137485-01120 SOLID AND CO-CRYSTAL FORMS OF A PYRIMIDINE TRIAZOLE COMPOUND CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Number 63/422,339, filed November 3, 2022, which is incorporated by reference in its entirety. FIELD The present disclosure relates to crystalline polymorph and amorphous forms of N2-(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 and cocrystals thereof for use in the treatment of peripheral and neurodegenerative diseases, including Parkinson’s disease. DESCRIPTION Combined genetic and biochemical evidence implicates certain kinase function in the pathogenesis of neurodegenerative disorders (Christensen, K.V. (2017) Progress in medicinal chemistry 56:37-80; Fuji, R.N. et al (2015) Science Translational Medicine 7(273):273ra15; Taymans, J.M. et al (2016) Current Neuropharmacology 14(3):214-225). Kinase inhibitors are under investigation for treatment of Alzheimer’s disease, Parkinson’s disease, ALS and other diseases (Estrada, A.A. et al (2015) J. Med. Chem.58(17): 6733-6746; Estrada, A.A. et al (2013) J. Med. Chem.57:921-936; Chen, H. et al (2012) J. Med. Chem.55:5536-5545; Estrada, A.A. et al (2015) J. Med. Chem. 58:6733-6746; Chan, B.K. et al (2013) ACS Med. Chem. Lett. 4:85-90; US 8354420; US 8569281; US8791130; US 8796296; US 8802674; US 8809331; US 8815882; US 9145402; US 9212173; US 9212186; US 9932325, US 10590114, US 11111235, and WO 2012/062783. Multiple crystal forms with different solid state properties of a drug substance can exhibit differences in bioavailability, shelf life, physical-chemical properties including melting point, crystal morphology, intrinsic dissolution rates, solubility and stability, and behavior during processing. X-ray powder diffraction (XRPD) is a powerful tool in identifying different crystal phases by their unique diffraction patterns. Other techniques such as solid-state Nuclear Magnetic resonance NMR spectroscopy, RAMAN spectroscopy, DSC (differential scanning calorimetry) are useful as well. The pharmaceutical industry is often confronted with the phenomenon of multiple 1 ME1 46604090v.1
137485-01120 polymorphs of the same crystalline chemical entity. Polymorphism is often characterized as the ability of a drug substance, i.e. Active Pharmaceutical Ingredient (API), to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattices giving the crystals different physicochemical properties. The ability to manufacture the selected polymorphic form reliably is a key factor for consistent performance of the drug product. Regulatory agencies worldwide require a reasonable effort to identify the polymorphs of the drug substance and check for polymorph interconversions. Due to the often unpredictable behavior of polymorphs and their respective differences in physicochemical properties, consistency in manufacturing between batches of the same product must be demonstrated. Proper understanding of the polymorph landscape and nature of the polymorphs of a pharmaceutical will contribute to manufacturing consistency. Crystal structure determination at the atomic level and intermolecular interactions offer important information to establish absolute configuration (enantiomers), phase identification, quality control, and process development control and optimization. X-ray diffraction is widely recognized as a reliable tool for the crystal structure analysis of pharmaceutical solids and crystal form identification. Availability of a single crystal of the drug substance is preferred due to the speed and accuracy of the structure determination. However, it is not always possible to obtain a crystal of suitable size for data collection. Synchrotron X-ray powder diffraction is a useful technique. In such situations the crystal structure can be solved from X-ray powder diffraction data obtained by measurements at ambient conditions and/or at variable temperature or humidity. There is a need to develop new polymorph forms and cocrystals of drug substances, and methods of preparing them. The present disclosure relates to crystalline, amorphous, and cocrystal forms of a LRRK2 inhibitor N2-(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, referred to herein as the Formula I compound and having the structure:
In one embodiment, provided is a crystalline compound of Formula I, selected from: 2 ME1 46604090v.1
137485-01120 a Form A polymorph that 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; and a Form B polymorph that 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. In some embodiments, provided is a Form A polymorph of Formula I exhibiting 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. In some embodiments, the Form A polymorph has a differential scanning calorimetry DSC shows a melting endotherm at about 107.1 °C onset. In some embodiments, the Form A polymorph is an anhydrate. In some embodiments, the Form A polymorph is characterized by the X-ray powder diffraction pattern shown in Figure 2. In other embodiments provided is a Form B polymorph of Formula I that 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. In some embodiments, provided is a crystalline compound of Formula I in substantially pure form. In other embodiments, provided is a cocrystal thereof of Formula I in substantially pure form. In some embodiments, the X-ray powder diffraction pattern of a crystalline compound or In some embodiments, provided is a crystalline compound, N2-(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 exhibiting an X-ray powder diffraction pattern having characteristic peaks expressed in ± 0.3 degrees 2-theta at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6. In some embodiments, provided is a pharmaceutical composition 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. In some embodiments, provided is an amorphous compound, amorphous Form C N2-(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. In some embodiments, provided is a pharmaceutical composition comprising an amorphous compound of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, 3 ME1 46604090v.1
137485-01120 or excipient. In some embodiments, provided is a process for preparing amorphous Form C of the compound N2-(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, comprising heating a crystalline form of the compound until dissolution followed by cooling to form the amorphous compound. In some embodiments, provided is a cocrystal comprising N2-(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 and a coformer, and hydrates thereof. In some embodiments, provided is a pharmaceutical composition comprising the cocrystal of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. In some embodiments, a process for preparing a cocrystal of any one of Formula I comprising contacting N2-(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 with the coformer. 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 Figure 1 shows the inter-conversion relationships between Formula I compound polymorph Forms A and B and amorphous form C in a schematic diagram. Figure 2 shows the XRPD pattern of Form A polymorph. Figure 3 shows an overlay of the XRPD patterns of Formula I compound polymorph Forms A and B. Figure 4 shows TGA and DSC data of Form A polymorph. Figure 5 shows the thermal ellipsoid drawing of an asymmetric unit molecule from the single crystal X-ray structure of Form A polymorph. Figure 6 shows XRPD Diffractogram of amorphous Form C. Figure 7 shows PLM image of the Form A single crystal. Figure 8 shows XRPD overlay comparing Form A after 6 months storage at 40 ºC/75%RH and 25 ºC/60%RH. Figure 9 shows XRPD overlay comparing Form A after 48 months storage at 25 ºC/60%RH. 4 ME1 46604090v.1
137485-01120 DEFINITIONS Unless defined otherwise, 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 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. As used herein, the term "about" or “approximately” when used in reference to X-ray powder diffraction pattern peak positions refers to the inherent variability of the peaks depending on, for example, the calibration of the equipment used, the process used to produce the polymorph, the age of the crystallized material and the like, depending on the instrumentation used. In this case the measure variability of the instrument was about plus/minus understand the use of "about" or “approximately” in this context unless specified otherwise (e.g. ± 0.05 degrees 2-theta). The term "about" or “approximately” in reference to other defined parameters, e.g., water content, Cmax, tmax, AUC, intrinsic dissolution rates, temperature, and time, indicates the inherent variability in, for example, measuring the parameter or achieving the parameter. A person skilled in the art, having the benefit of this disclosure, would understand the variability of a parameter as connoted by the use of the word about or approximately. "Polymorph", as used herein, refers to the occurrence of different crystalline forms of a compound differing in packing or conformation/configuration but with the same chemical composition. Crystalline forms have different arrangements and/or conformations of the molecule in the crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate. Hydrates/solvates may exist as polymorphs for compounds with the same solvent content but different lattice packing or conformation. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, morphology, density, flowability, compactibility and/or X-ray diffraction peaks. The solubility of each polymorph may vary, thus, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. 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 5 ME1 46604090v.1
137485-01120 polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffractometry and by other methods such as, infrared or Raman or solid-state NMR spectrometry. For a general review 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, Second 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. The acronym "XRPD" means X-ray powder diffraction, an analytical technique which measures the diffraction of X-rays in the presence of a solid component with a display of the X- Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern. Materials with similar unit cells will give X-ray diffraction patterns that are isostructural or isomorphous solvates. The intensity of the reflections varies according to the electron density causing diffraction as well as sample, sample preparation, and instrument parameters. Analysis of XRPD data is based upon the general appearance of the measured powder pattern(s) with respect 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 positions, shapes, widths, and relative intensity distributions can be used to characterize the type of solid state order in the powder sample. The position, shape, and intensity of any broad diffuse scatter (halos) on top of the instrumental 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 macro-structure of the sample. The term “cocrystal” refers to a crystalline molecular complex composed of two or more different molecular compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. The cocrystal consists of a hydrogen-bonded complex with a “pharmaceutically acceptable” coformer (Aitipamula, S. et al (2012) Cryst. Growth Des.12(5):2147–2152). Coformers include, but are not limited to, acetylsalicylic acid, trans-acontic 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. The term "hydrate" refers to the complex where the solvent molecule is water. The abbreviation "RH" refers to Relative Humidity 6 ME1 46604090v.1
137485-01120 FORMULA I COMPOUND The present disclosure includes polymorphs, cocrystal, and amorphous forms of Formula I compound, (CAS Registry Number 2170179-24-3), having the structure:
and named as: N2-(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 are incorporated by reference). PREPARATION OF FORMULA I COMPOUND
Methyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propanoate: 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 h. Then methyl 2-bromo-2-methyl-propanoate (547.62 g, 3.03 mol) was added dropwise during 1 h at 0 °C, then the mixture was 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 with anhydrous Na2SO4, filtered and concentrated 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. 1H NMR: (400 MHz, CDCl3 7.69 (s, 2 H), 3.74 (s, 3 H), 1.99 (s, 6 H). 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) was added n-BuLi (2.5 M in THF, 359.4 mL) drop wise at - 7 ME1 46604090v.1
137485-01120 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 for 1 h at -78 °C, then 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 mixture was adjusted the pH to 4~5 by aq.HCl (2 M), the aqueous phase was extracted with EtOAc (3 × 800 mL). The combined organic phase was washed with brine (800 mL), dried with anhydrous Na2SO4, filtered and concentrated reduced pressure to give the crude product that 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 purple solid. 1H NMR (400 MHz, CDCl3 3.11 (s, 2 H), 1.90 (s, 6 H). 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 con. HCl (12 M, 9.03 mL) in one portion at 25 °C under N2. The mixture was stirred at 90 °C for 10 h. Aq. NaHCO3 was added to the mixture and the pH was adjusted to 7-8. The aqueous phase was extracted with EtOAc (3 × 300 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated 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 yellow solid. 1H NMR (400 MHz, CDCl3 (m, 2 H), 1.04-1.01 (m, 2 H). N2-(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: 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.H2O (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 aq. NaHCO3 (1500 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 × 600 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated 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 to the solution at 70 °C in portions until the solid was dissolved. The hot solution was filtered. The filtrate was allowed to cool to room temperature and stand for 16 h. The resulting crystals were filtered, washed with a small amount of n-heptane to give N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5- 8 ME1 46604090v.1
137485-01120 (trifluoromethyl)pyrimidine-2,4-diamine (64 g, 47.03% ) as a yellow solid. 1 H NMR (400 MHz, - 3.47 (m, 2 H), 3.23 (tt, J=6.95, 3.59 Hz, 1 H), 2.10 (s, 6 H), 1.17 - 1.26 (m, 5 H), 1.08 - 1.16 (m, 2 H). MS: (M+H+) m/z: 422.2. POLYMORPH SCREENING OF FORMULA I COMPOUND Polymorph screening experiments were performed using a variety of crystallization or solid transition methods, including: anti-solvent addition, slow evaporation, slow cooling, slurry at room temperature, slurry cycling, solid vapor diffusion, liquid vapor diffusion, polymer induced crystallization, and melt/cool. By these methods, Forms A, B, and C were identified. 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 back to Form A after one month at room temperature. Heating Form A to 110 oC followed by cooling to – 20 oC forms amorphous Form C, which converts back to Form A on warming to room temperature. The 24 hours solubility evaluation showed that the solubility of Form A in water at was 29.9 µg/mL. DVS (dynamic vapor sorption) results indicated Form A is non-hygroscopic, as defined by less than 0.2% reversible water intake (Table 1). Table 1.
POLYMORPH SCREENING A total of 70 polymorph screening experiments were performed using different crystallization or solid transition methods. The methods utilized and crystal forms identified are summarized below in Table 2. Table 2.
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ANTI-SOLVENT ADDITION A total of 14 anti-solvent addition experiments were carried out. About 20 mg of the Formula I compound was dissolved in 0.1~0.7 mL solvent to obtain a clear solution, and the solution was magnetically stirred followed by addition of 0.1 mL anti-solvent per step until precipitate appeared or the total amount of anti-solvent reached 10.0 mL. The precipitate was isolated for XRPD analysis. Results in Table 3 below showed that Form A and A+B were generated. Table 3.
*10 mL of anti-solvent was added into corresponding solution, but a clear solution was obtained and then transferred to evaporate at room temperature. SLOW EVAPORATION Slow evaporation experiments were performed under eight conditions. Approximately 20 mg of the Formula I compound was dissolved in 0.5 mL of solvent in a 3-mL glass vial. If not 10 ME1 46604090v.1
137485-01120 and the filtrates were used instead for the follow-up steps. The visually clear solutions were subjected to evaporate at room temperature with vials sealed by Parafilm®. The solids were isolated for XRPD analysis, and the results summarized in Table 4 shows that only Form A was discovered. Table 4.
SLOW COOLING Slow cooling experiments were conducted in five different solvent systems. About 20 mg of the Formula I compound was suspended in 0.4~1.0 mL of solvent in a 5-mL vial. The suspension was then heated to 50 °C, equilibrated for about 2 hrs. If not dissolved completely, slowly cooled down from 50 °C to 5 °C at a rate of 0.1 °C/min. The obtained solids were collected for XRPD analysis. Results summarized in the Table 5A shows that Form A and a gel were generated. Table 5A.
*Clear solution was obtained after cooling and then transferred to evaporate at room temperature. SLURRY CONVERSION Slurry conversion experiments were conducted at room temperature in 15 different solvent systems. About 20 mg of the Formula I compound was suspended in 0.2~0.3 mL of solvent in a 1.5-mL glass vial. After the suspension was stirred magnetically for four days at 11 ME1 46604090v.1
137485-01120 room temperature, the remaining solids were isolated for XRPD analysis. From all of the experiments, only Form A was generated. Table 5B.
*Clear solution was obtained and then transferred to slurry at 5 °C. SLURRY CYCLING Slurry cycling experiments were conducted in eight different solvent systems. About 25 mg of the Formula I compound was suspended in 0.2~0.3 mL of solvent in a 1.5-mL glass vial. After stirred magnetically (~1000 rpm) at 70 °C for one day, the suspension was transferred to slurry at 50 °C for three days. Results summarized in the Table 5C below shows that only Form A was generated. Table 5C.
SOLID VAPOR DIFFUSION Solid vapor diffusion experiments were conducted using seven different solvents. About 12 ME1 46604090v.1
137485-01120 10 mg of the Formula I compound was weighed into a 3-mL vial, which was placed into a 20- mL vial with 4 mL of volatile solvent. The 20-mL vial was sealed with a cap and kept at room temperature for nine days, allowing solvent vapor to interact with sample. The solids were tested by XRPD and the results summarized in Table 6 below shows that Form A and gel were generated. Table 6.
*Clear solution was obtained and then transferred to evaporate at room temperature. LIQUID VAPOR DIFFUSION Nine liquid vapor diffusion experiments were conducted. Approximate 20 mg of Formula I compound was dissolved in 0.1~0.7 mL of appropriate solvent to obtain a clear solution in a 3-mL vial. If it was not completely dissolved, compound was filtered into a new vial. The solution was then placed into a 20-mL vial with 4 mL of volatile solvents (anti- solvent). The 20-mL vial was sealed with a cap and kept at room temperature, allowing sufficient time for anti-solvent vapor to interact with the solution. The precipitates were isolated for XRPD analysis. The results summarized in Table 7A below shows that only Form A was observed. Table 7A
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* Clear solution was obtained and then transferred to evaporate at room temperature POLYMER INDUCED CRYSTALLIZATION Polymer induced crystallization experiments were performed with two sets of polymer mixtures in four different solvent systems. Approximate 20 mg of Formula I compound was dissolved in 1.0-2.0 mL of appropriate solvent in a 3-mL glass vial containing about 2 mg of polymer mixture. Clear solutions were transferred to evaporate at room temperature. The obtained solids were collected for XRPD characterization. Results summarized in Table 7B below shows that only Form A was generated. Table 7B.
Polymer mixture A: polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinylchloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), methyl cellulose (MC) (mass ratio of 1:1:1:1:1:1). Polymer mixtureB: polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA) sodium alginate (SA), and hydroxyethyl cellulose (HEC) (mass ratio of 1:1:1:1:1). GENERAL METHODS XRPD XRPD pattern was collected using a PANalytical Empyrean X-ray powder diffract meter. The X-ray source was a Cu tube that was operated at 45 kV and 40 mA. The scan mode was continuous and the divergence slit automatic. Each sample was analyzed from 3° to 40° 2- theta with a step size of 0.0167° 2-theta and 18 sec scan step time. 14 ME1 46604090v.1
137485-01120 Table 8. Parameters for XRPD test
DSC/TGA DSC analysis was conducted on a TA Instruments Q2000 DSC. The DSC cell was kept under a nitrogen purge. The sample was placed in an aluminum crimped pan and was heated from 25 °C to 300 °C at a rate of 10 °C /min. TGA data was collected using a TA Q500/Q5000 TGA from TA Instruments. The TGA was performed using 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 conducted on a TA Instruments Q200/Q2000 DSC. The DSC cell was kept under a nitrogen purge. The sample was placed in an aluminum crimped pan and was heated from 25 °C to 300 °C at a rate of 10 °C /min. Table 9. Parameters for TGA and DSC test
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137485-01120 DVS DVS analysis was carried out using a SMS (Surface Measurement Systems) DVS Intrinsic analyzer. The relative humidity at 25 ºC was calibrated against the deliquescence point 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. The sample was analyzed at 25 ºC in a range of 0 to 95% relative humidity (RH), with 10% RH steps from 0 to 90% RH and a 5% RH step from 90 to 95% RH. The progression from one step to the next occurred either after satisfying the equilibrium criterion of 0.002 %/min weight change (dm/dt), or if the equilibrium criterion was not met, after 180 min. The minimum dm/dt stability duration of each step was 10 min. FORM A CHARACTERIZATION Form A was characterized by XRPD, TGA, DSC, DVS, and polarized light microscopy (PLM). XRPD (Figure 2, Table 10) revealed a highly crystalline structure. TGA indicated low weight loss, and DSC indicated a single sharp melt at around 107 ºC (Figure 4). DVS showed that Form A is non-hygroscopic with no form change after exposure to humidity. Examination of the PLM indicates irregular plate-like particles. Based on the characterization results, Form A is an anhydrate form. Table 10. Form A Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 5.421079 292.616100 0.100368 16.30226 9.68 7.417347 224.926700 0.083640 11.91863 7.44 9.212257 464.539300 0.100368 9.60005 15.37 9.714739 699.811200 0.083640 9.10460 23.15 10.529370 592.539400 0.083640 8.40196 19.60 10.851660 541.991200 0.100368 8.15313 17.93 11.138000 268.499100 0.066912 7.94417 8.88 12.422050 1855.240000 0.066912 7.12573 61.38 13.894790 1369.331000 0.100368 6.37359 45.31 14.224000 719.882100 0.083640 6.22681 23.82 14.462850 330.416300 0.083640 6.12451 10.93 14.833930 456.447600 0.083640 5.97213 15.10 15.161300 555.737900 0.100368 5.84390 18.39 15.748080 2080.974000 0.083640 5.62745 68.85 16 ME1 46604090v.1
137485-01120 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 16.276370 385.186400 0.083640 5.44597 12.74 16.443410 242.224700 0.050184 5.39102 8.01 16.861240 550.223000 0.083640 5.25836 18.20 17.072820 744.158800 0.100368 5.19367 24.62 17.302290 530.229200 0.100368 5.12530 17.54 18.340920 713.336700 0.100368 4.83734 23.60 18.819760 2881.377000 0.150552 4.71532 95.33 19.096160 839.291700 0.133824 4.64769 27.77 19.388570 976.708500 0.167280 4.57825 32.32 20.275920 455.813400 0.066912 4.37985 15.08 20.438010 427.424600 0.083640 4.34548 14.14 20.723140 220.927800 0.100368 4.28633 7.31 21.117380 1154.695000 0.117096 4.20719 38.20 21.530200 495.792000 0.066912 4.12745 16.40 21.755420 1232.721000 0.100368 4.08523 40.79 21.999510 850.546000 0.050184 4.04045 28.14 22.141850 3022.416000 0.100368 4.01480 100.00 22.385390 1191.534000 0.083640 3.97167 39.42 22.687480 2621.654000 0.083640 3.91946 86.74 22.979790 961.488300 0.083640 3.87026 31.81 23.465970 1607.096000 0.083640 3.79116 53.17 23.645910 712.008700 0.050184 3.76272 23.56 24.155120 540.993800 0.066912 3.68454 17.90 24.301470 579.326200 0.100368 3.66268 19.17 24.911450 243.123700 0.066912 3.57436 8.04 25.135970 195.778000 0.133824 3.54294 6.48 25.598240 107.599300 0.066912 3.48000 3.56 26.067820 716.321200 0.100368 3.41837 23.70 26.485630 450.658200 0.133824 3.36539 14.91 26.957080 545.243200 0.133824 3.30759 18.04 27.307470 482.697900 0.133824 3.26594 15.97 27.873180 372.340000 0.100368 3.20093 12.32 28.533940 405.375900 0.066912 3.12829 13.41 29.195540 128.013500 0.066912 3.05889 4.24 29.628390 283.333300 0.066912 3.01518 9.37 30.294290 107.314900 0.117096 2.95040 3.55 17 ME1 46604090v.1
137485-01120 STABILITY OF FORM A To evaluate the solid form stability, Form A was stored under 40 ºC/75%RH (relative humidity, accelerated) and 25 ºC/60%RH (long-term) conditions. Form A was demonstrated to be physically and chemically stable for up to 6 months at 40 ºC/75%RH and for up to 48 months at 25 ºC/60%RH. Samples were analyzed for appearance, HPLC purity, and polymorphic form. No form change was detected by XRPD and no changes in purity by HPLC were observed. Table 11. Stability Evaluation of Form A
Time point Condition Appearance XRPD Purity Total Impurities (%) Initial NA Off-white powder Form A 0.4 40 ºC/75%RH Off-white powder Form A 0.3 6 months
ºC/60%RH Off-white powder Form A 0.3 48 months 25 ºC/60%RH Off-white powder Form A 0.3 FORM A + B (MIXTURE) Form A + B mixture was prepared by adding cyclohexane (antisolvent) into a methyl isobutyl ketone solution. The Form A + B mixture was characterized by XRPD (Figure 3) Table 12. Diffraction peak list for Form A + B mixture
8.040031 647.488100 0.076752 10.99690 100.00 9.178742 103.390800 0.102336 9.63503 15.97 9.931249 76.670200 0.076752 8.90659 11.84 10.509380 124.220600 0.076752 8.41789 19.19 12.362780 358.379600 0.076752 7.15976 55.35 13.814890 125.699200 0.102336 6.41027 19.41 14.191680 91.339680 0.076752 6.24092 14.11 14.403340 79.310290 0.076752 6.14968 12.25 14.830910 156.307800 0.102336 5.97334 24.14 15.159580 132.673000 0.076752 5.84456 20.49 15.709770 114.289400 0.076752 5.64109 17.65 16.127980 170.184600 0.076752 5.49574 26.28 17.051560 133.386000 0.076752 5.20010 20.60 18 ME1 46604090v.1
137485-01120 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 17.285010 110.226500 0.076752 5.13039 17.02 18.788090 188.651000 0.076752 4.72320 29.14 19.053450 150.729300 0.102336 4.65801 23.28 19.429520 60.674270 0.102336 4.56870 9.37 19.914820 83.314620 0.127920 4.45845 12.87 20.746630 45.453600 0.127920 4.28153 7.02 21.130140 111.443400 0.076752 4.20468 17.21 22.169870 117.592900 0.102336 4.00979 18.16 22.666270 225.011500 0.102336 3.92308 34.75 23.234480 126.403500 0.076752 3.82841 19.52 24.256870 61.243640 0.204672 3.66931 9.46 26.293350 18.725340 0.614016 3.38956 2.89 Form C (amorphous) Form C (amorphous freebase) was prepared by heating Form A at 110 ºC until the solids were completely melted, and then transferring to -20 ºC. Form C was characterized by XRPD and DSC. The XRPD trace revealed a characteristic amorphous halo with no significant diffraction peaks (Figure 6). SINGLE CRYSTAL DETERMINATION OF FORM A Form A SXRPD Characterization A suitable single crystal was selected from block-like crystals and analyzed by a single- crystal X-ray diffractometer (SCXRD). The structure of the single crystal was determined successfully. The SCXRPD characterization and analysis suggested that the crystal system is triclinic and the space group is P1, the cell parameters and calculated cell volume are: a = 67.773(4)º, V = 1985.63(14). The formula weight is 421.44 g mol-1 with Z = 4, resulting in a calculated density of 1.410 g cm-3. Crystal Growth Procedure The block-like single crystals of Form A used for single-crystal X-ray diffractometry (SCXRD) characterization were obtained via liquid vapor diffusion from a DMSO and H2O solvent system at room temperature. PLM image of the Form A single crystals is shown in 19 ME1 46604090v.1
137485-01120 Figure 7. Data Collection A colorless block-like single crystal selected from the Form A single crystals sample was mounted in a random orientation and immersed in a stream of nitrogen at 150 K. Preliminary examination and data collection were performed on a Agilent SuperNova (Dual, Cu at zero, Eos) diffractometer, equipped with a SuperNova Microfocus X-ray source (Cu/K = 1.54184 Å) and a Eos CCD detector and analyzed with the CrysAlisPro (version: 1.171.38.41) software package. Cell constants and an orientation matrix for data collection were obtained from least-squares Data Reduction Frames were integrated with CrysAlisPro (Version: 1.171.38.41). A total of 14156 reflections were collected, of which 7446 were unique. Lorentz and polarization corrections radiation. A semi-empirical absorption correction was made (multi-scan method) using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Transmission coefficients ranged from 0.95582 to 1.00000. Intensities of equivalent reflections were averaged. The agreement factor for the averaging was 1.65% based on intensity. Single Crystal Structure Solution and Refinement The structure was solved with the Superflip structure solution program using Charge Flipping and refined with ShelXL (Version 2014/7) refinement package using full-matrix least- squares on F2 contained in OLEX2. Hydrogen atoms were refined as riding model on the atom to which they are bonded. Calculated X-ray Powder Diffraction (XRPD) Pattern The calculated XRPD pattern was generated for Cu radiation using 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 and the atomic coordinates, space group, and unit cell parameters from the single crystal structure. The calculated XRPD pattern generated from the Form A single crystal structure is in agreement with the experimental XRPD 20 ME1 46604090v.1
137485-01120 pattern. Single Crystal Structure Diagrams The crystal structure representations were generated by Diamond (Brandenburg, K. DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany). The thermal ellipsoids drawing was generated by ORTEP-III (J. Appl. Cryst. (2012).45, 849–854). Instruments and Parameters The single crystal X-ray diffraction data was collected at 150 K using Agilent SuperNova (Dual, Cu at zero, Eos) diffractometer (Cu/K radiation, = 1.54178 Å). The microscopic picture was captured using Shanghai Cewei PXS9-T stereo microscope. Table 13. SCXRD Instrument Parameters
Table 14. Crystallographic data and refinement parameters
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The thermal Ellipsoid Drawing of Form A Asymmetric Unit Molecule is shown in Figure 5. Table 15. Fractional atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2 × 103) for Freebase Type A single crystal (810014-28-A6).
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Ueq is defined as 1/3 of the trace of the orthogonalised Uij tensor. 24 ME1 46604090v.1
137485-01120 Table 16. Anisotropic displacement parameters (Å2 × 103) for Freebase Type A single crystal (810014-28-A6)
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2[h2a*2U11 + 2hka*b*U12 26 ME1 46604090v.1
137485-01120 Table 17. Bond lengths for Freebase Type A single crystal
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Table 18. Bond angles for Freebase Type A single crystal
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Table 19. Hydrogen atom coordinates (Å × 104) and isotropic displacement parameters (Å2 × 103) for Freebase Type A single crystal
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CO-CRYSTALS Cocrystal Screen Cocrystal screen experiments were conducted with approximately fifty-five coformers. Experiments were planned based on solubilities of the API and coformer and incorporated a variety of techniques, including slurry, grinds, co-melting, and cooling. For dicarboxylic acids, both 1:1 and 2:1 Formula I compound:coformer stoichiometries were employed. Details for experiments are summarized in Table 20. Table 20. Samples Generated and Analyzed
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CF = conformer; NC = non-crystalline, API = active pharmaceutical ingredient, RT = room temperature Twenty-six new materials were generated with the following coformers: 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, palmoic acid, propionic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, 38 ME1 46604090v.1
137485-01120 terephthalic acid, and vanillic acid. Table 21 below shows melting points as characterized by DSC analysis of select cocrystals that were formed. Table 21
GENERAL METHODS FOR CO-CRYSTAL ANALYSES DSC analysis was conducted on a TA Instruments Q2500 Discovery Series instrument. The instrument calibration was performed using Indium. The DSC cell was kept under a nitrogen purge of ~50 mL per minute during each analysis. The sample was placed in an 39 ME1 46604090v.1
137485-01120 aluminum crimped pan and was heated from approximately 25 °C to 350 °C at a rate of 10 °C per minute. PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS A polymorph form of Formula I, may be formulated in accordance with standard pharmaceutical practice and according to procedures of Example 9, for use in therapeutic treatment (including prophylactic treatment) in mammals including humans. The present disclosure provides a pharmaceutical composition comprising the Formula I compound in association with one or more pharmaceutically acceptable carrier, glidant, diluent, or excipient. 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. The formulations may be prepared using conventional dissolution and mixing procedures. The compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen. The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited 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 packaging, sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. Pharmaceutical formulations of a polymorph form of Formula I compound may be prepared for various routes and types of administration with pharmaceutically acceptable diluents, carriers, excipients, glidants or stabilizers (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA), in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. 40 ME1 46604090v.1
137485-01120 The pharmaceutical formulation can 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. The pharmaceutical formulation ordinarily can be stored as a solid composition, a tablet, a pill, a capsule, a lyophilized formulation or as an aqueous solution. The pharmaceutical formulations of the invention will be dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate 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 benzylalcohol; 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, 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 counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN , including Tween 80, PLURONICS or polyethylene glycol (PEG), including PEG400. The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles 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 drug formulations can be found in Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol 3, 2nd Ed., New York, NY. Tablets may comprise of one or more pharmaceutically acceptable excipient such as a 41 ME1 46604090v.1
137485-01120 carrier, glidant, diluent, binder, disintegrant, or lubricant. Pharmaceutically acceptable diluents maybe selected from microcrystalline cellulose, lactose, sodium starch glycolate, calcium carbonate, corn starch, sugar alcohols such as sorbitol, xylitol, mannitol, and combinations thereof. 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. Pharmaceutically acceptable binders may be selected from corn starch and pregelatinized starch, carboxymethylcellulose sodium, carmellose sodium, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, PEG (Polyethylene Glycol) povidone, compressible sugar, and combinations thereof. Pharmaceutically acceptable disintegrants may be selected from microcrystalline cellulose, powdered cellulose, carmellose sodium, carboxymethylcellulose calcium, sodium starch glycolate, crospovidone, and combinations thereof. Pharmaceutically acceptable lubricants may be selected from magnesium stearate, stearic acid, calcium stearate, sodium stearic fumarate, polyethylene glycols, colloidal silicon dioxide, talc, beeswax, hydrogenated vegetable oil, and combinations thereof. The pharmaceutical formulations include those suitable for the administration routes 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 generally are found in Remington's Pharmaceutical Sciences 18th 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 may be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may be a solution or a suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared from a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride 42 ME1 46604090v.1
137485-01120 solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. In another aspect, the present disclosure relates to a method of treating a disease or condition mediated, at least in part, by leucine-rich repeat kinase 2 (LRRK2). In particular, the disclosure provides methods for preventing or treating a disorder associated with LRRK2 in a mammal, comprising the step of administering to said 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, for example, a central nervous system (CNS) disorder, such as Parkinson's disease (PD), Alzheimer's disease (AD), dementia (including Lewy body dementia and cascular dementia), amyotrophic lateral sclerosis (ALS), age related memory dysfunction, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer’s disease), argyrophilic grain disease, lysosomal disorders (for example, Niemann-PickType C disease, Gaucher disease) corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms/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 organs including but not limited to brain, heart, kidney, and liver. 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, renal (including papillary renal), breast, lung, blood, and prostate cancers (e.g. solid tumor), leukemias (including acute myelogenous leukemia (AML)), or lymphomas. In some embodiments, the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, or multiple myeloma. In other embodiments, the presently disclosed compounds are used in methods for treatment of inflammatory disorders. In some embodiments, the disorder is an inflammatory disease of the intestines, such as Crohn’s disease or ulcerative colitis (both generally 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. In other embodiments, the presently disclosed compounds are used in methods for 43 ME1 46604090v.1
137485-01120 treatment of 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 mellitus, Sjogren’s syndrome, Devic’s disease, and inflammatory myopathies. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference. 44 ME1 46604090v.1