Solid and co-crystal forms of pyrimidine triazole compounds

Abstract

The present disclosure relates to crystalline and amorphous forms of N2-(3-(2-(2H-1, 2, 3-triazol-2-yl) propan-2-yl)-1-cyclopropyl-1 / / -pyrazol-5-yl)- / V7-ethyl-5-(trifluoromethyl) pyrimidine-2, 4-diamine, co-crystals, pharmaceutical compositions, and formulations thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 422,339, filed on November 3, 2022, which is incorporated by reference in its entirety. Technical Field

[0003] This disclosure relates to N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Crystalline polymorphs and amorphous forms of 5-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and co-crystals thereof are used to treat peripheral and neurodegenerative diseases, including Parkinson's disease. Background Art

[0004] Combined genetic and biochemical evidence suggests that certain kinases function in the pathogenesis of neurodegenerative disorders (Christensen, KV (2017) Progress in medicinal chemistry 56:37-80; Fuji, RN et al. (2015) Science Translational Medicine 7(273):273ra15; Taymans, JM et al. (2016) Current Neuropharmacolog y 14(3):214-225). Kinase inhibitors are being studied for the treatment of Alzheimer's disease, Parkinson's disease, ALS, and other diseases (Estrada, AA et al. (2015) J. Med. Chem. 58(17):6733-6746; Estrada, AA et al. (2013) J. Med. Chem. 57:921-936; Chen, H. et al. (2012) J. Med. Chem. 55:5536-5545; Estrada, AA et al. (2015) J. Med. Chem. 58:6733-6746; Chan, BK et al. (2013) ACS Med. Chem. Lett. 4:85-90; US 8354420; US 8569281; US ​​8791130; US 8796296; US 8802674; US 8809331; US ​​8815882; US 9145402; US 9212173; US 9212186; US 9932325; US10590114; US11111235; and WO 2012 / 062783.

[0005] Multiple crystalline forms of a drug substance with varying solid-state properties may exhibit differences in bioavailability, shelf life, physicochemical properties (including melting point, crystal morphology, intrinsic dissolution rate, solubility, stability, and in-process properties). X-ray powder diffraction (XRPD) is a powerful tool for identifying different crystalline phases through their distinctive diffraction patterns. Other techniques such as solid-state nuclear magnetic resonance (NMR) spectroscopy, Raman spectroscopy, and differential scanning calorimetry (DSC) are also available.

[0006] The pharmaceutical industry is often faced with the phenomenon of multiple polymorphs of the same crystalline chemical entity. Polymorphism is generally characterized by the ability of a drug substance (i.e., active pharmaceutical ingredient (API)) to exist in two or more crystalline phases with different molecular arrangements and / or conformations within the crystal lattice, thereby imparting distinct physicochemical properties to the crystal. The ability to reliably produce selected polymorphic forms is a key factor in consistent drug product performance.

[0007] Regulatory agencies worldwide require reasonable measures to identify polymorphs of drug substances and to check for polymorphic interconversion. Because polymorphs often have unpredictable properties and differ in their physicochemical characteristics, it is essential to demonstrate manufacturing consistency between batches of the same product. A sound understanding of the polymorphic profile and properties of drug polymorphs will facilitate manufacturing consistency.

[0008] Atomic-level crystal structure determination and intermolecular interactions provide crucial information for establishing absolute configuration (enantiomers), phase identification, quality control, and method development control and optimization. X-ray diffraction is widely recognized as a reliable tool for structural analysis of pharmaceutical solid crystals and identification of crystalline forms.

[0009] Single crystals of the drug substance are preferred due to the speed and accuracy of structure determination. However, it is not always possible to obtain crystals of a suitable size for data collection. Synchrotron X-ray powder diffraction is a useful technique. In such cases, the crystal structure can be solved based on X-ray powder diffraction data obtained through measurements under ambient conditions and / or variable temperature or humidity.

[0010] There is a need to develop new polymorphic forms and co-crystals of drug substances and methods for their preparation.

[0011] The present disclosure relates to LRRK2 inhibitors N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4

[00145] In crystalline, amorphous, and co-crystal forms of 5-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, the inhibitor is referred to herein as a compound of Formula I and has the following structure:

[0012]

[0013] In one embodiment, a crystalline compound of Formula I is provided, which is selected from:

[0014] the Form A polymorph which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2Θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6; and

[0015] The Form B polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2Θ at approximately 8.0, 9.9, 16.1, 19.9, and 23.2.

[0016] In some embodiments, a Form A polymorph of Formula I is provided that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6. In other embodiments, the Form A polymorph further comprises peaks at approximately 5.4 and 7.4 degrees 2θ.

[0017] In some embodiments, differential scanning calorimetry (DSC) of the Form A polymorph shows a melting endotherm with an onset at about 107.1 °C.

[0018] In some embodiments, the Form A polymorph is an anhydrate.

[0019] In some embodiments, the Form A polymorph is characterized by Figure 2 X-ray powder diffraction pattern shown.

[0020] In other embodiments, provided is Form B polymorph of Formula I which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2Θ at approximately 8.0, 9.9, 16.1, 19.9, and 23.2.

[0021] In some embodiments, a crystalline compound of Formula I is provided in substantially pure form. In other embodiments, a co-crystal thereof of Formula I is provided in substantially pure form.

[0022] In some embodiments, the X-ray powder diffraction pattern of the crystalline compound or co-crystal of Formula I is prepared using CuKα1 radiation.

[0023] In some embodiments, N is provided 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4

[00146] A crystalline compound of -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine exhibiting an X-ray powder diffraction pattern having characteristic peaks expressed in ±0.3 degrees 2Θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6.

[0024] In some embodiments, a pharmaceutical composition is provided comprising a crystalline polymorph of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. In some embodiments, the crystalline polymorph is Form A.

[0025] In some embodiments, an amorphous compound, an amorphous form CN is provided. 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine.

[0026] In some embodiments, a pharmaceutical composition is provided that comprises an amorphous compound of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

[0027] In some embodiments, the preparation of compound N is provided 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 A process for the preparation of Amorphous Form C of 5-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine comprising heating the crystalline form of the compound until dissolved, followed by cooling to form the amorphous compound.

[0028] In some embodiments, there is provided a 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Co-crystals of ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and a coformer, and hydrates thereof.

[0029] In some embodiments, a pharmaceutical composition is provided comprising a co-crystal of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

[0030] In some embodiments, there is provided a method of preparing a co-crystal of any one of Formula I comprising: 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine is contacted with the coformer.

[0031] In some embodiments, the coformer is selected from 4-acetamidobenzoic acid, acetylsalicylic acid, trans-aconitic acid, adipic acid, benzoic acid, butyric acid, cholic acid, gallic acid, glutaric acid, fumaric acid, 4-hydroxybenzoic acid, isobutyric acid, malonic acid, D,L-mandelic acid, propionic acid, salicylic acid, succinic acid, terephthalic acid, and vanillic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The interconversion relationship between polymorphic Forms A and B of the compound of Formula I and amorphous Form C is shown schematically.

[0033] Figure 2 The XRPD pattern showing the Form A polymorph.

[0034] Figure 3An overlay of the XRPD patterns of polymorph Form A and Form B of the compound of Formula I is shown.

[0035] Figure 4 TGA and DSC data showing Form A polymorph.

[0036] Figure 5 Thermal ellipsoid plot showing the asymmetric unit molecule of the single crystal X-ray structure of the Form A polymorph.

[0037] Figure 6 The XRPD diffraction pattern of amorphous Form C is shown.

[0038] Figure 7 PLM image showing a Form A single crystal.

[0039] Figure 8 Shown is an XRPD overlay comparing Form A after storage for 6 months at 40°C / 75% RH and 25°C / 60% RH.

[0040] Figure 9 Shown is an XRPD overlay comparing Form A after storage at 25°C / 60% RH for 48 months.

[0041] definition

[0042] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and are consistent with the following:

[0043] The words “comprise,” “comprising,” “include,” “including,” and “includes,” when used in this specification and claims, are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0044] As used herein, the term "about" or "approximately" when used in reference to the position of an X-ray powder diffraction pattern peak means that the peak depends on, for example, the calibration of the equipment used, the method used to generate the polymorph, the age of the crystalline material, etc., and on the inherent variability of the instrument used. In this case, the measurement variability of the instrument is about plus / minus ±0.3 degrees 2θ (θ). Unless otherwise stated, those skilled in the art who have the benefit of this disclosure will understand the use of "about" or "approximately" herein (e.g., ±0.05 degrees 2θ). The term "about" or "approximately" when referring to other defined parameters (e.g., water content, C max , t maxWhen the term "about" is used, it indicates the inherent variability in, for example, measuring the parameter or achieving the parameter. Those skilled in the art who have the benefit of this disclosure will understand the variability of the parameter as implied by the use of the word about or approximately.

[0045] As used herein, "polymorph" refers to the occurrence of different crystalline forms of a compound with different packing or conformation / configuration but the same chemical composition. Crystalline forms have different molecular arrangements and / or conformations in the crystal lattice. Solvates are crystalline forms that contain stoichiometric or non-stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is often referred to as a hydrate. For compounds with the same solvent content but different lattice packing or conformation, hydrates / solvates can exist as polymorphs. Thus, a single compound can produce multiple polymorphic forms, each with different and distinct physical properties, such as solubility profile, melting point temperature, hygroscopicity, particle shape, morphology, density, flowability, compressibility, and / or X-ray diffraction peaks. The solubility of each polymorph may vary, and therefore, identifying the presence of drug polymorphs is crucial for providing drugs with predictable solubility profiles. It is desirable to characterize and study all solid-state forms of a drug (including all polymorphic forms) and to determine the stability, dissolution, and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by X-ray diffraction and other methods such as infrared or Raman or solid-state NMR spectroscopy. For a general overview of polymorphs and the pharmaceutical applications of polymorphs, see G.M.Wall, Pharm Manuf. 3:33 (1986); J.K. Haleblian and W. McCrone, J. Pharm. Sci., 58:911 (1969); "Polymorphism in Pharmaceutical Solids, 2nd Edition (Drugs and the Pharmaceutical Sciences)", Harry G. Brittain, ed. (2011) CRC Press (2009); and J.K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

[0046] The acronym "XRPD" refers to X-ray powder diffraction, an analytical technique that measures X-ray diffraction in the presence of a solid component and displays an X-ray diffraction pattern. X-ray diffraction patterns can be produced using CuKα1 radiation. Materials that are crystalline and have a regularly repeating array of atoms produce a unique powder pattern. Materials with similar unit cells will produce X-ray diffraction patterns with similar positions (measured in degrees 2θ (θ)). Solvates that exhibit this behavior are called isostructural or isomorphous solvates. The intensity of the reflections varies depending on the electron density causing the diffraction, as well as the sample, sample preparation, and instrument parameters. Analysis of XRPD data is based on the overall appearance of the measured powder pattern relative to the known response of the X-ray diffraction system used to collect the data. For any diffraction peaks that may be present in the powder pattern, their position, shape, width, and relative intensity distribution can be used to characterize the type of solid-state order in the powder sample. The position, shape, and intensity of any broad, diffuse scattering (halo) above the instrument background can be used to characterize the level and type of solid-state disorder. A comprehensive interpretation of the solid-state order and disorder present in a powder sample provides a qualitative measure of the sample's macrostructure.

[0047] The term "co-crystal" refers to a crystalline molecular complex composed of two or more different molecular compounds, generally in a stoichiometric ratio, that is neither a solvate nor a simple salt. A co-crystal consists of a hydrogen-bonded complex with a "pharmaceutically acceptable" co-former (Aitipamula, S. et al. (2012) Cryst. Growth Des. 12(5):2147–2152). Co-formers include, but are not limited to, acetylsalicylic acid, trans-aconitic acid, adipic acid, L-ascorbic acid, benzoic acid, citric acid, fructose, fumaric acid, gallic acid, glucose, glutaric acid, hippuric acid, 4-hydroxybenzoic acid, maleic acid, malonic acid, mannitol, nicotinamide, nicotinic acid, phenylalanine, riboflavin, salicylic acid, succinic acid, and vanillic acid.

[0048] The term "hydrate" refers to a complex wherein the solvent molecule is water.

[0049] The abbreviation "RH" refers to relative humidity

[0050] Compounds of formula I

[0051] The present disclosure includes polymorphs, co-crystals, and amorphous forms of the compound of Formula I (CAS Registry No. 2170179-24-3), which has the following structure:

[0052]

[0053] And named: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (WO 2017 / 218843, US 9932325, each of which is incorporated by reference).

[0054] Preparation of compounds of formula I

[0055]

[0056] 2-Methyl-2-(2H-1,2,3-triazol-2-yl)propanoic acid methyl ester: To a mixture of 2H-1,2,3-triazole (190 g, 2.75 mol) in THF (800 mL) was added t-BuOK (339.54 g, 3.03 mol) at 0°C and then stirred for 1 hour. 2-Bromo-2-methyl-propionic acid methyl ester (547.62 g, 3.03 mol) was then added dropwise at 0°C over 1 hour, and the mixture was stirred at 25°C for 2 hours. The mixture was poured into ice water (2 L) and stirred for 5 minutes. The aqueous phase was extracted with EtOAc (3 x 800 mL). The combined organic phases were washed with brine (4 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO 2 , PE:EtOAc=100:1 to 1:1) to give methyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propanoate (245 g, 26.3%) as a yellow oil. 1 H NMR: (400MHz, CDCl3): δ7.69(s,2H),3.74(s,3H),1.99(s,6H).

[0057] 4-Methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile: To a mixture of MeCN (36.9 g, 898.5 mmol) in THF (1.00 L) at -78°C under N2 was added n-BuLi (2.5 M in THF, 359.4 mL) dropwise and stirred for 1 h. Methyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propanoate (76 g, 449.2 mmol) in THF (500 mL) was then added dropwise at -78°C over 1 h, and the reaction was stirred at -78°C for 1.5 h. The mixture was poured into ice water (1 L) and stirred for 5 min. The pH of the mixture was adjusted to 4-5 with aqueous HCl (2 M), and the aqueous phase was extracted with EtOAc (3 x 800 mL). The combined organic phases were washed with brine (800 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with MTBE (500 mL) and filtered to give 4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile (130 g, 81.2%) as a purple solid.1 H NMR (400MHz, CDCl3): δ7.38 (s, 2H), 3.11 (s, 2H), 1.90 (s, 6H).

[0058] 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine: To a mixture of 4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile (45 g, 252.5 mmol) and cyclopropylhydrazine dihydrochloride (54.9 g, 378.8 mmol) in EtOH (1 L) was added concentrated HCl (12 M, 9.03 mL) in one portion at 25 °C under N2. The mixture was stirred at 90 °C for 10 h. Aqueous NaHCO3 solution was added to the mixture and the pH was adjusted to 7-8. The aqueous phase was extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, PE:EtOAc = 100:1 to 1:1) to give 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (42 g, 71.6%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ7.6(s,2H),5.05(s,1H),3.72(br s,2H),3.14-3.09(m,1H),2.05(s,6H),1.14-1.12(m,2H),1.04-1.01(m,2H).

[0059] N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine: To a mixture of 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (42 g, 180.8 mmol) and 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidine-4-amine (40.8 g, 180.8 mmol) in 1,4-dioxane (840 mL) was added TsOH.HO (4.1 g, 21.7 mmol) in one portion at 25 °C under N2. The mixture was stirred at 90 °C for 10 h. The mixture was poured into aqueous NaHCO3 (1500 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 x 600 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (SiO2, PE: EtOAc = 100: 1 to 3: 1) and washing with MTBE gave a crude product (72 g). 70 g of the product was suspended in n-heptane (250 mL) and heated to 70 ° C with stirring. MTBE (210 mL) was added to the solution in batches at 70 ° C until the solid dissolved. The hot solution was filtered. The filtrate was cooled to room temperature and allowed to stand for 16 h. The resulting crystals were filtered and washed with a small amount of n-heptane to give N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (64 g, 47.03%). 1 HNMR (400MHz, CDCl3): δppm 8.13(s,1H),7.62(s,2H),7.29(br s,1H),6.12(s,1H),5.18(br s,1H),3.37-3.47(m,2H),3.23(tt,J=6.95,3.59Hz,1H),2.10(s,6H),1.17-1.26(m,5H),1.08-1.16(m,2H). MS:(M+H + )m / z:422.2.

[0060] Polymorph screening of compounds of formula I

[0061] Polymorph screening experiments were performed using a variety of crystallization or solid state transformation methods, including: antisolvent addition, slow evaporation, slow cooling, room temperature slurrying, slurry cycling, solid vapor diffusion, liquid vapor diffusion, polymer-induced crystallization, and melting / cooling. By these methods, Forms A, B, and C were identified.

[0062] like Figure 1As shown, Form A was found to be a stable crystalline form and could be converted to a mixture of Form A and Form B by crystallization from cyclohexane and methyl isobutyl ketone (MIBK). After one month at room temperature, the mixture reverted to Form A. Form A was heated to 110°C and then cooled to -20°C to form amorphous Form C, which converted back to Form A upon warming to room temperature.

[0063] The 24-hour solubility assessment showed that Form A has a solubility of 29.9 μg / mL in water. DVS (dynamic vapor sorption) results showed that Form A is not hygroscopic, as defined by a reversible water uptake of less than 0.2% (Table 1).

[0064] Table 1.

[0065]

[0066] Polymorph screening

[0067] A total of 70 polymorph screening experiments were performed using different crystallization or solid state transformation methods. The methods used and the crystal forms identified are summarized in Table 2 below.

[0068] Table 2.

[0069] method Number of experiments Identified crystal forms Antisolvent addition 14 Form A, Form A + Form B Slow evaporation 8 Form A Slow cooling 5 Form A, gel Room temperature slurry 15 Form A Circulation sizing 8 Form A Solid vapor diffusion 7 Form A, gel Liquid vapor diffusion 9 Form A polymer-induced crystallization 4 Form A total 70 Form A, Form A + Form B, gel

[0070] Antisolvent addition

[0071] A total of 14 antisolvent addition experiments were performed. Approximately 20 mg of the compound of Formula I was dissolved in 0.1-0.7 mL of solvent to obtain a clear solution. The solution was magnetically stirred, and then 0.1 mL of antisolvent was added in each step until precipitation occurred or the total amount of antisolvent reached 10.0 mL. The precipitate was isolated for XRPD analysis. The results in Table 3 below show that Form A and Form A + Form B were generated.

[0072] Table 3.

[0073]

[0074] *10 mL of anti-solvent was added to the corresponding solution, but a clear solution was obtained, and then transferred to evaporate at room temperature.

[0075] Slow evaporation

[0076] Slow evaporation experiments were performed under eight conditions. Approximately 20 mg of the compound of formula I was dissolved in 0.5 mL of solvent in a 3 mL glass vial. If not completely dissolved, the compound was filtered using a PTFE membrane (pore size 0.45 μm) and the filtrate was used in the subsequent step instead. The visually clear solution was washed with water at room temperature. The sealed vial was evaporated.The solid was isolated for XRPD analysis and the results summarized in Table 4 show that only Form A was found.

[0077] Table 4.

[0078]

[0079]

[0080] Slow cooling

[0081] Slow cooling experiments were performed in five different solvent systems. Approximately 20 mg of the compound of formula I was suspended in 0.4-1.0 mL of solvent in a 5 mL vial. The suspension was then heated to 50° C. and equilibrated for approximately 2 hours. If not completely dissolved, the compound was filtered using a PTFE membrane (pore size of 0.45 μm). The clear solution was slowly cooled from 50° C. to 5° C. at a rate of 0.1° C. / min. The resulting solid was collected for XRPD analysis. The results summarized in Table 5A show that Form A and a gel-like substance were generated.

[0082] Table 5A.

[0083] Solvent (v / v) Solid form <![CDATA[EtOH / H2O(1:4)]]> Gel* MIBK / n-heptane (1:4) Form A IPAc / cyclohexane (1:4) Form A MTBE / n-heptane (1:4) Form A Toluene / cyclohexane (1:4) Form A

[0084] *A clear solution was obtained after cooling and then transferred to evaporate at room temperature.

[0085] Slurry conversion

[0086] Slurry conversion experiments were conducted at room temperature in 15 different solvent systems. Approximately 20 mg of the compound of Formula I was suspended in 0.2-0.3 mL of solvent in a 1.5 mL glass vial. After the suspension was magnetically stirred at room temperature for four days, the remaining solid was isolated for XRPD analysis. In all experiments, only Form A was generated.

[0087] Table 5B.

[0088] Solvent (v / v) Solid form <![CDATA[H2O]]> Form A n-heptane Form A Cyclohexane Form A EtOH / n-heptane (1:4) Form A MEK / cyclohexane (1:4) Form A EtOAc / cyclohexane (1:9) Form A MTBE / n-heptane (1:4) Form A DCM / cyclohexane (1:4) Form A Toluene / n-heptane (1:4) Form A <![CDATA[THF / DMAc / H2O(1:1:8)]]> Form A IPAc / 1,4-dioxane / n-heptane (1:1:8) Form A <![CDATA[IPA / H2O(a w ~0.2,98:2)]]> Form A <![CDATA[IPA / H2O(a w ~0.4,96:4)]]> Form A <![CDATA[IPA / H2O(a w ~0.6,92:8)]]> Form A* <![CDATA[IPA / H2O(a w ~0.8 85:15)]]> Form A

[0089] *A clear solution was obtained and then transferred to a slurry at 5°C.

[0090] Slurry cycle

[0091] Slurry cycle experiments were performed in eight different solvent systems. Approximately 25 mg of the compound of formula I was suspended in 0.2-0.3 mL of solvent in a 1.5 mL glass vial. After magnetic stirring (approximately 1000 rpm) at 70° C. for one day, the suspension was transferred to a slurry at 50° C. and maintained for three days. The results summarized in Table 5C below show that only Form A was generated.

[0092] Table 5C.

[0093] Solvent (v / v) Solid form <![CDATA[H2O]]> Form A n-heptane Form A Cyclohexane Form A n-BuOH / n-heptane (1:9) Form A MIBK / cyclohexane (1:9) Form A Butyl acetate / n-heptane (1:9) Form A 2-MeTHF / cyclohexane (1:9) Form A <![CDATA[ACN / DMSO / H2O(1:1:18)]]> Form A

[0094] Solid vapor diffusion

[0095] Seven different solvents were used to conduct solid vapor diffusion experiments. Approximately 10 mg of the compound of Formula I was weighed into a 3 mL vial and placed into a 20 mL vial with 4 mL of a volatile solvent. The 20 mL vials were sealed with lids and stored at room temperature for nine days to allow the solvent vapor to interact with the sample. The solids were tested by XRPD, and the results summarized in Table 6 below show that Form A and a gel were generated.

[0096] Table 6.

[0097] solvent Solid form <![CDATA[H2O]]> Form A EtOH Form A* acetone Gel* EtOAc Form A* THF Form A* DCM Form A* Cyclohexane Form A

[0098] *A clear solution was obtained and then transferred to evaporate at room temperature.

[0099] Liquid vapor diffusion

[0100] Nine liquid vapor diffusion experiments were carried out. Approximately 20 mg of the compound of formula I was dissolved in 0.1 to 0.7 mL of an appropriate solvent to obtain a clear solution in a 3 mL vial. If it was not completely dissolved, the compound was filtered into a new vial. The solution was then placed in a 20 mL vial with 4 mL of a volatile solvent (anti-solvent). The 20 mL vial was sealed with a lid and stored at room temperature so that there was enough time for the anti-solvent vapor to interact with the solution. The precipitate was separated and used for XRPD analysis. The results summarized in Table 7A below show that only Form A was observed.

[0101] Table 7A

[0102]

[0103]

[0104] *A clear solution was obtained and then transferred to evaporate at room temperature

[0105] polymer-induced crystallization

[0106] Two groups of polymer mixtures were used to implement polymer-induced crystallization experiments in four different solvent systems. Approximately 20 mg of the compound of Formula I was dissolved in 1.0-2.0 mL of a suitable solvent in a 3 mL glass vial containing approximately 2 mg of the polymer mixture. The clear solution was transferred to evaporate at room temperature. The resulting solid was collected for XRPD characterization. The results summarized in Table 7B below show that only Form A was generated.

[0107] Table 7B

[0108]

[0109] Polymer mixture A: polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), methylcellulose (MC) (mass ratio of 1:1:1:1:1:1). Polymer mixture B: polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA), sodium alginate (SA), and hydroxyethyl cellulose (HEC) (mass ratio of 1:1:1:1:1).

[0110] General approach

[0111] XRPD

[0112] XRPD patterns were collected using a PANalytical Empyrean X-ray powder diffractometer. The X-ray source was a Cu tube operated at 45 kV and 40 mA. The scan mode was continuous, and the divergence slit was automatic. Each sample was analyzed from 3° to 40° 2θ with a step length of 0.0167° 2θ and a scan step time of 18 seconds.

[0113] Table 8. Parameters of XRPD test

[0114]

[0115] DSC / TGA

[0116] DSC analysis was performed on a TA Instruments Q2000 DSC. The DSC cell was maintained under a nitrogen purge. The sample was placed in an aluminum crimp pan and heated from 25°C to 300°C at a rate of 10°C / min.

[0117] TGA data were collected using a TA Instruments TA Q500 / Q5000 TGA. TGA was performed using a nitrogen purge. Each sample was placed in an open aluminum pan and heated from room temperature to 350°C at a rate of 10°C / min. DSC analysis was performed on a TA Instruments Q200 / Q2000 DSC. The DSC cell was maintained under a nitrogen purge. The samples were placed in aluminum crimp pans and heated from 25°C to 300°C at a rate of 10°C / min.

[0118] Table 9. Parameters of TGA and DSC tests

[0119]

[0120]

[0121] DVS

[0122] Use SMS (surface measurement system) DVS Intrinsic analyzer to implement DVS analysis. The relative humidity at 25 ℃ is calibrated for the deliquescence point of LiCl, Mg (NO 3 ) 2 and KCl. About 15-20mg sample is loaded into a dish and analyzed. A nitrogen flow rate of 200mL / min is used. The sample is analyzed at 25 ℃ and 0 to 95% relative humidity (RH), wherein from 0 to 90% RH, the step is 10% RH, from 90% to 95% RH, the step is 5% RH. The progress from one step to the next step occurs after meeting the equilibrium criterion of 0.002% / min weight change (dm / dt), or occurs after 180min when the equilibrium criterion is not met. The minimum dm / dt stable duration of each step is 10min.

[0123] Form A representation

[0124] Form A was characterized by XRPD, TGA, DSC, DVS, and polarized light microscopy (PLM). XRPD ( Figure 2 , Table 10) showed a highly crystalline structure. TGA indicated a low weight loss, and DSC indicated a single sharp melting at around 107°C ( Figure 4 DVS showed that Form A was not hygroscopic and did not undergo form changes upon exposure to humidity. PLM examination indicated irregular, plate-like particles. Based on the characterization results, Form A is the anhydrate form.

[0125] Table 10. Form A

[0126]

[0127]

[0128] Stability of Form A

[0129] To evaluate the stability of the solid form, Form A was stored at 40°C / 75% RH (relative humidity, accelerated) and 25°C / 60% RH (long-term). Form A demonstrated physical and chemical stability for up to 6 months at 40°C / 75% RH and up to 48 months at 25°C / 60% RH. Samples were analyzed for appearance, HPLC purity, and polymorphic form. No form changes were detected by XRPD, and no purity changes were observed by HPLC.

[0130] Table 11. Form A Stability Assessment

[0131]

[0132] Form A + Form B (mixture)

[0133] The Form A + Form B mixture was prepared by adding cyclohexane (antisolvent) to a methyl isobutyl ketone solution. The Form A + Form B mixture was characterized by XRPD ( Figure 3 )

[0134] Table 12. Diffraction peak list of Form A + Form B mixture

[0135]

[0136]

[0137] Form C (amorphous)

[0138] Form C (amorphous free base) was prepared by heating Form A at 110 °C until the solid was completely melted and then transferred to -20 °C.

[0139] Form C was characterized by XRPD and DSC. The XRPD trace showed a characteristic amorphous halo and no significant diffraction peaks ( Figure 6 ).

[0140] Single crystal determination of Form A

[0141] Form A SXRPD characterization

[0142] The appropriate single crystal was selected from the bulk crystal and analyzed by single crystal X-ray diffractometer (SCXRD). The structure of the single crystal was successfully determined. SCXRD characterization and analysis showed that the crystal system was triclinic and the space group was The unit cell parameters and calculated unit cell volume are: α=83.133(3)°,β=89.725(3)°,γ=67.773(4)°,V=1985.63(14).The formula weight is 421.44 g mol-1, and Z=4, resulting in a calculated density of 1.410 g cm-3.

[0143] Crystal growth procedure

[0144] Bulk single crystals of Form A for single crystal X-ray diffraction (SCXRD) characterization were obtained by liquid vapor diffusion from a DMSO and H2O solvent system at room temperature. The PLM image of Form A single crystal is shown in FIG. Figure 7 shown.

[0145] Data collection

[0146] Colorless bulk single crystals selected from the Form A single crystal sample were randomly oriented and immersed in a nitrogen stream at 150 K. The diffractometer was equipped with an Agilent SuperNova (dual, Cu at zero, Eos) diffractometer (equipped with a SuperNova microfocus X-ray source). Preliminary inspection and data collection were performed on a CrysAlisPro (CrysAlisPro, version 1.171.38.41) detector and analyzed using the CrysAlisPro software package. The unit cell constants and orientation matrix for the data collection were obtained from least-squares refinement using a set angle of 9816 reflections in the range 4.3580° < θ < 70.5170°. Data were collected at 150 K to a maximum diffraction angle (2θ) of 141.114°. The data set was 97.97% complete, with an average I / σ of 27.8 and a D min (Cu) of 1.

[0147] Data reduction

[0148] The frames were integrated using CrysAlisPro (version: 1.171.38.41). A total of 14,156 reflections were collected, of which 7,446 were unique. Lorentz and polarization corrections were applied to the data. The linear absorption coefficient of Cu / Kα radiation was 0.944 mm-1. Semi-empirical absorption correction was performed using spherical harmonics (multi-scan method), implemented in the SCALE3 ABSPACK scaling algorithm. The transmission coefficient range was 0.95582 to 1.00000. The intensities of equivalent reflections were averaged. The agreement factor for the average based on the intensity was 1.65%.

[0149] Single crystal structure solution and refinement

[0150] The structure was solved using the Superflip structure solver with Charge Flipping and refined using the ShelXL (version 2014 / 7) refinement package included in OLEX2 using F2 full-matrix least squares. Hydrogen atoms were refined as riding models on the atoms to which they are bonded.

[0151] Calculated X-ray powder diffraction (XRPD) patterns

[0152] Calculated XRPD patterns were generated using the Mercury (Macrae, CF, Edgington, PR, McCabe, P., Pidcock, E., Shields, GP, Taylor, R., Towler, M., and van de Streek, JJ Appl. Cryst. 2006, 39, 453–457) program and the atomic coordinates, space group, and unit cell parameters of the single crystal structure for Cu radiation. The calculated XRPD pattern generated from the Form A single crystal structure was consistent with the experimental XRPD pattern.

[0153] Single crystal structure diagram

[0154] The crystal structure representation was generated by Diamond (Brandenburg, K. DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany).Thermal ellipsoid plots were generated by ORTEP-III (J. Appl. Cryst. (2012). 45, 849-854).

[0155] Instruments and parameters

[0156] An Agilent SuperNova (double, Cu subzero, Eos) diffractometer (Cu / Kα radiation, ) Single crystal X-ray diffraction data were collected at 150 K. Micrographs were captured using a Shanghai Cewei PXS9-T stereo microscope.

[0157] Table 13. SCXRD instrument parameters

[0158]

[0159] Table 14. Crystallographic data and refinement parameters

[0160]

[0161]

[0162] The thermal ellipsoid diagram of the asymmetric unit molecule of form A is shown in Figure 5 shown.

[0163] Table 15. Fractional atomic coordinates (×10 4 ) and equivalent isotropic displacement parameters

[0164]

[0165]

[0166] U eq Defined as orthogonalized U ij 1 / 3 of the tensor's trace.

[0167] Table 16. Anisotropic displacement parameters of free base Form A single crystal (810014-28-A6)

[0168]

[0169]

[0170] The anisotropic displacement factor exponent is of the form: -2π 2 [h 2 a* 2 U 11 +2hka*b*U 12 +…].

[0171] Table 17. Bond lengths of free base Form A single crystals

[0172]

[0173]

[0174] Table 18. Bond angles of free base Form A single crystal

[0175]

[0176]

[0177] Table 19. Hydrogen Atom Coordinates of Free Base Form A Single Crystal and isotropic displacement parameters

[0178]

[0179]

[0180] eutectic

[0181] Cocrystal screening

[0182] Cocrystal screening experiments were conducted using approximately fifty-five coformers. Experiments were planned based on the solubility of the API and coformer and combined a variety of techniques, including slurrying, grinding, co-melting, and cooling. For the dicarboxylic acid, 1:1 and 2:1 compound of Formula I:coformer stoichiometries were employed. Experimental details are summarized in Table 20.

[0183] Table 20. Samples generated and analyzed

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193] CF = conformer; NC = non-crystalline, API = active pharmaceutical ingredient, RT = room temperature

[0194] Twenty-six new substances were generated using the following coformers: 4-acetamidobenzoic acid, acetylsalicylic acid, adipic acid, trans-aconitic acid, benzoic acid, butyric acid, cholic acid, fumaric acid, sodium glucoheptanoate, gallic acid, glutaric acid, 4-hydroxybenzoic acid, isobutyric acid, D,L-lactic acid, malonic acid, mandelic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, terephthalic acid, and vanillic acid. Table 21 below shows the melting points as characterized by DSC analysis of selected cocrystals formed.

[0195] Table 21

[0196]

[0197] General Methods for Cocrystal Analysis

[0198] DSC analyses were performed on a TA Instruments Q2500 Discovery Series instrument. Indium was used for instrument calibration. During each analysis, the DSC cell maintained a nitrogen purge of approximately 50 mL / min. The sample was placed in an aluminum crimp pan and heated from approximately 25°C to 350°C at a rate of 10°C / min.

[0199] Pharmaceutical compositions and formulations

[0200] Polymorphic forms of Formula I can be formulated for therapeutic treatment (including prophylactic treatment) of mammals (including humans) according to standard pharmaceutical practice and according to the procedures of Example 9. The present disclosure provides pharmaceutical compositions comprising a compound of Formula I in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, or excipients.

[0201] Suitable carriers, diluents, glidants and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

[0202] The formulations can be prepared using conventional dissolution and mixing procedures.The compounds of the present disclosure are typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

[0203] The pharmaceutical composition (or formulation) for use can be packaged in various ways, depending on the method used to administer the drug. Generally speaking, the product for distribution includes a container in which the pharmaceutical formulation of appropriate form is placed. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), blister packs, pouches, ampoules, plastic bags, metal cylinders, etc. The container may also include an anti-tamper fitting to prevent easy access to the contents of the package. In addition, a label describing the contents of the container is placed on the container. The label may also include appropriate warnings.

[0204] Pharmaceutical formulations of the polymorphic forms of the compound of Formula I can be prepared for various routes and types of administration using pharmaceutically acceptable diluents, carriers, excipients, glidants, or stabilizers (Remington's Pharmaceutical Sciences (1995) 18th Edition, Mack Publ. Co., Easton, PA) in the form of lyophilized formulations, ground powders, or aqueous solutions. Formulation can be performed by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration employed) at ambient temperature, an appropriate pH, and the desired purity. The pH of the formulation depends primarily on the specific application and the concentration of the compound, but can range from about 3 to about 8.

[0205] Pharmaceutical formulations can be sterile. Specifically, formulations for in vivo administration must be sterile. This sterilization is easily achieved by filtration through a sterile filtration membrane.

[0206] Pharmaceutical formulations can typically be stored as solid compositions, tablets, pills, capsules, lyophilized formulations or as aqueous solutions.

[0207] The pharmaceutical formulations of the present invention will be dosed and administered in a manner consistent with good medical practice (i.e., amount, concentration, schedule, course of treatment, vehicle, and route of administration). Factors to be considered in this context include the specific condition being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to medical practitioners.

[0208] Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethylammonium chloride; benzalkonium chloride, benzathonine chloride; phenol, butyl, ethanol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspartic acid, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as lactose, sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®. TM , including Tween 80, PLURONICS TM Or polyethylene glycol (PEG), including PEG400. The active pharmaceutical ingredient can also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 18th edition, (1995) Mack Publ. Co., Easton, PA. Other examples of pharmaceutical formulations can be found in Liberman, HA and Lachman, L., ed., Pharmaceutical Dosage Forms, Marcel Decker, Vol. 3, 2nd edition, New York, NY.

[0209] The tablet may comprise one or more pharmaceutically acceptable excipients, such as a carrier, a glidant, a diluent, a binder, a disintegrant or a lubricant. The pharmaceutically acceptable diluent may be selected from microcrystalline cellulose, lactose, sodium starch glycolate, calcium carbonate, corn starch, sugar alcohols such as sorbitol, xylitol, mannitol and combinations thereof.

[0210] Pharmaceutically acceptable glidants may be selected from silicon dioxide, powdered cellulose, metallic stearates, sodium aluminosilicate, sodium benzoate, calcium silicate, magnesium carbonate, asbestos-free talc, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.

[0211] Pharmaceutically acceptable binders may be selected from corn starch and pregelatinized starch, carboxymethylcellulose sodium, carmellose sodium, calcium carboxymethylcellulose, calcium glycolate, carmellose calcium, PEG (polyethylene glycol) povidone, compressible sugars, and combinations thereof.

[0212] The pharmaceutically acceptable disintegrant may be selected from microcrystalline cellulose, powdered cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium starch glycolate, crospovidone, and combinations thereof.

[0213] The pharmaceutically acceptable lubricant may be selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, colloidal silicon dioxide, talc, beeswax, hydrogenated vegetable oils, and combinations thereof.

[0214] Pharmaceutical formulations include those suitable for the routes of administration described in detail herein. The formulations can be conveniently present in unit dosage form and can be prepared by any method well known in the pharmaceutical field. Techniques and formulations can generally be found in Remington's Pharmaceutical Sciences 18th edition (1995) Mack Publishing Co., Easton, PA. Such methods include the step of combining the active ingredient with a carrier that constitutes one or more auxiliary ingredients. The formulation can be prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then molding the product if necessary.

[0215] The pharmaceutical composition can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. Sterile injectable preparations can be solutions or suspensions in non-toxic parenteral acceptable diluents or solvents (e.g., solutions in 1,3-butanediol) or prepared from lyophilized powders. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as solvents or suspending media as a rule, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0216] In another aspect, the present disclosure relates to methods for treating diseases or conditions mediated at least in part by leucine-rich repeat kinase 2 (LRRK2). Specifically, the present disclosure provides methods for preventing or treating conditions associated with LRRK2 in mammals, comprising administering to the mammal a therapeutically effective amount of a compound provided herein. In some embodiments, the disease or condition mediated at least in part by LRRK2 is a neurodegenerative disease, e.g., a central nervous system (CNS) disorder, such as Parkinson's disease (PD), Alzheimer's disease (AD), dementia (including Lewy body dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age-related memory dysfunction, mild cognitive impairment (e.g., including transition from mild cognitive impairment to Alzheimer's disease), argyrophilic grain disease, lysosomal disorders (e.g., Niemann-Pick Type C disease, Gaucher disease), corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and Parkinson's disease linked to chromosome 17 (FTDP-17), withdrawal symptoms / relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease. disease (HD) and HIV-associated dementia (HAD). In other embodiments, the disorder is an ischemic disease of an organ including but not limited to the brain, heart, kidney, and liver.

[0217] In some other embodiments, the disease or condition mediated at least in part by LRRK2 is cancer. In certain specific embodiments, the cancer is thyroid cancer, kidney cancer (including papillary kidney cancer), breast cancer, lung cancer, blood cancer and prostate cancer (e.g., solid tumors), leukemia (including acute myeloid leukemia (AML)), or lymphoma. In some embodiments, the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myeloid leukemia, or multiple myeloma.

[0218] In other embodiments, the compounds disclosed herein are used in methods of treating inflammatory conditions. In some embodiments, the condition is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis (both often collectively referred to as inflammatory bowel disease). In other embodiments, the inflammatory disease is leprosy, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis. In some embodiments, the inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

[0219] In other embodiments, the compounds disclosed herein are used in methods of treating multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes, Sjogren's syndrome, Devic's disease, and inflammatory myopathies.

[0220] Although the foregoing invention has been described in detail by way of illustration and example for purposes of clarity of understanding, the description and example should not be construed as limiting the scope of the invention. Therefore, all suitable modifications and equivalents are contemplated as falling within the scope of the invention as defined by the appended claims. The disclosures of all patents and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims

1. A crystalline compound N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine or a co-crystal thereof.

2. The crystalline compound according to claim 1, which is selected from: the Form A polymorph which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2Θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6; and The Form B polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2Θ at approximately 8.0, 9.9, 16.1, 19.9, and 23.

2.

3. The crystalline compound of claim 2, wherein the compound is the Form A polymorph exhibiting an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2Θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.

6.

4. The crystalline compound of claim 3, wherein the Form A polymorph further comprises peaks at approximately 5.4 and 7.4 degrees 2Θ.

5. The Form A polymorph of claim 2, wherein differential scanning calorimetry (DSC) shows a melting endotherm with an onset at about 107.1°C.

6. The crystalline compound of claim 2, wherein the Form A polymorph is an anhydrate.

7. The Form A polymorph of claim 2, wherein Figure 2 shows the X-ray powder diffraction pattern.

8. The crystalline compound of claim 2, wherein the compound is the Form B polymorph exhibiting an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2Θ at approximately 8.0, 9.9, 16.1, 19.9, and 23.

2.

9. The crystalline compound or co-crystal thereof according to any one of claims 1 to 8, wherein the compound is in substantially pure form.

10. The crystalline compound or co-crystal thereof according to any one of claims 1 to 7, wherein the X-ray powder diffraction pattern is obtained using CuKα1 radiation.

11. A crystalline compound N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in ±0.3 degrees 2Θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.

6.

12. A pharmaceutical composition comprising the crystalline polymorph of any one of claims 1 to 11 and a pharmaceutically acceptable carrier, glidant, diluent, binder, disintegrant or lubricant.

13. The pharmaceutical composition of claim 12, wherein the crystalline polymorph is Form A.

14. An amorphous compound, amorphous form CN 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine.

15. A pharmaceutical composition comprising the amorphous compound according to claim 14 and a pharmaceutically acceptable carrier, glidant, diluent, binder, disintegrant or lubricant.

16. A method for preparing compound N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 A process for the preparation of amorphous Form C of 5-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine comprising heating a crystalline form of the compound until dissolved, followed by cooling to form the amorphous compound.

17. A eutectic comprising N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and coformers, and hydrates thereof.

18. The co-crystal of claim 17, wherein the coformer is selected from 4-acetamidobenzoic acid, acetylsalicylic acid, trans-aconitic acid, adipic acid, benzoic acid, butyric acid, cholic acid, fumaric acid, gallic acid, glutaric acid, 4-hydroxybenzoic acid, isobutyric acid, malonic acid, D,L-mandelic acid, propionic acid, salicylic acid, succinic acid, terephthalic acid, and vanillic acid.

19. A pharmaceutical composition comprising the co-crystal according to any one of claims 17 to 18 and a pharmaceutically acceptable carrier, glidant, diluent, binder, disintegrant or lubricant.

20. A method for preparing the co-crystal according to any one of claims 17 to 18, comprising: 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine is contacted with the coformer.

Images