Crystalline forms of O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase inhibitors

Abstract

N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, Compound (I): Described herein are solid forms of JPEG2023536911000013.jpg53125, and processes for making such solid forms of Compound (I). The invention further relates to pharmaceutical compositions comprising crystalline Forms A and B of Compound (I), and methods of using such forms and pharmaceutical compositions in the treatment and prevention of Alzheimer's disease and related neurological disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119 of the filing date of U.S. Provisional Application No. 63 / 060,281, filed August 3, 2020, the entire contents of which are incorporated herein by reference.

[0002] The present invention generally relates to solid forms of N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide. The present invention further discloses processes for preparing the solid forms, pharmaceutical compositions containing the solid forms, and methods of using the solid forms and pharmaceutical compositions in the treatment or prevention of Alzheimer's disease or related neurodegenerative disorders. [Background technology]

[0003] Alzheimer's disease (AD) is one of the most prevalent neurological disorders worldwide and the most common and debilitating age-related condition, causing progressive memory loss, dementia, and ultimately global cognitive impairment and death. Currently, symptomatic medications such as cholinesterase inhibitors or other pharmaceuticals used to control secondary behavioral symptoms of AD are the only available pharmacological treatments. Investigational treatments targeting the AD pathogenic cascade include those aimed at inhibiting the development of neurofibrillary tangles (NFTs).

[0004] A wide range of cellular proteins, both nuclear and cytoplasmic, are post-translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine), attached via an O-glycosidic bond. This monosaccharide is generally referred to as O-linked N-acetylglucosamine, or O-GlcNAc. The enzyme responsible for the post-translational attachment of β-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues of many nucleocytoplasmic proteins is O-GlcNAc transferase (OGTase). A second enzyme, known as O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase, or O-GlcNAcase, or OGA, removes this post-translational modification, liberating the protein, making O-GlcNAc modification a dynamic cycle that occurs several times during the protein's lifetime.

[0005] O-GlcNAc-modified proteins regulate a wide range of vital cellular functions, including transcription, proteasomal degradation, and intracellular signaling. O-GlcNAc is also found in many structural proteins, including tau, a cytoskeletal protein responsible for stabilizing the critical cellular network of microtubules, which are essential for the distribution of proteins and nutrients within neurons. Importantly, tau has been clearly implicated in the pathogenesis of several diseases, including tauopathies, Alzheimer's disease, Parkinson's disease, dementia, and cancer.

[0006] It is well established that Alzheimer's disease and many related tauopathies, including progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS), are characterized in part by the development of neurofibrillary tangles (NFTs). These NFTs are aggregates of paired helical filaments (PHFs) composed of abnormal forms of tau. In AD patients, hyperphosphorylation of tau disrupts its normal function, leading to the formation of PHFs, which ultimately aggregate to form NFTs.

[0007] Six tau isoforms are found in the human brain. In AD patients, all six tau isoforms are found in NFTs, and all are significantly hyperphosphorylated. While tau in healthy brain tissue has only two or three phosphate groups, tau in the brains of AD patients has an average of eight phosphate groups.

[0008] It has recently been shown that increased phosphorylation levels decrease O-GlcNAc levels, and conversely, increased O-GlcNAc levels correlate with decreased phosphorylation levels. Decreased glucose availability in the brain has been shown to lead to hyperphosphorylation of tau. A gradual decline in glucose transport and metabolism leads to a decline in O-GlcNAc and hyperphosphorylation of tau (and other proteins). Therefore, inhibition of O-GlcNAcase (which prevents the removal of O-GlcNAc from tau and thereby tau hyperphosphorylation) should counteract the age-related decline in glucose metabolism in the brains of healthy individuals and patients with Alzheimer's disease or related neurodegenerative disorders.

[0009] However, a major challenge in developing inhibitors to block the function of mammalian glycosidases, including O-GlcNAcase, is the presence of numerous functionally related enzymes in the tissues of higher eukaryotes. Therefore, the use of nonselective inhibitors to study the physiological role of a single enzyme in cells and organisms becomes complicated, as simultaneous inhibition of such functionally related enzymes can result in complex phenotypes. In the case of β-N-acetylglucosaminidase, existing compounds that act to block the function of O-GlcNAcase (OGA) are nonspecific and potent, inhibiting lysosomal β-hexosaminidase.

[0010] Orally active OGA inhibitors have previously been described in PCT / US2019 / 051661. However, even after a particular compound has been identified as a promising candidate for use in a pharmaceutical composition, its properties need to be fine-tuned with respect to many important parameters, such as stability in solid and / or liquid formulations, hygroscopicity, crystallinity, toxicological considerations, melting point, or solubility in water and aqueous media.

[0011] In light of the above technical challenges, and considering the potential of modulating O-GlcNAcase to treat AD, tauopathies, and other neurological disorders, there remains a need for the discovery of potent, solid-state O-GlcNAcase inhibitors. Summary of the Invention

[0012] The present disclosure provides different forms of Compound (I). [ka]

[0013] Embodiments of these crystalline forms include those characterized as Form A and Form B. It is understood that the names used herein to characterize particular forms, e.g., Form A and Form B, should not be considered limiting with respect to other substances having similar or identical physical and chemical characteristics; rather, these designations are merely identifiers that should be interpreted in accordance with the characterization information presented herein.

[0014] In another aspect, provided herein is a pharmaceutical composition comprising crystalline Form A of Compound (I) and at least one pharmaceutically acceptable carrier or diluent.

[0015] In another aspect, provided herein is crystalline Form A of Compound (I) for use as a medicament.

[0016] In a further aspect, provided herein is crystalline Form A of Compound (I) for use in the treatment or prevention of Alzheimer's disease or a related neurological disorder.

[0017] In a further aspect, provided herein is a process for preparing crystalline Form A of Compound (I).

[0018] In another aspect, provided herein is a pharmaceutical composition comprising crystalline Form B of Compound (I) and at least one pharmaceutically acceptable carrier or diluent.

[0019] In another aspect, provided herein is crystalline Form B of Compound (I) for use as a medicament.

[0020] In a further aspect, provided herein is crystalline Form B of Compound (I) for use in the treatment or prevention of Alzheimer's disease or a related neurological disorder.

[0021] In a further aspect, provided herein is a process for preparing crystalline Form A of Compound (I). [Brief explanation of the drawings]

[0022] [Figure 1] 1 shows the X-ray powder diffraction pattern of the free form Type A of Compound (I). [Figure 1B] 1 shows the TGA / DSC curve of the free form Type A of Compound (I). [Figure 2] 1 shows the X-ray powder diffraction pattern of the free form Type B of Compound (I). [Figure 2B] 1 shows the TGA / DSC curve of the free form Type B of Compound (I). [Figure 3] 1 shows the X-ray powder diffraction pattern of the amorphous free form of Compound (I). [Figure 4] 1 shows the X-ray powder diffraction pattern of HCl salt Form A of Compound (I). [Figure 4B] 1 shows the TGA / DSC curve of HCl salt Form A of Compound (I). [Figure 5]1 shows the powder X-ray diffraction pattern of phosphate salt Form A of Compound (I). [Figure 5B] 1 shows the TGA / DSC curve of phosphate salt Form A of Compound (I). [Figure 6] 1 shows the powder X-ray diffraction pattern of tartrate salt Form B of Compound (I). [Figure 6B] 1 shows the TGA / DSC curve of tartrate salt Form B of Compound (I). [Figure 7] 1 shows the powder X-ray diffraction pattern of tartrate salt Form A of Compound (I). [Figure 7B] 1 shows the TGA / DSC curve of tartrate salt Form A of Compound (I). [Figure 8] 1 shows the powder X-ray diffraction pattern of tartrate salt Form C of Compound (I). [Figure 8B] 1 shows the TGA / DSC curve of Compound (I) tartrate salt Form C. [Figure 9] 1 shows the powder X-ray diffraction pattern of tartrate salt Form D of Compound (I). [Figure 9B] 1 shows the TGA / DSC curve of tartrate salt Form D of Compound (I). [Figure 10] 1 shows the X-ray powder diffraction pattern of HBr salt Form A of Compound (I). [Figure 10B] 1 shows the TGA / DSC curve of HBr salt Form A of Compound (I). [Figure 11] 1 shows the powder X-ray diffraction pattern of fumarate salt Form A of Compound (I). [Figure 11B] 1 shows the TGA / DSC curve of fumarate salt Form A of Compound (I). [Figure 12] 1 shows the powder X-ray diffraction pattern of fumarate salt Form B of Compound (I). [Figure 12B] 1 shows the TGA / DSC curve of fumarate salt Form B of Compound (I). [Figure 13] 1 shows the powder X-ray diffraction pattern of fumarate salt Form C of Compound (I). [Figure 13B] 1 shows the TGA / DSC curve of fumarate salt Form C of Compound (I). [Figure 14]1 shows the powder X-ray diffraction pattern of fumarate salt Form D of Compound (I). [Figure 14B] 1 shows the TGA / DSC curve of fumarate salt Form D of Compound (I). [Figure 15] 1 shows the powder X-ray diffraction pattern of fumarate salt Form E of Compound (I). [Figure 15B] 1 shows the TGA / DSC curve of fumarate salt Form E of Compound (I). [Figure 16] 1 shows the powder X-ray diffraction pattern of fumarate salt Form F of Compound (I). [Figure 16B] 1 shows the TGA / DSC curve of fumarate salt Form F of Compound (I). [Figure 17] 1 shows the powder X-ray diffraction pattern of fumarate salt Form G of Compound (I). [Figure 17B] 1 shows the TGA / DSC curve of fumarate salt Form G of Compound (I). DETAILED DESCRIPTION OF THE INVENTION

[0023] In one aspect, provided herein is crystalline Form A of Compound (I).

[0024] In another aspect, provided herein is crystalline Form B of Compound (I).

[0025] The present invention provides a polymorphic form of N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, Form A. N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, also known as "the compound of Formula 1" or "Compound (I)" or "Compound 1," was originally described in PCT / US2019 / 051661, Examples 1-22. The synthetic disclosures of PCT / US2019 / 051661, particularly Examples 1-22, are incorporated herein by reference in their entirety.

[0026] As described herein, the free base of Compound 1 can be in a crystalline form that exists as one or more polymorphic forms, including an anhydrous form. These polymorphic forms (also known in the art as polymorphs or crystalline forms) differ with respect to their X-ray powder diffraction patterns, spectroscopic, physicochemical and pharmacokinetic properties, and their thermodynamic stability.

[0027] For several reasons, it is desirable to have access to different polymorphic forms of Compound 1. Different polymorphic forms may exhibit different physical properties, such as melting point, hygroscopicity, solubility, flow properties, or thermodynamic stability, and therefore allow for the selection of the form most suitable for a given application or aspect, for example, in different dosage forms such as capsules, or in the manufacture of a drug form with optimal pharmacokinetic properties.

[0028] It has surprisingly been discovered that under certain conditions, new solid forms of N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide can be provided, hereinafter referred to as Form A, Form B, and an amorphous form, which have advantageous utilities and properties. In particular, Form A of the compound of Formula 1 exhibits superior stability when exposed to stress conditions. A particular polymorphic form of Compound 1, namely Form A, is more stable than all other solid forms of Compound 1 disclosed herein. This high degree of stability of Form A provides advantageous properties and advantages with respect to its suitability for use in pharmaceutical compositions, for example, with respect to its shelf life and ease of manufacture.

[0029] The present invention provides a crystalline form of N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 1) in free form. The term "free form" refers to a compound that does not itself form a salt.

[0030] Also disclosed herein are the free forms anhydrous Form A, anhydrous tartrate Form B, anhydrous HCl salt Form A, and anhydrous phosphate Form A, anhydrous HBr salt Form A, anhydrous fumarate Forms A, B, C, D, E, F, G.

[0031] Anhydrous Form B is also disclosed herein.

[0032] Anhydrous tartrate salt forms A, C, and D are also disclosed herein.

[0033] In one embodiment, the compound of Formula 1 is crystalline Form A. Crystalline Form A can be defined by reference to one or more characteristic signals resulting from analytical measurements including, but not limited to, the X-ray powder diffraction pattern in Figure 1, the differential scanning calorimetry (TGA / DSC) thermogram in Figure 1B. Crystalline Form A (also referred to herein as polymorphic Form A) can also be defined by reference to one or more of the following characteristic signals:

[0034] In one embodiment, crystalline form A has an X-ray powder diffraction pattern having at least one, two, or three peaks having refraction angle 2-theta (θ) values ​​selected from 4.3, 8.6, and 12.0 degrees, said values ​​being plus or minus 0.2 degrees 2θ, when measured using CuKα radiation.

[0035] In one embodiment, crystalline form A has an X-ray powder diffraction pattern having at least one, two, or three peaks having refraction angle 2-theta (θ) values ​​selected from 10, 11, and 19.9 degrees, said values ​​being plus or minus 0.2 degrees 2θ, when measured using CuKα radiation.

[0036] In one embodiment, crystalline form A has an X-ray powder diffraction pattern having at least one, two, or three peaks having refraction angle 2-theta (θ) values ​​selected from 13.5, 14.9, 21.1, 24.4, and 27.2 degrees, said values ​​being plus or minus 0.2 degrees 2θ, when measured using CuKα radiation.

[0037] In one embodiment, crystalline form A has an X-ray powder diffraction pattern with at least one, two, three, four, or five peaks having refraction angle two-theta (θ) values ​​selected from 4.3, 8.6, 10, 11, 12, 13.5, 14.9, 19.9, 21.1, 24.4 degrees, said values ​​being plus or minus 0.2 degrees two-theta, when measured using CuKα radiation.

[0038] In one embodiment, crystalline Form A of the compound of Formula 1 exhibits an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 1, when measured using CuKα radiation.

[0039] In a further embodiment, crystalline Form A of the compound of Formula 1 exhibits a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 1B.

[0040] In a further embodiment, crystalline Form A of the compound of Formula 1 exhibits a differential scanning calorimetry (DSC) thermogram with an onset of melting at about 171°C.

[0041] In one embodiment of the present invention, there is provided N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin)-1-yl)methyl)thiazol-2-yl)acetamide, crystalline form A in substantially pure form.

[0042] As used herein, "substantially pure," when used in reference to crystalline and amorphous forms of N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, means having a purity of greater than 90% by weight, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, and even equal to about 100% by weight, of N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, based on the weight of the compound.

[0043] In another embodiment, the compound of Formula 1 is in the free form. The free form can be defined by reference to one or more characteristic signals resulting from analytical measurements, including, but not limited to, the powder X-ray diffraction pattern of Figure 1. The free form can also be defined by reference to one or more of the following characteristic signals: In one embodiment, Form A has an X-ray powder diffraction pattern having at least one, two, or three peaks having refraction angle 2-theta (θ) values ​​selected from 12, 19.9, and 24.4 degrees, when measured using CuKα radiation, with values ​​being plus or minus 0.2 degrees 2θ.

[0044] In one embodiment, Free Form A has an X-ray powder diffraction pattern having at least one, two, or three peaks having refraction angle 2-theta (θ) values ​​selected from 4.3, 8.6, 19.9, 21.1, 24.4°, said values ​​being plus or minus 0.2° 2θ, when measured using CuKα radiation.

[0045] In one embodiment, Free Form A has an X-ray powder diffraction pattern having at least one, two, three, four, or five peaks having refraction angle 2-theta (θ) values ​​selected from 4.3, 8.6, 10, 11, 12, 13.5, 14.9, 19.9, 21.1, 24.4 degrees, when measured using CuKα radiation, said values ​​being plus or minus 0.2 degrees 2θ.

[0046] In one embodiment, free form A of the compound of formula 1 exhibits an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 1, when measured using CuKα radiation.

[0047] The term "substantially the same" with respect to X-ray diffraction peak positions means that typical peak position and intensity variations are taken into account. For example, those skilled in the art will understand that peak positions (2θ) typically exhibit instrumental variations of the order of 0.2°. Furthermore, those skilled in the art will understand that relative peak intensities may exhibit instrumental variability, as well as variability due to crystallinity, preferred orientation, sample surface preparation, and other factors known to those skilled in the art, and should be taken only as a quality measure. A reference to crystalline form A having "substantially the same X-ray powder diffraction pattern as that shown in FIG. 1" can be interchanged with a reference to crystalline form A having "a powder diffraction pattern characterized by the representative X-ray powder diffraction pattern shown in FIG. 1."

[0048] Those skilled in the art will also understand that X-ray diffraction patterns are obtained with measurement errors that depend on the measurement conditions used. In particular, it is generally known that the intensities of X-ray diffraction patterns may vary depending on the measurement conditions used. It should be further understood that relative intensities may also change depending on the experimental conditions, and therefore, the exact order of intensities should not be taken into consideration. Furthermore, the measurement error of the diffraction angle in a conventional X-ray diffraction pattern is typically about 5% or less, and this degree of measurement error should be taken into consideration with respect to the aforementioned diffraction angles. Therefore, it should be understood that the crystalline form of the present invention is not limited to a crystalline form that provides an X-ray diffraction pattern completely identical to the X-ray diffraction pattern shown in the attached FIG. 1 disclosed herein. Any crystalline form that provides an X-ray diffraction pattern substantially identical to that disclosed in the attached FIG. 1 falls within the scope of the present invention. The ability to confirm the substantial identity of an X-ray diffraction pattern is within the skill of a person skilled in the art.

[0049] Crystalline Form B can be defined by reference to one or more characteristic signals resulting from analytical measurements, including, but not limited to, the X-ray powder diffraction pattern of Figure 2 and the differential scanning calorimetry (DSC) thermogram of Figure 2B. Crystalline Form B (also referred to herein as polymorphic Form B) can also be defined by reference to one or more of the following characteristic signals: Crystalline Form B has an X-ray powder diffraction pattern having at least one, two, or three peaks having refraction angle two-theta (θ) values ​​selected from 8.6, 11.1, and 15.0 degrees, as measured using CuKα radiation, said values ​​being plus or minus 0.2 degrees two-theta.

[0050] Crystalline Form B has an X-ray powder diffraction pattern having at least one, two, or three peaks having refraction angle 2-theta (θ) values ​​selected from 8.6, 11.1, 12.0, 13.7, and 15.0 degrees, said values ​​being plus or minus 0.2 degrees 2θ, when measured using CuKα radiation.

[0051] Crystalline Form B has an X-ray powder diffraction pattern having at least one, two, three, four, or five peaks having refraction angle 2-theta (θ) values ​​selected from 8.6, 9.5, 9.9, 11.1, 12.0, 13.7, 15.0, 21.5, and 23.8 degrees, plus or minus 0.2 degrees 2θ, when measured using CuKα radiation.

[0052] Crystalline Form B of the compound of Formula 1 exhibits an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 2, when measured using CuKα radiation.

[0053] Crystalline Form B of the compound of Formula 1 exhibits a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 2B.

[0054] The amorphous form can be defined by analytical measurements, including but not limited to, by reference to an XRPD pattern substantially similar to the pattern shown in FIG.

[0055] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a specific polymorph or to control the particle size distribution of the crystalline product. Therefore, calculating the amount of seeds required depends on the size of the available seeds and the desired average product particle size, as described, for example, in "Programmed Cooling of Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small seeds are required to effectively control crystal growth within a batch. Small seeds can be generated by sieving, milling, or micronizing larger crystals or by microcrystallizing a solution. Care must be taken to ensure that milling or micronizing the crystals does not alter the desired crystal morphology (i.e., converting them to amorphous or another polymorph).

[0056] Treatment method The present invention also provides a method for treating or preventing diseases, conditions and / or disorders modulated by OGA inhibition, e.g., as described herein, in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a crystalline form of the compound of formula 1.

[0057] In one embodiment of this method, the OGA inhibition is an inhibition of O-GlcNAcase.

[0058] In another embodiment of this method, the disease or disorder is Alzheimer's disease or a related neurological disorder.

[0059] In one embodiment, the present invention provides the use of crystalline Form A of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0060] In another aspect, provided herein is crystalline Form A of the compound of Formula 1 for use as a medicament.

[0061] In a further aspect, provided herein is crystalline Form A of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0062] In one embodiment, the present invention provides the use of crystalline HCl Form A of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0063] In another aspect, provided herein is crystalline HCl Form A of the compound of Formula 1 for use as a medicament.

[0064] In a further aspect, provided herein is crystalline HCl Form A of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0065] In one embodiment, the present invention provides the use of crystalline phosphate salt Form A of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0066] In another aspect, provided herein is a crystalline form of the compound of Formula 1, Phosphate A, for use as a medicament.

[0067] In a further aspect, provided herein is crystalline phosphate salt Form A of the compound of formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0068] In one embodiment, the present invention provides the use of crystalline form B of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0069] In another aspect, provided herein is crystalline Form B of the compound of Formula 1 for use as a medicament.

[0070] In a further aspect, provided herein is crystalline Form B of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0071] In one embodiment, the present invention provides the use of crystalline tartrate Form B of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0072] In another aspect, provided herein is crystalline tartrate Form B of the compound of Formula 1 for use as a medicament.

[0073] In a further aspect, provided herein is crystalline tartrate Form B of the compound of formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0074] In one embodiment, the present invention provides the use of crystalline tartrate Form A of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0075] In another aspect, provided herein is crystalline tartrate Form A of the compound of Formula 1 for use as a medicament.

[0076] In a further aspect, provided herein is crystalline tartrate Form A of the compound of formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0077] In one embodiment, the present invention provides the use of crystalline tartrate Form C of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0078] In another aspect, provided herein is crystalline tartrate Form C of the compound of Formula 1 for use as a medicament.

[0079] In a further aspect, provided herein is crystalline tartrate Form C of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0080] In one embodiment, the present invention provides the use of crystalline tartrate Form D of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0081] In another aspect, provided herein is crystalline tartrate Form D of the compound of Formula 1 for use as a medicament.

[0082] In a further aspect, provided herein is crystalline tartrate Form D of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0083] In one embodiment, the present invention provides the use of the crystalline HBr salt Form A of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0084] In another aspect, provided herein is a crystalline HBr salt Form A of the compound of formula (I) for use as a medicament.

[0085] In a further aspect, provided herein is a crystalline HBr salt Form A of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0086] In one embodiment, the present invention provides the use of crystalline fumarate salt Form A of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0087] In another aspect, provided herein is crystalline fumarate salt Form A of the compound of Formula 1 for use as a medicament.

[0088] In a further aspect, provided herein is crystalline fumarate salt Form A of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0089] In one embodiment, the present invention provides the use of crystalline fumarate salt Form B of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0090] In another aspect, provided herein is crystalline fumarate salt Form B of the compound of Formula 1 for use as a medicament.

[0091] In a further aspect, provided herein is crystalline fumarate salt Form B of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0092] In one embodiment, the present invention provides the use of crystalline fumarate salt Form C of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0093] In another aspect, provided herein is crystalline fumarate salt Form C of the compound of Formula 1 for use as a medicament.

[0094] In a further aspect, provided herein is crystalline fumarate salt Form C of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0095] In one embodiment, the present invention provides the use of crystalline fumarate salt Form D of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0096] In another aspect, provided herein is crystalline fumarate salt Form D of the compound of Formula 1 for use as a medicament.

[0097] In a further aspect, provided herein is crystalline fumarate salt Form D of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0098] In one embodiment, the present invention provides the use of crystalline fumarate salt Form E of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0099] In another aspect, provided herein is crystalline fumarate salt Form E of the compound of Formula 1 for use as a medicament.

[0100] In a further aspect, provided herein is crystalline fumarate salt Form E of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0101] In one embodiment, the present invention provides the use of crystalline fumarate salt Form F of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0102] In another aspect, provided herein is crystalline fumarate salt Form F of the compound of Formula 1 for use as a medicament.

[0103] In a further aspect, provided herein is crystalline fumarate salt Form F of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0104] In one embodiment, the present invention provides the use of crystalline fumarate Form G of the compound of formula 1 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0105] In another aspect, provided herein is crystalline fumarate salt Form G of the compound of Formula 1 for use as a medicament.

[0106] In a further aspect, provided herein is crystalline fumarate salt Form G of the compound of Formula 1 for use in the treatment or prevention of Alzheimer's disease or a related neurodegenerative disorder.

[0107] Also provided is a method for treating a subject suffering from a disease or condition selected from a neurodegenerative disease, a tauopathy, diabetes, cancer, and stress, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0108] Also provided is a method for inhibiting O-GlcNAcase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0109] Also provided is a method for treating a disease or condition characterized by hyperphosphorylation of tau in the brain, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one embodiment, the disease or condition characterized by hyperphosphorylation of tau in the brain is Alzheimer's disease.

[0110] One aspect of the present invention is a method for treating a disease or condition caused, mediated, and / or propagated by the activity of O-GlcNAcase in a subject, the method comprising administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof to the subject. Preferably, the disease or condition is neuropathy, diabetes, cancer, or stress. More preferably, the disease or condition is neuropathy. In one embodiment, the neurological disorder is acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBP), dementia pugilistica, diffuse neurofibrillary tangles with calcifications, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupe syndrome. and one or more tauopathies selected from Parkinsonism type 1, Hallervorden-Spatz disease (neurodegenerative disease with cerebral iron deposition type 1), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontonigral degeneration, Guam Parkinsonism-Dementia Complex, Pick's disease (PiD), post-encephalitic Parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD) and variant Creutzfeldt-Jakob disease (vCJD)), fatal familial insomnia, kuru, progressive supercortical gliosis, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary senile dementia, Huntington's disease, and Parkinson's disease. In another embodiment, the neurological disorder is one or more tauopathies selected from acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, epilepsy, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease. In yet another embodiment, the neurological disorder is Alzheimer's disease.

[0111] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0112] As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be a therapeutic effect. This includes partially or substantially achieving one or more of the following results: reducing the severity of a disease, disorder, or syndrome; improving or reversing clinical symptoms or indicators associated with the disorder; and inhibiting or reducing the likelihood of progression of the disease, disorder, or syndrome.

[0113] The term "effective amount" refers to an amount of Compound (I), or a pharmaceutically acceptable salt thereof, that, when administered to a subject, produces a beneficial or desired result, including a clinical result, i.e., reverses, alleviates, inhibits, reduces, or slows the progression of a disease or condition treatable by Compound (I), or a pharmaceutically acceptable salt thereof, and reduces the likelihood of recurrence of a disease or condition treatable by Compound (I), or a pharmaceutically acceptable salt thereof, or one or more symptoms thereof, as determined by clinical symptoms, e.g., compared to a control, e.g., 0.1 mg to 1000 mg per kg of body weight. The term "effective amount" also includes an amount that is effective to improve normal physiological function, e.g., 0.01 mg / kg to 500 mg / kg per day.

[0114] Another embodiment of the present invention is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0115] Also included herein is a pharmaceutical composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating one or more diseases or conditions described herein, including the use of Compound (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating one or more diseases or conditions described herein. Also included is a pharmaceutical composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier, for use in treating a subject having one or more diseases or conditions described herein. Further included is a pharmaceutical composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier, for use in treating one or more diseases or conditions described herein.

[0116] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, diluent, adjuvant, vehicle, or excipient that does not adversely affect the pharmacological activity of the compound with which it is formulated and is safe for human use. Pharmaceutically acceptable carriers that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium 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, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropylmethylcellulose, lactose monohydrate, sodium lauryl sulfate, and croscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0117] Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens, may also be included. A more complete list of suitable excipients is found in the Handbook of Pharmaceutical Excipients (5th Ed., a Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for selecting and preparing suitable formulations are found, for example, in Remington's Pharmaceutical Sciences (2003, 20th edition) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP24NF19).

[0118] Compound (I), or a pharmaceutically acceptable salt thereof, or a composition of the present teachings may be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, bucally, vaginally, transdermally, via a patch, a pump, or via an implanted reservoir, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal, and topical administration methods. Parenteral administration may be by continuous infusion over a selected period of time.

[0119] Other dosage forms encompassed by the present disclosure are described in WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142 and WO2015 / 023915, the contents of which are incorporated herein by reference.

[0120] Pharmaceutical Composition The compound of Formula 1, particularly polymorphic tartrate Form B, is suitable as an active agent in pharmaceutical compositions that are particularly effective in the treatment or prevention of diseases, conditions, and / or disorders modulated by OGA inhibition, such as Alzheimer's disease or related neurodegenerative diseases. In various embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of the crystalline compound of Formula 1, particularly polymorphic tartrate Form B, together with one or more pharmaceutically acceptable carriers.

[0121] As used herein, a "pharmaceutical composition" comprises tartrate salt Form B and at least one pharmaceutically acceptable carrier in a unit dose solid form suitable for oral administration (typically a capsule, more particularly a hard gelatin capsule). Lists of pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences.

[0122] Thus, in one aspect, provided herein is a pharmaceutical composition comprising polymorphic tartrate Form B of the compound of Formula 1. In one embodiment, the pharmaceutical composition comprises polymorphic tartrate Form B of the compound of Formula 1 and at least one pharmaceutically acceptable carrier.

[0123] definition As used herein, the terms “Compound 1,” “Cmpd1,” and “compound of Formula 1” refer to N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide, having the following structural formula: [ka]

[0124] In Example 1, using an alternative chemical naming format, "Compound 1" is also referred to as N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide.

[0125] As used herein, "crystalline form A," "polymorph form A," and "form A" are used interchangeably and have no difference in meaning.

[0126] As used herein, "crystalline form B," "polymorph form B," and "form B" are used interchangeably and have no difference in meaning.

[0127] As used herein, the terms "Free Form" or "Free Form" refer to a compound that does not itself contain a salt.

[0128] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, that would be known to one skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Any conventional carrier is contemplated for use in therapeutic or pharmaceutical compositions, unless it is incompatible with the active ingredient.

[0129] As used herein, the term "Alzheimer's disease" or "AD" encompasses both preclinical Alzheimer's disease and clinical Alzheimer's disease, unless the context makes it clear that either only preclinical Alzheimer's disease or only clinical Alzheimer's disease is intended.

[0130] As used herein, the term "treatment of Alzheimer's disease" refers to administering a compound of Formula 1, particularly polymorphic Form A, to a patient to ameliorate at least one symptom of Alzheimer's disease.

[0131] As used herein, the term "preventing Alzheimer's disease" refers to the prophylactic treatment of AD or delaying the onset or progression of AD. List of abbreviations ACN Acetonitrile APP amyloid precursor protein Aβ beta amyloid peptide aq. aqueous solution Boc2O Di-tert-butyl dicarbonate bp boiling point BuLi or nBuLi n-butyllithium C concentration CI confidence interval CDCl3 deuterated chloroform cone. concentration CSF cerebrospinal fluid Cu2O Copper(I) oxide d number of days δ chemical shift (ppm) DCM dichloromethane DMFA / , A / -dimethylformamide DMSO dimethyl sulfoxide DSC Differential Scanning Calorimetry EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ESI electrospray ionization EtOAc ethyl acetate g grams h hour(s) HCl Hydrochloric acid Hex HOAt 1-hydroxy-7-azabenzotriazole HPLC High Performance Liquid Chromatography, Liquid Chromatography IPAc Isopropyl acetate K2CO3 Potassium Carbonate kJ kilojoule kg kilogram KOtBu Potassium tert-butoxide kV kilovolts LC-MS / MS tandem mass spectrometry mA milliampere mDSC Modulated Differential Scanning Calorimetry MeOH Methanol MHz Megahertz min ml / mL milliliter mm millimeters μl microliter μm micrometer μM micromolar μmol micromol min Minute(s) mmol millimole MS mass spectrometry NaHCO3 - Sodium bicarbonate Na2SO4 Sodium Sulfate NEt3 Triethylamine nm nanometer nM nanomolar concentration NMR nuclear magnetic resonance spectroscopy PI Pharmaceutical Intermediates PK Pharmacokinetics ppm parts per million qd or QD once daily Rf retention factor RH Relative Humidity rpm Revolutions per minute Rt retention time (min) RT, rt room temperature s seconds SD Single Dose Abbreviation T time TBME tert-butyl methyl ether TFA trifluoroacetic acid TGA thermogravimetric analysis THF tetrahydrofuran TLC thin layer chromatography UPLC Ultra High Performance Liquid Chromatography v / v volume w / w weight WL Copper Ka emission wavelength (h Cu =1.5406A) wt Weight ratio based on the amount of starting material XRPD X-ray powder diffraction [Example]

[0132] The following examples illustrate various aspects of the present invention. Examples 1 and 2 show how Compound 1 was prepared and crystallized to produce Form A. Example 3 shows how Compound 1 was prepared and crystallized to produce Form B. Example 4 describes XRPD and DSC data analysis of HCl Form A. Example 5 describes phosphate salt Form A and the corresponding XRPD data. Example 6 describes tartaric acid salt Form B and the corresponding XRPD data.

[0133] The preparation of Compound (I) is described in PCT / US2019 / 051661 (Examples 1-22). Compound (I) can also be prepared as described below.

[0134] Example 1 [ka] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: To a mixture of crude 4-methoxy-6-[(3R,5S)-5-methylpyrrolidin-3-yl]oxy-pyrimidine trifluoroacetic acid salt (1.65 g, 2.81 mmol) and N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide (429 mg, 2.28 mmol, prepared according to literature procedures described in WO2018 / 140299A1) in 20 mL of EtOAc was added N,N-diisopropylethylamine (1.19 mL, 6.84 mmol). The mixture was heated to 50° C. for 5 minutes and then cooled to room temperature. To the mixture was added sodium triacetoxyborohydride (1.45 g, 6.84 mmol). The mixture was heated to 50 °C for 1 h and then cooled to room temperature. To the mixture was added saturated NaHCO3 (aq) and EtOAc. The aqueous layer was removed and back-extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with heptane / EtOAc to give a pink solid (329 mg). The mother liquor was concentrated in vacuo, and the residue was purified on SiO2 (50% EtOAc / heptane) to give a yellow solid (98 mg). The solid (427 mg) was dissolved in MeOH (30 mL) and treated with charcoal. The suspension was filtered through Celite, and the eluent was concentrated in vacuo to give the title compound (402 mg, 46% yield). LCMS (ESI): [M+H] 382. 1 HNMR (400MHz, methanol-d4) δ8.35(s,1H),6.13(s,1H),5.21-5.47(m,1H),3.85-4.03(m,4H),3.55(d,J=14.56 Hz,1H),3.13(d,J=11.29Hz,1H),2.47-2.73(m,3H),2.17(s,3H),1.52-1.72(m,1H),1.23(d,J=5.52Hz,3H). or N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: Sodium triacetoxyborohydride (100.3 g, 473.1 mmol) was added to a mixture of 4-methoxy-6-[(3R,5S)-5-methylpyrrolidin-3-yl]oxy-pyrimidine (33 g, 158 mmol) and acetic acid (18.9 g, 315 mmol, 18.0 mL) in EtOAc (743 mL) at 40° C. After 5 minutes, N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide (30.7 g, 163 mmol) was added to the mixture. After 2 hours at 40° C., the mixture was cooled to room temperature and stirred overnight. A 1N HCl solution (315 mL) was slowly added to the reaction. The aqueous layer was separated and the organic layer was extracted with additional 1N HCl (150 mL). The combined HCl layers were treated with 50% NaOH while cooling in an ice bath to a final pH of approximately 11. The mixture was extracted with DCM, and the organics were dried over MgSO, filtered, and concentrated in vacuo. The residue was triturated with MeOH to give a pink solid. The solid was purified in two batches on SiO (220 g, 20% to 60% heptane / (3:1 EtOAc:EtOH 2% NHOH) to give the title compound (29 g, 48% yield). LCMS (ESI): [M+H] 382. 1 HNMR:(500MHz,CDCl3)δ11.16(brs,1H),8.36-8.41(m,1H),6.04-6.08(m,1H),5.28-5.39(m,1H),3.98(d,J=14.6Hz,1H),3.89-3.94(m,3H),3.64( d,J=14.6Hz,1H),3.16(d,J=11.1Hz,1H),2.65(dd,J=11.1,6.1Hz,1H),2. 48-2.57(m,2H),2.29-2.34(m,3H),1.60-1.72(m,2H),1.20-1.29(m,4H). 19 FNMR: (471MHz, CDCl3)δ-116(s, 1F).

[0135] Example 2: Free Form Type A Free Form Type A is the original form obtained during synthesis and does not change when exposed to various conditions, indicating that Free Form Type A is a stable form.

[0136] Example 3: Free Form Type B Free form Type B was obtained by the fast cooling method with MeOH. The XRPD pattern is shown in Figure 2. The TGA / DSC curve displayed in Figure 2B showed a 2.9% weight loss up to 150 °C and one endotherm at 162.1 °C (onset temperature). Based on the low TGA weight loss and the single DSC endotherm, it was assumed that free form Type B was anhydrous.

[0137] Example 4: Hydrochloric Acid Form Type A 1.700.1 mg of the free form is weighed into a 50 mL vial, followed by the addition of 25 mL of acetone to dissolve the free form. 2.154.0 μL of HCl (12 mol / L) was slowly added to the clear solution with stirring, and precipitation was observed. 3. The mixture was stirred at room temperature at 1000 rpm for 1 day, and the XRPD result showed that HCl salt Type A was obtained. 4. The solid was isolated by filtration and the sample was dried under vacuum at room temperature for 2 days and at 50° C. overnight. 650.6 mg of solid was obtained.

[0138] Example 5: Phosphate Form Type A 1.700.2 mg of the free form is weighed into a 50-mL vial, followed by the addition of 25 mL of acetone to dissolve the free form. 2.132 μL of H3PO4 (15 mol / L) was slowly added to the clear solution with stirring, and precipitation was observed. 3. The mixture was stirred at room temperature at 1000 rpm for 1 day, and the XRPD results showed that Type A Phosphate was obtained. 4. The solid was separated by filtration and the sample was dried under vacuum at room temperature for 2 days. 819.2 mg of solid was obtained.

[0139] Example 6: Tartrate Salt Form Type B [ka] 1. Weigh 100.0 mg of the free form into a 20 mL vial, then add 4 mL of acetone to dissolve the free form. Weigh 2.39.6 mg of L-tartaric acid into a 3 mL vial, followed by the addition of 2 mL of acetone to dissolve the acid. 3. The L-tartaric acid solution was added to the free form solution and a precipitate was observed after stirring for approximately 1 hour. 4. The mixture was stirred at 1000 rpm at room temperature for 6 hours, and the XRPD results showed that tartrate Form B was obtained. 5. The solid was separated by centrifugation (10,000 rpm, 2 min) and the sample was dried under vacuum at room temperature for 2 days. 6.126.9 mg of solid was obtained.

[0140] 1.1 Equipment and methods 1.1.1 XRPD A PANalytical Empyrean / X'Pert3 X-ray powder diffractometer was used for the XRPD analysis, and the XRPD parameters used are listed in Table 1-1. [Table 1] 1.1.2 TGA / DSC TGA data were collected using a TA Instruments TAQ500 / Q5000TGA. DSC was performed using a TA Instruments TAQ200 / Q2000DSC. The parameters used are detailed in Table 1-2. [Table 2]

[0141] Salt screening A total of 108 polymorph screening experiments were performed on the free form of Compound (I). Based on comparison of X-ray powder diffraction (XRPD), two crystalline forms (free form Type A and Type B) were discovered and further characterized by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), suggesting that both forms are anhydrous. Competitive slurry experiments indicated that Type A is thermodynamically more stable than Type B from room temperature to 50°C.

[0142] Salt screening was performed under 315 conditions using 31 acids / bases (two charge ratios for four acids) in nine solvent systems according to the approximate solubility and predicted pKa values ​​of the free-form starting materials. The starting materials and the corresponding salt formers were added to HPLC glass vials in 1:1, 1:2, or 2:1 molar ratios, followed by the addition of 0.5 or 1.0 mL of solvent. The mixtures were then stirred at 1,000 rpm for approximately 70 hours at room temperature. The resulting suspensions were centrifuged (10,000 rpm, 2 minutes) to collect the solids, which were then dried under vacuum at room temperature. If a clear solution was obtained, the samples were transferred to 5°C and slurried overnight. The resulting solids were isolated and dried under vacuum at room temperature overnight. If a clear solution was still obtained, the samples were transferred and evaporated at room temperature. All solids were then analyzed by XRPD.

[0143] Reconstitution of salt Based on the characterization results (low TGA weight loss, sharp DSC endotherm at high temperature) and the safety class of the salt formers, HCl salt Type A, phosphate salt Type A, and tartrate salt Type B were selected for reformulation, which were successfully obtained via solution crystallization on the 50 / 100 mg scale and then on the 700-mg scale. The 700-mg scale reformulated salts were characterized by XRPD, TGA, DSC, and HPLC / IC, and the characterization results are summarized in Tables 1-3 and 1-4. [Table 3] [Table 4-1] [Table 4-2] Table 4-3

Claims

1. A compound of formula (I) in crystalline form, said compound having the formula (I) 【Chemistry 1】 N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide represented by the formula The crystalline form (i) anhydrous tartrate salt Form B characterized by an X-ray powder diffraction pattern having at least three peaks having refractive angle two-theta (θ) values ​​selected from 12.7, 13.2, 14.6, 17.3, and 20.9, when measured using CuKα radiation, said values ​​being plus or minus 0.2 degrees two-theta; or (ii) anhydrous hydrochloride salt Form A characterized by an X-ray powder diffraction pattern having at least three peaks having refractive angle two-theta (θ) values ​​selected from 9.6, 15.6, 21.5, and 23.6, when measured using CuKα radiation, said values ​​being plus or minus 0.2 degrees two-theta; The compound in said crystalline form.

2. The compound in a crystalline form described in claim 1, wherein the crystalline form is anhydrous hydrochloride form A.

3. The compound in a crystalline form described in claim 1, wherein the crystalline form is anhydrous tartrate form B.

4. 3. The crystalline form of the compound of claim 2, characterized by an X-ray powder diffraction pattern having at least four peaks having refraction angle 2-theta (θ) values ​​selected from 9.6, 15.6, 17.1, 20.4, 21.5, 23.6, and 26.5, when measured using CuKα radiation, said values ​​being plus or minus 0.2° 2θ.

5. 3. The crystalline form of the compound of claim 2, characterized by an X-ray powder diffraction pattern having at least five peaks having refraction angle 2-theta (θ) values ​​selected from 9.6, 10.2, 12.2, 15.2, 15.6, 17.1, 20.4, 21.5, 23.6, and 26.5, said values ​​being plus or minus 0.2 degrees 2θ, when measured using CuKα radiation.

6. Figure 4 below 【Chemistry 2】 3. The compound of claim 2 in crystalline form, characterized by an X-ray powder diffraction spectrum identical to the X-ray powder diffraction spectrum shown in

7. 4. The crystalline form of the compound of claim 3, characterized by an X-ray powder diffraction pattern having at least four peaks having refraction angle 2-theta (θ) values ​​selected from 12.7, 13.2, 14.6, 17.3, 20.9, 21.8, and 24.4, when measured using CuKα radiation, said values ​​being plus or minus 0.2° 2θ.

8. The crystalline form of the compound described in claim 3, characterized by an X-ray powder diffraction pattern having at least five peaks having refraction angle 2-theta (θ) values ​​selected from 12.7, 13.2, 14.6, 16.5, 17.3, 20.9, 21.8, 24.4, 25.7, 26.9, and 28.8 when measured using CuKα radiation, said values ​​being plus or minus 0.2° 2θ.

9. Figure 6 below 【Transformation 3】 4. The compound of claim 3 in crystalline form, characterized by an X-ray powder diffraction spectrum identical to the X-ray powder diffraction spectrum shown in 10. The compound of claim 2 in crystalline form, having a DSC endotherm with an onset temperature of 198.5°C.

11. Figure 4B below 【Chemistry 4】 3. The crystalline form of the compound of claim 2, having a differential scanning calorimetry (DSC) thermogram identical to that shown in 12. The compound of claim 3 in crystalline form, having a DSC endotherm with an onset temperature of 186.8°C.

13. Figure 6B below 【Transformation 5】 4. The crystalline form of the compound of claim 3, having a differential scanning calorimetry (DSC) thermogram identical to that shown in

14. A pharmaceutical composition comprising a compound in crystalline form according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier or diluent.

15. 14. A pharmaceutical composition for use in treating a disease in a patient, said disease being Alzheimer's disease, said pharmaceutical composition comprising an effective amount of a compound in crystalline form according to any one of claims 1 to 13.

16. 14. A pharmaceutical composition for use in preventing the progression of mild cognitive impairment to Alzheimer's disease in a patient, said pharmaceutical composition comprising an effective amount of a crystalline form of a compound of any one of claims 1 to 13.

17. A pharmaceutical composition for use in treating a disease in a patient, comprising an effective amount of a crystalline form of a compound described in any one of claims 1 to 13, wherein the disease is progressive supranuclear palsy.

18. A composition comprising at least 90% by weight of the compound in crystalline form according to any one of claims 1 to 13, based on the weight of the composition.

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