Solid and co-crystalline forms of pyrimidinetriazole compounds

Abstract

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 The present invention relates to crystalline and amorphous forms of -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound of formula I), co-crystals, pharmaceutical compositions, and preparations thereof. TIFF2026504627000045.tif4857

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 422,339, filed November 3, 2022, which is incorporated by reference in its entirety.

[0002] The present disclosure provides a method for the treatment of peripheral and neurodegenerative diseases, including Parkinson's disease, comprising administering to a subject a therapeutically effective amount of N-acetylglucosamine. 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 This paper relates to the crystalline polymorphs and amorphous forms of 5-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and its co-crystals. Summary of the Invention

[0003] Combining genetic and biochemical evidence implicates specific kinase function in the pathogenesis of neurodegenerative disorders (Christensen, KV (2017) Progress in medicinal chemistry 56:37-80; Fuji, RNet al (2015) Science Translational Medicine 7 (273): 273ra15; Taymans, JMet al (2016) Current Neuropharmacology 14 (3): 214-225). Kinase inhibitors are under investigation 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; US354420; US8569281; US8791130; US8796296; US8802674; US8809331; US8815882; US9145402; US9212173; US9212186; US9932325, US10590114, US11111235, and WO2012 / 062783).

[0004] Multiple crystalline forms of a drug substance with different solid-state properties can exhibit differences in bioavailability, shelf life, physicochemical properties including melting point, crystalline morphology, intrinsic dissolution rate, solubility and stability, and behavior during processing. X-ray powder diffraction (XRPD) is a powerful tool for distinguishing different crystalline phases by their unique diffraction patterns. Other techniques, such as solid-state nuclear magnetic resonance (NMR) spectroscopy, Raman spectroscopy, and differential scanning calorimetry (DSC), are similarly useful.

[0005] The pharmaceutical industry is often faced with the phenomenon of multiple polymorphism of the same crystalline chemical entity. Polymorphism is often characterized as the property of a drug substance, i.e., active pharmaceutical ingredient (API), to exist as two or more crystalline phases with different arrangements and / or conformations of the molecules in the crystal lattice that impart different physicochemical properties to the crystal. The ability to reliably manufacture a selected polymorphic form is a key factor for the consistent performance of a drug product.

[0006] Regulatory authorities worldwide require reasonable efforts to identify polymorphic forms of drug substances and to confirm polymorphic conversion. Due to the unpredictable behavior of polymorphs and their respective differences in physicochemical properties, it is necessary to demonstrate manufacturing consistency between batches of the same product. A proper understanding of the polymorphic landscape and properties of a drug contributes to manufacturing consistency.

[0007] The determination of crystal structures and intermolecular interactions at the atomic level provides important information for establishing absolute configuration (enantiomers), phase differentiation, quality control, and process development management and optimization. X-ray diffraction is widely recognized as a reliable tool for crystal structure analysis and differentiation of crystalline forms of pharmaceutical solids.

[0008] For speed and accuracy of structure determination, it is preferable that single crystals of the drug substance be available. However, it is not always possible to obtain crystals of a size suitable for data collection. Synchrotron X-ray powder diffraction is a useful technique. In such situations, the crystal structure can be elucidated from X-ray powder diffraction data obtained at ambient conditions and / or by measurements at variable temperature and humidity.

[0009] There is a need to develop new polymorphic forms and co-crystals of drug substances and methods for their preparation. The present disclosure provides LRRK2 inhibitors N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4This invention relates to crystalline, amorphous, and co-crystalline forms of -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, referred to herein as the compound of formula I, whose structure is as follows:

[0010] [ka]

[0011] In one embodiment, a crystalline compound of Formula I is provided, selected from: Form A polymorph, which exhibits an X-ray powder diffraction pattern with characteristic peaks, expressed in degrees 2-theta, at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6; and Form B polymorph, which exhibits an X-ray powder diffraction pattern with characteristic peaks, expressed in degrees 2-theta, at approximately 8.0, 9.9, 16.1, 19.9, and 23.2.

[0012] In some embodiments, there is provided a Form A polymorph of Formula I, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta 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 2-theta.

[0013] In some embodiments, the Form A polymorph exhibits a melting endotherm peak with an onset at about 107.1° C. by differential scanning calorimetry (DSC). In some embodiments, the Form A polymorph is anhydrous.

[0014] In some embodiments, the Form A polymorph is characterized by the X-ray powder diffraction pattern shown in FIG. In another embodiment, there is provided the Form B polymorph of Formula I, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.0, 9.9, 16.1, 19.9, and 23.2.

[0015] 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. In some embodiments, the X-ray powder diffraction pattern of the crystalline compound or co-crystal of Formula I is generated using CuKα1 radiation.

[0016] In some embodiments, the crystalline compound, N, exhibits an X-ray powder diffraction pattern with characteristic peaks expressed at about 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6 ±0.3 degrees 2θ. 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.

[0017] 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.

[0018] In some embodiments, provided is an amorphous compound, the 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.

[0019] In some embodiments, a pharmaceutical composition is provided that includes an amorphous compound of formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. In some embodiments, N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4

[0010] A process for preparing amorphous Form C of -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine is provided, the process comprising heating a crystalline form of the compound to dissolve it, followed by cooling to form the amorphous compound.

[0020] In some embodiments, N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Co-crystals comprising -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and a co-crystal former, as well as hydrates thereof, are provided.

[0021] In some embodiments, a pharmaceutical composition is provided comprising a cocrystal of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. In some embodiments, the process for preparing a co-crystal of any one of Formula I comprises N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 the method comprises contacting -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine with a co-crystal former.

[0022] In some embodiments, the co-crystal former 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 explanation of the drawings]

[0023] [Figure 1] 1 is a schematic diagram illustrating the interconversion relationship between polymorphic Forms A and B and amorphous Form C of the compound of Formula I. [Figure 2] 1 shows the XRPD pattern of Form A polymorph. [Figure 3] 1 shows an overlay of the XRPD patterns of polymorphic Forms A and B of the compound of formula I. [Figure 4] 1 shows TGA and DSC data for the Form A polymorph. [Figure 5] 1 shows a thermal ellipsoid diagram of the asymmetric unit molecule from the single crystal X-ray structure of the Form A polymorph. [Figure 6] 1 shows the XRPD diffractogram of amorphous Form C. [Figure 7] 1 shows a PLM image of Form A single crystal. [Figure 8] 1 shows an XRPD overlay comparing Form A after 6 months of storage at 40° C. / 75% RH and 25° C. / 60% RH. [Figure 9] 1 shows an XRPD overlay comparing Form A after 48 months storage at 25° C. / 60% RH. DETAILED DESCRIPTION OF THE INVENTION

[0024] definition Unless otherwise defined, technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs and are consistent with the following:

[0025] 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 exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0026] As used herein, the term "about" or "approximately" when used in reference to peak positions in an X-ray powder diffraction pattern refers to the inherent variability of the peaks depending on the instrument used, for example, the calibration of the instrument used, the process used to generate the polymorph, and the aging of the crystallized material. In this case, the instrument measurement variation was approximately plus / minus ±0.3 degrees 2θ (θ). Those of skill in the art with the benefit of this disclosure will understand the use of "about" or "approximately" in this context, unless otherwise specified (e.g., ±0.05 degrees 2θ). The term "about" or "approximately" is intended to be used in conjunction with other defined parameters, such as water content, C max , t max With respect to other defined parameters, such as AUC, intrinsic dissolution rate, temperature, and time, these values ​​reflect the inherent variability, for example, in measuring the parameter or achieving the parameter. One of ordinary skill in the art having the benefit of this disclosure will understand the variability of a parameter implied by the use of the words about or approximately.

[0027] As used herein, "polymorphism" refers to the occurrence of crystalline forms of a compound that have the same chemical composition but differ in packing or conformation / arrangement. Crystalline forms have different arrangements and / or conformations of molecules within the crystal lattice. Solvates are crystalline forms that contain stoichiometric or non-stoichiometric amounts of solvent. When the solvent involved is water, the solvate is commonly known as a hydrate. Hydrates / solvates can exist as polymorphs of a compound that differ in lattice packing or conformation but have the same solvent content. Thus, a single compound can produce various polymorphic forms, each with distinct and different physical properties, such as solubility characteristics, 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 existence of pharmaceutical polymorphs is essential to providing pharmaceuticals with predictable dissolution characteristics. It is desirable to characterize and investigate 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 spectroscopy, Raman spectroscopy, and solid-state NMR spectroscopy. For general reviews of polymorphism and its pharmaceutical uses, see G. M. Wall, Pharm Manuf. 3:33 (1986); J. K. Halebian and W. McCrone, J. Pharm. Sci., 58:911 (1969); "Polymorphism in Pharmaceutical Solids, Second Edition (Drugs and the Pharmaceutical Sciences)", Harry G. Brittain, Ed. (2011) CRC Press (2009), and J. Khalebian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

[0028] The acronym "XRPD" stands for X-ray powder diffraction, an analytical technique that involves displaying an X-ray diffraction pattern and measuring the diffraction of X-rays in the presence of solid components. X-ray diffraction patterns can be created using CuKα1 radiation. Materials with crystalline, regularly repeating atomic arrangements produce characteristic powder patterns. Materials with similar unit cells exhibit X-ray diffraction patterns with similar positions measured in °2θ (theta). Solvates that exhibit this characteristic are called isomorphous solvates or isomorphous solvates. The intensity of 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 general appearance of the measured powder pattern(s) in relation to the known response of the X-ray diffraction system used to collect the data. For 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) superimposed on the instrument background can be used to characterize the level and type of solid-state disorder. The combined interpretation of the solid-state order and disorder present in a powder sample provides a qualitative measure of the sample's macrostructure.

[0029] The term "cocrystal" refers to a crystalline molecular complex that is not a solvate or a simple salt and is generally composed of two or more different molecular compounds in a stoichiometric ratio. Cocrystals consist of a hydrogen-bonded complex with a "pharmaceutically acceptable" cocrystal former (Aitipadula, S. et al. (2012) Cryst. Growth Des. 12(5):2147-2152). Cocrystal 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.

[0030] The term "hydrate" refers to the complex where the solvent molecule is water. The abbreviation "RH" refers to relative humidity. Compounds of Formula I The present disclosure includes polymorphs, co-crystals, and amorphous forms of the compound of Formula I, (CAS Registry Number 2170179-24-3), having the following structure:

[0031] [ka]

[0032] 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 (WO2017 / 218843, US9932325, each of which is incorporated by reference). Preparation of Compounds of Formula I

[0033] [ka]

[0034] Methyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propanoate: 2H-1,2,3-triazole (190 g, 2.75 mol) was mixed in THF (800 mL), and t-BuOK (339.54 g, 3.03 mol) was added at 0 °C and stirred for 1 h. Methyl 2-bromo-2-methylpropanoate (547.62 g, 3.03 mol) was then added dropwise over 1 h at 0 °C, and the mixture was then stirred at 25 °C for 2 h. The mixture was poured into ice water (2 L) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 × 800 mL). The combined organic phase was washed with brine (4 × 500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, 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): δ 7.69(s,2H), 3.74(s,3H), 1.99(s,6H).

[0035] 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), n-BuLi (2.5 M in THF, 359.4 mL) was added dropwise at −78°C under N2 and stirred for 1 h. Then, methyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propanoate (76 g, 449.2 mmol) in THF (500 mL) was added dropwise at −78°C for 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 × 800 mL). The combined organic phase was washed with brine (800 mL), dried over anhydrous NaSO, 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. 1H NMR (400 MHz, CDCl3): δ7.38 (s, 2H), 3.11 (s, 2H), 1.90 (s, 6H).

[0036] 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 N. The mixture was stirred at 90 °C for 10 h. Aqueous NaHCO was added to the mixture to adjust the pH to 7-8. The aqueous phase was extracted with EtOAc (3 × 300 mL). The combined organic phase was dried over anhydrous NaSO, 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 (400 MHz, CDCl3): δ 7.6 (s,2 H),5.05 (s,1 H),3.72 (br s,2 H),3.14-3.09 (m,1 H),2.05 (s, 6H), 1.14-1.12(m, 2H), 1.04-1.01(m, 2H).

[0037] N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4N-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)pyrimidin-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 N. The mixture was stirred at 90 °C for 10 h. The mixture was poured into aqueous NaHCO (1500 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 × 600 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (SiO2, PE: EtOAc = 100:1 to 3:1) and washing with MTBE gave the 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 portionwise to the solution 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 hours. The resulting crystals were filtered, washed with a small amount of n-heptane, and purified with N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 To this was obtained 1,4-dimethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (64 g, 47.03%) as a yellow solid. 1 H NMR (400 MHz,CDCl3): δ ppm 8.13 (s,1 H),7.62 (s,2 H),7.29 (br s,1 H),6.12 (s,1 H),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.

[0038] Polymorph Screening of Compounds of Formula I Polymorph screening experiments were performed using a variety of crystallization or solid-state transition methods, including antisolvent addition, slow evaporation, slow cooling, room temperature slurrying, slurry circulation, solid-state vapor diffusion, liquid-state vapor diffusion, polymer-induced crystallization, and melting / cooling. Forms A, B, and C were identified by these methods.

[0039] As shown in Figure 1, Form A was found to be a stable crystalline form and can be converted to a mixture of Forms A and B by crystallization from cyclohexane and methyl isobutyl ketone (MIBK). The mixture reverts to Form A after one month at room temperature. Heating Form A to 110°C and then cooling to -20°C forms amorphous Form C, which reverts to Form A upon warming to room temperature.

[0040] A 24-hour solubility evaluation showed that Form A had a solubility of 29.9 μg / mL in water. DVS (dynamic vapor sorption) results showed that Form A was non-hygroscopic, as defined by a reversible water absorption of less than 0.2% (Table 1).

[0041] [Table 1]

[0042] Polymorphism Screening A total of 70 polymorph screening experiments were performed using different crystallization or solid-state transformation methods. The methods utilized and the crystalline forms identified are summarized in Table 2 below.

[0043] [Table 2]

[0044] Anti-solvent addition A total of 14 anti-solvent addition experiments were performed. Approximately 20 mg of 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 anti-solvent was added stepwise in 0.1 mL increments until a precipitate appeared or the total volume of anti-solvent reached 10.0 mL. The precipitate was isolated for XRPD analysis. The results in Table 3 below indicated that Forms A and A+B were produced.

[0045] [Table 3]

[0046] Slow evaporation 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 next step instead. The visually clear solution was evaporated at room temperature using a vial sealed with Parafilm®. The solid was isolated for XRPD analysis, and the results, summarized in Table 4, indicate that only Form A was found.

[0047] [Table 4]

[0048] slow cooling Slow cooling experiments were conducted with 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 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, indicate that Form A and a gel were produced.

[0049] [Table 5]

[0050] Slurry Conversion Slurry conversion experiments were conducted in 15 different solvent systems at room temperature. 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. The suspension was magnetically stirred at room temperature for 4 days, after which the remaining solid was isolated for XRPD analysis. All experiments produced Form A.

[0051] [Table 6]

[0052] Slurry Circulation Slurry circulation experiments were performed with 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 1 day, the suspension was transferred to a slurry at 50°C for 3 days. The results, summarized in Table 5C below, indicate that only Form A was produced.

[0053] [Table 7]

[0054] solid vapor diffusion Solid vapor diffusion experiments were conducted using seven different solvents. Approximately 10 mg of the compound of Formula I was weighed into a 3 mL vial, which was then placed in a 20 mL vial with 4 mL of a volatile solvent. The 20 mL vial was sealed with a cap and kept at room temperature for 9 days to allow the solvent vapor to interact with the sample. The solid was examined by XRPD, and the results, summarized in Table 6 below, indicate that Form A and a gel were formed.

[0055] [Table 8]

[0056] Liquid Vapor Diffusion Nine liquid vapor diffusion experiments were performed. Approximately 20 mg of the compound of Formula I was dissolved in 0.1–0.7 mL of an appropriate solvent to obtain a clear solution in a 3 mL vial. If complete dissolution was not achieved, 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 (antisolvent). The 20 mL vial was sealed with a cap and kept at room temperature to allow sufficient time for the antisolvent vapor to interact with the solution. The precipitate was isolated for XRPD analysis. The results, summarized in Table 7A below, indicate that only Form A was observed.

[0057] [Table 9]

[0058] Polymer-induced crystallization Polymer-induced crystallization experiments were conducted with two sets of polymer mixtures in four different solvent systems. Approximately 20 mg of the compound of Formula I was dissolved in 1.0-2.0 mL of the appropriate solvent in a 3 mL glass vial containing approximately 2 mg of the polymer mixture. The clear solution was decanted and allowed to evaporate at room temperature. The resulting solid was collected for XRPD characterization. The results, summarized in Table 7B below, indicate that only Form A was produced.

[0059] [Table 10]

[0060] Polymer mixture A: Polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), methylcellulose (MC) (mass ratio 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 1:1:1:1:1).

[0061] General method XRPD 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 size of 0.0167° 2θ and a scan step time of 18 seconds.

[0062] [Table 11]

[0063] DSC / TGA DSC analysis was performed on a TA Instruments Q2000 DSC. The DSC cell was kept under a nitrogen purge. Samples were placed in aluminum crimp pans and heated from 25°C to 300°C at a rate of 10°C / min.

[0064] TGA data were collected using a TA Instruments TA Q500 / Q5000 TGA. TGA was performed using a nitrogen purge gas. 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 kept under a nitrogen purge. Samples were placed in aluminum crimp pans and heated from 25°C to 300°C at a rate of 10°C / min.

[0065] [Table 12]

[0066] DVS DVS analysis was performed using a DVS Intrinsic analyzer manufactured by SMS (Surface Measurement Systems). Relative humidity at 25°C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. Approximately 15–20 mg of sample was loaded into a pan for analysis. A nitrogen gas flow rate of 200 mL / min was used. Samples were analyzed at 25°C over the range of 0 to 95% relative humidity (RH), in 10% RH steps from 0 to 90% RH and in 5% RH steps from 90 to 95% RH. Progression from one step to the next was determined by meeting an equilibrium criterion of 0.002% / min weight change (dm / dt) or after 180 min if the equilibrium criterion was not met. The minimum dm / dt stability duration for each step was 10 min.

[0067] Characterization of Form A Form A was characterized by XRPD, TGA, DSC, DVS, and polarized light microscopy (PLM). XRPD (Figure 2, Table 10) revealed a highly crystalline structure. GA showed low weight loss, and DSC showed a single sharp melt at approximately 107°C (Figure 4). DVS indicated that Form A did not change morphology after exposure to humidity and is non-hygroscopic. Examination of PLM shows irregular plate-like particles. Based on the characterization results, Form A is an anhydrous form.

[0068] [Table 13-1]

[0069] [Table 13-2]

[0070] Stability of Form A To evaluate the stability of the solid form, Form A was stored under 40°C / 75% RH (relative humidity, accelerated) and 25°C / 60% RH (long-term) conditions. Form A was demonstrated to be physically and chemically stable 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 change in form was detected by XRPD, and no change in purity was observed by HPLC.

[0071] [Table 14]

[0072] Form A+B (mixture) A mixture of Forms A+B was prepared by adding cyclohexane (antisolvent) to a methyl isobutyl ketone solution and characterized by XRPD (Figure 3).

[0073] [Table 15]

[0074] Form C (amorphous) Form C (amorphous free base) was prepared by heating Form A at 110°C until the solid was completely melted, then transferring to -20°C.

[0075] Form C was characterized by XRPD and DSC. The XRPD trace showed a characteristic amorphous halo with no prominent diffraction peaks (Figure 6). Single crystal determination of Form A SXRPD characterization of Form A A suitable single crystal was selected from the block crystals and analyzed by single crystal X-ray diffractometer (SCXRD). The structure of the single crystal was successfully determined. Characterization and analysis of SCXRD revealed that the crystal system was triclinic and the space group was 1.

[0076] [ka]

[0077] and the cell parameters and calculated cell volume are a = 10.3230(4) Å, b = 12.7742(6) Å, c = 16.3999(5) Å, 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, Z = 4, resulting in a calculated density of 1.410 g cm-3.

[0078] Crystal growth procedure Block-shaped single crystals of Form A used for single crystal X-ray diffraction (SCXRD) characterization were obtained by liquid vapor diffusion from a DMSO and HO solvent system at room temperature. A PLM image of a single crystal of Form A is shown in Figure 7.

[0079] Data collection A colorless block-shaped single crystal selected from a single crystal sample of Form A was mounted in a random orientation and immersed in a nitrogen stream at 150 K. Preliminary examination and data collection were performed on an Agilent SuperNova (Dual, Cu at zero, Eos) diffractometer equipped with a SuperNova Microfocus X-ray source (Cu / Kα = 1.54184 Å) and an Eos CCD detector, and analyzed with the CrysAlisPro (version: 1.171.38.41) software package. The cell constant and orientation matrix for data collection were obtained from least-squares refinement using set angles of 9816 reflections in the range 4.3580° < θ < 70.5170°. Data were collected at a maximum diffraction angle (2θ) of 141.114° and a temperature of 150 K. The completeness of the data set was 97.97%, with an average I / σ of 27.8 and D min (Cu) of 0.82 Å.

[0080] Data Reduction Frames were integrated with CrysAlisPro (version: 1.171.38.41). A total of 14,156 reflections were collected, of which 7,446 were unique. Lorentzian and polarization corrections were applied to the data. The linear absorption coefficient was 0.944 mm-1 for Cu / Kα radiation. A semi-empirical absorption correction (multiscan method) was performed using spherical harmonics implemented in the SCALE3 ABSPACK scaling algorithm. Transmission coefficients ranged from 0.95582 to 1.00000. The intensities of equivalent reflections were averaged. The coincidence factor for averaging was 1.65% based on the intensity.

[0081] Solution and refinement of single crystal structures The structure was solved with the Superflip structure solver using charge flipping and refined with the ShelXL (version 2014 / 7) refinement package using full-matrix least-squares for F2 in OLEX2. Hydrogen atoms were refined as riding models for the bonded atoms.

[0082] Calculated X-ray powder diffraction (XRPD) patterns A calculated XRPD pattern was generated for Cu radiation using the Mercury (Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. J. Appl. Cryst. 2006, 39, 453-457) program, with atomic coordinates, space group, and unit cell parameters obtained from the single crystal structure. The calculated XRPD pattern generated from the single crystal structure of Form A is consistent with the experimental XRPD pattern.

[0083] Single crystal structure diagram Crystal structure representations were generated by Diamond (Brandenburg, K. DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany). Thermal ellipsoid diagrams were generated by ORTEP-III (J. Appl. Cryst. (2012). 45, 849-854).

[0084] Equipment and parameters Single-crystal X-ray diffraction data were collected using an Agilent SuperNova (Dual, Cu at zero, Eos) diffractometer (Cu / Kα radiation, λ = 1.54178 Å) at 150 K. Micrographs were captured using a Shanghi Cewei PXS9-T stereomicroscope.

[0085] [Table 16]

[0086] [Table 17]

[0087] A thermal ellipsoid diagram of the Form A asymmetric unit molecule is shown in FIG.

[0088] [Table 18-1]

[0089] [Table 18-2]

[0090] [Table 19-1]

[0091] [Table 19-2]

[0092] [Table 20]

[0093] [Table 21-1]

[0094] [Table 21-2]

[0095] [Table 22-1]

[0096] [Table 22-2]

[0097] Cocrystals Cocrystal screening Co-crystal screening experiments were conducted with approximately 55 co-crystal formers. Experiments were designed based on the solubility of the API and co-crystal formers and incorporated a variety of techniques, including slurry, grinding, co-melting, and cooling. For dicarboxylic acids, stoichiometric ratios of compound of Formula I:co-crystal former of 1:1 and 2:1 were used. Experimental details are summarized in Table 20.

[0098] [Table 23-1]

[0099] [Table 23-2]

[0100] [Table 23-3]

[0101] [Table 23-4]

[0102] [Table 23-5]

[0103] [Table 23-6]

[0104] [Table 23-7]

[0105] [Table 23-8]

[0106] [Table 23-9]

[0107] [Table 23-10]

[0108] [Table 23-11]

[0109] Twenty-six new materials were produced using the following co-crystal formers: 4-acetamidobenzoic acid, acetylsalicylic acid, adipic acid, trans-aconitic acid, benzoic acid, butyric acid, cholic acid, fumaric acid, sodium glucoheptonate, gallic acid, glutaric acid, 4-hydroxybenzoic acid, isobutyric acid, D,L-lactic acid, malonic acid, mandelic acid, palmitic acid, palmonic 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 co-crystals formed.

[0110] [Table 24]

[0111] General methods for cocrystal analysis DSC analyses were performed on a TA Instruments Q2500 Discovery series instrument. The instrument was calibrated using indium. The DSC cell was kept under a nitrogen purge of approximately 50 mL / min during each analysis. Samples were placed in aluminum crimp pans and heated from approximately 25°C to 350°C at a rate of 10°C / min.

[0112] Pharmaceutical Compositions and Formulations The polymorphic forms of Formula I may be formulated for use in therapeutic treatment (including prophylactic treatment) in mammals, including humans, according to standard pharmaceutical practice and in accordance with the procedure of Example 9. The present disclosure provides pharmaceutical compositions comprising a compound of Formula I in association with one or more pharmaceutically acceptable carriers, fluidizers, diluents, or excipients.

[0113] Suitable carriers, diluents, flow agents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0114] 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 drug dosage and to enable patient compliance with a prescribed regimen.

[0115] Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for sale includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), blister packs, sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-evident mechanism to prevent inadvertent access to the contents of the package. In addition, a label is disposed on the container that describes the contents of the container. The label may also include appropriate warnings.

[0116] Pharmaceutical formulations of polymorphic forms of the compound of Formula I may be prepared using pharmaceutically acceptable diluents, carriers, excipients, glidants, or stabilizers (see Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA) can be prepared for various routes and types of administration in the form of lyophilized formulations, milled powders, or aqueous solutions. Formulations may be made by mixing at ambient temperature, at the appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosages and concentrations employed. The pH of the formulation will depend primarily on the specific application and concentration of compound, but may range from about 3 to about 8.

[0117] Pharmaceutical formulations may be sterile. In particular, formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.

[0118] Pharmaceutical formulations may typically be stored as solid compositions, tablets, pills, capsules, lyophilized formulations, or as aqueous solutions. The pharmaceutical formulations of the present invention are formulated, prescribed, and administered in a manner consistent with good medical practicality, i.e., in amounts, concentrations, schedules, courses, vehicles, and routes of administration. Factors to consider in this context include the particular disorder being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0119] Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citric acid, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium 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; serum albumin, gelatin, etc. or proteins such as immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, 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™, including TWEEN 80, or polyethylene glycols (PEG), including PEG 400. The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., in hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively, 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 Publishing Co., Easton, PA. Other examples of formulations are found in Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol. 3, 2002. ndEd., New York, NY.

[0120] Tablets may contain one or more pharmaceutically acceptable excipients such as carriers, glidants, diluents, binders, disintegrants, or lubricants. The pharmaceutically acceptable diluents may be selected from microcrystalline cellulose, lactose, sodium carboxymethyl starch, calcium carbonate, corn starch, sugar alcohols such as sorbitol, xylitol, mannitol, and combinations thereof.

[0121] Pharmaceutically acceptable glidants can be selected from silicon dioxide, powdered cellulose, metal stearates, sodium aluminosilicate, sodium benzoate, calcium silicate, magnesium carbonate, asbestos-free talc, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.

[0122] Pharmaceutically acceptable binders can be selected from cornstarch and pregelatinized starch, sodium carboxymethylcellulose, carmellose sodium, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, PEG (polyethylene glycol), povidone, compressible sugar, and combinations thereof.

[0123] Pharmaceutically acceptable disintegrants can be selected from microcrystalline cellulose, powdered cellulose, carmellose sodium, carboxymethylcellulose calcium, carboxymethyl starch sodium, crospovidone, and combinations thereof.

[0124] Pharmaceutically acceptable lubricants can be selected from magnesium stearate, stearic acid, calcium stearate, sodium fumarate stearate, polyethylene glycol, colloidal silicon dioxide, talc, beeswax, hydrogenated vegetable oils, and combinations thereof.

[0125] Pharmaceutical formulations include those suitable for routes of administration as detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences 18 th Ed. (1995) Mack Publishing Co., Easton, PA. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. The formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0126] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, an aqueous or oleaginous sterile injectable suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable preparations can be solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or can be prepared from lyophilized powders. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils, including synthetic monoglycerides or diglycerides, are commonly used as solvents or suspending media. Additionally, fatty acids, such as oleic acid, can also be used in the preparation of injectables.

[0127] In another aspect, the present disclosure relates to methods for treating a disease or condition mediated, at least in part, by leucine-rich repeat kinase 2 (LRRK2). In particular, the present disclosure provides a method for preventing or treating an LRRK2-associated disorder in a mammal, 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 disorder of the central nervous system (CNS) such as Parkinson's disease (PD), Alzheimer's disease (AD), dementia (including dementia with Lewy bodies and Cassian dementia), amyotrophic lateral sclerosis (ALS), age-related memory impairment, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer's disease), chromatid granular disease, lysosomal disorders (e.g., Niemann-Pick disease type C, Gaucher disease), corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal / relapse associated with drug addiction, L-dopa-induced dyskinesia, Huntington's 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.

[0128] In some other embodiments, the disease or condition mediated at least in part by LRRK2 is cancer. In certain embodiments, the cancer is thyroid cancer, kidney cancer (including renal papillary surface), 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.

[0129] In other embodiments, the compounds of the present disclosure are used in methods for treating inflammatory diseases. In some embodiments, the disorder is an inflammatory disease of the intestine, such as Crohn's disease or ulcerative colitis (both commonly known together 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.

[0130] In other embodiments, compounds of the present disclosure are used in methods for multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red blood cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes, Sjogren's syndrome, Devic's disease, and inflammatory myopathies.

[0131] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, these descriptions and examples should not be construed as limiting the scope of the invention. Accordingly, all suitable modifications and equivalents may be resorted to within the scope of the invention as defined by the following claims. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entireties.

Claims

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

2.

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

6.

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

6. 3. The crystalline compound of claim 2, wherein the Form A polymorph is anhydrous.

7. 3. The Form A polymorph of claim 2, characterized by the X-ray powder diffraction pattern shown in Figure 2.

8. 3. 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 2-theta at approximately 8.0, 9.9, 16.1, 19.9, and 23.

2.

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

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

11. A crystalline compound, N, exhibiting an X-ray powder diffraction pattern with characteristic peaks expressed in ±0.3 degrees 2θ at about 12.3, 13.8, 15.7, 18.7, 22.1, and 22.

6. 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.

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

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

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

17. N ２ -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ４ Co-crystals comprising -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and a co-crystal former, and hydrates thereof.

18. 18. The co-crystal of claim 17, wherein the co-crystal former is selected from 4-acetamidobenzoic acid, acetylsalicylic acid, trans-aconitic acid, adipic acid, benzoic acid, butyric acid, cholic acid, fumaric acid, 7-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. 19. A pharmaceutical composition comprising the cocrystal of any one of claims 17 to 18 and a pharmaceutically acceptable carrier, glidant, diluent, binder, disintegrant, or lubricant.

20. A process for preparing the co-crystal of any one of claims 17 to 18, comprising the steps of: ２ -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ４ the process comprising contacting 5-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine with a co-crystal former.

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