Crystalline forms of 3-(5-(4-((3,3-dimethyl-4-((1-(6-(5-(1-methylcyclopropoxy)-1hindazol-3-YL)pyrimidin-4-YL)piperidin-4-YL)methyl)piperazin-1-YL)methyl)piperidin-1-YL)-4-fluoro-1-oxoisoindolin-2-YL)piperidine-2,6-dione

Abstract

Provided are crystalline forms of 3-(5-(4-((3,3-dimethyl-4-((1-(6-(5-(1- methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin-1- yl)methyl)piperidin-1-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2, 6-dione, pharmaceutical compositions comprising the crystalline form, and their use in treating conditions associated with LRRK2, such as Parkinson's disease, dementia, Progressive Supranuclear Palsy, Huntington's disease, or neuroinflammation.

Description

CRYSTALLINE FORMS OF 3-(5-(4-((3,3-DIMETHYL-4-((l-(6-(5-(l- METHYLCYCLOPROPOXY)-lH-INDAZOL-3-YL)PYRIMIDIN-4-YL)PIPERIDIN- 4-YL)METHYL)PIPERAZIN-l-YL)METHYL)PIPERIDIN-l-YL)-4-FLUORO-l- OXOISOINDOLIN-2-YL)PIPERIDINE-2, 6-DIONERELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 662,586, filed on June 21, 2024. The entire contents of the foregoing application are expressly incorporated herein by reference.BACKGROUND

[0002] Leucine-rich repeat kinase 2 (LRRK2) is a member of the leucine-rich repeat kinase family. There are several dominant gain-of-function pathogenic and characterized mutations to LRRK2, located either in the Roco domains (N1437H, R1441G / C / H, Y1699C), effecting GTP hydrolysis, or in the kinase domain (G2019S and I2020T). The G2019S mutation is the most common LRRK2 mutation linked to Parkinson’s disease (PD), which is a progressive neurodegenerative disorder characterized by resting tremors, rigidity, decreased movement (bradykinesia), and postural instability.

[0003] The G2019S and I2020T mutations lie within the DFG motif (DYGI in the case of LRRK2), common to all kinases, which controls catalytic activity. These mutations are thought to disrupt the inactive conformation and thus increase catalytic activity (Schmidt SH, et al. Proc Natl Acad Sci USA 2019, 116: 14979-14988). Several of the other mutations (R1441C / G, Y1699C and I2020T) suppress phosphorylation of LRRK2 at Ser910 and Ser935, which in turn reduces LRRK2 association with 14-3-3 proteins, thought to represent an inactive form of LRRK2 ( Nichols J, et al. Biochem J. 2010, 430:393-404). Indeed, mutations increasing LRRK2 activity, such as G2019S, increase the aggregation of alpha- synuclein in neurons and mouse models of PD.

[0004] Due to the correlation of LRRK2 over-activity with PD, LRRK2 kinase inhibitors have been proposed as having the potential to treat mutation-driven PD, where there is an increase in LRRK2 activity, such as G2019S, and idiopathic PD, where the activity of LRRK2 is increased. However, there is some evidence to suggest that the G2019S mutant form of LRRK2 is resistant to inhibition by kinase inhibitors in the CNS, potentially reducing their disease modifying effect (Kelly K, et al. Exp Neurol. 2018 Nov; 309: 1-13). In an alternative to inhibition, depletion of LRRK2 with anti-sense oligionucleotides and deletion of LRRK2 at a genomic level have been shown to reduce alpha-synuclein mediatedpathology in mouse models of PD (Zhao HT, et al. Nucleic acids 2017, 8:508-519 and Lin X, et al. Neuron 2009, 64:807-827). Thus, there is a need for compounds which would either inhibit or degrade / deplete the levels of LRRK2 in order to treat PD or other diseases associated with LRRK2 over-activation, such as neuroinflammation.SUMMARY

[0005] Provided herein are crystalline forms of the LRRK2 degrader 3-(5-(4-((3,3- dimethyl-4-((l-(6-(5-(l -methylcyclopropoxy)- lH-indazol-3-yl)pyrimidin-4-yl)piperidin-4- yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2-yl)piperidine- 2, 6-dione.

[0006] Also provided are pharmaceutical compositions comprising the described crystalline forms as well as methods for their preparation and uses for treating conditions responsive to the degradation of LRRK2.BRIEF DESCRIPTION OF THE FIGURES

[0007] Figure 1 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form A of 3 -(5 -(4-((3 , 3 -dimethyl-4-(( 1 -(6-(5 -( 1 -methyl cyclopropoxy)- 1 H-indazol-3 -yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0008] Figure 2 depicts a differential scanning calorimetry (DSC) plot for crystalline Form A of 3 -(5 -(4-((3 , 3 -dimethyl-4-(( 1 -(6-(5 -( 1 -methyl cyclopropoxy)- 1 H-indazol-3 -yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0009] Figure 3 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form B of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0010] Figure 4 depicts a differential scanning calorimetry (DSC) plot for crystalline Form B of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0011] Figure 5 depicts an X-ray powder diffraction pattern (XRPD) for crystalline FormC of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0012] Figure 6 depicts a differential scanning calorimetry (DSC) plot for crystalline Form C of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0013] Figure 7 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form F of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0014] Figure 8 depicts a differential scanning calorimetry (DSC) plot for crystalline Form F of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0015] Figure 9 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form G of 3 -(5 -(4-((3 , 3 -dimethyl-4-(( 1 -(6-(5 -( 1 -methyl cyclopropoxy)- 1 H-indazol-3 -yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0016] Figure 10 depicts a differential scanning calorimetry (DSC) plot for crystalline FormG of 3 -(5 -(4-((3 , 3 -dimethyl-4-(( 1 -(6-(5 -( 1 -methyl cyclopropoxy)- 1 H-indazol-3 -yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0017] Figure 11 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form H of 3 -(5 -(4-((3 , 3 -dimethyl-4-(( 1 -(6-(5 -( 1 -methyl cyclopropoxy)- 1 H-indazol-3 -yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0018] Figure 12 depicts a differential scanning calorimetry (DSC) plot for crystalline FormH of 3 -(5 -(4-((3 , 3 -dimethyl-4-(( 1 -(6-(5 -( 1 -methyl cyclopropoxy)- 1 H-indazol-3 -yl)pyrimidin- 4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione.

[0019] Figure 13 depicts an X-ray powder diffraction pattern (XRPD) for amorphous 3-(5- (4-((3,3-dimethyl-4-((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin-4- yl)piperidin-4-yl)methyl)piperazin-l-yl)methyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione prepared as described in WO 2022 / 198112.DETAILED DESCRIPTIONA. General Description of Compound Forms

[0020] Provided are crystalline Forms A, B, C, D, E, F, G, and H of 3-(5-(4-((3,3-dimethyl- 4-(( 1 -(6-(5-( 1 -methylcy clopropoxy)- lH-indazol-3 -yl)pyrimidin-4-yl)piperidin-4- yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2-yl)piperidine- 2, 6-dione.B. Definitions

[0021] As used herein, the recitation of a range of values is intended to serve as a shorthand method of referring individually to each separate value falling within the range as well as the highest and lowest values that define the range and that each value is incorporated into the specification as if it were individually recited herein, unless expressly stated to the contrary. For example, a range of values from X to Y includes both X and Y and all the values in between X and Y.

[0022] The use of any and all examples, or exemplary language (e.g., “such as” and “e.g.”) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. Phrases such as “in one aspect”, “in one embodiment”, “in another aspect”, “in another embodiment”, “in embodiments”, and the like should not be construed as indicating that such elements occur or exist in isolation or that such elements are not shared by other aspects or embodiments of the disclosure. Rather, it should be understood that all aspects and embodiments may be freely combined with any and all other aspects and embodiments of the disclosure as described herein. No language in the specification should be construed as indicating that any non-claimed element is essential to the practice of the disclosure.

[0023] 3-(5-(4-((3, 3-dimethyl-4-((l -(6-(5-(l -methylcy clopropoxy)-lH-indazol-3- yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 - oxoisoindolin-2-yl)piperidine-2, 6-dione and Compound 1 may be used interchangeably and each refer to the compound having the following chemical structure:the preparation of which is described in WO 2022 / 198112.

[0024] As used herein, “crystalline” refers to a solid form of Compound 1 where there exists long-range atomic order in the positions of the atoms. The crystalline nature of Compound 1 can be confirmed, for example, by examination of the X-ray powder diffraction pattern.

[0025] When used alone, the terms “Form A”, “Form B”, “Form C”, “Form D”, Form E”, “Form F”, “Form G”, and “Form H” refer to the crystalline “Form A”, “Form B”, “Form C”, “Form D”, Form E”, “Form F”, “Form G”, or “Form H” of Compound 1, respectively, as described herein.

[0026] In one embodiment, the crystalline forms described herein are each single crystalline forms. A “single crystalline form” means that the recited compound, i.e., Compound 1, is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, or Form H). Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal form(s) present plus the weight of amorphous form, if present, multiplied by 100%. In some instances, crystalline Forms A, B, C, D, E, F, G, or H, as described herein are at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% a single crystalline form. “Pure single crystalline form” means that Compound 1 is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form with no other detectable amounts of other crystal forms present and / or amorphous forms.

[0027] As use herein, “substantially free of amorphous form” or “substantially free of amorphous form of the compound” means that the recited compound, i.e., Compound 1 is present in the described crystalline form in which there is no detectable amount of amorphous form of the compound.

[0028] The 2-theta (20) values of the X-ray powder diffraction patterns for the crystalline form described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation due to factors such as temperature variation, sample displacement, and the presence or absence of an internalstandard. Therefore, unless otherwise defined, the XRPD patterns / assignments recited herein are not to be construed as absolute and can vary ± 0.2 degrees. It is well known in the art that this variability will account for the above factors without hindering the unequivocal identification of a crystal form. Unless otherwise specified, the 2-theta values provided herein were obtained using Cu Kai radiation.

[0029] Temperature values, e.g., for DSC peaks herein may vary slightly from one instrument to another and also depending on variations in sample preparation, batch to batch variation, heating rate of the method, and environmental factors. Therefore, unless otherwise defined, temperature values recited herein are not to be construed as absolute and can vary ± 5 degrees or ± 2 degrees.

[0030] “Substantially the same XRPD pattern” or “an X-ray powder diffraction pattern substantially similar to” a defined figure means that for comparison purposes, at least 90%, at least 95%, at least 99%, of the peaks shown are present. It is to be further understood that for comparison purposes some variability in peak intensities from those shown are allowed, such as ± 0.2 degrees.

[0031] The term “amorphous” refers to a solid that is present in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).

[0032] The term “anhydrous” and “anhydrate” are used interchangeably and mean that the referenced crystalline form has substantially no water in the crystal lattice, e.g., less than 1% by weight as determined by Karl Fisher analysis.

[0033] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0034] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or othersusceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0035] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0036] The term “effective amount” or “therapeutically effective amount” refers to an amount of a crystalline form described herein that will elicit a desired or beneficial biological or medical response of a subject e.g., a dosage of between about 0.01 mg / kg to about 100 mg / kg body weight / day.C. Exemplary Forms

[0037] In embodiments, provided herein is crystalline Form A of 3-(5-(4-((3,3-dimethyl-4- ((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin-4-yl)piperidin-4- yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 -oxoisoindolin-2-yl)piperidine- 2, 6-dione.

[0038] In embodiments, crystalline Form A of Compound 1 is characterized by an X-ray powder diffraction peak at 20 angle 5.5 and at least two additional X-ray powder diffraction peaks at 20 angles selected from 8.2, 14.4, 15.8, and 17.8. In other embodiments, crystalline Form A of Compound 1 is characterized by an X-ray powder diffraction peak at 20 angle 5.5 and at least three additional X-ray powder diffraction peaks at 20 angles selected from 8.2, 14.4, 15.8, and 17.8. In other embodiments, crystalline Form A of Compound 1 is characterized by at least three X-ray powder diffraction peaks selected from 5.5, 8.2, 14.4, 15.8, and 17.8. In other embodiments, crystalline Form A of Compound 1 is characterized by at least four X-ray powder diffraction peaks selected from 5.5, 8.2, 14.4, 15.8, and 17.8. In other embodiments, the crystalline Form A of Compound 1 is characterized by X-ray powder diffraction peaks at 5.5, 8.2, 14.4, 15.8, and 17.8. In other embodiments, crystalline Form A of Compound 1 is characterized by at least four X-ray powder diffraction peaks selected from5.5, 8.2, 14.4, 15.8, and 17.8. In other embodiments, crystalline Form A of Compound 1 is characterized by X-ray powder diffraction peaks at 5.5, 8.2, 10.1, 11.7, 13.6, 14.4, 15.5, 15.8,16.5, 17.8, 18.5, 19, 19.7, 20.8, 21.2, 22.2, 23.4, 24.4, 25, 25.6, 26.6, 27.1, 27.6, 28.3, 29.2, and 29.9. In other embodiments, crystalline Form A of Compound 1 is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty -two, at least twenty-three, at least twenty- four, at least twenty-five, at least twenty-six, or at least twenty-seven X-ray powder diffraction peaks at 20 angles selected from those in Table 1. In other embodiments, crystalline Form A of Compound 1 is characterized by an X-ray powder diffraction substantially similar to Figure 1. In other embodiments, crystalline Form A of Compound 1 is characterized by a differential scanning calorimetry thermogram having an endotherm with a peak temperature of 290 °C. In other embodiments, crystalline Form A of Compound 1 is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 2. In other embodiments, crystalline Form A of Compound 1 is anhydrous.Table 1

[0039] Also provided herein is a crystalline Form B of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5- (l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin-l- yl)methyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0040] In embodiments, crystalline Form B of Compound 1 is characterized by an X-ray powder diffraction peak at 20 angle 9.8 and at least two additional X-ray powder diffraction peaks at 20 angles selected from 17.1, 17.7, 18.5, and 19.4. In other embodiments, crystalline Form B of Compound 1 is characterized by an X-ray powder diffraction peak at 20 angle 9.8 and at least three additional X-ray powder diffraction peaks at 20 angles selected from 17.1, 17.7, 18.5, and 19.4. In other embodiments, crystalline Form B of Compound 1 is characterized by at least three X-ray powder diffraction peaks at 20 angles selected from 16.5, 17.1, 17.7, 18.5, and 19.4. In other embodiments, crystalline Form B of Compound 1 is characterized by at least four X-ray powder diffraction peaks at 20 angles selected from 16.5, 17.1, 17.7, 18.5, and 19.4. In other embodiments, crystalline Form B of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 16.5, 17.1, 17.7, 18.5, and 19.4. In other embodiments, crystalline Form B of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 9.8, 17.1, 17.7, 18.5, and 19.4. In other embodiments, crystalline Form B of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 4.7, 5.3, 7, 8, 8.9, 9.8, 11.2, 11.4, 12.1, 12.7, 14.4, 15.5, 16.1, 16.5, 17.1, 17.7, 18.5, 19.4, 19.8, 20.2, 20.7, 22, 22.6, 23.3, 23.7, 25.4, 26.7, 27.9, and 29.3. In other embodiments, crystalline Form B of Compound 1 is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty -two, at least twenty -three, at least twenty-four, at least twenty -five, at least twenty-six, at least twenty-seven, at least twenty-eighth, or at least twenty-nine X-ray powder diffraction peaks at 20 angles selected from those in Table 2. In other embodiments, crystalline Form B of Compound 1 is characterized by an X-ray powder diffraction substantially similar to Figure 3. In other embodiments, crystalline Form B of Compound 1is characterized by a differential scanning calorimetry thermogram having endotherms with peak temperatures of 174 °C, 213 °C, and 282 °C. In other embodiments, crystalline Form B of Compound 1 is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 4. In other embodiments, crystalline Form B of Compound 1 is a solvate. In other embodiments, crystalline Form B of Compound l is a 2,2,2- trifluoroethanol solvate.Table 2

[0041] Also, provided herein is a crystalline Form C of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5- (l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin-l- yl)methyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0042] In embodiments, crystalline Form C of Compound 1 is characterized by an X-ray powder diffraction peak at 20 angle 10.6 and at least two additional X-ray powder diffraction peaks at 20 angles selected from 14.5, 15.9, 16.3, and 18.9. In other embodiments, crystalline Form C of Compound 1 is characterized by an X-ray powder diffraction peak at 20 angle 10.6 and at least three additional X-ray powder diffraction peaks at 20 angles selected from14.5, 15.9, 16.3, and 18.9. In other embodiments, crystalline Form C of Compound 1 is characterized by at least three X-ray powder diffraction peaks at 20 angles selected from10.6, 14.5, 15.9, 16.3, and 18.9. In other embodiments, crystalline Form C of Compound 1 is characterized by at least four X-ray powder diffraction peaks at 20 angles selected from 10.6,14.5, 15.9, 16.3, and 18.9. In other embodiments, crystalline Form C of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 10.6, 14.5, 15.9, 16.3, and 18.9. In other embodiments, crystalline Form C of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 5.3, 7.3, 10.6, 12.1, 14.5, 15.5, 15.9, 16.3, 17.7, 18.9, 19.9,21.5, 22.5, 23.1, 23.9, 26.5, 26.9, 27.6, 29.7, and 32.4. In other embodiments, crystalline Form C of Compound 1 is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, or at least twenty diffraction peaks at 20 angles selected from those in Table 3. In other embodiments, crystalline Form C of Compound 1 is characterized by an X-ray powder diffraction substantially similar to Figure 5. In other embodiments, crystalline Form C of Compound 1 is characterized by a differential scanning calorimetry thermogram having endotherms with a peak temperatures of 133 °C and 282 °C. In other embodiments, crystalline Form C of Compound 1 is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 6. In other embodiments, crystalline Form C of Compound l is a solvate. In other embodiments, crystalline Form C of Compound l is a dimethyl sulfoxide solvate.Table 3

[0043] Also provided herein is a crystalline Form F of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5- (l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin-l- yl)methyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0044] In embodiments, crystalline Form F of Compound 1 is characterized by an X-ray powder diffraction peak at 20 angle 4.1 and at least two additional X-ray powder diffraction peaks at 20 angles selected from 8.0, 8.7, 10.0, and 12.1. In other embodiments, crystalline Form F of Compound 1 is characterized by an X-ray powder diffraction peak at 20 angle 4.1 and at least three additional X-ray powder diffraction peaks at 20 angles selected from 8.0, 8.7, 10.0, and 12.1. In other embodiments, crystalline Form F of Compound 1 is characterized by at least three X-ray powder diffraction peaks at 20 angles selected from 4.1, 8.0, 8.7, 10.0, and 12.1. In other embodiments, crystalline Form F of Compound 1 is characterized by at least four X-ray powder diffraction peaks at 20 angles selected from 4.1, 8.0, 8.7, 10.0, and 12.1. In other embodiments, crystalline Form F of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 4.1, 8.0, 8.7, 10.0, and 12.1. In other embodiments, crystalline Form F of Compound 1 is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, or at least twenty -two diffraction peaks at 20 angles selected from those in Table 4. In other embodiments, crystalline Form F of Compound 1 ischaracterized by an X-ray powder diffraction substantially similar to Figure 7. In other embodiments, crystalline Form F of Compound 1 is characterized by a differential scanning calorimetry thermogram having endotherms with a peak temperatures of 144 °C, 174 °C, 207 °C, and 284 °C. In other embodiments, crystalline Form F of Compound 1 is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 8. In other embodiments, crystalline Form F of Compound l is a solvate. In other embodiments, crystalline Form F of Compound 1 is an ethanol solvate.Table 4

[0045] Also provided herein is a crystalline Form G of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5- (l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin-l- yl)methyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0046] In embodiments, crystalline Form G of Compound 1 is characterized by at least three X-ray powder diffraction peaks at 20 angles selected from 7.7, 9.3, 15.3, 16.5, and 19.2. In other embodiments, crystalline Form G of Compound 1 is characterized by at least four X-ray powder diffraction peaks at 20 angles selected from 7.7, 9.3, 15.3, 16.5, and 19.2.In other embodiments, crystalline Form G of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 7.7, 9.3, 15.3, 16.5, and 19.2. In other embodiments, crystalline Form G of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 7.7, 9.3, 15.3, 16, 16.5, 17.3, 17.5, 17.9, 18.3, 18.6, 19.2, 19.6, 21, 22.4 and 22.8. In other embodiments, crystalline Form G of Compound 1 is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen diffraction peaks at 20 angles selected from those in Table 5. In other embodiments, crystalline Form G of Compound 1 is characterized by an X-ray powder diffraction substantially similar to Figure 9. In other embodiments, crystalline Form G of Compound 1 is characterized by a differential scanning calorimetry thermogram having endotherms with a peak temperatures of 182 °C, 188 °C, and 290 °C. In other embodiments, crystalline Form G of Compound 1 is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 10. In other embodiments, crystalline Form G of Compound 1 is a solvate. In other embodiments, crystalline Form G of Compound 1 is a dimethylformamide solvate.Table 5

[0047] Also provided herein is a crystalline Form H of 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5- (l-methylcyclopropoxy)-lH-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin-l- yl)methyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0048] In embodiments, crystalline Form H of Compound 1 is characterized by at least three X-ray powder diffraction peaks at 20 angles selected from 4.7, 7.1, 9.4, 11.8, and 18.9. In other embodiments, crystalline Form H of Compound 1 is characterized by at least four X- ray powder diffraction peaks at 20 angles selected from 4.7, 7.1, 9.4, 11.8, and 18.9. In other embodiments, crystalline Form H of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 4.7, 7.1, 9.4, 11.8, and 18.9. In other embodiments, crystalline Form H of Compound 1 is characterized by X-ray powder diffraction peaks at 20 angles 4.7, 7.1, 9.4, 11.8, 14.1, 16.5, 17.3, 18.9, and 19.5. In other embodiments, crystalline Form H of Compound 1 is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine diffraction peaks at 20 angles selected from those in Table 6. In other embodiments, crystalline Form H of Compound 1 is characterized by an X-ray powder diffraction substantially similar to Figure 11. In other embodiments, crystalline Form H of Compound 1 is characterized by a differential scanning calorimetry thermogram having an endotherm with a peak temperatures of 154 °C. In other embodiments, crystalline Form H of Compound 1 is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 12. In other embodiments, crystalline Form H of Compound 1 is a solvate. In other embodiments, crystalline Form H of Compound 1 is a 1,4 dioxane solvate.Table 6D. Uses, Formulations, and Administration

[0049] The crystalline forms and compositions described herein are generally useful for degrading LRRK2.

[0050] In some aspects, the crystalline forms and compositions described herein are useful in treating a condition associated with LRRK2. In some aspects, the crystalline forms and compositions described herein are useful in treating a condition associated with LRRK2overexpression or over activity. Thus, provided herein are methods of treating disease, a disorder, or a symptom responsive to the degradation of LRRK2, comprising administering to a subject in need thereof a crystalline form described herein or a pharmaceutical composition comprising a disclosed crystalline form.

[0051] Also provided is the use of a crystalline form described herein, or a pharmaceutical composition comprising a disclosed crystalline form, for the manufacture of a medicament for treating a disease, a disorder, or a symptom responsive to the degradation of LRRK2. Also provided is a crystalline form described herein or a pharmaceutical composition comprising a disclosed crystalline form for use in treating a disease, a disorder, or a symptom responsive to the degradation of LRRK2.

[0052] In some aspects, the crystalline forms and pharmaceutical compositions described herein are useful in treating Parkinson’s disease (PD), LRRK2 mutation associated PD, primary tauopathies, lewy body dementia, Crohn’s Disease, Leprosy, neuroinflammation, Progressive Supranuclear Palsy, Picks disease, FTDtau, TDP-43 Frontal Temporal Dementia, TDP-43 ALS, c9orf ALS, Huntington’s disease, spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy (DRPLA), Kennedy’s disease, Alzheimer’s disease, multiple systems atrophy, acute kidney injury, Rhabdomyolysis, Lipofusinosis, Fabry’s disease, Batten’s disease, ulcerative colitis, irritable bowel disease, Kufor-Rakeb syndrome, gaucher disease, or systemic lupus erythematosus (SLE).

[0053] In some aspects, the pharmaceutical compositions are administered orally.

[0054] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.EXEMPLIFICATIONAbbreviationsA = angstromsACN = MeCN = acetonitrileCu = copperDCM = dichloromethaneDMSO = dimethyl sulfoxideEtOH = ethanolEtOAc = ethyl acetate IP A = isopropanol IP Ac = isopropyl acetate kV = kilo Volts2-MeTHF = 2-methyltetrahydrofuranMeOH = methanolMEK = methyl ethyl ketoneDMAc = N,N-dimethylacetamide DMF = N,N-dimethylformamide mA = milli-ampsMtBE = tert-butyl methyl etherRT = room temperature THF = tetrahydrofuran TFA = tri fluoroacetic acid TFE = trifluoroethanol

[0055] The representative examples that follow are intended to help illustrate the present disclosure, and are not intended to, nor should they be construed to, limit the scope of the invention.

[0056] 3-(5-(4-((3,3-dimethyl-4-((l-(6-(5-(l-methylcyclopropoxy)-lH-indazol-3- yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-4-fluoro- 1 - oxoisoindolin-2-yl)piperidine-2, 6-dione was prepared according to the procedures described for Example 224 of WO 2022 / 198112. This procedure leads to the formation of an amorphous formic acid salt form of Compound 1. An XRPD of the amorphous formic acid salt is shown by Figure 13.

[0057] Crystalline Form A was synthesized using the procedure below:

[0058] To a three necked bottom (3 L) was added a solution of 3-[6-[4-[(2,2- dimethylpiperazin-l-yl)methyl]-l-piperidyl]pyrimidin-4-yl]-5-(l-methylcyclopropoxy)-lH- indazole (108.58 g, 185.60 mmol, 1.1 eq, 3.0 HC1) in N,N-dimethylformamide (600 mL), then N-methylmorpholine (51.20 g, 506.19 mmol, 55.65 mL, 3 eq) was added. The mixture was stirred at 20°C for 10 min. Next, l-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin- 5-yl]piperidine-4-carbaldehyde (63 g, 168.73 mmol, 1 eq) and sodium triacetoxy borohydride (71.52 g, 337.46 mmol, 2 eq) was added to the mixture. The resulting mixture was stirred at 20°C for 12 h. The mixture was poured into water (IL) and the suspension was stirred at 20°C for 30 min, then filtered. The filter cake was triturated with water (1L*3) at 20 °C for 30 min each time, then filtered. The cake was further triturated with a mixture of N,N- dimethylformamide and acetonitrile (1 : 1, volume ratio, 800 mL * 4) at 90 °C for 1 h each time. After filtering through a Buchner funnel, the solid was washed with acetonitrile (800 mL *3) and dried by vacuum (0.01 to 0.02 MPa) at 30 °C over 5 h to a constant weight to afford 3-[5-[4-[[3,3-dimethyl-4-[[l-[6-[5-(l-methylcyclopropoxy)-lH-indazol-3- yl]pyrimidin-4-yl]-4-piperidyl]methyl]piperazin-l-yl]methyl]-l-piperidyl]-4-fluoro-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione (70 g, 50%) Form A as a white solid.

[0059] XRPD analysis was performed using either a Rigaku MiniFlex 600 in reflection mode (i.e. Bragg-Brentano geometry) or Bruker D8 Advance equipped with LYNXEYE detector in reflection mode (i.e. Bragg-Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters for XRPD methods used are listed below:

[0060] Differential Scanning Calorimetry (DSC) tests were performed using a Mettler Toledo DSC3+. The sample (1-5 mg) was weighed directly in a 40 pL hermetic aluminum pan with a pinhole and analyzed according to the parameters below:

[0061] Simultaneous Thermogravimetric Analysis and Differential Scanning Calorimetry (TGA and DSC) were performed on the same sample simultaneously using a Mettler Toledo TGA / DSC3+. Protective and purge gas was nitrogen at a flowrate of 20-30 mL / min and 50- 100 mL / min, respectively. The desired amount of sample (5-10 mg) was weighed directly in a hermetic aluminum pan with pinhole and analyzed according to the parameters in the table above for the DSC method.

[0062] Dynamic Vapor Sorption (DVS) was performed using a Q5000SA. The sample (5- 15 mg) was loaded into a metallic quartz sample pan, suspended from a microbalance, andexposed to a humidified stream of nitrogen gas. Weight changes were relative to a matching empty reference pan opposite the sample, suspended from the microbalance. The sample was held for a minimum of 10 min at each level and only progressed to the next humidity level if there was < 0.002 % change in weight between measurements (interval: 5 s) or 45 min had elapsed (for 5-65 % RH) or 2 h had elapsed (for 80 and 95 % RH). The following program was used:1 - Equilibration at 50 % RH2 - 50 % to 5 %. (50 %, 35 %, 20 %, and 5 %)3 - 5 % to 95 % (5 %, 20 %, 35 %, 50 %, 65 %, 80 %, and 95 %)4 - 95 % to 5 % (95 %, 80 %, 65 %, 50 %, 35 %, 20 %, and 5 %)5 - 5 % to 50 % (5 %, 20 %, 35 %, and 50 %)

[0063] High Performance Liquid Chromatography (HPLC) was conducted an Agilent 1220 Infinity 2 LC equipped with diode array detector (DAD). Flow rate range of the instrument is 0.2-5.0 mL / min, operating pressure range is 0-600 bar, temperature range is 5 °C above ambient to 60 °C, and wavelength range is 190-600 nm The HPLC method used in this study is shown below:

[0064] Karl Fischer (KF) Titration for water determination was performed using a Mettler Toledo C20S Coulometric KF Titrator equipped with a current generator cell with a diaphragm, and a double-platinum-pin electrode. The range of detection of the instrument is 1 ppm to 5 % water. Aquastar™ CombiCoulomat fritless reagent was used in both the anode and cathode compartments. Samples of approximately 0.03-0.10 g were dissolved in theanode compartment and titrated until the solution potential dropped below 100 mV. Hydranal 1 wt. % water standard was used for validation prior to sample analysis.Brief Summary of Polymorph FormsForm A

[0065] Form A was the predominant form observed during the polymorph screen (see below), and was the only crystalline form isolated from 57 short-term slurry and 21 antisolvent addition experiments. Most evaporative crystallization, amorphous slurry, and vapor diffusion onto amorphous solid experiments also resulted in Form A, making it the most stable polymorphic form identified. The XRPD pattern of Form A is shown in Figure 1. The DSC curve is of Form A is shown in Figure 2, which showed one endotherm at 290.24 °C (peak). TGA mass loss and Karl Fischer analysis showed Form A to be anhydrous (water content of 0.34 weight % and TGA mass loss of 0.04 weight %).Form B

[0066] Form B was made via evaporative crystallization of Form A in TFE. The XRPD pattern of Form B is shown in Figure 3. The DSC curve is of Form B is shown in Figure 4, which showed three endotherms at 174.31 °C, 212.84 °C, and 281.62 °C (peak). NMR showed Form B to be a TFE solvate (1.06 eq.).Form C

[0067] Form C was made via slow-cooling of Form A in DMSO or fast-cooling of Form A in DMSO:acetone (85: 15 vol.). The XRPD pattern of Form C is shown in Figure 5. The DSC curve is of Form C is shown in Figure 6, which showed two endotherms at 132.67 °C and 281.83 °C (peak). NMR analysis showed Form C to be a DMSO solvate (1.12 eq.).Form D

[0068] Form D was discovered in the wet solid when slow-cooling Form A in DMSO or fast-cooling Form A in DMSO:acetone (85: 15 vol.). Form D converted to Form C upon drying.Form E

[0069] Form E was made via a humidification of Form C, but degraded upon drying.Form F

[0070] Form F was made via slow- or fast-cooling of Form A in DCMMeOH (8:2 vol.) or DCM:EtOH (9: 1 vol.). The XRPD pattern of Form F is shown in Figure 7. The DSC curve is of Form F is shown in Figure 8, which showed four endotherms at 143.71 °C, 173.89, °C207.10 °C, and 284.11 °C (peak). NMR analysis showed Form F to be an EtOH solvate (0.37 eq.). Form F decreased in crystallinity upon drying.Form G

[0071] Form G was made via evaporation at RT of the Form A slow-cooling DMF solution experiment. The XRPD pattern of Form G is shown in Figure 9. The DSC curve is of Form G is shown in Figure 10, which showed three endotherms at 181.80, 188.44, and 289.50 °C (peak). NMR analysis showed Form G to be a DMF solvate (1.30 eq.).Form H

[0072] Form H was made via evaporation at RT of the Form A slow- and fast-cooling 1,4- dioxane solution experiments. The XRPD pattern of Form H is shown in Figure 11. The DSC curve is of Form H is shown in Figure 12, which showed one endotherm at 153.85 °C (peak). NMR analysis showed Form H to be a 1,4-dioxane solvate (1.02 eq.).Summary of Polymorph Results / Properties

[0073] Short-term slurries were carried out at two temperatures in a wide range of solvents during the initial screening along with gravimetric solubility assessment. In each case, approximately 20-30 mg of Form A was added to a 2 mL vial, followed by 1 mL of solvent. Slurries were stirred at a constant temperature for three days. If all solids dissolved, more solid was added until a slurry was formed, within reason. After stirring for three days, the slurries were centrifuged, then recovered for X-ray powder diffraction (XRPD) analysis. A summary of the results is presented in the table below. All solids obtained from the shortterm slurry experiments were determined to be Form A by XRPD.NT = Not Tested due to low boiling point of the solvent

[0074] Supernatant from gravimetric solubility slurries was recovered for evaporative crystallization. The solutions were evaporated to dryness at 50 °C in atmosphere overnight, then placed at 50 °C under vacuum (-29 in Hg) for 5 h. If sufficient solids were available after evaporation and drying, they were analyzed by XRPD. The results are summarized in the table below.

[0075] Due to the relatively low solubility of the salt in most solvent systems, there were insufficient solids available for XRPD analysis in many cases. Solids that were isolated weremostly Form A. A shoulder peak at 5.2 °29 was observed upon evaporation of the supernatant from the RT slurry in THF, with the majority of the solid being Form A. An almost amorphous pattern was isolated upon evaporation of the supernatant from the RT slurry in DMF. A low-crystalline pattern was also obtained from DCM:MeOH (9: 1 vol.). Form B, was isolated upon evaporation of the supernatants from both RT and 50 °C slurries in TFE.NT = Not Tested due to low boiling point of the solvent

[0076] Cooling crystallization was conducted in a range of solvent systems. Two cooling regimens were employed: slow cooling from 60 °C to 5 °C and fast cooling from 60 °C to 0 °C. For all experiments, 20-30 mg of Form A was weighed into a 4 mL vial. Solvent was then added incrementally at 60 °C until dissolution. In all experiments, solids were completely dissolved before cooling.

[0077] For slow cooling, the solutions were cooled at 5 °C per hour, while mixing, to 5 °C using a programmable chiller. For fast cooling, the solutions were transferred to an ice-water bath near 0 °C without mixing. After 10 min in the ice-water bath, mixing was resumed. If solids did not precipitate from solution either overnight at 5 °C or after 1 h at 0 °C, the solutions were further cooled to -20 °C by placing in a freezer without mixing.

[0078] To expand the list of solvents assessed, cooling in three different DCM solvent mixtures was explored. Those solutions were cooled from 30 °C to 5 °C during slow cooling and from 30 °C to 0 °C during fast cooling. The results from fast and slow cooling are summarized in the tables below.

[0079] No solid was isolated from most cooling crystallization experiments, indicating that the solutions tended to hold supersaturation. Form A was isolated from the crust in THF:water (9: 1 vol.), and DCM:MeOH (8:2 vol.). For fast cooling, solid was only isolated from DMSO:acetone (85: 15 vol.). A mixture of Forms C + D were observed from DMSO and DMSO:acetone (85: 15 vol.).

[0080] All samples from the cooling experiments without solids were transferred to a - 20 °C freezer. Solids were observed in a few cases, as specified in the tables below. Form D was isolated from DMSO:acetone (85: 15 vol.), whereas Form F was isolated from DCM:MeOH (8:2 vol.) and DCM:EtOH (9: 1 vol ).

[0081] After 1.5 weeks in the freezer, the rest of the solutions were removed, and the vials were uncapped to allow the solvents to evaporate at RT. XRPD analysis was conducted on the resulting solids, and summarized in the table below. Form G was isolated from DMF, andForm H from 1,4-di oxane.ND = Not Determined

[0082] Antisolvent crystallization was completed in various solvent systems.Approximately 20-30 mg of Form A was dissolved in solvent. Antisolvent crystallizations were then carried out using either the direct or reverse addition method. The results of all antisolvent crystallizations are given in the table below.

[0083] For reverse antisolvent addition, the solution was transferred all at once to at least twice the solvent volume of antisolvent with rapid stirring. For example, if solids dissolved in 0.5 mL solvent, then the solution was added at once to 1.0 mL antisolvent while stirring.Once solids were formed, the slurries were filtered, and the solids were recovered for XRPD analysis.

[0084] For direct antisolvent addition, twice the volume of solvent was used as antisolvent and was added dropwise in four equal portions over 1 h. For example, if solids dissolved in 0.5 mL solvent, then 1.0 mL antisolvent was added over 1 h. Solutions / slurries were mixed during antisolvent addition.

[0085] Most isolated solids were Form A by XRPD. Form A was less crystalline when isolated by reverse addition rather than direct addition. The solid isolated from reverse antisolvent addition of DMAc / water appeared to deliquesce during XRPD analysis, resulting in an amorphous pattern.

[0086] The solid isolated from the direct antisolvent addition of DMAc / water was analyzed in an airtight holder to prevent potential deliquescence in the presence of atmospheric humidity, resulting in low-crystalline Form A by XRPD. A few drops of DMAc were placed next to the solid, and the sample holder was enclosed in the airtight holder. This was done to allow diffusion of DMAc vapor onto the solid to access a potential new form. The sample was analyzed by XRPD after two days, showing a slightly more crystalline Form A.

[0087] Dry and solvent-drop milling was performed using a Patterson Dental Amalgamator ball mill with ’A” stainless steel ball as milling media. Approximately 30 mg of Form A was weighed into a milling capsule and 1 vol. of solvent (solvent drop) was added. Milling was carried out three times for 16 s at 3500 rpm. A summary of the milling experiments are shown in the table below.

[0088] A soft, white powder was observed from the dry milling experiment. XRPD analysis of that powder showed a low-crystalline Form A. Slightly tacky / paste-like solids were isolated from the solvent-drop milling experiments. The solids were high-crystallineForm A by XRPD.

[0089] Approximately 15 mg of amorphous Compound 1 as prepared following the procedures described in WO 2022 / 198112 was weighed into 2 mL vials. To each vial, 5 vol.(~75 pL) of solvent was added at RT and the solutions / slurries were left to stir. Initial dissolution was observed in most cases, followed by conversion to a slurry within 30 min. An aliquot of these solids was analyzed by XRPD. In the cases where the samples became immobile, an extra 5-15 vol. solvent was added until a flowable slurry was obtained.

[0090] Amorphous slurries were set up in eight additional process solvents. These were set up using approximately 8 mg of amorphous Compound 1, and 5 vol. of solvent. A very thick slurry or immobile paste was observed within minutes in all cases. Therefore, an extra 15-25 vol. of solvent was added until a flowable slurry was obtained.

[0091] Form A was isolated in most cases. An amorphous, gummy solid persisted in toluene. Form F was isolated from DCM / MeOH and DCM / EtOH. Trace Form A was seen from drying Form F at 50 °C under active vacuum overnight. Form D was isolated from DMSO / acetone but converted to Form C at 50 °C under active vacuum overnight. The results are outlined in the table below.ND = Not Determined

[0092] Vapor diffusion experiments onto amorphous Compound 1 were set up using a wide range of solvents. Approximately 10 mg of amorphous Compound 1 was added to 4 mL vials. Each vial was then placed inside a 20 mL scintillation vial containing approximately 3 mL of the corresponding solvent. The solids were analyzed by XRPD after 1 week.

[0093] A summary of the results is listed in the table below. Form A was isolated in most cases, while relatively high-crystalline Form F was isolated from DCM:EtOH (9: 1 vol.). A decrease in crystallinity was observed as this solid was left to air-dry overnight under ambient conditions and for 2 h at 50 °C under active vacuum.ND = Not DeterminedInter conversion Studies

[0094] Thermal treatment was carried out on Forms B, C, F, and G, as well as amorphous Compound 1 by heating the compound past the endo / exothermic events observed in the DSC thermogram. The solids isolated after heating past both the endotherm and exotherm were all found to be Form A by XRPD. The results are summarized in the table below.

[0095] Competitive slurries were carried out at two temperatures (RT and either 35 °C or 50 °C) in five solvents / solvent systems. First, saturated solutions of Form A were prepared at each temperature in each solvent system. To make the saturated solutions, the solid was added to 2 mL of solvent already stirring at the desired temperature. Once a slurry was observed, the samples were left to equilibrate. After 3 h, the stir bars were removed to allow the solids to settle. Where solids did not settle adequately for supernatant collection, thesamples were centrifuged at the appropriate temperature, and 600 pL of supernatant was pipetted into clean 2 mL vials, each containing a 6.3 mm stir bar.

[0096] The supernatant was then left to stir for an additional 15 min prior to adding seed (one spatula tip, ~5 mg) of Form A and Form F. Samples of each slurry were plated for XRPD analysis immediately after seeding. Form A and Form F were both observed by XRPD post seeding in DCM:MeOH (3 : 1 vol.) and in DCM at RT and 35 °C. However, in most cases, only Form A was observed post seeding, suggesting rapid conversion of Form F to Form A. Only Form A was observed from all slurries at RT and elevated temperatures after stirring overnight. For the slurries where only Form A was observed, another spatula tip (~5 mg) of Form F was added.

[0097] The slurries at RT were transferred to 5 °C while stirring, then seeded with one spatula tip of Form F from vapor diffusion of DCM:EtOH (9: 1 vol.) onto an amorphous solid overnight. Samples of each slurry were plated for XRPD analysis immediately after seeding. Form A and Form F were both observed by XRPD post seeding in DCM at 5 °C. This slurry was sampled again after 3 days, showing predominantly Form A and trace Form F. A summary of the competitive slurries is given in the table below.ND = Not DeterminedFurther Evaluation of Form A

[0098] The solubility of Form A was measured by the gravimetric method in a wide range of solvents at RT and 50 °C. In each case, approximately 20-30 mg of solid was added to a 2 mL vial, followed by 1 mL of solvent. Slurries were stirred at a constant temperature for three days. If all solids dissolved, more solid was added until a slurry was formed, within reason. After stirring for three days, slurries were centrifuged, and the supernatant was recovered for gravimetric solubility assessment. Where solids did not settle adequately for collection of the supernatant, the slurries were filtered through a 0.2 pm syringe filter. Supernatant solutions were evaporated to dryness at 50 °C in atmosphere on a hot plate, then placed at 50 °C under vacuum for 5 h at approximately -29 in Hg before final weighing.

[0099] The solubility in DCM:TFE (9: 1 vol.) was assessed by the addition method due to high solubility (77-83 mg / mL). Form A was determined to be soluble (33-100 mg / mL) in DMAc at both RT and 50 °C and in DMSO:acetone (85: 15 vol.) at 50 °C. Form A was found to be sparingly soluble (10-33 mg / mL) in DMF, DMSO, THF) water (9:1 vol.) at both RT and 50 °C; in DCM:MeOH (9: 1 vol. and 8:2 vol.); DMSO:acetone (85: 15 vol.) at RT; and in1,4-di oxane at 50 °C. The solubility data are given in the table below:NT = Not Tested due to low boiling point of the solvent

[0100] While we have described a number of embodiments, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0101] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

CLAIMSWhat is claimed is:

1. A crystalline Form A, Form B, Form C, Form F, Form G, or Form H of a compound having the following structural formula:

2. The crystalline Form A of claim 1, wherein said crystalline form is characterized by an X-ray powder diffraction peak at 20 angle 5.5 and at least two additional X-ray powder diffraction peaks at 20 angles selected from 8.2, 14.4, 15.8, and 17.8.

3. The crystalline Form A of claim 1 or 2, wherein said crystalline form is characterized by an X-ray powder diffraction peak at 20 angle 5.5 and at least three additional X-ray powder diffraction peaks at 20 angles selected from 8.2, 14.4, 15.8, and 17.8.

4. The crystalline Form A of any one of claims 1 to 3, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 5.5, 8.2, 14.4, 15.8, and 17.8.

5. The crystalline Form A of any one of claims 1 to 4, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 5.5, 8.2, 10.1, 11.7, 13.6, 14.4, 15.5, 15.8, 16.5, 17.8, 18.5, 19, 19.7, 20.8, 21.2, 22.2, 23.4, 24.4, 25, 25.6, 26.6, 27.1, 27.6, 28.3, 29.2, and 29.9.

6. The crystalline Form A of any one of claims 1 to 5, wherein said crystalline form is characterized by an X-ray powder diffraction substantially similar to Figure 1.

7. The crystalline Form A of any one of claims 1 to 6, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram having an endotherm with a peak temperature of 290 °C.

8. The crystalline Form A of any one of claims 1 to 7, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 2.

9. The crystalline Form A of any one of claims 1 to 8, wherein said crystalline form is anhydrous.

10. The crystalline Form B of claim 1, wherein said crystalline form is characterized by an X-ray powder diffraction peak at 20 angle 9.8 and at least two additional X-ray powder diffraction peaks at 20 angles selected from 17.1, 17.7, 18.5, and 19.4.

11. The crystalline Form B of claim 1 or 10, wherein said crystalline form is characterized by an X-ray powder diffraction peak at 20 angle 9.8 and at least three additional X-ray powder diffraction peaks at 20 angles selected from 17.1, 17.7, 18.5, and 19.4.

12. The crystalline Form B of any one of claims 1, 10, or 11, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 9.8, 17.1, 17.7, 18.5, and 19.4.

13. The crystalline Form B of any one of claims 1 or 10 to 12, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 4.7, 5.3, 7, 8, 8.9, 9.8,11.2, 11.4, 12.1, 12.7, 14.4, 15.5, 16.1, 16.5, 17.1, 17.7, 18.5, 19.4, 19.8, 20.2, 20.7, 22, 22.6,23.3, 23.7, 25.4, 26.7, 27.9, and 29.3.

14. The crystalline Form B of any one of claims 1 or 10 to 13, wherein said crystalline form is characterized by an X-ray powder diffraction substantially similar to Figure 3.

15. The crystalline Form B of any one of claims 1 or 10 to 14, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram having endotherms with peak temperatures of 174 °C, 213 °C, and 282 °C.

16. The crystalline Form B of any one of claims 1 or 10 to 15, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 4.

17. The crystalline Form B of any one of claims 1 or 10 to 16, wherein said crystalline form is a solvate.

18. The crystalline Form B of claim 17, wherein solvate crystalline form is a 2,2,2- trifluoroethanol solvate.

19. The crystalline Form C of claim 1, wherein said crystalline form is characterized by an X-ray powder diffraction peak at 20 angle 10.6 and at least two additional X-ray powder diffraction peaks at 20 angles selected from 14.5, 15.9, 16.3, and 18.9.

20. The crystalline Form C of claim 1 or 19, wherein said crystalline form is characterized by an X-ray powder diffraction peak at 20 angle 10.6 and at least three additional X-ray powder diffraction peaks at 20 angles selected from 14.5, 15.9, 16.3, and 18.9.

21. The crystalline Form C of any one of claims 1, 19, or 20, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 10.6, 14.5, 15.9, 16.3, and 18.9.

22. The crystalline Form C of any one of claims 1 or 19 to 21, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 5.3, 7.3, 10.6, 12.1, 14.5, 15.5, 15.9, 16.3, 17.7, 18.9, 19.9, 21.5, 22.5, 23.1, 23.9, 26.5, 26.9, 27.6, 29.7, and 32.4.

23. The crystalline Form C of any one of claims 1 or 19 to 22, wherein said crystalline form is characterized by an X-ray powder diffraction substantially similar to Figure 5.

24. The crystalline Form C of any one of claims 1 or 19 to 23, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram having endotherms with peak temperatures of 133 °C and 282 °C.

25. The crystalline Form C of any one of claims 1 or 19 to 24, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 6.

26. The crystalline Form C of any one of claims 1 or 19 to 25, wherein said crystalline form is a solvate.

27. The crystalline Form C of claim 26, wherein solvate crystalline form is a dimethyl sulfoxide solvate.

28. The crystalline Form F of claim 1, wherein said crystalline form is characterized by an X-ray powder diffraction peak at 20 angle 4.1 and at least two additional X-ray powder diffraction peaks at 20 angles selected from 8.0, 8.7, 10.0, and 12.1.

29. The crystalline Form F of claim 1 or 28, wherein said crystalline form is characterized by an X-ray powder diffraction peak at 20 angle 4.1 and at least three additional X-ray powder diffraction peaks at 20 angles selected from 8.0, 8.7, 10.0, and 12.1.

30. The crystalline Form F of any one of claims 1, 28, or 29, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 4.1, 8.0, 8.7, 10.0, and 12.1.

31. The crystalline Form F of any one of claims 1 or 28 to 30, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 4.1, 6.0, 8.0, 8.7, 10.0, 11.6, 12.1, 12.9, 14.0, 15.7, 16.3, 16.4, 17.5, 18.0, 18.5, 19.5, 23.1, 24.1, 25.0, 26.1, 28.2, and 28.9.

32. The crystalline Form F of any one of claims 1 or 28 to 31, wherein said crystalline form is characterized by an X-ray powder diffraction substantially similar to Figure 7.

33. The crystalline Form F of any one of claims 1 or 28 to 32, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram having endotherms with peak temperatures of 144 °C, 174 °C, 207 °C, and 284 °C.

34. The crystalline Form F of any one of claims 1 or 28 to 33, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 8.

35. The crystalline Form F of any one of claims 1 or 28 to 34, wherein said crystalline form is a solvate.

36. The crystalline Form F of claim 36, wherein solvate crystalline form is an ethanol solvate.

37. The crystalline Form G of claim 1, wherein said crystalline form is characterized by at least three X-ray powder diffraction peaks at 20 angles selected from 7.7, 9.3, 15.3, 16.5, and 19.2.

38. The crystalline Form G of claim 1 or 37, wherein said crystalline form is characterized by at least four X-ray powder diffraction peaks at 20 angles selected from 7.7, 9.3, 15.3, 16.5, and 19.2.

39. The crystalline Form G of any one of claims 1, 37, or 38, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 7.7, 9.3, 15.3, 16.5, and19.2.

40. The crystalline Form G of any one of claims 1 or 37 to 39, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 7.7, 9.3, 15.3, 16, 16.5,17.3, 17.5, 17.9, 18.3, 18.6, 19.2, 19.6, 21, 22.4 and 22.8.

41. The crystalline Form G of any one of claims 1 or 37 to 40, wherein said crystalline form is characterized by an X-ray powder diffraction substantially similar to Figure 9.

42. The crystalline Form G of any one of claims 1 or 37 to 41, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram having endotherms with peak temperatures of 182 °C, 188 °C, and 290 °C.

43. The crystalline Form G of any one of claims 1 or 37 to 42, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 10.

44. The crystalline Form G of any one of claims 1 or 37 to 43, wherein said crystalline form is a solvate.

45. The crystalline Form G of claim 36, wherein solvate crystalline form is a dimethylformamide solvate.

46. The crystalline Form H of claim 1, wherein said crystalline form is characterized by at least three X-ray powder diffraction peaks at 20 angles selected from 4.7, 7.1, 9.4, 11.8, and 18.9.

47. The crystalline Form H of claim 1 or 46, wherein said crystalline form is characterized by at least four X-ray powder diffraction peaks at 20 angles selected from 4.7, 7.1, 9.4, 11.8, and 18.9.

48. The crystalline Form H of any one of claims 1, 46, or 47, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 4.7, 7.1, 9.4, 11.8, and 18.9.

49. The crystalline Form H of any one of claims 1 or 46 to 48, wherein said crystalline form is characterized by X-ray powder diffraction peaks at 20 angles 4.7, 7.1, 9.4, 11.8, 14.1, 16.5, 17.3, 18.9, and 19.5.

50. The crystalline Form H of any one of claims 1 or 46 to 49, wherein said crystalline form is characterized by an X-ray powder diffraction substantially similar to Figure 11.

51. The crystalline Form H of any one of claims 1 or 49 to 50, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram having an endotherm with a peak temperature of 154 °C.

52. The crystalline Form H of any one of claims 1 or 46 to 51, wherein said crystalline form is characterized by a differential scanning calorimetry thermogram substantially similar to Figure 12.

53. The crystalline Form H of any one of claims 1 or 46 to 52, wherein said crystalline form is a solvate.

54. The crystalline Form H of claim 53, wherein solvate crystalline form is a 1,4 dioxane solvate.

55. The crystalline Form A, Form B, Form C, Form F, Form G, or Form H of any one of claims 1 to 54, wherein the crystalline form is at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% a single crystalline form.

56. The crystalline Form A, Form B, Form C, Form F, Form G, or Form H of any one of claims 1 to 55, wherein the crystalline form is substantially free from an amorphous form of the compound.

57. A pharmaceutical composition comprising the crystalline Form A, Form B, Form C, Form F, Form G, or Form H of any one of claims 1 to 56, and a pharmaceutically acceptable carrier.

58. A method of treating disease, a disorder, or a symptom causally related to LRRK2 in a subject, the method comprising administering to the subject the crystalline Form A, Form B, Form C, Form F, Form G, or Form H of any one of claims 1 to 56, or the pharmaceutical composition of claim 57.

59. The method of claim 58, wherein the disease or disorder is Parkinson’s disease (PD), LRRK2 mutation associated PD, primary tauopathies, lewy body dementia, Crohn’s Disease, Leprosy, neuroinflammation, Progressive Supranuclear Palsy, Picks disease, FTDtau, TDP- 43 Frontal Temporal Dementia, TDP-43 ALS, c9orf ALS, Huntington’s disease, spinocerebellar ataxias (SC As) 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy(DRPLA), Kennedy’s disease, Alzheimer’s disease, multiple systems atrophy, acute kidney injury, Rhabdomyolysis, Lipofusinosis, Fabry’s disease, Batten’s disease, ulcerative colitis, irritable bowel disease, Kufor-Rakeb syndrome, gaucher disease, or systemic lupus erythematosus (SLE).

60. The method of claim 59, wherein the disease or disorder is Parkinson’s disease.

61. A method of treating Parkinson’s disease in a subject, the method comprising administering to the subject the crystalline Form A, Form B, Form C, Form F, Form G, or Form H of any one of claims 1 to 56, or the pharmaceutical composition of claim 57.

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