Pharmaceutical salts, polymorphs of benzothiazole compounds and methods for their preparation

Abstract

The present disclosure provides polymorphs and salts of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide, pharmaceutical compositions containing the compounds, methods for making the compounds, and methods for treating neurodegenerative disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 825,102, filed March 28, 2019. The entire disclosures of the applications identified in this paragraph are incorporated herein by reference.

[0002] Field The present disclosure relates generally to salts and polymorphs of compounds that have enzyme inhibitor activity, methods for making the compounds, and methods of using the compounds to treat disorders.

[0003] background Alpha-synuclein is part of a large family of proteins that includes beta- and gamma-synuclein and synoretin. Alpha-synuclein is expressed in normal conditions associated with synapses and is thought to play a role in neuroplasticity, learning and memory. Several studies have implicated Alpha-synuclein as a central role in the pathogenesis of Parkinson's disease. Molecular changes in Alpha-synuclein protein that increase protein misfolding and aggregation play a direct role in the pathogenesis of the disease. Aggregation of Alpha-synuclein contributes to the formation of Lewy bodies and neurites, pathological hallmarks of Parkinson's disease and Alpha-synucleinopathies. Activation of the tyrosine kinase c-abl contributes to Alpha-synuclein-induced neurodegeneration.

[0004] The tyrosine kinase c-abl is a tightly regulated non-receptor protein tyrosine kinase involved in a wide range of cellular processes including growth, survival and stress response (Nat Rev Mol Cell Biol, 2004, 5:33-44), and c-abl is involved in the regulation of several cellular processes and is involved in the development of the central nervous system by controlling neurogenesis. Furthermore, in recent years, increasing evidence from various experimental model systems has revealed that c-abl is activated in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Niemann-Pick C disease and tauopathy (Human Molecular Genetics, 2014, Vol. 23, No.11).

[0005] The stress-signaling non-receptor tyrosine kinase c-abl links sporadic Parkinson's disease to parkin through tyrosine phosphorylation. Tyrosine phosphorylation of parkin by c-abl is the major post-translational modification that leads to loss of parkin function and disease progression in sporadic Parkinson's disease. Inhibition of c-abl provides a new therapeutic opportunity to halt Parkinson's disease progression (The Journal of Neuroscience, 2011, 31(1):157-163). Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron death. Knockdown of c-abl by small interfering RNA (siRNA) also rescued ALS motor neuron degeneration (Imamura et al., Sci. Transl. Med. 9, 2017). Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disease for which no treatment currently exists. In MSA, accumulation of α-synuclein is observed in neurons and oligodendrocytes of the substantia nigra, striatum, olivopontocerebellar structures and spinal cord (J Neural Transm Vienna Austria 1996. 2016;123(6)).

[0006] Administration of the tyrosine kinase inhibitor nilotinib reduces c-abl activity and improves autophagic clearance of α-synuclein in transgenic and lentiviral gene transfer models. Activation of c-abl in the mouse forebrain induces neurodegeneration in the hippocampus and striatum. Thus, phosphorylation-mediated increase in c-abl activity may be related to α-synuclein pathology detected in Parkinson's disease and other neurodegenerative diseases (Hum Mol Genet. 2013 Aug 15).

[0007] US Patent Application No. 16 / 148,265 describes benzothiazole compounds as c-abl inhibitors useful for treating diseases or disorders such as α-synucleinopathy, Parkinson's disease, Alzheimer's disease, ALS, dementia with Lewy bodies, and MSA. The present disclosure describes novel salts and polymorphs of benzothiazole compounds that can improve the physicochemical properties and solubility of the compounds.

[0008] Summary of the Invention The present disclosure provides a compound of formula (I): [ka] The present invention provides a crystalline form of a compound of the formula: and salts thereof, and a method for preparing said compound. The compound is suitable for pharmaceutical development and industrial processes.

[0009] In one embodiment, the disclosure provides the hydrochloride, sulfate, L-aspartate, maleate, phosphate, L-(+)-tartrate, fumarate, citrate, L-malate and methane sulfate salts of compound of formula (I) and crystalline forms thereof.

[0010] In another embodiment, the present disclosure provides a process for preparing various crystalline salts of the compound of formula (I) comprising reacting (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base with an acid in a solvent.

[0011] Crystalline forms can be characterized by the interstitial spacing determined by X-ray powder diffraction patterns (XRPD). XRPD diffractograms are typically represented as a plot of peak intensity versus peak position, i.e., diffraction angle 2θ (2 theta) (degrees). Intensities are often given in parentheses with the following abbreviations: very strong = vst; strong = st; medium = m; weak = w; and very weak = vw. Characteristic peaks of a given XRPD can be selected according to peak position and their relative intensity to conveniently distinguish this crystalline structure from others. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows an optical microscope photograph of the crystalline form of formula (I). [Diagram 2] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of formula (I). [Diagram 3] FIG. 3 shows the differential scanning calorimetry (DSC) and thermogravimetry (TGA) of formula (I). [Figure 4] FIG. 4 shows the XRPD spectra of pattern A of formula (I) in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Diagram 5] FIG. 5 shows the overlaid XRPD spectra of the salt formation of formula (I) with hydrochloric acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 6]FIG. 6 shows the overlaid XRPD spectra of the salt formation of formula (I) with sulfuric acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 7] FIG. 7 shows the overlaid XRPD spectra of the salt formation of formula (I) with L-aspartic acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 8] FIG. 8 shows the overlaid XRPD spectra of the salt formation of formula (I) with maleic acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 9] FIG. 9 shows the overlaid XRPD spectra of the salt formation of formula (I) with phosphoric acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 10] FIG. 10 shows the overlaid XRPD spectra of the salt formation of formula (I) with L(+)-tartaric acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 11] FIG. 11 shows the overlaid XRPD spectra of the salt formation of formula (I) with fumaric acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 12] FIG. 12 shows the overlaid XRPD spectra of the salt formation of formula (I) with citric acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 13]FIG. 13 shows the overlaid XRPD spectra of the salt formation of formula (I) with L-malic acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 14] FIG. 14 shows the overlaid XRPD spectra of the salt formation of formula (I) with methanesulfonic acid in various solvents: 1- from acetone, 2- from ethyl acetate, 3- from acetonitrile, 4- from isopropanol / water (95 / 5, v / v). [Figure 15] FIG. 15 shows the XRPD pattern of the hydrochloride salt of formula (I) (Pattern I). [Figure 16] FIG. 16 shows the overlaid DSC and TGA spectra of the hydrochloride salt of formula (I) (Pattern I). [Figure 17] FIG. 17 shows the XRPD pattern of the sulfate salt of formula (I) (Pattern II). [Figure 18] FIG. 18 shows the overlaid DSC and TGA spectra of the sulfate salt of formula (I) (Pattern II). [Figure 19] FIG. 19 shows the XRPD pattern of the maleate salt of formula (I) (Pattern III). [Figure 20] FIG. 20 shows the overlaid DSC and TGA spectra of the maleate salt of formula (I) (Pattern III). [Figure 21] FIG. 21 shows the 1H-NMR spectrum of the maleate salt of formula (I) (Pattern III). [Figure 22] FIG. 22 shows the XRPD pattern of the fumarate salt of formula (I) (Pattern IV). [Diagram 23] FIG. 23 shows the overlaid DSC and TGA spectra of the fumarate salt of formula (I) (Pattern IV). [Figure 24] FIG. 24 shows the 1H-NMR spectrum of the fumarate salt of formula (I) (Pattern IV). [Diagram 25] FIG. 25 shows the XRPD pattern of the mesylate salt of formula (I) (Pattern V). [Figure 26]FIG. 26 shows the overlaid DSC and TGA spectra of the mesylate salt of formula (I) (Pattern V). [Figure 27] FIG. 27 shows the 1H-NMR spectrum of the mesylate salt of formula (I) (Pattern V). [Figure 28] FIG. 28 shows the 1H-NMR spectrum of the monohydrochloride salt of formula (I) (Pattern I). [Figure 29] FIG. 29 shows the overlaid XRPD patterns of the monohydrochloride and dihydrochloride salts of formula (I). [Diagram 30] FIG. 30 shows the overlaid DSC and TGA spectra of the monohydrochloride salt of formula (I) (Pattern I). [Diagram 31] FIG. 31 shows the 1H-NMR spectrum of the dihydrochloride salt of formula (I) (Pattern VI). [Diagram 32] FIG. 32 shows the XRPD pattern of the dihydrochloride salt of formula (I) (Pattern VI). [Diagram 33] FIG. 33 shows the overlaid DSC and TGA spectra of the dihydrochloride salt of formula (I) (Pattern VI). [Diagram 34] FIG. 34 shows the overlaid XRPD spectra of the solids (part I) obtained from the slurry experiment at 25° C. [Diagram 35] FIG. 35 shows the overlaid XRPD spectra of the solids (part II) obtained from the slurry experiment at 25° C. [Diagram 36] FIG. 36 shows the overlaid XRPD spectra of the solids (part I) obtained from the slurry experiment at 50° C. [Figure 37] FIG. 37 shows the overlaid XRPD spectra of the solids obtained from the slurry experiment at 50° C. (part II). [Figure 38] FIG. 38 shows the overlaid XRPD spectra of the solids obtained from the heating-cooling experiment. [Figure 39] FIG. 39 shows the overlaid XRPD spectra of the solids obtained from the slow evaporation experiment. [Diagram 40]FIG. 40 shows the overlaid XRPD spectra of the solids obtained from the anti-solvent experiment. [Diagram 41] FIG. 41 shows the overlaid XRPD spectra of the solids obtained from dry and wet milling.

[0013] Detailed Description The following description is merely exemplary in nature and is in no way intended to limit the present disclosure, application, or uses.

[0014] definition As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier or other ingredient that is pharma-ceutically acceptable and with which a compound of the invention is administered.

[0015] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that can enhance the desired pharmacological activity. Examples of pharmaceutical acceptable salts include acid addition salts formed with inorganic or organic acids, metal salts, and amine salts. Examples of acid addition salts formed with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of acid addition salts formed with organic acids include, for example, salts with acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p- Examples of salts include salts with chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic) acid, 3-phenylpropionic acid, trimethyl-acetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxy-naphthoic acid, salicylic acid, stearic acid and muconic acid. Examples of metal salts include salts with sodium, potassium, calcium, magnesium, aluminum, iron and zinc ions. Examples of amine salts include salts with ammonia and organic nitrogen bases strong enough to form salts with carboxylic acids.

[0016] As used herein, the term "therapeutically effective amount" when applied to a compound of the present invention is intended to refer to an amount of the compound sufficient to ameliorate, alleviate, stabilize, reverse, slow or delay the progression of a disorder or disease state, or a symptom of a disorder or disease. In one embodiment, the method of the present invention provides for the administration of a combination of compounds. In such a case, the "therapeutically effective amount" is the amount of the compound of the present invention in the combination sufficient to cause the intended biological effect.

[0017] As used herein, the term "treatment" or "treating" means improving or reversing the progression or severity of a disease or disorder, or improving or reversing one or more symptoms or side effects of such a disease or disorder. As used herein, "treatment" or "treating" also means inhibiting or arresting (as in by slowing, halting, inhibiting, hindering or blocking) the progression of a disease or disorder system, condition, or state. For purposes of the present invention, "treatment" or "treating" further refers to an approach for obtaining beneficial or desired clinical results. In this case, "beneficial or desired clinical results" include, but are not limited to, alleviation of symptoms, whether partial or total, reduction in the extent of the disorder or disease, stabilized (i.e., not worsening) disease or disorder state, delaying or slowing the disease or disorder state, improvement or palliation of the disease or disorder state, and remission of the disease or disorder.

[0018] In another embodiment, the compounds of Formula (I) are used to modulate the activity of the protein kinase c-abl.

[0019] As used herein, the term "modulate" or "modulation" refers to a change in the catalytic activity of a protein kinase. In particular, "modulate" refers to the activation or inhibition, or more preferably, the inhibition of the catalytic activity of a protein kinase, depending on the concentration of a compound or salt to which the protein kinase is exposed. As used herein, the term "catalytic activity" refers to the rate of phosphorylation of tyrosine, serine, or threonine under the direct or indirect influence of a protein kinase.

[0020] As used herein, the phrase "compounds of the present disclosure" includes any compound of formula (I) and its clathrates, hydrates, solvates or polymorphs. Also, even if the term "compounds of the present disclosure" does not refer to a pharma- ceutically acceptable salt, the term includes the salt. In one embodiment, the compounds of the present disclosure include stereochemically pure compounds, e.g., compounds that are substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee, or greater than 99% ee). That is, when the compounds of formula (I) of the present disclosure or salts thereof are tautomers and / or stereoisomers (e.g., geometric and conformational isomers), such isolated isomers and mixtures thereof are also included within the scope of the present disclosure. When the compounds of the present disclosure or salts thereof have asymmetric carbons in their structure, their active optical isomers and racemic mixtures thereof are also included within the scope of the present disclosure.

[0021] As used herein, the term "polymorph" refers to a solid crystalline form of a compound of the present disclosure or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., against heat or light), compressibility and density (important for formulation and product manufacturing) and dissolution rate (which may affect bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., differences in oxidation, resulting in a dosage form discoloring more quickly when composed of one polymorph than when composed of another), or mechanical properties (e.g., a tablet that disintegrates on storage because a kinetically favored polymorph converts to a thermodynamically more stable polymorph), or both (e.g., a tablet of one polymorph is more susceptible to decomposition at high humidity). Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates or may be more difficult to filter or wash free of impurities than another polymorph, e.g., because of its particle shape or size distribution.

[0022] As used herein, the term "X-ray powder diffraction pattern" or "XRPD pattern" refers to an experimentally observed diffractogram or parameters derived therefrom. X-ray powder diffraction patterns are typically characterized by peak positions (abscissa) and peak intensities (ordinate). The term "peak intensity" refers to the relative signal intensities within a given X-ray diffraction pattern. Factors that can affect the relative peak intensities are sample thickness and preferred orientation (i.e., crystalline grains are not randomly distributed).

[0023] As used herein, the term "peak position" refers to the position of the X-ray reflections measured and observed in an X-ray powder diffraction experiment. The peak positions are directly related to the dimensions of the unit cell. The peaks identified by each peak position were extracted from the diffraction patterns for various polymorphs of the salt of formula (I).

[0024] As used herein, the term "2-theta value" refers to the peak position (degrees) based on the experimental setup of an X-ray diffraction experiment, which is the common abscissa unit in a diffraction pattern. In general, the experimental setup requires that the reflected beam is recorded at an angle 2-theta (2θ) when the reflected light is diffracted when the incident beam makes an angle theta (θ) with respect to a particular lattice plane. It should be understood that references herein to specific 2θ values ​​for a particular polymorph are intended to mean the 2θ values ​​(degrees) measured using the X-ray diffraction experimental conditions described herein.

[0025] As used herein, the term "amorphous" refers to any solid material that (i) lacks order in three dimensions, or (ii) exhibits order in less than three dimensions, or only over short distances (e.g., less than 10 Å), or both. Thus, amorphous materials include partially crystalline materials and crystalline mesophases, for example, with one or two dimensional translational order (liquid crystals), orientational disorder (orientationally disordered crystals), or conformational disorder (conformationally disordered crystals). Amorphous solids can be characterized by known techniques, including X-ray powder diffraction (XRPD) crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or some combination of these techniques. Amorphous solids typically give a diffuse XRPD pattern consisting of one or two broad peaks (i.e., peaks with base widths of about 5° or more in 2θ).

[0026] As used herein, the term "crystalline" refers to any solid material that exhibits three-dimensional order that gives a characteristic XRPD pattern with sharply defined peaks, in contrast to amorphous solid materials.

[0027] As used herein, the term "crystalline purity" refers to the percentage of a crystalline compound in a sample, which may contain an amorphous form of the same compound, at least one other crystalline form of the compound, or a mixture thereof.

[0028] As used herein, the term "substantial crystalline purity" refers to a crystalline purity of at least about 95%, preferably about 97%, more preferably about 99%, and most preferably about 100%.

[0029] As used herein, the term "detectable amount" refers to an amount or amount per unit volume that can be detected using conventional techniques, such as, for example, X-ray powder diffraction, differential scanning calorimetry, HPLC, Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, and the like.

[0030] As used herein, the term "sample" includes any compound and its clathrates, hydrates, solvates, polymorphs, or intermediate compounds.

[0031] As used herein, the term "solvent" refers to a substance capable of completely dissolving, partially dissolving, dispersing or partially dispersing another substance, preferably a solid or a mixture of solids, and is preferably a liquid or a mixture of two or more liquids that are miscible, partially miscible or immiscible. Since many solvents and anti-solvents contain impurities, it is intended that the levels of impurities in solvents and anti-solvents for the practice of the invention are understood to be at a sufficiently low concentration so that the impurities, if present, do not interfere with the intended use of the solvent in which they are present.

[0032] As used herein, the term "solvate" refers to a compound of the present disclosure or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and / or acceptable for administration to humans in trace amounts.

[0033] As used herein, the term "hydrate" means a compound of the present disclosure or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0034] As used herein, the term "relative humidity" refers to the ratio, expressed as a percentage, of the amount of water vapor in the air at a given temperature to the maximum amount of water vapor that it can hold at that temperature and pressure.

[0035] As used herein, the term "slurry" refers to a solid material suspended in a liquid medium, typically water or an organic solvent.

[0036] As used herein, the term "under vacuum" refers to typical pressures that can be obtained with a laboratory oil or oil-free diaphragm vacuum pump.

[0037] As used herein, the term "clathrate" means a compound or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) in which guest molecules (e.g., solvent or water) are trapped.

[0038] Compounds of the Disclosure In one embodiment, the present disclosure provides a compound of formula (I): [ka] The present invention provides a salt of a compound represented by the formula:

[0039] wherein the salt is an acid addition salt, the acid being selected from the group consisting of hydrochloric acid, sulfuric acid, L-aspartic acid, maleic acid, phosphoric acid, L-(+)-tartaric acid, fumaric acid, citric acid, L-malic acid and methane sulfate.

[0040] In certain embodiments, the salt is a monohydrochloride salt, which has desirable properties such as high crystallinity and desirable non-hygroscopicity while maintaining good solubility.

[0041] In certain other embodiments, the disclosure provides crystalline forms of the compounds and methods for their preparation, which are suitable for pharmaceutical development and industrial processes.

[0042] In certain embodiments, the present disclosure provides a (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base crystalline form designated crystalline "Pattern A." Pattern A has been characterized by XRPD, DSC, TGA and solubility studies as described herein. Crystalline Pattern A is characterized by XRPD as having peaks at diffraction angles (2θ) of 9.8±0.2, 11.6±0.2, 13.2±0.2, 14.0±0.2, 16.7±0.2, 17.6±0.2, 20.6±0.2, 22.9±0.2, 26.2±0.2, 29.3±0.2, 30.7±0.2, 31.6±0.2 and by DSC as having an onset melting point of about 267° C. and a peak temperature of about 268° C.

[0043] In another embodiment, the disclosure provides a hydrochloride salt of formula (I), characterized by XRPD as having peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, 26.7±0.2 and by DSC as having a melting point of about 240° C.

[0044] In certain embodiments, the present disclosure provides a method for preparing various crystalline salts of the compound of formula (I) comprising reacting (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base with an acid in a solvent.

[0045] New XRPD patterns were found in the acid formation experiments with five kinds of counter ions, including hydrochloric acid (pattern I), sulfuric acid (pattern II), maleic acid (pattern III), fumaric acid (pattern IV) and methanesulfonic acid (pattern V). Meanwhile, amorphous solids can be obtained after salt formation with phosphoric acid, which also indicates the possible formation of salts.

[0046] Those skilled in the art will recognize that measurements of XRPD peak positions and / or intensities for a given crystalline form of the same compound will vary within a margin of error. The values ​​of the angle 2θ allow for a suitable margin of error. Typically, this margin of error is expressed as "±". For example, an angle 2θ of about "8.7±0.3" means a range from about 8.7+0.3, i.e., about 9.0, to about 8.7±0.3, i.e., about 8.4. Depending on the sample preparation technique, the calibration technique applied to the instrument, human operating variability, etc., those skilled in the art will recognize that a suitable margin of error for XRPD may be ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, ±0.05 or less. In certain embodiments of the present invention, the margin of error for XRPD is ±0.2. Further details of the method and instrument used for XRPD analysis are provided in the Examples section.

[0047] All of these potential salts can be further characterized by DSC and TGA, and especially the organic salts can be characterized by 1H-NMR to confirm salt formation and the stoichiometry of the acid / base ratio.

[0048] To investigate the effect of the ratio of hydrochloric acid on the salt formation process, salt formation experiments can be carried out at different acid ratios (1.1 and 2.2 equivalents).

[0049] For (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride having pattern I, polymorph screening studies can be carried out by slurry method, heat-cool method, slow evaporation method and anti-solvent method.

[0050] Dry and wet milling can also be performed to test the physical stability of the monohydrochloride salt during the milling process. XRPD results showed that the crystallinity of the residual solid decreased after dry milling, but the crystal form did not change after the dry milling or wet granulation process.

[0051] In yet another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharma- ceutically acceptable salt, or a crystalline form thereof, and at least one pharma- ceutically acceptable carrier.

[0052] In another embodiment, a method for treating a neurodegenerative disease or disorder is provided, comprising administering to a subject in need of the treatment a therapeutically effective amount of a compound of formula (I), its pharma- ceutically acceptable salt or its crystalline form. That is, a medical use of formula (I), its pharma- ceutically acceptable salt or its crystalline form is provided, wherein formula (I), its pharma- ceutically acceptable salt or its crystalline form is used as an active ingredient. In one embodiment, the medical use is for the treatment or prevention of a neurodegenerative disease or disorder, such as alpha-synucleinopathy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy (MSA), Alzheimer's disease and / or amyotrophic lateral sclerosis (ALS).

[0053] Medical Uses and Methods of Treatment Using the Compounds of the Disclosure The present disclosure further provides a method for treating a neurodegenerative disease or disorder in a subject having or susceptible to having a neurodegenerative disease or disorder by administering to the subject a therapeutically effective amount of one or more of the compounds described above. In one embodiment, the treatment is a preventive treatment. In another embodiment, the treatment is a palliative treatment. In another embodiment, the treatment is a restorative treatment.

[0054] 1. Disease or condition The compounds of the present disclosure for inhibiting c-abl activity are useful for treating or preventing neurodegenerative diseases or disorders. The compounds inhibit or interfere with c-abl kinase activity and can be used to treat neurodegenerative diseases or disorders or prevent the worsening of such diseases. Thus, the present disclosure provides a method for inhibiting or interfering with c-abl activity in a cell, contacting the cell with an effective amount of a compound of the present disclosure. In one embodiment, such a cell is present in a subject (e.g., an Alzheimer's patient). In another embodiment, a medical use is provided for treating or preventing a neurodegenerative disease or disorder in a subject using a compound of the present disclosure. The method of the present disclosure includes administering to a subject in need of treatment or prevention a pharmaceutical composition containing a therapeutically or prophylactically effective amount of a c-abl inhibitor. Neurodegenerative diseases or disorders include, but are not limited to, alpha-synucleinopathy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy (MSA), Alzheimer's disease, or amyotrophic lateral sclerosis (ALS).

[0055] 2. Target Subjects suitable for treatment according to the present disclosure include mammalian subjects. Mammals of the present disclosure include, but are not limited to, humans, dogs, cats, cows, goats, horses, sheep, pigs, rodents, rabbits, primates, etc., including mammals in utero. Subjects may be of both genders and at any stage of development. In one embodiment, subjects suitable for treatment according to the present disclosure are humans.

[0056] 3. Administration and Dosage The compounds of the present disclosure are generally administered in a therapeutically effective amount. The compounds of the present disclosure can be administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. An effective dose is typically in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg / day, in single or divided doses. Depending on the age, species, and disease or condition being treated, dosage levels below the lower end of this range may be appropriate. In other cases, even higher doses may be used without adverse side effects. Also, larger doses may be administered in several small doses throughout the day. Methods for determining appropriate doses are well known in the art to which the present disclosure pertains. For example, Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000 may be used.

[0057] Pharmaceutical compositions, dosage forms and routes of administration For the treatment of the above mentioned diseases or conditions, the compounds described herein, or a pharma- ceutically acceptable salt thereof, can be administered as follows.

[0058] Oral route Compounds of the disclosure may be administered orally (including by swallowing) so that the compound enters the gastrointestinal tract or may be absorbed into the blood stream directly from the mouth (e.g., buccal or sublingual administration).

[0059] Compositions suitable for oral administration include solid, liquid, gel or powder preparations, having dosage forms such as tablets, lozenges, capsules, granules or powders.

[0060] Compositions for oral administration may be formulated as immediate or modified release (including delayed or sustained release), optionally with an enteric coating.

[0061] Liquid formulations may include solutions, syrups and suspensions, which may be used in soft or hard capsules. Such formulations may contain pharma- ceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose or oils. The formulations may also contain one or more emulsifying agents and / or suspending agents.

[0062] In tablet dosage forms, the amount of drug present may be from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the dosage form. In addition, tablets may contain a disintegrant, which comprises from about 0.5% to about 35% by weight, more typically from about 2% to about 25% by weight of the dosage form. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0063] Suitable lubricants for use in tablets may be present in an amount of about 0.1% to about 5% by weight and include, but are not limited to, talc, silicon dioxide, stearic acid, calcium, zinc, or magnesium stearic acid, sodium stearyl fumarate, and the like.

[0064] Binders suitable for use in tablets include, but are not limited to, gelatin, polyethylene glycol, sugars, gums, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. Diluents suitable for use in tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose and starch.

[0065] Solubilizers suitable for use in tablets may be present in an amount of about 0.1% to about 3% by weight and include, but are not limited to, polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, castor oil (natural or hydrogenated), HCOR™ (Nikkol), oleyl esters, Gelucire™, caprylic / caprylic acid mono / diglycerides, sorbitan fatty acid esters, and Solutol HS™.

[0066] Parenteral Administration The compounds of the present disclosure can be administered directly into the bloodstream, muscle, or an internal organ. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous, intraarterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needle and needle-free syringes) and infusion techniques.

[0067] Compositions for parenteral administration can be formulated as immediate release or modified release (including delayed or sustained release). Most parenteral formulations are aqueous solutions containing excipients including salts, buffers and isotonicity agents. Parenteral formulations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with a suitable vehicle, e.g., sterile water. Solubility enhancers can also be used in the preparation of parenteral solutions.

[0068] Transdermal Administration The compounds of the present disclosure can be administered topically or transdermally to the skin. The formulation for topical administration can include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol, etc. Topical or transdermal administration can also be performed by electroporation, iontophoresis, sonophoresis, etc.

[0069] Compositions for topical administration may be formulated as immediate or modified release (including delayed or sustained release).

[0070] Combination therapy The pharmaceutical composition of the present disclosure may contain one or more additional therapeutic agents, for example, to improve efficacy or reduce side effects.Thus, in some embodiments, the pharmaceutical composition further contains one or more additional therapeutic agents selected from active ingredients useful for treating or inhibiting diseases directly or indirectly mediated by c-abl kinase.Examples of such active ingredients include, but are not limited to, agents for treating neurodegenerative diseases or disorders.

[0071] References for preparing pharmaceutical compositions Methods for preparing pharmaceutical compositions for treating or preventing a disease or condition are well known in the art to which this disclosure pertains. th ed.), Remington: The Science and Practice of Pharmacy(20 th ed.), Encyclopedia of Pharmaceutical Technology(3 rd Pharmaceutically acceptable excipients, carriers, additives, etc. can be selected based on the principles of the present invention and then mixed with the compounds of the present disclosure to prepare pharmaceutical compositions.

[0072] The present disclosure provides compounds having various pharmacological effects, for example by inhibiting c-abl activity, pharmaceutical compositions having the compounds as active ingredients, medical uses of the compounds, particularly for treating neurodegenerative diseases or disorders, and methods of treatment or prevention comprising administering the compounds to subjects in need of such treatment or prevention. The compounds of the present disclosure, their pharma- ceutically acceptable salts and / or their crystalline forms have good safety and high selectivity for c-abl, and therefore exhibit excellent properties as drugs.

[0073] Working Example The following examples further illustrate the preparation and characterization of the distinct polymorphic salt forms of Formula (I), but are not intended to limit the scope of the invention described or claimed herein. Unless otherwise noted, all temperatures are given in degrees Celsius and all parts and percentages are by weight.

[0074] It is intended to be understood that peak heights in powder X-ray diffraction patterns may vary and will depend on variables such as temperature, crystal size, crystal habit, sample preparation, or sample height in the analytical well of the Scintagx2 Diffraction Pattern System.

[0075] It is also intended to be understood that peak positions may vary when measured with different radiation sources, for example, Cu-Kα1, Mo-Kα, Co-Kα and Fe-Kα radiation, having wavelengths of 1.54060 Å, 0.7107 Å, 1.7902 Å and 1.9373 Å, respectively, may give peak positions that differ from those measured with Cu-Kα radiation.

[0076] Although the digital output from a powder X-ray diffractometer can be set to show peak positions to two and three decimal places, diffractometers cannot make experimental determinations accurate beyond one decimal place, therefore, peak positions reported herein are rounded to one decimal place.

[0077] Analytical Instruments and Methods (1) X-ray powder diffractometer (XRPD) The samples were run by XRPD using the following method. -Tube: Cu:K-alpha (λ=1.54179Å) -Generator: Voltage: 40kV, Current: 40mA -Scan range: 3~40 degrees -Sample rotation speed: 15 rpm

[0078] (2) Differential scanning calorimetry (DSC) The details of the DSC method used for the testing are given below. - Samples (approximately 1 mg) were tested using sealed aluminum pans with a pinhole and heated from 25°C to 300°C at a rate of 10°C / min.

[0079] (3) Thermogravimetric analysis (TGA) Details of the TGA method used for the testing are given below. -Samples (3-5 mg) were placed in an open platinum pan and heated under 25 mL / min of N2 at a rate of 10 °C / min from 30 °C to 300 °C or until the mass % was less than 80%.

[0080] (4) Polarized Light Microscope (PLM) The polarized light microscopy techniques used in the testing are detailed below. -Nikon LV100POL with 5 megapixel CCD -Physical lens: 10x / 20x

[0081] (5) Dynamic Vapor Sorption (DVS) The sample (approximately 10 mg) was transferred to the DVS instrument and the weight change was recorded versus ambient humidity at 25° C. using the following parameters: - Balance: dm / dt: 0.01% / min (min: 10 min and max: 180 min) -Drying: 0% RH, 120 minutes -RH(%) during measurement process: 10% -RH(%) range during measurement process: 0~90~0%

[0082] (6) Proton Nuclear Magnetic Resonance (1H NMR) DMSO-d6 or MeOH-d4 solvent, 400MHz Bruker Temperature: 27℃

[0083] Example 1. Physical properties of formula (I) physical properties The appearance of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base is a pale yellow powder. The physical and thermal properties of the free base were subsequently characterized. The respective results are summarized in Table 1 and listed in Figures 1-3. The free base of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide exhibited birefringence and a cubic crystal-like shape according to the polarized light micrograph (Figure 1). Meanwhile, the starting free base showed a high degree of crystallinity according to the XRPD results (Figure 2). The DSC scan (Figure 3) showed a single endotherm with an onset of 265.94 °C. Meanwhile, the TGA scan showed a mass loss of about 1.07% from 23.5° C. to 240.0° C. This free base form was designated as Pattern A.

[0084] [Table 1] TIFF0007604387000004.tif27165

[0085] Solubility test of free base in solvent Approximately 4 mg (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide was weighed into a 2.0 mL glass vial, and then the selected solvent was added stepwise to the vial until all solids were dissolved. Experiments were performed at 25° C. and 50° C. by manual dilution combined with visual observation. The total amount of solvent added was recorded.

[0086] The results are listed in Table 2. (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide showed relatively low solubility in most commonly used solvents and relatively high solubility in DMF and DMSO.

[0087] [Table 2]

[0088] Solubility testing of free bases in biologically relevant media and buffers Approximately 5 mg of starting free base was weighed into a 2 mL vial. Then, 1.0 mL of biorelevant media (SGF, FaSSIF and FeSSIF) and buffer were added to the vial. All vials were placed in a thermomixer and maintained at 37°C (700 r / min). After shaking for 24 h at 37°C, the mother liquor obtained by filtration was analyzed by HPLC either as is or after dilution 20-40 times with ACN / water. The solubility results are summarized in Table 3. According to the solubility results, the free base showed moderate solubility (2.0-2.5 mg / mL) in SGF and pH 2.0 buffer.

[0089] [Table 3]

[0090] Example 2. Preliminary salt screening experiments Based on the calculated pKa values ​​of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base of 5.53, -0.74 and -8.39, ten acids were initially selected as counter ions for salt screening studies. Meanwhile, acetone, EtOAc, ACN and IPA / water (95 / 5, v / v) were selected as salt screening solvents. The details of the salt screening procedure are listed below.

[0091] For solid counter ions, 50 mg of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base and 1.1 equivalents of counter ion were weighed into a 2 mL vial, and then 1.0 mL of solvent was added to the vial. For liquid counter ions, 50 mg of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base was weighed into a 2 mL vial, followed by 850 μL of solvent. Then, a solution of 1.1 equivalents of counter ion in the corresponding solvent (concentration: 0.1 g / mL) was added to the vial. Concurrently, (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base slurried in 1.0 mL of the same solvent was used as a control. All vials were placed in a thermomixer and heated to 50° C. After holding at 50° C. for 14 hours, the vials were then cooled to 25° C. in 2 hours. After holding at 25° C. for 5 hours, the solids in the suspension were isolated by centrifugation and dried in a vacuum oven at 30° C. for 3 days. The resulting dried solids were then characterized by XRPD. The results of the salt screening are listed in Table 4 and Figures 4-14.

[0092] In this study, the XRPD pattern of the starting free base was initially named pattern A. A total of five new XRPD patterns were found in the salt formation experiments using five different counter ions, including hydrochloric acid (pattern I), sulfuric acid (pattern II), maleic acid (pattern III), fumaric acid (pattern IV) and methanesulfonic acid (pattern V). After salt formation using phosphoric acid, an amorphous solid was obtained, which also indicated the formation of a possible salt.

[0093] [Table 4]

[0094] The five new salt forms were further characterized by XRPD, DSC and TGA, in particular to confirm the salt formation and the stoichiometry of the acid / base ratio, and to determine the organic salts. 1 It was also characterized by H-NMR, and the characterization results are listed in Table 5 and Figures 15-27.

[0095] Characterization results showed that the resulting sulfate salt exhibited low crystallinity and poor thermal properties.

[0096] [Table 5] TIFF0007604387000009.tif26169

[0097] Example 3. Comparative study of monohydrochloride and dihydrochloride salts To investigate the effect of the ratio of hydrochloric acid to compounds on the salt formation process, salt formation experiments with different acid ratios (1.1 equivalents and 2.2 equivalents) were carried out. The details of the operating procedure are described below.

[0098] 1) The experimental procedure for monohydrochloride formation includes the following steps: 1. 00 g of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide free base is suspended in 15.0 mL of acetone at 50° C. 2. Hold at 50°C for 1 hour (suspension). 3. Add 1.1 equivalents of hydrochloric acid in acetone (6.72 mL, 0.5 mmol / mL) dropwise to the suspension (suspension). 4. Hold at 50°C for 3 hours (suspension). 5. Cool to 25°C and hold at 25°C for 17 hours (suspension). 6. Measure the XRPD of the wet solid. 7. Continue slurrying at 25°C for 5 hours. 8. Filter the suspension through a funnel and wash the wet cake with 3.0 mL of solvent. 9. Dry the wet cake in vacuum at 35°C for 16 hours. 10. A total of 1.00 g dry solid was obtained.

[0099] 2) The experimental procedure for dihydrochloride formation includes the following steps: 1. 1.00 g of API is suspended in 15.0 mL of acetone at 50° C. 2. Hold at 50°C for 1 hour (suspension). 3. Drop 2.2 equivalents of hydrochloric acid in acetone (6.72 mL, 1.0 mmol / mL) into the suspension. The system was frozen. The slurry was not very good. Add another 5.0 mL of acetone to the system (suspension). 4. Hold at 50°C for 3 hours (suspension). 5. Cool to 25°C and hold at 25°C for 17 hours (suspension). 6. Measure the XRPD of the wet solid. 7. Continue slurrying at 25°C for 5 hours. 8. Filter the suspension through a funnel and wash the wet cake with 3.0 mL of solvent. 9. Dry the wet cake in vacuum at 35°C for 16 hours. 10. A total of 1.13 g of dry solid was obtained.

[0100] The comparison results between the monohydrochloride and dihydrochloride salts are listed in Table 6 and shown in Figures 28-33. 1 It was characterized by H-NMR, XRPD, DSC and TGA. According to the XRPD results, the dihydrochloride salt showed low crystallinity as pattern VI.

[0101] [Table 6]

[0102] 3) Solubility test in bio-related media The solubility of the monohydrochloride and dihydrochloride salts in biorelevant media was tested at 37° C. The details of the procedure are listed below.

[0103] Approximately 15 mg of each of the obtained salts was weighed into a 2 mL vial. Then, 1.0 mL of biorelevant media (SGF, FaSSIF and FeSSIF) was added to the vial. All vials were placed in a thermomixer and maintained at 37 °C (700 r / min). After shaking for 17 h at 37 °C, the clear solutions obtained by centrifugation were analyzed by HPLC after dilution 10-50 times with ACN / water (1v / 1v). The pH values ​​of all the systems were also measured. The solubility results are summarized in Table 7.

[0104] [Table 7]

[0105] Example 4. Polymorph Screening Study of (1S,2S)-2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide Monohydrochloride Polymorph screening studies of the monohydrochloride salt with pattern I were conducted by slurry method, heat-cool method, slow evaporation method and anti-solvent method. No new XRPD patterns were found by these methods. Dry milling and wet milling were performed to test the physical stability of the monohydrochloride salt in the milling process. XRPD results showed that the crystallinity of the residual solid decreased after dry milling, but the crystal form did not change after the dry milling or wet granulation process.

[0106] One polymorph of the monohydrochloride salt (Pattern I) was observed in polymorph screening experiments.

[0107] 1) Slurry method Approximately 50 mg (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride was suspended in 1.0 mL of the selected pure or binary solvent in a 2.0 mL glass vial. The suspension was placed in a thermomixer at 25° C. and 50° C. at a speed of 700 r / min. After 4 days, the slurry and suspension were centrifuged (8,000 r / min, 5 min) and the remaining solid was dried in a vacuum oven at 35° C. for 4 h. The obtained dried solid was then characterized by XRPD and the results are summarized in Table 8.

[0108] As shown by the XRPD results of the solids obtained after slurrying at 25° C. and 50° C. for 4 days in FIGS. 34-37, all solids were still in Pattern I, and no new XRPD patterns were found.

[0109] [Table 8]

[0110] Heating-cooling method Approximately 50 mg of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride was suspended in 1.0 mL of the selected pure or binary solvent in a 2.0 mL glass vial with stirring at a speed of 500 r / min at 50° C. The suspension was then filtered through a 0.45 μm filter into a clean 2.0 mL glass vial and placed on a hot plate and stirred at 500 r / min at 50° C. After stirring at 50° C. for 1.5 h, the system was cooled to 25° C. After stirring at 25° C. for 16 h, some solids were produced from MeOH, EtOH / H2O (5 / 1, v / v) and acetone / H2O (5 / 1, v / v) systems, but almost no solids were produced from the EtOH system. MeOH, EtOH / H2O (5 / 1, v / v) and acetone / H2O (5 / 1, v / v) systems were then centrifuged at 10000 r / min for 5 min and the residual solids were dried in a vacuum oven at 35°C for 3 h. The resulting dried solids were then characterized by XRPD. The analytical results are summarized in Table 8 and Figure 38. All the resulting solids were pattern I and no new XRPD patterns were obtained by the heating-cooling method.

[0111] [Table 9]

[0112] Slow Evaporation Method Approximately 30 mg of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride was weighed into a 2.0 mL glass vial and then 1.5 mL of MeOH was added. The solution was then filtered through a 0.45 μm filter into a clean 4.0 mL glass vial. The vial was covered with aluminum film with a pinhole and placed in a fume hood. After 4 days of evaporation, the resulting solid was dried in a vacuum oven at 35° C. for 4 hours and then characterized by XRPD. As shown by the XRPD results of the resulting solid in FIG. 39, the evaporation method yielded an amorphous solid from the MeOH system.

[0113] Antisolvent method Based on the solubility results of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride, MeOH, DMF, DMSO and water were selected as good solvents for dissolving this compound, since (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride showed relatively high solubility in these solvents. Meanwhile, MtBE, IPA and acetone were selected as poor solvents.

[0114] Approximately 50 mg of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride was weighed into an 8.0 mL glass vial, and then 0.5-2.0 mL of the selected good solvent was added. All vials were placed on a hot plate and stirred at 50° C. at a speed of 500 r / min. After stirring at 50° C. for 30 min, all systems were clear. The selected poor solvent was then added stepwise until a solid was formed or the volume ratio of poor solvent / good solvent reached 10:1. All systems were kept at 50° C. for 1 h and then cooled to 25° C. After keeping at 25° C. for 16 h or 3 days, the suspension was centrifuged. The wet solid was then dried in a vacuum oven, and the resulting dry solid was further characterized by XRPD. The results are summarized in Table 10 and Figure 40. All the solids obtained were of Pattern I, and no new XRPD patterns were found by the anti-solvent method.

[0115] [Table 10]

[0116] Grinding method To test the physical stability of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride in the milling process, dry milling and wet granulation were carried out.

[0117] For the dry grinding experiment, about 50 mg of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride was added to a mortar and ground with a pestle for about 5 minutes, and the remaining solid was then characterized by XRPD.

[0118] For the wet granulation experiments, approximately 50 mg of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide monohydrochloride was added to a mortar, followed by a few drops of the solvent EtOH until the solid was completely wetted. The wet solid was manually ground with a pestle for approximately 5 minutes, and the remaining solid was then characterized by XRPD.

[0119] As shown by the XRPD results of the solid obtained after milling in FIG. 41, the crystallinity of the residual solid decreased after dry milling, but the crystal form did not change after the dry milling and wet milling processes.

Claims

1. A crystal of (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide (Compound I) or a pharma- ceutically acceptable salt thereof, The crystals are as follows: A crystal of the free base of Compound I having peaks at diffraction angles (2θ) of 9.8±0.2, 11.6±0.2, 13.2±0.2, 14.0±0.2, 16.7±0.2, 17.6±0.2, 20.6±0.2, 22.9±0.2, 26.2±0.2, 29.3±0.2, 30.7±0.2, and 31.6±0.

2. Crystals of the hydrochloride salt of Compound I having peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2; Crystals of the sulfate salt of Compound I having peaks at diffraction angles (2θ) of 8.7±0.2, 10.9±0.2, 12.9±0.2, 15.4±0.2, 16.4±0.2, 18.9±0.2, 20.3±0.2, 22.1±0.2, 22.7±0.2, and 24.9±0.2; A crystal of the maleate salt of Compound I having peaks at diffraction angles (2θ) of 9.4±0.2, 10.1±0.2, 14.8±0.2, 18.0±0.2, 23.0±0.2, 25.4±0.2, and 29.2±0.2; A crystal of the fumarate salt of Compound I having peaks at diffraction angles (2θ) of 5.3±0.2, 10.6±0.2, 17.2±0.2, 19.8±0.2, and 26.5±0.2; A crystal of mesylate of Compound I having peaks at diffraction angles (2θ) of 5.1±0.2, 10.2±0.2, 15.2±0.2, 18.6±0.2, 20.5±0.2, and 21.9±0.2; and Crystals of the dihydrochloride salt of Compound I having peaks at diffraction angles (2θ) of 6.6±0.2, 13.9±0.2, 15.9±0.2, 22.0±0.2, 23.8±0.2, 24.6±0.2, and 26.8±0.2 A crystal selected from the group consisting of:

2. The crystals are crystals of a free base of Compound I having peaks at diffraction angles (2θ) of 9.8±0.2, 11.6±0.2, 13.2±0.2, 14.0±0.2, 16.7±0.2, 17.6±0.2, 20.6±0.2, 22.9±0.2, 26.2±0.2, 29.3±0.2, 30.7±0.2, and 31.6±0.2; 2. The crystal of claim 1, wherein the crystal has an onset melting point of 267°C and a peak temperature of 268°C.

3. The crystal is a crystal of the hydrochloride salt of Compound I having peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2; 2. The crystal of claim 1, wherein the crystal has a melting point of 240°C.

4. The crystals are crystals of sulfate of Compound I having peaks at diffraction angles (2θ) of 8.7±0.2, 10.9±0.2, 12.9±0.2, 15.4±0.2, 16.4±0.2, 18.9±0.2, 20.3±0.2, 22.1±0.2, 22.7±0.2, and 24.9±0.2; 2. The crystal of claim 1, wherein the crystal has a first melting point of 212°C and a second melting point of 229°C.

5. The crystal is a crystal of maleate of Compound I having peaks at diffraction angles (2θ) of 9.4±0.2, 10.1±0.2, 14.8±0.2, 18.0±0.2, 23.0±0.2, 25.4±0.2, and 29.2±0.2; The crystal of claim 1, wherein the crystal has a melting point of 174°C.

6. The crystal is a crystal of a fumarate salt of Compound I having peaks at diffraction angles (2θ) of 5.3±0.2, 10.6±0.2, 17.2±0.2, 19.8±0.2, and 26.5±0.2; 2. The crystal of claim 1, wherein the crystal has a melting point of 227°C.

7. the crystal is a crystal of mesylate of Compound I having peaks at diffraction angles (2θ) of 5.1±0.2, 10.2±0.2, 15.2±0.2, 18.6±0.2, 20.5±0.2, and 21.9±0.2; 2. The crystal of claim 1, wherein the crystal has a melting point of 194°C.

8. The crystal is a crystal of dihydrochloride of Compound I having peaks at diffraction angles (2θ) of 6.6±0.2, 13.9±0.2, 15.9±0.2, 22.0±0.2, 23.8±0.2, 24.6±0.2, and 26.8±0.2; The crystal of claim 1, wherein the crystal has a melting point of 168°C.

9. A composition comprising the crystal of claim 1 and at least one pharma- ceutically acceptable carrier.

10. The crystal is a crystal of hydrochloride of Compound I having peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2; 10. The composition of claim 9, wherein the crystals have a melting point of 240°C.

11. A pharmaceutical composition for treating a neurodegenerative disease, comprising a therapeutically effective amount of the crystal of claim 1.

12. The crystal is a crystal of hydrochloride of Compound I having peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2; 12. The pharmaceutical composition of claim 11, wherein the crystal has a melting point of 240°C.

13. The pharmaceutical composition according to claim 11 or 12, wherein the neurodegenerative disease is α-synucleinopathy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy (MSA), Alzheimer's disease, or amyotrophic lateral sclerosis (ALS).

14. 13. Use of the crystal of claim 1 in the manufacture of a medicament for treating a neurodegenerative disease.

15. The crystal is a crystal of hydrochloride of Compound I having peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2; 15. The use according to claim 14, wherein the crystals have a melting point of 240°C.

16. The use according to claim 14 or 15, wherein the neurodegenerative disease is α-synucleinopathy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy (MSA), Alzheimer's disease or amyotrophic lateral sclerosis (ALS).

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