretinitis, iritis, aseptic conjunctivitis, keratitis, episcleritis, dry eye disease, meibomian gland dysfunction, allergic conjunctivitis, glaucoma, or retinal diseases; as anti-inflammatory agents; for treating skin diseases; for treating cardiovascular diseases; for treating autoimmune disorders, including but not limited to, rheumatoid arthritis, Crohn's disease, and ulcerative colitis; or for treating diseases characterized by abnormal growth, including but not limited to, cancer, including but not limited to, prostate cancer.

[0018] definition Certain terms, whether used alone or as part of a phrase or another term, are defined below.

[0019] The articles "a" and "an" refer to one or to more than one of the grammatical object of the article.

[0020] Numerical values ​​relating to measurement are subject to measurement errors, which place limitations on their accuracy. For this reason, all numerical values ​​provided herein should be understood to be modified by the term "about" unless otherwise specified. Accordingly, the last decimal place of a numerical value provided herein indicates its degree of accuracy. Unless other error tolerances are given, the maximum tolerance is ascertained by rounding to the last decimal place or by applying the last significant digit if a decimal does not exist in a given numerical value.

[0021] The term "amelioration" refers to a reduction in the severity of at least one indicator of a condition or disease, e.g., 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 measures known to those skilled in the art.

[0022] The term "composition" refers to a mixture of at least two or more components.

[0023] The terms "effective amount" and "therapeutically effective amount" refer to the amount of a therapeutic compound, a combination of compounds, or a composition, either as a single dose or as part of a series of doses, that is effective to produce the desired therapeutic effect. Generally, a therapeutically effective amount can be initially estimated in cell culture assays or mammalian models, such as non-human primates, mice, rabbits, dogs, or pigs. Animal models can also be used to determine the appropriate concentration range and administration route. Such information can then be used to determine the dosage and route that are useful for administration in non-human subjects and human subjects.

[0024] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid filler, solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting at least one compound described herein within or to a patient so that the compound can perform its intended function. A given carrier must be "acceptable" in the sense of being compatible with the other ingredients of a particular formulation, including the compound described herein, and not harmful 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.

[0025] The term "pharmaceutical composition" refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound, or a combination thereof, to a patient or subject. There are numerous techniques for administering a compound, combination, or composition, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0026] The term "treatment" or "treating" refers to the application of one or more specific procedures used to ameliorate a disease. "Prophylactic" treatment refers to slowing 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.

[0027] The description of ranges of values ​​herein is intended only as a shorthand for individually referring to each individual value within this range.Unless otherwise specified herein, each individual value is incorporated herein as if it were individually described herein.Therefore, when describing numerical ranges herein, each intervening value with the same precision is explicitly considered.For example, for the range of 6 to 9, the numbers 7 and 8 are considered in addition to 6 and 9, and for the range of 6.0 to 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 explicitly considered.

[0028] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples provided herein, or the use of illustrative language (e.g., "such as"), are intended only to better illustrate the described subject matter and do not limit the scope of any otherwise claimed subject matter. No language in the specification should be construed as indicating any non-claimed element essential to practicing the described subject matter.

[0029] Groupings of alternative elements or embodiments of the present disclosure should not be construed as limitations. Each member of a group can be referenced and claimed individually or in any combination with other members of the group or other elements found herein. Furthermore, stated members of a group may be included in or excluded from another stated group for reasons of convenience or patentability. When any such inclusion or exclusion occurs, the specification is deemed to include the group as modified to satisfy all Markush group descriptions used in the appended claims.

[0030] Throughout this specification, references have been made to patents and printed publications, each of which is individually incorporated herein by reference in its entirety.

[0031] It is to be understood that the embodiments of the present disclosure are illustrative, and therefore, the present disclosure is not limited to that precisely as shown and described.

[0032] polymorphic form Provided herein are polymorphic forms of Compound 1. Also provided herein are amorphous forms of Compound 1.

[0033] Thus, in some embodiments, provided herein are polymorphic forms of Compound 1 comprising one or more XRPD signals at 2θ, ±0.2, selected from 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.

[0034] Thus, in some embodiments, provided herein are polymorphic forms of Compound 1 comprising one or more XRPD signals at 2θ, ±0.2, selected from 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.

[0035] In some embodiments, the polymorphic form of Compound 1 is Form 1, Form 2, Form 3, Form 4, or Form 5.

[0036] In some embodiments, the polymorphic form of Compound 1 is a crystalline form of Compound 1.

[0037] In some embodiments, the polymorphic form of Compound 1 is Form 1 and comprises one or more XRPD signals at 2θ, ±0.2, selected from 7.3, 11.5, 28.5, or 29.7.

[0038] In some embodiments, the polymorphic form of Compound 1 is Form 2 and comprises one or more XRPD signals at 2θ, ±0.2, selected from 2.8, 5.8, 9.9, or 22.9.

[0039] In some embodiments, the polymorphic form of Compound 1 is Form 3 and comprises one or more XRPD signals at 2θ, ±0.2, selected from 7.7 or 17.4.

[0040] In some embodiments, the polymorphic form of Compound 1 is Form 4 and comprises one or more XRPD signals at 2θ, ±0.2, selected from 4.5, 9.3, or 9.7.

[0041] In some embodiments, the polymorphic form of Compound 1 is Form 5, which comprises an XRPD signal at 14.6±0.2 2θ.

[0042] composition 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.

[0043] process Also provided herein are processes for preparing the polymorphic forms of Compound 1 described herein.

[0044] Thus, in some embodiments, provided herein are methods for preparing polymorphic forms of Compound 1, the methods comprising lyophilizing or crystallizing Compound 1 from a solvent or solvent system as described herein.

[0045] method Provided herein are methods of using the polymorphic forms of Compound 1 described herein. In some embodiments, the methods include administering a form of Compound 1 to a subject.

[0046] Thus, in some embodiments, the polymorphic forms of Compound 1 described herein are useful for treating kinase-related diseases, for inhibiting kinases, or for preparing pharmaceuticals, including, but not limited to, on a commercially relevant scale.

[0047] 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 an amorphous form as prepared herein, a form provided herein, including Compound 1 in Form 1, Form 2, Form 3, Form 4, or Form 5, or a composition thereof, which may 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 one, two, three, or more iterations of recrystallization, lyophilization, or a combination thereof.

[0048] In some embodiments, the kinase-associated disease or disorder can include a JAK1 or TYK2-associated disease or disorder. In some embodiments, diseases or disorders treated by administration of a form of Compound 1 provided herein include ophthalmic diseases or disorders (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).

[0049] In some embodiments, the kinase-related disease or disorder may include, but is not limited to, ocular diseases such as glaucoma, ocular hypertension, ocular wound repair, neurodegenerative ocular diseases, retinal detachment, and non-ocular diseases such as nerve injury, or skin wound repair.

[0050] In some embodiments, provided herein are methods of treating ocular dryness, blurred vision, foreign body sensation, discomfort, irritation, or pain.

[0051] kit In some embodiments, provided herein is a packaged form, packaged composition, or packaged pharmaceutical composition 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 of the methods provided herein.

[0052] This form of Compound 1 and related materials can be commercialized by standard procedures, such as appropriate sterilization and packaging, as practiced in the art. For example, at doses of 25-35 kGy, both e-beam and gamma radiation can effectively sterilize pharmaceuticals. Alternatively, materials can be treated with UV / visible radiation (200-500 nm) using, for example, photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably water-soluble initiators (e.g., Irgacure 2959). Such irradiation is typically carried out for 1-60 minutes, although longer irradiation times can be applied depending on the specific method. Materials according to the present disclosure can be terminally sterilized and packaged in a suitable container (e.g., a box) (e.g., with a specific product information leaflet) to maintain sterility until use.

[0053] According to further embodiments, the particles can also be provided in the form of a kit in combination with other components necessary for administering a substance to a patient. For example, the disclosed kits, such as those used for eye treatment or cancer treatment, can further include, for example, the substance to be administered.

[0054] The kits can be designed in a variety of forms based on which particular defect they are designed to treat.

[0055] The Compound 1 forms or compositions provided herein can be prepared and placed in a container for storage at ambient or elevated temperatures. When Compound 1 forms or compositions are stored in a polyolefin plastic container, for example, compared to a polyvinyl chloride plastic container, discoloration of the form (e.g., the compound in particles) or composition can be reduced, whether suspended in a liquid composition (e.g., an aqueous or organic liquid solution) or in a solid state. Without wishing to be bound by theory, the container can reduce exposure of the contents of the container to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UV B light) or about 320-380 nm (UV A light)). Some containers also include the ability to reduce exposure of the contents of the container to infrared light, or a second component with such ability. Some containers further include the ability to reduce exposure of the contents of the container to heat or humidity. Containers that can be used include those made of polyolefins, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container, including but not limited to an amber glass container. The container can be placed 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 contents of the container to UV light, visible light, or infrared light. Manufactured articles that benefit from reducing discoloration, degradation, or both during storage include dosage forms containing the compound 1 forms or compositions described herein. The compound 1 forms or compositions provided herein may require storage for up to 3 months or longer; in some cases, up to 1 year or longer. The container can be in any form suitable for containing the contents, such as a bag, a bottle, or a box, or any combination thereof.

[0056] The compounds and processes of the present invention will be better understood with reference to the following examples, which are intended to illustrate, but not limit, the scope of the invention. [Example]

[0057] Unless otherwise stated, the following instrumentation and methodology were used in the examples below.

[0058] Instrumentation and Methodology X-ray powder diffraction (XRPD): Bruker AXS D8 Advance. XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA) in reflection geometry and a theta-2theta 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 XRD Commander, and data analysis was with HighScore Plus. Samples were run under ambient conditions as flat specimens using as-received powder. Samples were prepared on polished, zero-background (510) silicon wafers by lightly pressing them onto a flat surface or filling a milled cavity. Samples were rotated in their own plane. Standard data collection method details are as follows: angle range: 2–42° 2θ; step size: 0.05° 2θ; and collection time: 0.5 s / step (total collection time: 6.40 min).

[0059] X-ray powder diffraction (XRPD): PANalytical Empyrean. XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. A 0.04 rad Soller slit was used on the incident beam, including a 0.5° slit, a 4 mm mask, and a focusing mirror. A PIXcel placed on the diffracted beam 3DThe detector was equipped with a receiving slit and a 0.04 rad Soller slit. The software used for data collection was X'Pert Data Collector with the X'Pert Operator Interface. Data were analyzed and presented using HighScore Plus. Samples were prepared and analyzed in transmission mode in either metal or Millipore 96-well plates. An X-ray transparent membrane was used between the metal sheets in the metal well plates, and as-received powder (approximately 1–2 mg) was used. With Millipore plates, a small amount of suspension was added directly to the plate, after which the solid was isolated from the suspension by filtration under a slight vacuum and analyzed. The scan mode for the metal plates used a gonioscan axis, while 2θ scanning was utilized for the Millipore plates. The details of the standard screening data collection method were as follows: angular range: 2.5–32.0° 2θ; step size: 0.0130° 2θ; and collection time: 12.75 s / step (total collection time of 2.07 min).

[0060] The software used for data collection was X'Pert Data Collector and data were analyzed and presented using Highscore Plus.

[0061] 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. Samples were prepared in DMSO-d6 solvent unless otherwise noted. Automated experiments were acquired using ICON-NMR configuration within Topspin software using standard Bruker-equipped experiments ( 1 H, 13 C{ 1 H}, DEPT135). Offline analysis was performed using an ACD Spectrus Processor.

[0062] 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 heated in a pinhole-equipped aluminum pan from 25°C to 300°C at 10°C / min. A 50 mL / min purge of dry nitrogen was maintained over the sample. Temperature-modulated DSC (MDSC) was performed using a base heating rate of 2°C / min and temperature modulation parameters of ±0.636°C (amplitude) every 60 seconds (duration). The instrument control software was Advantage for Q Series and Thermal Advantage, and data were analyzed using Universal Analysis or TRIOS.

[0063] Differential Scanning Calorimetry (DSC): TA Instruments Discovery DSC. DSC data were collected on a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, 0.5-3 mg of each sample was heated in a pinhole aluminum pan from 25°C to 300°C at 10°C / min. A purge of dry nitrogen at 50 mL / min was maintained over the sample. The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0064] 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 loaded into a pre-weighed aluminum DSC pan and heated from ambient temperature to 350 °C at 10 °C / min. A nitrogen purge at 60 mL / min was maintained over the sample. The instrument control software was Advantage for Q Series and Thermal Advantage, and data were analyzed using Universal Analysis or TRIOS.

[0065] Thermogravimetric Analysis (TGA): TA Instruments Discovery TGA. TGA data were collected on a TA Instruments Discovery TGA equipped with a 25-position autosampler. Typically, 5-10 mg of each sample was loaded into a pre-weighed aluminum DSC pan and heated from ambient temperature to 350 °C at 10 °C / min. A nitrogen purge at 25 mL / min was maintained over the sample. The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0066] Polarized Light Microscopy (PLM): Leica LM / DM Polarized Light Microscope. Samples were analyzed with a Leica LM / DM Polarized Light 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 cover slip. Samples were viewed under appropriate magnification and partially polarized light coupled with a λ false color filter. Images were captured using StudioCapture or Image ProPlus software.

[0067] Scanning Electron Microscopy (SEM). Data were collected on a Phenom Pro scanning electron microscope. A small sample was attached to an aluminum stub using conductive double-sided adhesive tape. A thin layer of gold was deposited using a sputter coater (20 mA, 120 seconds).

[0068] Gravimetric Vapor Sorption (GVS): SMS DVS Intrinsic. Sorption isotherms were obtained using an SMS DVS Intrinsic moisture sorption analyzer controlled by DVS Intrinsic Control software. Sample temperature was maintained at 25°C by the instrument control. Humidity was controlled by mixing dry and humid nitrogen streams at a total flow rate of 200 mL / min. Relative humidity was measured with a calibrated Rotronic probe (dynamic range of 1.0-100% RH) positioned near the sample. Sample weight change (mass relaxation) as a function of % RH was constantly monitored with a microbalance (accuracy of ±0.005 mg). Typically, 5-30 mg of sample was placed in a weighed mesh stainless steel basket under ambient conditions. Samples were loaded and unloaded at 40% RH and 25°C (typical room conditions). Moisture sorption isotherms were performed as outlined below (two scans per complete cycle). Standard isotherms were performed at 25°C over a RH range of 0-90% at 10% RH intervals. Typically, duplicate cycles (4 scans) were performed. Data analysis was performed in Microsoft Excel using the DVS Analysis Suite. Samples were generally collected after completion of the isotherm and reanalyzed by XRPD. [Table 1]

[0069] Chemical purity determination 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. The overall method details are shown in Table 2. [Table 2]

[0070] Liquid Chromatography Mass Spectrometry (LC-MS). LC-MS data were collected on an Agilent 1260 equipped with a PDA and iQ mass spectrometer (single quadrupole with electrospray ionization (ESI)). Samples (approximately 1 mg) were dissolved in 50:50 acetonitrile:water (1 mL) to give a final concentration of approximately 1 mg / mL. Details of the LC-MS method are shown in Table 3. Data were processed using total ion counting (TIC) chromatograms in positive and negative modes. Mass spectra for each peak were extracted at the peak apex, and confirmed ions were identified where possible. [Table 3]

[0071] Water Determination Method by Karl Fischer Titration (KF). The water content of each sample was measured with a Metrohm 874 Oven Sample Processor at 150°C with an 851 Titrano Coulometer using Hydranal Coulomat AG oven reagent and a nitrogen purge. A weighed solid sample was introduced into a sealed sample vial. Approximately 10 mg of sample was used per titration, and duplicate determinations were made. The average of these results is presented unless otherwise stated. Data collection and analysis were performed using Tiamo software.

[0072] Thermodynamic aqueous solubility. Aqueous solubility was determined by suspending sufficient compound in the relevant medium to achieve a maximum final concentration of 10 mg / mL or greater of the parent form of the compound. The suspension was equilibrated at 37°C for 24 hours on a Heidolph plate shaker set at 750 rpm. The pH of the saturated solution was then measured, and the suspension was centrifuged (13,400 rpm, 2 minutes) before filtering through a glass fiber C filter (particle retention 1.2 μm) and diluting appropriately. Quantitation was performed by HPLC with reference to a standard solution of approximately 0.15 mg / mL in DMSO. Various volumes of standard diluted and undiluted sample solutions were injected. Solubility was calculated using peak areas determined by integration of the peak identified at the same retention time as the main peak in the standard injection. Analysis was performed on an Agilent HP1100 / Infinity II 1260 Series system equipped with a diode array detector using OpenLAB software. [Table 4]

[0073] Ion Chromatography (IC). Data were collected on a Metrohm 930 Compact IC Flex equipped with an 858 Professional autosampler and an 800 Dosino dosage unit monitor using IC MagicNet software. Accurately weighed samples were prepared as stock solutions in suitable solvents. Quantitation was achieved by comparison with standard solutions of known concentrations of the ions being analyzed. Analyses were performed in duplicate, and the average of values ​​is given unless otherwise stated. [Table 5] [Table 6]

[0074] Fourier transform infrared (FTIR). Data were collected on a Perkin-Elmer Spectrum 3 fitted with a universal ATR sampling accessory using a one-bounce diamond / ZnSe crystal. Spectra were collected from 4000 to 650 cm over 16 scans. -1 Data was collected using Spectrum IR software and processed using an ACD Spectrus Processor.

[0075] Static Stability Experiments. Solid materials were placed in open vials in elevated storage conditions unless otherwise stated. These conditions were achieved using saturated salt solutions in sealed containers at specified temperatures. Storage containers were pre-equilibrated before sample placement. [Table 7]

[0076] Freeze-dryer: Telstar Lyoquest. Samples were freeze-dried using a Telstar Lyoquest laboratory freeze-dryer with a pressure of less than 10 mbar and a condenser temperature of -85°C. The freeze-drying solution was filtered through a 0.45 μm nylon filter and then flash-frozen using dry ice / acetone. The frozen samples were then connected to the freeze-dryer and freeze-dried for approximately 20 hours. The heat energy required for freeze-drying was provided by direct contact of the sample container with the ambient environment.

[0077] Example 1 Preparation of Compound 1 Form 1 A solution of Compound 1 in dichloromethane was solvent exchanged into isopropanol. Isopropanol and water were added to obtain 15 volumes of an isopropanol / water (80:20) mixture. This mixture was then heated to 80°C until complete dissolution. The mixture was then cooled with stirring at 65°C and seeded with 2.5 wt.%. The mixture was then cooled to approximately 10°C over 4 hours and stirred for an additional 16 hours. The solid was filtered, and the filter cake was washed with isopropanol (2 volumes) before drying in a vacuum oven at 50°C. This yielded Compound 1 as an off-white solid. The final drug substance is not hygroscopic and is packaged at temperatures below 25°C. Melting point: 212°C. 1 H NMR (600 MHz, DMSO-d6) δ 8.76 (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, 8.0 Hz, 4H), 3.77 (s, 3H), 3.48 (ddd, J = 16.5, 10.4, 6.3 Hz, 1H), 3.04 (d, J = 2.1 Hz, 2H), 2.90 (dt, J = 10.1, 5.0 Hz, 2H), 2.69 (d, J = 10.7 Hz, 1H), 2.33 (dtd, J = 12.9, 9.8, 8.5, 3.9 Hz, 2H), 2.29-2.18 (m, 2H), 2.03 (s, 3H), 1.99 (t, J = 10.0 Hz, 1H), 1.91 (ddd, J = 27.1, 13.7, 5.3 Hz, 1H), 1.68-1.54 (m, 1H).

[0078] Example 2 Solubility of Form 1 of Compound 1 Form 1 of Compound 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-methyl-THF; 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. Form 1 of Compound 1 was determined to be somewhat soluble in 1,4-dioxane or nitromethane, and more soluble in dichloromethane (DCM) and dimethyl sulfoxide (DMSO).

[0079] Surprisingly, upon cooling the suspension in nitromethane at 50° C. to 5° C. and subsequent filtration, the purity of Form 1 of Compound 1, as assessed by HPLC, was confirmed to improve from 98.8% with four impurities present at greater than 0.1% to 99.3% with two impurities present at greater than 0.1%. XRPD analysis confirmed that the solid form of Compound 1 maintained Form 1 before and after this series of purification steps.

[0080] Form 1 of Compound 1 can be rendered amorphous by dissolving in warm 1:1 acetonitrile:water followed by freeze-drying. Example 3 Characterization of Form 1 of Compound 1 from Example 1 [Table 8-1] [Table 8-2] Example 4 Characterization of amorphous compound 1 [Table 9]

[0081] The amorphous material is not stable under static storage conditions (25°C / 97% RH or 40°C / 75% RH) and changes to either XRPD Pattern 1 (e.g., crystallization or rearrangement of Compound 1 Form 1) or Pattern 5 (Form 5) of Compound 1, which are poorly crystalline materials.

[0082] Example 5 Preparation of polymorphs of compound 1 Polymorphism screening starting from amorphous Compound 1 yielded materials with four new XRPD patterns: Pattern 2, Pattern 3, Pattern 4, and Pattern 5. A summary of the results of the polymorphism screening can be found in Table 10.

[0083] Isothermal slurries (cold slurries) were performed at 5°C. A stir bar was added to each HPLC vial, and one aliquot of solvent or solvent system was added as follows: Approximately 31–32 mg of amorphous Compound 1 was combined with 5 volumes (160 μL) or 10 volumes (320 μL) of solvent and stirred at 500 rpm at 5°C for approximately 24 hours. Samples in 1,4-dioxane and DMSO were stirred at 25°C due to the high melting points of the solvents. After the initial treatment period, all samples were suspensions. An aliquot of each suspension was pipetted onto an XRPD plate, the solvent was 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 was evaporated, and the solid was transferred to the XRPD plate.

[0084] Maturation. To each HPLC vial, a stir bar was added, and one aliquot of solvent or solvent system was added as follows: Approximately 31–32 mg of amorphous Compound 1 was combined with 5 volumes (160 μL) or 10 volumes (320 μL) of solvent, followed by shaking for approximately 24 hours in a maturation chamber cycled between room temperature and 50 °C every 4 hours. After the initial treatment period, all samples were suspensions, except for the sample containing DMSO solvent, which was a clear solution after 1 day. This sample was allowed to mature for an additional 4 days, by which time the sample had formed a suspension. An aliquot of each suspension was pipetted onto an XRPD plate, the solvent was 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 was evaporated, and the solid was transferred to the XRPD plate.

[0085] Isothermal slurries (warm slurries) at 50 °C. To each HPLC vial, a stir bar was added, and one aliquot of solvent or solvent system was added as follows: Approximately 31–32 mg of amorphous Compound 1 was combined with 5 volumes (160 μL) or 10 volumes (320 μL) of solvent and then stirred at 50 °C and 500 rpm for approximately 21 hours. After the initial treatment period, all samples were suspensions, except for the sample containing DMSO solvent, which was a clear solution after 1 day. This sample was stirred at 50 °C for an additional 5 days, by which time the sample had formed a suspension. An aliquot of each suspension was pipetted onto an XRPD plate, the solvent was 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 was evaporated, and the solid was transferred to the XRPD plate. [Table 10-1] [Table 10-2]

[0086] Material designated as Pattern 2 was produced from the cold slurry, hot slurry, and maturation techniques. Surprisingly, material identified as Pattern 3 by XRPD was produced only from the cold slurry technique. Samples containing Pattern 4 material were produced only from heptane in both the warm slurry and maturation screenings. Finally, material designated as Pattern 5 based on XRPD was produced from the maturation screening in methanol / water (5% v / v) and from the warm slurries in methanol / water (5% v / v) or ethanol / water (5% v / v). There were also samples that were mixtures of Pattern 5 and Pattern 1 obtained from water. Pattern 5 was also observed in amorphous samples of Compound 1 after 6 days of static storage at 25°C / 97% RH.

[0087] The purity of Pattern 1 samples under various conditions can be improved compared to that of samples from Example 1, as shown in Table 11. [Table 11]

[0088] This purity analysis suggests that the process of creating amorphous material followed by treatment in a solvent to obtain material with an XRPD pattern of 1 improves the purity of the material. In particular, the presence of ACN in the solvent appears to provide the best improvement in purity.

[0089] Samples containing each new pattern by XRPD were selected for isolation and characterization. Isolation was accomplished by air-drying the sample on filter paper or by filtering the sample through a small frit under positive pressure, followed by drying under vacuum for approximately 1 hour.

[0090] Upon isolation, the sample originally identified as having Pattern 2 was found to have converted to Pattern 1 material. A second sample was isolated and again found to have converted to Pattern 1. Therefore, Pattern 2 was determined to be unstable and was not further characterized. The XRPD pattern after isolation can be seen in Figure 3.

[0091] Forms 1, 3, 4, and 5 of Compound 1, which were stable to isolation, were 1 Characterization was performed using 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 can be found in Table 12. Data can be found in Data Section 6 - Characterization of New Patterns. [Table 12-1] [Table 12-2]

[0092] Form 3-Dry was prepared by dissolving amorphous Compound 1 in 1:2 v / v ACN:water, followed by stirring at 5° C. to obtain crystalline material. Form 3-Dry (Pattern 3) is crystalline and has a high purity of 99.5%, with only one major impurity present. 1 The H NMR spectrum is consistent with the initial material, with no trace of ACN solvent. DSC analysis shows 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 melting of Form 1). TGA shows an 11.4% weight loss before 105 °C, consistent with the loss of approximately 3 equivalents of water. The solid form remains unchanged during 6 days of storage at 40 °C / 75% RH, retaining its chemical integrity with a high purity of 99.4%. Pattern 3 is believed to be a hydrate form, which may convert to Form 1 anhydrous material above 147.9 °C.

[0093] Form 4-Dry was prepared by suspending amorphous Compound 1 in heptane followed by maturation cycling between 5° C. and 50° C. to obtain crystalline material. Form 4-Dry (Pattern 4) is a crystalline material with good purity (98.8%). 1The H NMR spectrum is consistent with the initial material, with traces of heptane solvent. DSC analysis shows a small endotherm at 181.5°C, an exotherm at 184.8°C (potentially indicative of recrystallization / form conversion), and a sharp endotherm at 216.5°C (consistent with melting of Form 1). TGA shows no weight loss before the onset of decomposition. The sample is stable during storage, remaining 98.9% pure Form 4 for 6 days at 40°C / 75% RH. Form 4 is believed to be the anhydrous form and may convert to anhydrous Form 1 above 184.8°C.

[0094] Form 5-Dry was prepared by suspending amorphous Compound 1 in 5% v / v methanol:water, followed by maturation cycling between 5° C. and 50° C. to obtain crystalline material. Form 5-Dry (Pattern 5) was shown to be crystalline by XRPD and had a high purity of 99.1%. 1 The H NMR spectrum is consistent with the initial material, with no trace of methanol solvent. DSC analysis shows 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 melting of Form 1 material from Example 1). TGA shows a 9.6% weight loss before 103.1°C, consistent with the loss of approximately 2.5 equivalents of water. The sample partially converts to Form 1 during 6 days of storage at 40°C / 75% RH and maintains a high purity of 99.0% under these accelerated storage conditions. Pattern 5 is believed to be a hydrate form, which loses water and then undergoes an exothermic event believed to result in Form 1, followed by melting.

[0095] In summary, the polymorphism screen yielded materials with novel patterns by XRPD.

[0096] For example, Form 3 of Compound 1 obtained from a cold slurry in ACN:water 1:2 v / v (Pattern 3) appears to be the trihydrate with the highest purity of the new patterns and good stability.

[0097] For example, Form 4 of Compound 1 (Pattern 4) obtained from a maturation screen in heptane appears to be anhydrous and has good stability, however, some traces of solvent remain and the material does not have a clear increase in purity compared to Form 1 of Compound 1 from Example 1.

[0098] For example, Form 5 of Compound 1 (Pattern 5) obtained from maturation screening in methanol:water 5% v / v appears to be a hydrate with higher purity compared to Form 1 of Compound 1 from Example 1. However, Pattern 5 is not stable to storage at 40°C / 75% RH and partially converts to the same form as Form 1 of Compound 1 from Example 1.

[0099] Purity analysis was performed on selected samples from the polymorphism screen that exhibited Pattern 1 by XRPD. The lyophilization and screening conditions appear to slightly improve the purity of these materials compared to Form 1 of Compound 1 from Example 1.

[0100] In particular, the solvent ACN appears to produce samples of increased purity, as observed in both the slight increase in purity of the Pattern 1 samples where the solvent contained ACN, and the high purity of Form 3-Dry (Pattern 3) obtained from ACN:water 1:2 v / v.

[0101] Amorphous Compound 1 was successfully prepared by lyophilization from a 1:1 ACN:water solvent and was confirmed to have good purity (99.0%) with no significant traces of solvent. This process was therefore chosen as it would be useful for producing bulk amorphous Compound 1, for example, on a commercially relevant scale. However, melt-quench cooling mDSC analysis of crystalline Form 1 of Compound 1 indicates that amorphous material can also be prepared by heating the sample to approximately 220°C followed by rapid cooling in an ice bath.

[0102] Polymorphism screening was performed using amorphous Compound 1 and 28 native process-acceptable solvent systems under three conditions: slurry at 5°C, maturation cycling between 5°C and 50°C, and slurry at 50°C. While many of the materials from the screening had the same pattern as Form 1 of Compound 1, four new patterns were obtained by XRPD. Following isolation, only three of the four materials retained their native new XRPD pattern, while one converted to Pattern 1 upon isolation.

[0103] Table 13 contains a list of XRPD diffractogram signals for Form 1 of Compound 1, with the corresponding XRPD diffractogram shown in Figure 4. Table 14 contains a list of XRPD diffractogram signals for Form 2 of Compound 1, with the corresponding XRPD diffractogram shown in Figure 5. Table 15 contains a list of XRPD diffractogram signals for Form 3 of Compound 1, with the corresponding XRPD diffractogram shown in Figure 6. Table 16 contains a list of XRPD diffractogram signals for Form 4 of Compound 1, with the corresponding XRPD diffractogram shown in Figure 7. Table 17 contains a list of XRPD diffractogram signals for Form 5 of Compound 1, with the corresponding XRPD diffractogram shown in Figure 8. [Table 13] [Table 14-1] [Table 14-2] [Table 15] [Table 16-1] [Table 16-2] [Table 17]

[0104] Example 6 ROCK and JAK assays ROCK kinase inhibition assay All compounds are initially prepared as 10 mM stocks in anhydrous dimethyl sulfoxide (DMSO). 20 μL aliquots of the 10 mM solution are transferred to individual wells in column 1 of a 96-well polypropylene microtiter plate (Corning #3363) and diluted with DMSO to obtain a final compound concentration of 4 mM. Test compounds are then serially diluted 1:5 in DMSO for an 11-point concentration response and further diluted in assay buffer to give a final range of all compound concentrations from 100 μM to 10 pM in 2.5% DMSO. Assays are performed in white 96-well flat-bottom half-area non-binding assay plates (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. A 10 μL aliquot of compound from each well of the intermediate dilution plate and 20 μL of a 2× substrate / enzyme solution containing the 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) are added to all wells. The reaction is initiated by adding 10 μL of 4× stock ATP (2 μM). The reaction is thoroughly mixed manually, covered, and incubated at room temperature for 75 minutes. Protein kinase activity is quantified using Promega's KINASE-GLO™ luminescent Kinase Assay Kit according to the manufacturer's instructions. The ATP concentration remaining in the test wells after the enzyme reaction is completed is compared to that of control wells (CTRL) containing an equivalent amount of DMSO without inhibitor. ATP concentrations in both test and CTRL wells are normalized to background (BKG) ATP concentrations in wells containing inhibitor at a concentration that completely inhibited the protein kinase under investigation (i.e., a concentration that prevented any consumption of ATP during the incubation period). Percent of control (POC) values ​​are determined for each concentration of compound tested using the following equation: POC = ((Test well value - BKG) / (CTRL - BKG)) x 100 I C 50 Values ​​are calculated using the following four-parameter logistic curve fitting algorithm: f(x)=(A+((BA) / (1+((x / C)^D)))) Convert IC50 values ​​to Ki values ​​using the Cheng-Prusoff equation: K i =IC 50 / (1+([ATP] / Km ATP])). Forms of Compound 1 described herein, such as the polymorph of Example 5, inhibit assayed kinases at commercially or therapeutically relevant levels.

[0105] JAK kinase assay The compounds are prepared in exactly the same manner as described for the ROCK kinase assay, except for the substrate and enzyme. The JAK 2x substrate / enzyme solution contains the acceptor substrate (800 nM of Abl peptide 12-mer with a MW of 1336.5, e.g., Enzo Life Sciences, product number BML-P216-0001), JAK1, TYK2, JAK2, or JAK3 enzyme (10 nM), and DTT (2 μM). All other steps and solutions remain the same as in the ROCK kinase assay described above. Forms of Compound 1 described herein, such as the polymorph of Example 5, inhibit the assayed kinase at commercially or therapeutically relevant levels.

[0106] Example 7 PTM-HTM assay Pig trabecular meshwork cells (PTM) were isolated from freshly obtained, excised pig eyes. Immortalized human trabecular meshwork cells (TM-1) were kindly provided by Donna Peters, Department of Ophthalmology and Visual Sciences, University of Wisconsin. Cells were plated onto fibronectin-coated glass-bottom 96-well plates and allowed to adhere overnight. The medium was removed and replaced with test compounds in medium containing 1% fetal bovine serum and incubated for various periods of time. After incubation, cells were formaldehyde-fixed, Triton®-solubilized, and stained. PTM cells were stained with Alexa Fluor® 488 phalloidin (F-actin) and Hoechst 33342 (nuclei). TM-1 cells were stained with anti-paxillin, followed by Alexa Fluor® 488 goat-anti-mouse IgG (focal adhesion) and Hoechst 33342 (nuclei). All staining reagents are obtained from Invitrogen. Images are collected using an INCell 2200 imager equipped with a 20x objective. Actin fiber length and total focal adhesion area are analyzed using custom algorithms developed in the INCell Developer Toolbox, v1.9.3. Collected data are converted to percent of control (untreated cells). Curves are fitted to the data in GraphPad Prizm using a sigmoidal dose-response, with the top and bottom constrained to 100% and 0%, respectively. Forms of Compound 1 described herein, such as the polymorph of Example 5, improve actin fiber length or total focal adhesion area at commercially or therapeutically relevant levels.

[0107] Example 8 treatment A topical drop ophthalmic pharmaceutical composition for treating inflammatory or dry eye disease is prepared, comprising a form of Compound 1 described herein, such as the polymorph of Example 5. When such a composition is administered topically once daily to one or both eyes of a subject, the composition reduces ocular inflammation in the eyes of a subject suffering from meibomian gland dysfunction (MGD) or DED.

Claims

1. The compound is 【Chemistry 2】 A solid form of the compound, 【Request Item 2】 【Chemistry 3】 2. The solid form of claim 1, wherein the solid form is a crystalline solid form of

3. 10. The solid form of claim 1, wherein the solid form is precipitated or crystallized from at least one solvent.

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

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

6. 2. The solid form of claim 1, comprising one or more XRPD signals at ±0.2 two-theta selected from 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. 2. The solid form of claim 1, comprising one or more XRPD signals at ±0.2 two-theta selected from 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. 2. 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. 2. The solid form of claim 1, wherein the solid form is Form 1 and comprises one or more XRPD signals at ±0.2 2θ selected from 7.3, 11.5, 28.5, or 29.

7.

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

9.

11. 10. The solid form of claim 1, which is Form 3 and comprises one or more XRPD signals at ±0.2 2θ selected from 7.7 or 17.

4.

12. 10. The solid form of claim 1, which is Form 4 and comprises one or more XRPD signals at ±0.2 2θ that are selected from 4.5, 9.3, or 9.

7.

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

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

15. from at least one solvent 【Chemistry 4】 10. The solid form of claim 1, prepared by a process comprising one or more of: freeze-drying or crystallizing

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

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

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

19. 19. The composition of any one of claims 16 to 18 in the form of a solid (e.g., an implantable 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 a solid form according to any one of claims 1 to 15 or a composition according to any one of claims 16 to 19.

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

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

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

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

25. 20. 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. 20. A method of treating dry eye 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 to 15 or the composition of any one of claims 16 to 19.

Images