Polymorphism of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide

Abstract

Crystalline forms of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide, pharmaceutical compositions, methods of use and methods of preparation thereof are provided.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 340,348, filed May 10, 2022, the contents of which are incorporated herein by reference.

[0002] The present disclosure relates to novel crystalline polymorphs of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. These polymorphs can be used to treat disorders responsive to inhibition of Bruton's tyrosine kinase. In another aspect, the disclosure relates to a process for preparing the novel polymorphs. [Background technology]

[0003] Protein kinases are a large multigene family of over 500 proteins that play important roles in the development and treatment of many human diseases in oncology, neurology and immunology. Tec kinases are non-receptor tyrosine kinases consisting of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T cell kinase, also known as Emt or Tsk), Rlk (resting lymphocyte kinase, also known as Txk) and Bmx (myeloid tyrosine kinase gene on the X chromosome, also known as Etk)) and are predominantly expressed in hematopoietic cells, although expression of Bmx and Tec has been detected in endothelial cells and hepatocytes. Tec kinases (Itk, Rlk and Tec) are expressed in T cells and all are activated downstream of the T cell receptor (TCR). Btk is a downstream mediator of B cell receptor (BCR) signaling involved in regulating B cell activation, proliferation and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). Binding of PIP3 induces Btk to phosphorylate phospholipase C (PLCy), which hydrolyzes PIP2 to generate two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate the protein kinase PKC, which in turn induces further B cell signaling. Mutations that impair Btk enzymatic activity result in the primary immunodeficiency disorder XLA syndrome (X-linked agammaglobulinemia). Given that Tec kinase plays a key role in both B and T cell signaling, it is an intended target in the case of autoimmune disorders.

[0004] Thus, there is a great need in the art for effective inhibitors of Btk. Summary of the Invention

[0005] The present disclosure relates to a crystalline form (or polymorph) of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (Compound 1) or a salt thereof. In certain embodiments, the crystalline forms of the present application have improved stability and suitability for pharmaceutical use. Other advantages may include favorable pharmacokinetic properties, ease of isolation, process reproducibility, suitability for large-scale manufacturing processes, etc.

[0006] In one embodiment, the disclosure provides crystalline Form A of Compound 1.

[0007] In another embodiment, the present disclosure provides crystalline form B of Compound 1.

[0008] In another embodiment, the present disclosure provides crystalline Form I of the maleate salt of Compound 1.

[0009] In another embodiment, the present disclosure provides crystalline Form II of the tartrate salt of Compound 1.

[0010] In yet another embodiment, the present disclosure provides crystalline Form III of the tartrate salt of Compound 1.

[0011] In another embodiment, the present disclosure provides crystalline Form IV of the citrate salt of Compound 1.

[0012] In another embodiment, the present disclosure provides crystalline Form V of the proline salt of Compound 1.

[0013] The present disclosure also provides pharmaceutical compositions comprising at least one polymorph described herein and at least one pharma- ceutically acceptable excipient.

[0014] One aspect of the disclosure provides a method of treating a disorder responsive to Btk inhibition in a subject, the method comprising administering to the subject an effective amount of a composition (e.g., a pharmaceutical composition) comprising a polymorph described herein.

[0015] The disclosure also includes the use of a composition (e.g., a pharmaceutical composition) comprising a polymorph as described herein for the manufacture of a medicament for the treatment of a disorder responsive to Btk inhibition. Also provided is a polymorph as described herein for use in the treatment of a disorder responsive to Btk inhibition. [Brief description of the drawings]

[0016] [Figure 1] 1 shows the powder X-ray diffraction (PXRD) pattern of crystalline form A of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Diagram 2] FIG. 1 shows a single crystal structural representation of the asymmetric unit cell structure of crystalline form A of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Diagram 3] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline form A of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 4] 1H NMR spectrum of crystalline form A of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Diagram 5] 3 shows the powder X-ray diffraction (PXRD) pattern of crystalline form B of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 6]A single crystal structural representation of the asymmetric unit cell structure of crystalline form B of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is shown. [Figure 7] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline form B of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 8] 1H NMR spectrum of crystalline form B of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 9] 1 shows the powder X-ray diffraction (PXRD) pattern of crystalline form I of the maleate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 10] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline form I of the maleate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 11] 1H NMR spectrum of crystalline form I of the maleate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 12]1 shows the powder X-ray diffraction (PXRD) pattern of crystalline form II of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 13] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline form II of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 14] 1H NMR spectrum of crystalline form II of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 15] 1 shows the powder X-ray diffraction (PXRD) pattern of crystalline Form III of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 16] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline form III of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 17] 1H NMR spectrum of crystalline form III of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide tartrate salt. [Figure 18]1 shows the powder X-ray diffraction (PXRD) pattern of crystalline Form IV of the citrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 19] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline Form IV of the citrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 20] 1H NMR spectrum of crystalline Form IV of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide citrate salt. [Figure 21] 1 shows the powder X-ray diffraction (PXRD) pattern of crystalline form V of the proline salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Figure 22] 1 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline form V of the proline salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. [Diagram 23] 1H NMR spectrum of crystalline form V of the proline salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] As used herein, the term "compound" refers to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. The structure of this compound is shown below. [ka]

[0018] As used herein, the terms "crystalline", "crystalline form", or "polymorph" refer to a solid form having a crystal structure in which the individual molecules have a highly uniform, regular, fixed chemical organization. Crystalline forms can be characterized by analytical methods such as powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and NMR.

[0019] As used herein, the "anti-solvent crystallization" method involves adding an anti-solvent to a solution containing a compound, which dramatically reduces the solubility of the compound, causing the compound to precipitate or crystallize. The compound may precipitate immediately or slowly over time. In some embodiments, after the addition of the anti-solvent, the resulting mixture may be cooled to a low temperature (e.g., below room temperature, 0°C to 10°C, or 0°C to 5°C) to promote the precipitation of the crystalline form. The precipitate (crystals) may then be easily separated by filtration, decantation, or centrifugation.

[0020] As used herein, the term "anti-solvent" refers to a solvent in which a compound is insoluble or very poorly soluble. Suitable anti-solvents include, but are not limited to, water, petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, and hydrocarbons including n-butanol.

[0021] As used herein, the "reverse anti-solvent crystallization" method involves adding a solution of a compound (obtained by dissolving the compound in a solvent to form a clear solution) to an anti-solvent until a precipitate appears. Alternatively, the solution is added to a certain amount of anti-solvent. Over time, the desired crystalline form may slowly form or precipitate. In some embodiments, after the addition of the solvent, the resulting mixture may be cooled to a low temperature (e.g., below room temperature, 0°C to 10°C, or 0°C to 5°C) to promote precipitation or crystallization of the crystalline form. The precipitate (crystals) may then be easily separated by filtration, decantation, or centrifugation.

[0022] As used herein, the "slurry cycling crystallization" method involves suspending a compound in a solvent, followed by heating and slowly cooling, and the heating and cooling steps can be optionally repeated 1-10 times to obtain a desired crystal form. The mixture of the compound and the solvent can be heated to a temperature of 30°C to 150°C, 30°C to 100°C, 30°C to 70°C, or 40°C to 60°C. In one embodiment, the mixture can be heated to 50°C. The mixture can be heated at the desired temperature for a period of time, for example, 10 minutes to 10 hours, 10 minutes to 5 minutes, 10 minutes to 2 hours, 10 minutes to 1 hour, 20 minutes to 40 minutes, or 1 hour to 5 hours. In one embodiment, the mixture is heated for 30 minutes. The heated mixture can then be slowly cooled to room temperature, or to a low temperature of 0°C to 15°C, or 0°C to 10°C, or 0°C to 5°C. In one embodiment, the mixture can be cooled to 5°C. The cooling is carried out slowly, for example, at a rate of 0.1 to 0.5° C. / min (eg, 0.1° C. / min).

[0023] As used herein, the "slurry conversion crystallization" process involves stirring a suspension of a compound in a solvent for a sufficient time for the conversion of the compound from one solid form to another solid form. In some embodiments, the mixture of the compound and the solvent may be stirred for 1-5 hours, 1-10 hours, 1 hour to 1 day, 1 day to 10 days, or 1 day to 5 days. In some embodiments, the mixture is stirred for 1 day, 2 days, 3 days, 4 days, or 5 days.

[0024] As used herein, a "slurry" process includes "slurry cycling crystallization" and "slurry conversion crystallization." In some embodiments, the slurry process is "slurry conversion crystallization."

[0025] As used herein, the "liquid vapor diffusion crystallization" method involves diffusing the vapor of a volatile solvent into a solution containing an insoluble or poorly soluble compound. The vapor of the volatile solvent diffuses into the solution, reducing the overall solubility of the compound and causing the compound to precipitate out of the solution. In some embodiments, the method is carried out by adding a volatile solvent to the solution and keeping the resulting mixture in a closed container. In some embodiments, the solution is allowed to evaporate to dryness at room temperature.

[0026] As used herein, the "ionic liquid induced crystallization" method involves dissolving a compound in a solvent in the presence of an ionic liquid and slowly evaporating the solvent to obtain the desired solid form of the compound. An example of an ionic liquid is 1,3-dimethylimidazolium trifluoroacetate ([dmim]CF 3 COOH), 1,3-dimethylimidazolium perchlorate ([dmim]ClO 4 ), 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF 6 ) and 1-ethyl-3-methylimidazolium hexafluoroantimonate ([emim]SbF 6 ), but are not limited to these.

[0027] As used herein, the "polymer-induced crystallization" method involves stirring a solution of a compound in a solvent in the presence of a polymer mixture to obtain a desired solid form. Examples of polymer mixtures include, but are not limited to, mixtures of polymers selected from polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), and methylcellulose (MC). In some embodiments, the polymer mixture is a mixture of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), and methylcellulose (MC) in a mass ratio of 1:1:1:1:1:1.

[0028] As used herein, the "fast evaporative crystallization" method involves dissolving a solid form of a compound in a solvent, followed by fast evaporation of the solvent to obtain a desired crystalline form. For example, the solvent can be evaporated at a fast rate by exposing a solution of the compound to air at room temperature to evaporate the volatile solvent. Alternatively, the solvent can be evaporated under vacuum and / or at elevated temperatures (e.g., above room temperature).

[0029] The terms "Form A", "Form B", "Form I", "Form II", "Form III", "Form IV" or "Form V" refer to a specific crystalline form of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide or a specific salt thereof as defined below.

[0030] The present disclosure relates to various crystalline polymorphs of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide or certain salts thereof, and the process for preparing same. Any suitable crystallization method known in the art can be used to prepare the crystalline forms of the compounds described herein or salts thereof. Examples of crystallization methods include, but are not limited to, anti-solvent crystallization, reverse anti-solvent crystallization, slurry cycling crystallization, slurry conversion crystallization, liquid vapor diffusion crystallization, polymer-induced crystallization, and fast evaporative crystallization.

[0031] In one aspect, the disclosure provides crystalline Form A of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (Compound 1).

[0032] In one embodiment, crystalline form A is characterized by at least three, at least four, at least five, at least six, or at least seven powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 10.1°, 10.6°, 14.3°, 16.9°, 17.8°, 18.2°, 19.4°, and 25.1°. In another embodiment, crystalline form A is characterized by PXRD peaks at 2θ angles of 10.1°, 10.6°, 14.3°, 16.9°, 17.8°, 18.2°, 19.4°, and 25.1°. In another embodiment, crystalline Form A is characterized by at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 PXRD peaks at 2θ angles selected from 10.1°, 10.6°, 11.9°, 14.3°, 16.9°, 17.8°, 18.2°, 19.4°, 21.3°, 22.2°, 23.0°, 24.0°, 25.1°, and 27.8°. In yet another embodiment, crystalline Form A is characterized by PXRD peaks at 2θ angles selected from 10.1°, 10.6°, 11.9°, 14.3°, 16.9°, 17.8°, 18.2°, 19.4°, 21.3°, 22.2°, 23.0°, 24.0°, 25.1°, and 27.8°. In some embodiments, the peaks set forth in the above embodiments of crystalline Form A have a relative intensity of at least 1%, at least 2%, at least 5%, at least 10%, or at least 15%. In some embodiments, crystalline Form A has a PXRD pattern substantially identical to the PXRD pattern shown in FIG. 1.

[0033] As used herein, the term "relative intensity" refers to the ratio of the peak intensity of a peak of interest to the peak intensity of the largest peak.

[0034] In some embodiments, crystalline Form A is characterized by single crystal X-ray structure data obtained from a single crystal of a preferred Form A of Compound 1 using CuKα radiation. The crystal structure is characterized as space group P-1. In related embodiments of the present disclosure, crystalline Form A of Compound 1 is characterized by an asymmetric unit cell structure having the parameters listed in Table 1B. In one embodiment, the asymmetric unit cell has a size of 904.872 Å. 3 and three-dimensional parameters of a = 5.98064 Å, b = 10.28273 Å, and c = 14.91842 Å. The unit cell is also characterized by a Mercury diagram, shown in Figure 2. The unit cell consists of two molecules of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

[0035] In some embodiments, crystalline form A has a DSC profile substantially identical to the DSC profile shown in Figure 3. In particular, crystalline form A is characterized in the DSC profile by an onset temperature of 137.3±2°C. In another embodiment, crystalline form A has a melting temperature of 138.4°C±2°C.

[0036] In some embodiments, crystalline Form A has a TGA profile substantially identical to the TGA profile shown in Figure 3. In particular, the TGA profile indicates that crystalline Form A is a non-hygroscopic anhydrate.

[0037] In another embodiment, crystalline form A has the structure shown in FIG. 1 Characterized by H NMR.

[0038] In some embodiments, crystalline form A is, for example: 1 H NMR DSC, TGA, and PXRD. In one embodiment, crystalline form A is characterized by PXRD alone or in combination with the above DSC, TGA, and PXRD. 1H NMR in combination with one or more of the following:

[0039] As used herein, "non-hygroscopic" means that the crystalline form cannot readily absorb or adsorb water from its surroundings.

[0040] As used herein, "anhydrous" or "anhydrous" means a crystalline form that is substantially free of water in the crystal lattice, e.g., less than 1% by weight, as measured, such as by TGA analysis or other quantitative analysis.

[0041] In some embodiments, crystalline form A exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Purity of form A is measured by dividing the weight of crystalline form A in a composition comprising Compound 1 by the total weight of the compounds in the composition. In one embodiment, the disclosure provides a composition comprising Compound 1, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9% by weight of the compounds in the composition are crystalline form A compounds.

[0042] In one aspect, the disclosure provides a method for preparing crystalline form A of compound 1. In one embodiment, the method is a slurry method as described herein. In certain embodiments of the methods disclosed above, crystalline form A can be obtained by using crystalline form B as the starting material and isopropyl alcohol (IPA) as the solvent. In one embodiment, crystalline form A can be obtained by slurrying (stirring) crystalline form B in IPA at room temperature (RT) for a period of time sufficient to form form A (e.g., 1 hour to 8 hours, 1 hour to 4 hours, 1 day to 1 week, 2 weeks or more, 1, 2, 3, 4, 5, 6, or 7 days, etc.). In some embodiments, crystalline form A can be obtained by slurrying crystalline form B in IPA at room temperature (RT) for 6 days.

[0043] In another aspect, the disclosure provides crystalline form B of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

[0044] In one embodiment, crystalline form B is characterized by at least three, at least four, at least five, at least six, or at least seven powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 8.6°, 9.3°, 10.2°, 14.4°, 16.0°, 17.3°, 20.4°, and 25.4°. In another embodiment, crystalline form B is characterized by PXRD peaks at 2θ angles of 8.6°, 9.3°, 10.2°, 14.4°, 16.0°, 17.3°, 20.4°, and 25.4°. In another embodiment, crystalline form B is characterized by at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 PXRD peaks at 2θ angles selected from 8.6°, 9.3°, 10.2°, 14.4°, 16.0°, 17.3°, 18.7°, 20.4°, 21.4°, 21.9°, 22.7°, 25.4°, and 28.4°. In yet another embodiment, crystalline form B is characterized by PXRD peaks at 2θ angles selected from 8.6°, 9.3°, 10.2°, 14.4°, 16.0°, 17.3°, 18.7°, 20.4°, 21.4°, 21.9°, 22.7°, 25.4°, and 28.4°. In some embodiments, the peaks set forth in the above embodiments of crystalline Form B have a relative intensity of at least 1%, at least 2%, at least 5%, at least 10%, or at least 15%. In some embodiments, crystalline Form B has a PXRD pattern substantially identical to the PXRD pattern shown in FIG.

[0045] In some embodiments, crystalline form B is characterized by single crystal X-ray structure data obtained from a single crystal of the preferred form B of compound 1 using CuKα radiation. The crystal structure is characterized as space group P21 / c. In related embodiments of the present disclosure, crystalline form B of compound 1 is characterized by an asymmetric unit cell structure with the parameters listed in Table 2B. In one embodiment, the asymmetric unit cell has a volume of 1859.45 Å3 and three-dimensional parameters of a=9.4633 Å, b=20.6615 Å, and c=9.5408 Å. The unit cell is also characterized by Mercury, which is shown in FIG. 6. The unit cell consists of four N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide molecules.

[0046] In some embodiments, crystalline form B has a DSC profile substantially identical to the DSC profile shown in Figure 7. In particular, crystalline form B is characterized by an onset temperature in the DSC profile of 147.3±2°C. In another embodiment, crystalline form B has a melting temperature of 148.3°C±2°C.

[0047] In some embodiments, crystalline form B has a TGA profile substantially identical to the TGA profile shown in Figure 7. In particular, the TGA profile indicates that crystalline form B is a non-hygroscopic anhydrate.

[0048] In another embodiment, crystalline form B has the structure shown in FIG. 1 Characterized by H NMR.

[0049] In some embodiments, crystalline form B is, for example, 1 H NMR DSC, TGA, and PXRD. In one embodiment, crystalline form B is characterized by PXRD alone or in combination with the above DSC, TGA, and PXRD. 1 H NMR in combination with one or more of the following:

[0050] In some embodiments, crystalline form B exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. The purity of form B is measured by dividing the weight of crystalline form B in a composition comprising Compound 1 by the total weight of the compounds in the composition. In one embodiment, the disclosure provides a composition comprising Compound 1, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9% by weight of the compounds in the composition are crystalline form B compounds.

[0051] In one aspect, the disclosure provides a method for preparing crystalline form B of compound 1. In one embodiment, the method is a slurry method as described herein. In certain embodiments of the methods disclosed above, crystalline form B can be obtained by using crude compound 1 (e.g., amorphous or other solid form) as the starting material and ethyl acetate as the solvent. In one embodiment, crystalline form B can be obtained by slurrying crude compound 1 (e.g., amorphous or other solid form) in ethyl acetate at room temperature (RT) or below room temperature (0°C to 20°C, 0°C to 15°C, or 0°C to 10°C, or 5°C, 10°C, 15°C, or 20°C) for a period of time (e.g., 1 hour to 8 hours, 1 hour to 4 hours, 1 day to 1 week, 2 weeks or more, 1, 2, 3, 4, 5, 6, or 7 days, etc.) sufficient to form form B. In some embodiments, crystalline form B can be obtained by slurrying crude compound 1 in ethyl acetate at 10°C.

[0052] In another aspect, the disclosure provides crystalline Form I of the maleate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (the maleate salt of Compound 1).

[0053] In one embodiment, crystalline Form I is characterized by at least three or at least four powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 3.9°, 11.4°, 15.2°, 16.6°, and 19.2°. In another embodiment, crystalline Form I is characterized by PXRD peaks at 2θ angles of 3.9°, 11.4°, 15.2°, 16.6°, and 19.2°. In another embodiment, crystalline Form I is characterized by at least three, at least four, at least five, or at least six PXRD peaks at 2θ angles selected from 3.9°, 11.4°, 12.4°, 15.2°, 16.6°, 19.2°, and 21.3°. In yet another embodiment, crystalline Form I is characterized by PXRD peaks at 2θ angles of 3.9°, 11.4°, 12.4°, 15.2°, 16.6°, 19.2°, and 21.3°. In some embodiments, the peaks set forth in the above embodiments of crystalline Form I have a relative intensity of at least 1%, at least 2%, at least 5%, at least 10%, or at least 15%. In some embodiments, crystalline Form I has a PXRD pattern substantially identical to the PXRD pattern shown in Figure 9.

[0054] In some embodiments, crystalline Form I has a DSC profile substantially identical to the DSC profile shown in Figure 10. In particular, crystalline Form I has a melting temperature of 94.6°C ± 2°C.

[0055] In some embodiments, crystalline Form I has a TGA profile substantially identical to the TGA profile shown in FIG.

[0056] In another embodiment, crystalline Form I has the structure shown in FIG. 1 Characterized by H NMR.

[0057] In some embodiments, crystalline Form I is, for example, 1The crystalline form I is characterized by H NMR DSC, TGA, and PXRD. In one embodiment, the crystalline form I is characterized by PXRD alone or in combination with the above DSC, TGA, and PXRD. 1 H NMR in combination with one or more of the following:

[0058] In some embodiments, crystalline Form I exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Purity of Form I is measured by dividing the weight of crystalline Form I in a composition comprising a maleate salt of Compound 1 by the total weight of the maleate salt of the compound in the composition. In one embodiment, the disclosure provides a composition comprising a maleate salt of Compound 1, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9% by weight of the maleate salt of the compound in the composition is crystalline Form I.

[0059] In one aspect, the disclosure provides a method for preparing crystalline Form I of the maleate salt of Compound 1. In one embodiment, the method is a slurry method as described herein. In certain embodiments of the methods disclosed above, crystalline Form I can be obtained using Form B and maleic acid as starting materials and isopropyl acetate (IPAC) as a solvent. In certain embodiments, Form B of Compound 1 and maleic acid are mixed in isopropyl acetate at room temperature to obtain a clear solution. The solution is then cooled to a low temperature to form a solid, and then slurried at a low temperature for a period of time (e.g., 1 hour to 8 hours, 1 hour to 4 hours, 1 day to 1 week, 2 weeks or more, 1, 2, 3, 4, 5, 6, or 7 days, etc.) sufficient to form crystalline Form I of the maleate salt of Compound 1. In some embodiments, 0.5 to 1.5, 0.8 to 1.2, or 0.9 to 1.1 molar equivalents of maleic acid relative to Compound 1 can be used. In some embodiments, the solution is cooled to a temperature of -30°C to 0°C, -30°C to -5°C, -30°C to -10°C, or -25°C to -15°C. In some embodiments, the solution is cooled to -20°C. In some embodiments, crystalline Form I can be obtained by dissolving Compound 1 Form B and maleic acid in isopropyl acetate at room temperature to form a clear solution, followed by cooling the solution to -20°C to form a solid, and slurrying the solid at -20°C for 1 day.

[0060] In another aspect, the present disclosure provides crystalline Form II of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (the tartrate salt of Compound 1).

[0061] In one embodiment, crystalline Form II is characterized by at least three or at least four powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 4.6°, 9.2°, 13.1°, 17.2°, and 21.7°. In another embodiment, crystalline Form II is characterized by PXRD peaks at 2θ angles of 4.6°, 9.2°, 13.1°, 17.2°, and 21.7°. In another embodiment, crystalline Form II is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten PXRD peaks at 2θ angles selected from 4.6°, 9.2°, 13.1°, 14.0°, 14.4°, 17.2°, 18.6°, 19.4°, 21.7°, 22.1°, and 26.1°. In yet another embodiment, crystalline Form II is characterized by PXRD peaks at 2θ angles of 4.6°, 9.2°, 13.1°, 14.0°, 14.4°, 17.2°, 18.6°, 19.4°, 21.7°, 22.1°, and 26.1°. In some embodiments, the peaks set forth in the above embodiments of crystalline Form II have a relative intensity of at least 1%, at least 2%, at least 5%, at least 10%, or at least 15%. In some embodiments, crystalline Form II has a PXRD pattern substantially identical to the PXRD pattern shown in FIG. 12.

[0062] In some embodiments, crystalline Form II has a DSC profile substantially identical to the DSC profile shown in Figure 13. In particular, crystalline Form II is characterized by endothermic peaks at 140.4°C ± 2°C and 149.2°C ± 2°C, and an exothermic peak at 165.5°C ± 2°C.

[0063] In some embodiments, crystalline Form II has a TGA profile substantially identical to the TGA profile shown in FIG.

[0064] In another embodiment, crystalline Form II is as shown in FIG. 1 Characterized by H NMR.

[0065] In some embodiments, crystalline Form II is, for example, 1 H NMR DSC, TGA, and PXRD. In one embodiment, crystalline Form II is characterized by PXRD alone or in combination with the above DSC, TGA, and PXRD. 1 H NMR in combination with one or more of the following:

[0066] In some embodiments, crystalline Form II exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. The purity of Form II is measured by dividing the weight of crystalline Form II in a composition comprising a tartrate salt of Compound 1 by the total weight of the tartrate salt of the compound in the composition. In one embodiment, the present disclosure provides a composition comprising a tartrate salt of Compound 1, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9% by weight of the tartrate salt of the compound in the composition is crystalline Form II.

[0067] In one aspect, the disclosure provides a method for preparing crystalline Form II of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. In one embodiment, the method is a slurry method described herein. In certain embodiments of the above-disclosed method, crystalline Form II can be obtained using crystalline Form B and L-tartaric acid as starting materials and IPA as a solvent. In certain embodiments, Form B of Compound 1 and tartaric acid are mixed in IPA at room temperature to obtain a clear solution. The solution is then cooled to a low temperature to form a solid, followed by slurrying at a low temperature for a period of time (e.g., 1 hour to 8 hours, 1 hour to 4 hours, 1 day to 1 week, 2 weeks or more, 1, 2, 3, 4, 5, 6, or 7 days, etc.) sufficient to form crystalline Form II of the tartrate salt of Compound 1. In some embodiments, 0.5-1.5, 0.8-1.2, or 0.9-1.1 molar equivalents of tartaric acid relative to Compound 1 can be used. In some embodiments, the solution is cooled to a temperature of -20°C to 10°C, -10°C to 10°C, 0°C to 10°C, or 0°C to 5°C. In some embodiments, the solution is cooled to 5°C. In some embodiments, crystalline Form II can be obtained by dissolving Compound 1 Form B and tartaric acid (1:1 molar equivalents) in IPA at room temperature to form a clear solution, then cooling the solution to 5°C to form a solid, and slurrying the solid at 5°C for 1 day. In some embodiments, the tartaric acid and tartrate salts are L-tartaric acid and L-tartrate salts, respectively.

[0068] In another aspect, the disclosure provides crystalline Form III of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (the tartrate salt of Compound 1).

[0069] In one embodiment, crystalline Form III is characterized by at least three, at least four, at least five, at least six, or at least seven powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 4.9°, 7.3°, 9.7°, 13.2°, 14.6°, 16.4°, 18.6°, and 23.3°. In another embodiment, crystalline Form III is characterized by PXRD peaks at 2θ angles of 4.9°, 7.3°, 9.7°, 13.2°, 14.6°, 16.4°, 18.6°, and 23.3°. In another embodiment, crystalline Form III is characterized by at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 PXRD peaks at 2θ angles selected from 4.9°, 7.3°, 9.7°, 13.2°, 14.4°, 14.6°, 15.3°, 16.4°, 17.0°, 18.6°, 20.1°, 20.9°, 23.3°, and 24.5°. In yet another embodiment, crystalline Form III is characterized by PXRD peaks at 2θ angles of 4.9°, 7.3°, 9.7°, 13.2°, 14.4°, 14.6°, 15.3°, 16.4°, 17.0°, 18.6°, 20.1°, 20.9°, 23.3°, and 24.5°. In some embodiments, the peaks described in the above embodiments of crystalline Form III have a relative intensity of at least 1%, at least 2%, at least 5%, at least 10%, or at least 15%. In some embodiments, crystalline Form III has a PXRD pattern substantially identical to the PXRD pattern shown in FIG. 15.

[0070] In some embodiments, crystalline Form III has a DSC profile substantially identical to the DSC profile shown in Figure 16. In particular, crystalline Form III is characterized in the DSC profile by a melting temperature of 147.7°C ± 2°C and an exotherm peak of 172.2°C ± 2°C.

[0071] In some embodiments, crystalline Form III has a TGA profile substantially identical to the TGA profile shown in FIG.

[0072] In another embodiment, crystalline Form III has the structure shown in FIG. 1 Characterized by H NMR.

[0073] In some embodiments, crystalline Form III is, for example, 1 H NMR DSC, TGA, and PXRD. In one embodiment, crystalline Form III is characterized by PXRD alone or in combination with the above DSC, TGA, and PXRD. 1 H NMR in combination with one or more of the following:

[0074] In some embodiments, crystalline Form III exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. The purity of Form III is measured by dividing the weight of crystalline Form III in a composition comprising the tartrate salt of Compound 1 by the total weight of the tartrate salt of Compound 1 in the composition. In one embodiment, the present disclosure provides a composition comprising the tartrate salt of Compound 1, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9% by weight of the tartrate salt of Compound 1 in the composition is crystalline Form III.

[0075] In one aspect, the disclosure provides a method for preparing crystalline Form III of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. In one embodiment, the method is a slurry method as described herein. In certain embodiments of the above-disclosed method, crystalline Form III can be obtained using crystalline Form B and L-tartaric acid as starting materials and IPAc as a solvent. In certain embodiments, Form B of Compound 1 and tartaric acid are mixed in IPAc and stirred at room temperature for a period of time sufficient to form crystalline Form III of the tartrate salt of Compound 1 (e.g., 1 hour to 8 hours, 1 hour to 4 hours, 1 day to 1 week, 2 weeks or more, 1, 2, 3, 4, 5, 6, or 7 days, etc.). In some embodiments, 0.5-1.5, 0.8-1.2, or 0.9-1.1 molar equivalents of tartaric acid relative to compound 1 can be used. In one embodiment, crystalline Form III can be obtained by stirring crystalline Form B and tartaric acid (1:1 molar equivalents) in IPAc at room temperature for 1 day. In some embodiments, the tartaric acid and tartrate salt are L-tartaric acid and L-tartrate salt, respectively.

[0076] In another aspect, the disclosure provides crystalline Form IV of the citrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

[0077] In one embodiment, crystalline Form IV is characterized by at least three, at least four, at least five, or at least six powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 4.9°, 8.6°, 9.9°, 12.2°, 14.9°, 18.0°, and 19.9°. In another embodiment, crystalline Form IV is characterized by PXRD peaks at 2θ angles of 4.9°, 8.6°, 9.9°, 12.2°, 14.9°, 18.0°, and 19.9°. In another embodiment, crystalline Form IV is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine PXRD peaks at 2θ angles selected from 4.9°, 8.6°, 9.9°, 12.2°, 14.9°, 15.8°, 18.0°, 19.9°, 21.2°, and 22.7°. In yet another embodiment, crystalline Form IV is characterized by PXRD peaks at 2θ angles of 4.9°, 8.6°, 9.9°, 12.2°, 14.9°, 15.8°, 18.0°, 19.9°, 21.2°, and 22.7°. In some embodiments, the peaks described in the above embodiments of crystalline Form IV have a relative intensity of at least 1%, at least 2%, at least 5%, at least 10%, or at least 15%. In some embodiments, crystalline Form IV has a PXRD pattern substantially identical to the PXRD pattern shown in FIG.

[0078] In some embodiments, crystalline Form IV has a DSC profile substantially identical to the DSC profile shown in Figure 19. In particular, crystalline Form IV is characterized by a melting temperature of 96.1°C ± 2°C and an exotherm peak at 167.1°C ± 2°C.

[0079] In some embodiments, crystalline Form IV has a TGA profile substantially identical to the TGA profile shown in FIG.

[0080] In another embodiment, crystalline Form IV has the structure shown in FIG. 1 Characterized by H NMR.

[0081] In some embodiments, crystalline Form IV is, for example, 1 H NMR DSC, TGA, and PXRD. In one embodiment, crystalline Form IV is characterized by PXRD alone or in combination with the above DSC, TGA, and PXRD. 1 H NMR in combination with one or more of the following:

[0082] In some embodiments, crystalline Form IV exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. The purity of Form IV is measured by dividing the weight of crystalline Form IV in a composition comprising a citrate salt of Compound 1 by the total weight of the citrate salt of the compound in the composition. In one embodiment, the disclosure provides a composition comprising a citrate salt of Compound 1, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9% by weight of the citrate salt of the compound in the composition is crystalline Form IV.

[0083] In one aspect, the disclosure provides a method for preparing crystalline Form IV of the citrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. In one embodiment, the method is a slurry method described herein. In certain embodiments of the above-disclosed method, crystalline Form IV can be obtained using crystalline Form B and citric acid as starting materials and IPAc as a solvent. In certain embodiments, Form B of Compound 1 and citric acid are mixed in IPAc and stirred at room temperature for a period of time (e.g., 1 hour to 8 hours, 1 hour to 4 hours, 1 day to 1 week, 2 weeks or more, 1, 2, 3, 4, 5, 6, or 7 days, etc.) sufficient to form crystalline Form IV of the tartrate salt of Compound 1. In some embodiments, 0.5-1.5, 0.8-1.2, or 0.9-1.1 molar equivalents of citric acid can be used relative to compound 1. In one embodiment, crystalline Form IV can be obtained by stirring crystalline Form B and citric acid (1:1 molar equivalents) in IPAc at room temperature for 1 day.

[0084] In another aspect, the disclosure provides crystalline Form V of the proline salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (the proline salt of Compound 1).

[0085] In one embodiment, crystalline form V is characterized by at least three powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 8.6°, 17.3°, 19.1°, and 26.0°. In another embodiment, crystalline form V is characterized by PXRD peaks at 2θ angles selected from 8.6°, 17.3°, 19.1°, and 26.0°. In another embodiment, crystalline form V is characterized by at least three, at least four, at least five, or at least six PXRD peaks at 2θ angles selected from 8.6°, 14.7°, 17.3°, 19.1°, 22.9°, 25.2°, and 26.0°. In yet another embodiment, crystalline form V is characterized by PXRD peaks at 2θ angles selected from 8.6°, 14.7°, 17.3°, 19.1°, 22.9°, 25.2°, and 26.0°. In some embodiments, the peaks set forth in the above embodiments of crystalline Form V have a relative intensity of at least 1%, at least 2%, at least 5%, at least 10%, or at least 15%. In some embodiments, crystalline Form V has a PXRD pattern substantially identical to the PXRD pattern shown in FIG.

[0086] In some embodiments, crystalline Form V has a DSC profile substantially identical to the DSC profile shown in Figure 22. In particular, crystalline Form V is characterized by two endothermic peaks at 57.9°C ± 2°C and 86.1°C ± 2°C, and a melting temperature of 148.4°C ± 2°C.

[0087] In some embodiments, crystalline Form V has a TGA profile substantially identical to the TGA profile shown in FIG.

[0088] In another embodiment, crystalline form V has the structure shown in FIG. 1 Characterized by H NMR.

[0089] In some embodiments, crystalline form V is, for example, 1H NMR DSC, TGA, and PXRD. In one embodiment, crystalline form V is characterized by PXRD alone or in combination with the above DSC, TGA, and PXRD. 1 H NMR in combination with one or more of the following:

[0090] In some embodiments, crystalline Form V exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. The purity of Form V is measured by dividing the weight of crystalline Form V in a composition comprising a proline salt of Compound 1 by the total weight of the proline salt of the compound in the composition. In one embodiment, the disclosure provides a composition comprising a proline salt of a compound, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9% by weight of the proline salt of the compound in the composition is crystalline Form V of the compound.

[0091] In one aspect, the disclosure provides a method for preparing crystalline Form V of the proline salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide. In one embodiment, the method is a slurry method described herein. In certain embodiments of the above-disclosed method, crystalline Form V can be obtained using crystalline Form B and proline as starting materials and IPA as a solvent. In certain embodiments, Form B of Compound 1 and proline are mixed in IPA and stirred at room temperature for a period of time (e.g., 1 hour to 8 hours, 1 hour to 4 hours, 1 day to 1 week, 2 weeks or more, 1, 2, 3, 4, 5, 6, or 7 days, etc.) sufficient to form crystalline Form V of the proline salt of Compound 1. In some embodiments, 0.5-1.5, 0.8-1.2, or 0.9-1.1 molar equivalents of proline can be used relative to compound 1. In one embodiment, crystalline form V can be obtained by stirring crystalline form B and proline (1:1 molar equivalents) in IPA at room temperature for 1 day.

[0092] It will be understood that the 2θ values ​​of the PXRD patterns of crystalline forms A, B, I, II, III, IV, or V may vary slightly from instrument to instrument and may vary depending on sample preparation. Therefore, the PXRD peak positions of these crystalline forms should not be interpreted as absolute values ​​and may vary by ±0.2°.

[0093] As intended herein, "a PXRD pattern substantially identical to the PXRD pattern shown in Figure x" means that, for comparison purposes, at least 80%, at least 90%, or at least 95% of the peaks shown in Figure x are present. Figure x is Figure 1, Figure 5, Figure 9, Figure 12, Figure 15, Figure 18, or Figure 21. It should be further understood that, for comparison purposes, the peak positions shown in Figure x are allowed to vary to some extent, such as ±0.2°. Similarly, for comparison purposes, some variation is allowed from the peak positions shown in the DSC and TGA profiles and NMR spectra described herein. For example, the peak positions may vary from the peak positions shown in Figure 4 by ±0.5 ppm, etc. The onset and / or melting temperatures may vary from those shown in Figure 3, Figure 7, Figure 10, Figure 13, Figure 16, Figure 19, or Figure 22 by ±2°, etc.

[0094] In one aspect, the disclosure provides a pharmaceutical composition comprising a crystalline form described herein, e.g., Form A, B, I, II, III, IV, or crystalline Form V, and a pharma- ceutically acceptable excipient.

[0095] Another aspect of the disclosure provides a method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase in a subject, comprising administering to the subject an effective amount of Form A, B, I, II, III, IV, or crystalline Form V, or a composition (e.g., a pharmaceutical composition) comprising Form A, B, I, II, III, IV, or crystalline Form V.

[0096] In some embodiments of the above-disclosed aspects, the disorder is an autoimmune disorder. In some additional embodiments of the above-disclosed aspects, the autoimmune disorder is multiple sclerosis.

[0097] The term "autoimmune disorder" includes diseases or disorders involving an inappropriate immune response to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis. The term "inflammatory disorder" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. In some embodiments, the present disclosure provides methods of treating rheumatoid arthritis or lupus. In some embodiments, the present disclosure provides methods of treating multiple sclerosis.

[0098] The term "cancer" includes diseases or disorders involving abnormal growth and / or proliferation of cells, such as, for example, glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability high colon carcinoma). In some embodiments, the present disclosure provides a method of treating leukemia or lymphoma.

[0099] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0100] The term "treating" or "treatment" as used herein refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the severity of a disease, disorder or syndrome; ameliorating or improving clinical symptoms or indicators associated with a disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0101] An effective dose of a compound provided herein, or a pharma- ceutically acceptable salt thereof, to be administered to a subject can be from 10 μg to 500 mg.

[0102] Administering the compounds described herein to mammals includes any suitable delivery method.Administering the compounds described herein to mammals includes administering the compounds described herein to mammals topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.Administering the compounds described herein to mammals also includes administering the compounds metabolized to the compounds described herein in or on the mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.

[0103] Thus, the compounds described herein may be administered systemically, e.g., orally, in combination with a pharma- ceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly combined with the food of the patient's diet. For therapeutic oral administration, the compounds described herein may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be from about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions may be such that an effective dosage level will be obtained.

[0104] The tablets, troches, pills, capsules and the like can contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; or a sweetening or flavoring agent such as sucrose, fructose, lactose or aspartame.

[0105] The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

[0106] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

[0107] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients as mentioned above, as required, and then sterilizing by filtration. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying, which can produce a powder of the active ingredient and any desired additional ingredient from a previously sterile-filtered solution.

[0108] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols or glycols or mixtures of water and alcohols / glycols, optionally with the aid of a non-toxic surfactant, in which the compounds described herein can be dissolved or dispersed at effective concentrations.

[0109] Effective dosages of the compounds described herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art (see, e.g., U.S. Pat. No. 4,938,949, which is incorporated by reference in its entirety).

[0110] The amount of the compounds described herein required for therapeutic use will vary depending on the particular salt selected, as well as the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be left to the discretion of the attending physician or clinician. Generally, however, dosages may range from about 0.1 to about 10 mg / kg body weight per day.

[0111] The compounds described herein can conveniently be administered in unit dosage form, for example, containing 0.01 to 10 mg, or 0.05 to 1 mg of active ingredient per unit dosage form, In some embodiments, dosages of 5 mg / kg or less may be suitable.

[0112] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0113] The disclosed method can include a kit, which includes a compound described herein and instructions for use that can explain administering the compound described herein or a composition comprising the compound described herein to a cell or subject.This should be understood to include other embodiments of the kit known to those skilled in the art, such as a kit that includes a solvent (e.g., sterile) for dissolving or suspending the compound or composition described herein before administering the compound or composition described herein to a cell or subject.In some embodiments, the subject can be a human. EXAMPLES

[0114] Powder X-ray diffraction The crystallinity of the compounds was investigated using an XRD-D8 X-ray powder diffractometer (Bruker, Madison, WI) using CuKa radiation. The instrument was equipped with a high-precision microfocus X-ray tube. The tube voltage and amperage were set at 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1°, and the receiving slit was set at 0.15 mm. Diffracted radiation was detected with a Lynxeye detector. A θ-2θ continuous scan of 1.6° / min from 3° to 42° 2θ was used. The samples were placed on a zero background plate and the samples were prepared for analysis.

[0115] Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) The compounds were thermally characterized using a Discovery Differential Scanning Calorimeter (DSC) (TA Instruments) and a Discovery Thermogravimetric Analyzer (TGA) (TA Instruments). Samples were sealed in closed aluminum DSC pans for DSC analysis and in open aluminum pans for TGA analysis. Thermal analysis was performed with a linear gradient from 25°C to 300°C at 10°C per minute for both DSC and TGA.

[0116] Single crystal X-ray diffraction Clean crystals were selected and mounted in LV cryo-oil™ in plastic loops. Specimens (dimensions 0.157 mm x 0.095 mm x 0.070 mm) were used for X-ray crystal structure analysis. X-ray intensity data were measured at 100 K with a Rigaku Synergy-S single crystal diffractometer equipped with a HyPix-6000HE hybrid photon counting detector at a wavelength of λ = 1.54178 Å. The structure was solved and refined using the OLEX2 package with SHELX XS and XL programs.

[0117] Synthesis of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (Compound 1) [ka] Synthesis of tert-butyl methyl((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate [ka] In a 100 mL one-neck round-bottom flask equipped with a condenser, potassium hexamethyldisilazide (1 M in THF, 2.2 mL) was added to a solution of tert-butyl ((1s,3s)3-hydroxy-3-methylcyclobutyl)carbamate (150 mg, 0.75 mmol) in dioxane (7.5 mL) at room temperature under nitrogen atmosphere. After 5 min, a solution of 4,6-dichloropyrazolo[1,5-a]pyrazine (128 mg, 0.68 mmol) in dioxane (2.5 mL) was added dropwise to the thick white suspension. Iodomethane (240 mg, 1.70 mmol, 105 μL) was added to the resulting orange suspension at room temperature and stirring was continued for another 30 min. The resulting reaction mixture was degassed by purging with nitrogen for 30 min, after which a degassed solution of potassium phosphate tribasic (531 mg, 2.50 mmol) in water (2.5 mL) was added at room temperature. The clear orange reaction mixture was purged with nitrogen for an additional 10 min, after which a previously degassed solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (212 mg, 1.02 mmol) in dioxane (2.0 mL) was added, followed by solid Pd-PEPPSI™-IPr catalyst (93 mg, 0.14 mmol). The reaction mixture was purged with nitrogen for an additional 15 min, after which the reaction mixture was heated to reflux for 3 h. To the vigorously stirred reaction mixture was added ethyl acetate (20 mL), followed by water (20 mL). After 30 min, the organic phase was separated and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (40 g silica gel, 2% NH in heptane). 4 Purification with OH modifier 0-80% [3:1 EtOAc:EtOH]) afforded the title compound as a pale yellow oil (130 mg, 47% yield). LCMS m / z=413.1 (M+H)+. 1 H NMR (500 MHz, methanol-d 4)δ ppm 8.42 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.91 (d, J=2.44 Hz, 1H), 6.77 (d, J=1.22 Hz, 1H), 4.10-4.45 (m, 1H), 3.95 (s, 3H), 2.82 (s, 3H), 2.74-2.81 (m, 2H), 2.67 (br s, 2H), 1.81 (s, 3H), 1.46 (s, 9H).

[0118] Synthesis of (1s,3s)-N,3-dimethyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutan-1-amine [ka] To a solution of tert-butyl methyl((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate (4.05 g, 9.82 mmol) in HFIP (45 mL) was added TFA (2.24 g, 19.6 mmol, 1.5 mL) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. Ethyl acetate (50 mL) was added followed by saturated NaHCO 3 After 30 min of vigorous stirring with added aqueous solution (25 mL) and brine (10 mL), the organic phase was separated, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (24 g silica gel, 2% NH in heptane). 4 Purification with OH modifier 80-100% [3:1 EtOAc:EtOH]) afforded the title compound as a pale yellow gum (2.53 g, 82% yield). LCMS m / z=313.1 (M+H)+. 1 H NMR (500 MHz, methanol-d 4)δ ppm 8.41 (d, J=1.22 Hz, 1H), 8.05 (s, 1H), 7.86-7.97 (m, 2H), 6.72-6.81 (m, 1H), 3.95 (s, 3H), 2.96-3.11 (m, 1H), 2.76-2.90 (m, 2H), 2.31 (s, 3H), 2.25-2.31 (m, 2H), 2.25-2.31 (m, 2H), 1.80 (s, 3H).

[0119] Synthesis of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide [ka] To a solution of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (4.05 g, 9.82 mmol) and DIPEA (2.81 g, 21.7 mmol, 3.8 mL) in THF (50 mL) was added acryloyl chloride (819 mg, 9.04 mmol, 740 μL) at 0° C. After 30 min, the reaction mixture was diluted with EtOAc (50 mL) and saturated NaHCO 3 Aqueous solution (50 mL) was added. The vigorously stirred biphasic mixture was allowed to reach room temperature and stirring was continued for an additional 30 min. The organic phase was separated and washed with water (25 mL) and brine (25 mL) and diluted with Na 2 SO 4 The resulting residue was purified by column chromatography (80 g of silica gel, 2% NH in heptane). 4 Purification was performed using 0-100% [3:1 EtOAc:EtOH] containing OH modifier. The colorless solid was recrystallized from EtOAc / heptane (1 / 3, 45 mL) to give the title compound as a free-flowing crystalline solid (1.8 g, 68% yield). Melting point = 137.5 °C LCMS m / z = 389.1.1 (M+Na)+. 1 H NMR (500 MHz, methanol-d 4)δ ppm 8.44 (s, 1H), 8.06 (s, 1H), 7.85-7.98 (m, 2H), 6.67-6.85 (m, 2H), 6.12-6.26 (m, 1H), 5.74 (br d, J=9.16 Hz, 1H), 4.45-4.77 (m, 1H), 3.95 (s, 3H), 2.94-3.12 (m, 3H), 2.62-2.94 (m, 4H), 1.86 (s, 3H).

[0120] Example 1. Preparation of Crystal Form A Form A was obtained by slurrying Form B in IPA at room temperature for 6 days. Crystalline Form A was analyzed using PXRD, TGA, and DSC. The PXRD pattern of crystalline Form A is shown in FIG. 1 and the major peaks are listed in Table 1A. A maximum weight loss of 0.6% at 150° C. was observed on the TGA curve as shown in FIG. 3. The DSC profile showing one endothermic peak at 137.3° C. (onset temperature) is shown in FIG. 3. 1 H NMR results (Figure 4) showed that no IPA was detected. The single crystal structure is shown in Figure 2. [Table 1] [Table 2]

[0121] Negligible weight loss in TGA and a clean DSC profile were observed, indicating that Form A is anhydrous.

[0122] Example 2. Preparation of Crystalline Form B [ka] THF (2.53 L) and compound 6 (230 g, 1.00 equiv.) were added to a 5 L reactor at 15°C-20°C. DIEA (285 g, 3.00 equiv.) was added to the solution at 15°C-20°C over 10 min. The mixture was cooled to 0°C for 5 min. Acryloyl chloride (83.3 g, 1.25 equiv.) was added to the mixture at 0°C-5°C. The mixture was stirred at 0°C for 1 h. Upon completion of the reaction (monitored by HPLC), water (1150 mL) was added slowly to quench the reaction. The organic layer was separated and the aqueous layer was extracted with MTBE (3 x 920 mL). The combined organic layers were washed with 0.2 M HCl (575 mL), separated and diluted with Na. 2 SO 4 The crude material was dried at 40° C., filtered and concentrated. The crude material was slurried with EtOAc (1150 mL) at 10° C. to give crystalline Form B (99.6% purity, QNMR 97.0%) as a white solid. The PXRD pattern of crystalline Form B is shown in FIG. 5 and the major peaks are listed in Table 2A. A weight loss of 0.5% was observed on the TGA curve at a maximum of 150° C. as shown in FIG. 7. The DSC profile showing one endothermic peak at 147.3° C. (onset temperature) is shown in FIG. 7, indicating no residual solvent. 1 H NMR (Figure 8) was detected. The single crystal structure is shown in Figure 6. [Table 3] [Table 4]

[0123] Negligible weight loss in TGA and a clean DSC profile were observed, indicating that Form B is anhydrous.

[0124] Example 3. Preparation of Crystalline Form I Equimolar amounts of Form B and maleic acid were slurried in IPAc at room temperature to give a clear solution. The mixture was cooled to -20°C for 1 day to give Form I as a solid. The solid was dried in vacuum at room temperature before characterization. The PXRD pattern of crystalline Form I is shown in Figure 9 and the major peaks are listed in Table 3. 1H NMR shows that the molar ratio of maleic acid to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is 1.0, and the molar ratio of residual solvent IPAc to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is 0.01 (0.2 wt%). As shown in Figure 10, a weight loss of 5.2% at a maximum of 90 °C was observed on the TGA curve. DSC analysis shows that Form I has a melting temperature of 94.6 °C (Figure 10). [Table 5]

[0125] Example 4. Preparation of Crystalline Form II Equimolar amounts of Form B and L-tartaric acid were slurried in IPA at room temperature to give a clear solution. The mixture was cooled at 5° C. for 1 day to give Form II as a solid. The solid was dried under vacuum at room temperature before characterization. The PXRD pattern of crystalline Form II is shown in FIG. 12 and the major peaks are listed in Table 4. 1 H NMR shows that the molar ratio of L-tartaric acid to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is 1.0, and the molar ratio of residual solvent IPA to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is 0.01 (0.2 wt%). As shown in FIG. 13, a maximum weight loss of 3.8% at 120° C. was observed on the TGA curve. DSC analysis shows that Form II has two endothermic signals (peaks) at 140.4° C., 149.2° C., and one exothermic signal at 165.5° C. (FIG. 13). [Table 6]

[0126] Example 5. Preparation of Crystalline Form III Equimolar amounts of Form B and L-tartaric acid were slurried in IPAc at room temperature to give Form III as a solid. The solid was dried under vacuum at room temperature before characterization. The PXRD pattern of crystalline Form III is shown in Figure 15 and the major peaks are listed in Table 5. 1 H NMR shows that the molar ratio of L-tartaric acid to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is 1.0, and the molar ratio of residual solvent IPAc to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is 0.01 (0.2 wt%). As shown in FIG. 16, a weight loss of 2.2% at a maximum of 120° C. was observed on the TGA curve. DSC analysis shows that Form III has one endothermic signal (peak) at 147.7° C. and one exothermic signal at 172.2° C. (FIG. 16). [Table 7]

[0127] Example 6. Preparation of Crystalline Form IV Equimolar amounts of Form B and citric acid were slurried in IPAc at room temperature to give Form IV as a solid. The solid was dried under vacuum at room temperature before characterization. The PXRD pattern of crystalline Form IV is shown in Figure 18 and the major peaks are listed in Table 6. 1H NMR shows that the molar ratio of citric acid to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is 1.22 (partially overlapped) and the molar ratio of residual solvent IPAc to N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide is 0.22 (3.9 wt%). As shown in FIG. 19, a weight loss of 7.9% at a maximum of 120° C. was observed on the TGA curve. DSC analysis shows that Form IV has one endothermic signal (peak) at 96.1° C. and one exothermic signal at 167.1° C. (FIG. 19). [Table 8]

[0128] Example 7. Preparation of crystalline form V Equimolar amounts of Form B and L-proline were slurried in IPA at room temperature to give Form V as a solid. The solid was dried under vacuum at room temperature before characterization. The PXRD pattern of crystalline Form V is shown in Figure 21 and the major peaks are listed in Table 7. 1 H NMR showed that the molar ratio of L-proline and N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide was 2.5, and no residual solvent IPAc was observed. As shown in FIG. 22, a weight loss of 5.7% at a maximum of 100° C. was observed on the TGA curve. DSC analysis shows that Form V has three endothermic signals (peaks) at 57.9° C., 86.1° C., and 148.4° C. (FIG. 22). [Table 9]

Claims

1. Crystal form A of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

2. 2. The crystalline form A of claim 1, wherein the crystalline form is characterized by at least three, at least four, at least five, at least six, or at least seven powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 10.1°, 10.6°, 14.3°, 16.9°, 17.8°, 18.2°, 19.4°, and 25.1°.

3. 2. The crystalline form A of claim 1, wherein the crystalline form is characterized by PXRD peaks at 2θ angles of 10.1°, 10.6°, 14.3°, 16.9°, 17.8°, 18.2°, 19.4°, and 25.1°.

4. 4. Form A according to any one of claims 1 to 3, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 10.1°, 10.6°, 11.9°, 14.3°, 16.9°, 17.8°, 18.2°, 19.4°, 21.3°, 22.2°, 23.0°, 24.0°, 25.1°, and 27.8°.

5. The crystalline form A according to any one of claims 1 to 4, wherein said crystalline form A is characterized by a melting temperature of 138.4°C ± 2°C as measured by Differential Scanning Calorimetry (DSC) analysis.

6. The crystalline form A according to any one of claims 1 to 5, wherein the crystalline form A is a non-hygroscopic anhydrate.

7. The crystalline form A of claim 1, wherein the crystalline form is characterized as space group P-1.

8. The crystal form has a molecular weight of 904.872 Å. ３ and three-dimensional parameters of a=5.98064 Å, b=10.28273 Å, and c=14.91842 Å.

9. 9. The crystalline form A of any one of claims 1 to 8, wherein the crystalline form A exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%.

10. Crystal form B of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

11. 11. The crystalline form B of claim 10, wherein the crystalline form is characterized by at least three, at least four, at least five, at least six, or at least seven powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 8.6°, 9.3°, 10.2°, 14.4°, 16.0°, 17.3°, 20.4°, and 25.4°.

12. 11. The crystalline form B of claim 10, wherein the crystalline form is characterized by PXRD peaks at 2θ angles of 8.6°, 9.3°, 10.2°, 14.4°, 16.0°, 17.3°, 20.4°, and 25.4°.

13. 13. Crystalline Form B according to any one of claims 10 to 12, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 8.6°, 9.3°, 10.2°, 14.4°, 16.0°, 17.3°, 18.7°, 20.4°, 21.4°, 21.9°, 22.7°, 25.4°, and 28.4°.

14. The crystalline form B according to any one of claims 10 to 13, characterized by a melting temperature of 148.3°C ± 2°C as measured by Differential Scanning Calorimetry (DSC) analysis.

15. The crystalline form B according to any one of claims 10 to 14, wherein the crystalline form B is a non-hygroscopic anhydrate.

16. The crystalline form B of claim 10, wherein the crystalline form is characterized as space group P21 / c.

17. The crystal form has a molecular weight of 1859.45 Å. ３ and three-dimensional parameters: a = 9.4633 Å, b = 20.6615 Å, c = 9.5408 Å.

18. 18. The crystalline form B of any one of claims 10 to 17, wherein the crystalline form B exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%.

19. Crystalline Form I of the maleate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

20. 20. The crystalline form I of claim 19, wherein the crystalline form is characterized by at least three or at least four powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 3.9°, 11.4°, 15.2°, 16.6°, and 19.2°.

21. 20. The crystalline form I of claim 19, wherein the crystalline form is characterized by PXRD peaks at 2θ angles of 3.9°, 11.4°, 15.2°, 16.6°, and 19.2°.

22. 22. Crystalline Form I according to any one of claims 19 to 21, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 3.9°, 11.4°, 12.4°, 15.2°, 16.6°, 19.2°, and 21.3°.

23. 23. The crystalline form I of any one of claims 19 to 22, wherein the crystalline form I is characterized by a melting temperature of 94.6°C ± 2°C as measured by Differential Scanning Calorimetry (DSC) analysis.

24. 24. The crystalline form I of any one of claims 19 to 23, wherein the crystalline form I exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%.

25. Crystalline Form II of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

26. 26. The crystalline form II of claim 25, wherein the crystalline form is characterized by at least three or at least four powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 4.6°, 9.2°, 13.1°, 17.2°, and 21.7°.

27. 26. The crystalline form II of claim 25, wherein the crystalline form is characterized by PXRD peaks at 2θ angles of 4.6°, 9.2°, 13.1°, 17.2°, and 21.7°.

28. 28. Crystalline Form II according to any one of claims 25 to 27, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 4.6°, 9.2°, 13.1°, 14.0°, 14.4°, 17.2°, 18.6°, 19.4°, 21.7°, 22.1°, and 26.1°.

29. 29. The crystalline form II of any one of claims 25 to 28, wherein the crystalline form II is characterized by endothermic peaks at 140.4°C ± 2°C and 149.2°C ± 2°C as measured by differential scanning calorimetry (DSC) analysis.

30. 30. The crystalline form II of any one of claims 25 to 29, wherein the crystalline form II exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%.

31. Crystalline Form III of the tartrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

32. 32. The crystalline Form III of claim 31 , wherein the crystalline form is characterized by at least three, at least four, at least five, at least six, or at least seven powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 4.9°, 7.3°, 9.7°, 13.2°, 14.6°, 16.4°, 18.6°, and 23.3°.

33. 32. The crystalline Form III of claim 31, wherein the crystalline form is characterized by PXRD peaks at 2θ angles of 4.9°, 7.3°, 9.7°, 13.2°, 14.6°, 16.4°, 18.6°, and 23.3°.

34. 34. The crystalline Form III of any one of claims 31 to 33, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 4.9°, 7.3°, 9.7°, 13.2°, 14.4°, 14.6°, 15.3°, 16.4°, 17.0°, 18.6°, 20.1°, 20.9°, 23.3°, and 24.5°.

35. 35. The crystalline form III of any one of claims 31 to 34, wherein the crystalline form III is characterized by a melting temperature of 147.7°C ± 2°C as measured by Differential Scanning Calorimetry (DSC) analysis.

36. 36. The crystalline form III of any one of claims 31 to 35, wherein the crystalline form III exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%.

37. Crystalline Form IV of the citrate salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

38. 38. Crystalline Form IV according to claim 37, wherein the crystalline form is characterized by at least three, at least four, at least five, or at least six powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 4.9°, 8.6°, 9.9°, 12.2°, 14.9°, 18.0°, and 19.9°.

39. 38. Crystalline Form IV according to claim 37, wherein the crystalline form is characterized by PXRD peaks at 2θ angles of 4.9°, 8.6°, 9.9°, 12.2°, 14.9°, 18.0°, and 19.9°.

40. 40. The crystalline form IV of any one of claims 37 to 39, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 4.9°, 8.6°, 9.9°, 12.2°, 14.9°, 15.8°, 18.0°, 19.9°, 21.2°, and 22.7°.

41. 41. The crystalline form IV of any one of claims 37 to 40, wherein the crystalline form IV is characterized by a melting temperature of 96.1°C ± 2°C as measured by Differential Scanning Calorimetry (DSC) analysis.

42. 42. The crystalline form IV of any one of claims 37 to 41, wherein the crystalline form IV exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%.

43. Crystal form V of the proline salt of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide.

44. 44. The crystalline form V of claim 43, wherein the crystalline form is characterized by at least three powder X-ray diffraction (PXRD) peaks at 2θ angles selected from 8.6°, 17.3°, 19.1°, and 26.0°.

45. 44. Crystalline Form V according to claim 43, wherein the crystalline form is characterized by PXRD peaks at 2θ angles of 8.6°, 17.3°, 19.1°, and 26.0°.

46. 46. ​​Form V according to any one of claims 43 to 45, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 8.6°, 14.7°, 17.3°, 19.1°, 22.9°, 25.2°, and 26.0°.

47. 47. The crystalline form V of any one of claims 43 to 46, wherein the crystalline form V is characterized by a melting temperature of 148.4°C ± 2°C as measured by Differential Scanning Calorimetry (DSC) analysis.

48. 48. The crystalline form V of any one of claims 43 to 47, wherein the crystalline form V exhibits a purity of at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%.

49. 1. A pharmaceutical composition comprising a pharma- ceutical acceptable excipient and (i) crystalline form A according to any one of claims 1 to 9, or (ii) crystalline form B according to any one of claims 10 to 18, or (iii) crystalline form I according to any one of claims 19 to 24, or (iv) crystalline form II according to any one of claims 25 to 30, or (v) crystalline form III according to any one of claims 31 to 36, or (vi) crystalline form IV according to any one of claims 37 to 42, or (vii) crystalline form V according to any one of claims 43 to 48.

50. 13. A method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase in a subject, comprising administering to the subject an effective amount of (i) crystalline form A according to any one of claims 1 to 9, or (ii) crystalline form B according to any one of claims 10 to 18, or (iii) crystalline form I according to any one of claims 19 to 24, or (iv) crystalline form II according to any one of claims 25 to 30, or (v) crystalline form III according to any one of claims 31 to 36, or (vi) crystalline form IV according to any one of claims 37 to 42, or (vii) crystalline form V according to any one of claims 43 to 48.

51. 51. The method of claim 50, wherein the disorder is an autoimmune disorder.

52. 52. The method of claim 51, wherein the autoimmune disorder is multiple sclerosis.

Images