Phosphate of pyrrolopyridine derivative and preparation method therefor

Abstract

Provided are phosphate of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, various crystal forms thereof, a pharmaceutical composition thereof, and the use thereof in the treatment of AAK1-related diseases.

Description

Phosphates of pyrrolopyridine derivatives and their preparation methods

[0001] This application claims priority to an earlier application filed by the applicant with the China National Intellectual Property Administration on November 29, 2024, with patent application number 202411744873.3, entitled "Phosphates of Pyrrolopyridine Derivatives and Methods for their Preparation Thereof". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention relates to the pharmaceutical field, and more specifically to a phosphate and crystal form of a pyrrolopyridine derivative and a method for preparing the same. Background Technology

[0003] Linkin-associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two spliced ​​forms, known as short and long forms. The long form is predominant and highly expressed in the brain and heart (Henderson and Conner, Mol. Biol. Cell. 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal preparations and co-localizes with endocytic structures in cultured cells. AAK1 regulates claatherin-coated endocytosis, a crucial process in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 binds to the AP2 complex, a heterotetramer that links receptor cargoes to claatherin-coated kinases. Clathrin binding to AAK1 stimulates AAK1 kinase activity (Conner et al., Traffic 2003, 4, 885-890; Jackson et al., J. Cell. Biol. 2003, 163, 231-236). AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes the binding of mu-2 to the tyrosine-containing sorting motif on the carrier receptor (Ricotta et al., J. Cell Bio. 2002, 156, 791-795; Conner and Schmid, J. Cell Bio. 2002, 156, 921-929). Mu2 phosphorylation is not essential for receptor uptake, but it increases the efficiency of internalization (Motely et al., Mol. Biol. Cell. 2006, 17, 5298-5308).

[0004] (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine, with the structural formula shown in Formula I (hereinafter referred to as Compound I), is a novel and highly active AKK1 inhibitor compound. This compound has promising applications in the prevention and / or treatment of AKK1 inhibition-related indications such as Alzheimer's disease, bipolar disorder, Kimberly's disease, schizophrenia, diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, or peripheral neuropathy. The structural formula is as follows.

[0005] Nearly half of drug molecules exist and are administered in the form of salts. Salt formation can improve certain undesirable physicochemical or biopharmaceutical properties of drugs, such as altering solubility or dissolution rate, reducing hygroscopicity, improving stability, changing melting point, improving grinding performance, facilitating preparation and purification, and increasing permeability. Therefore, selecting a suitable salt form for drug development is essential.

[0006] The specification of patent CN118772152A discloses (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine and its trihydrochloride in Example 26. No reports have been made on the phosphate salt.

[0007] Against this background, screening for more salt forms of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine with excellent properties is of great significance for the pharmaceutical development and industrial production of this compound. Summary of the Invention

[0008] The purpose of this invention is to screen the salt forms and crystal forms of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine with excellent properties, providing a solid form more favorable for pharmaceutical development. This invention also investigated the preparation, drug metabolism, and physicochemical properties of various salts of the compound shown in formula (I) and their crystal forms. It was found that the phosphates of the compound shown in formula (I) and their crystal forms possess properties such as good solubility, good stability, low hygroscopicity, excellent pharmacokinetics, high bioavailability, simple preparation methods, and suitability for industrial-scale production.

[0009] In one aspect, this invention provides a phosphate salt of compound (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine with phosphoric acid, as shown in the following formula.

[0010] As a preferred technical solution, the salt is phosphate crystal form A, and the X-ray powder diffraction pattern of phosphate crystal form A has diffraction peaks at the following 2θ angles: 4.25±0.2°, 5.60±0.2°, 20.94±0.2°; or

[0011] The salt is phosphate crystal form B, and the X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at the following 2θ angles: 7.88±0.2°, 15.69±0.2°, 18.96±0.2°, 20.43±0.2°; or

[0012] The salt is phosphate crystal form C, and the X-ray powder diffraction pattern of phosphate crystal form C has diffraction peaks at the following 2θ angles: 4.15±0.2°, 5.62±0.2°, 6.42±0.2°, 19.69±0.2°.

[0013] As a preferred technical solution, the salt is phosphate crystal form A, and the X-ray powder diffraction pattern of phosphate crystal form A has diffraction peaks at the following 2θ angles: 4.25±0.2°, 5.60±0.2°, 11.32±0.2°, 15.78±0.2°, 17.46±0.2°, 18.85±0.2°, 19.16±0.2°, 20.94±0.2°, 25.35±0.2°; or

[0014] The salt is phosphate crystal form B, and the X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at the following 2θ angles: 7.88±0.2°, 13.62±0.2°, 15.69±0.2°, 17.12±0.2°, 18.96±0.2°, 20.43±0.2°, 23.63±0.2°, 25.26±0.2°; or

[0015] The salt is phosphate crystal form C, and the X-ray powder diffraction pattern of phosphate crystal form C has diffraction peaks at the following 2θ angles: 4.15±0.2°, 5.62±0.2°, 6.42±0.2°, 8.28±0.2°, 19.69±0.2°, 20.96±0.2°.

[0016] As a preferred technical solution, the salt is phosphate crystal form A, and the X-ray powder diffraction pattern of phosphate crystal form A has diffraction peaks at the following 2θ angles: 4.25±0.2°, 5.60±0.2°, 11.32±0.2°, 14.03±0.2°, 15.78±0.2°, 17.46±0.2°, 18.85±0.2°, 19.16±0.2°, 20.06±0.2°, 20.94±0.2°, 23.54±0.2°, 25.35±0.2°, 26.34±0.2°, 27.73±0.2°, 31.58±0.2°; or

[0017] The salt is phosphate crystal form B, and the X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at the following 2θ angles: 7.88±0.2°, 13.07±0.2°, 13.62±0.2°, 14.92±0.2°, 15.24±0.2°, 15.69±0.2°, 17.12±0.2°, 18.96±0.2°, 20.43±0.2°, 23.63±0.2°, 24.38±0.2°, 25.26±0.2°, 26.22±0.2°, 28.45±0.2°; or

[0018] The salt is phosphate crystal form C, and the X-ray powder diffraction pattern of phosphate crystal form C has diffraction peaks at the following 2θ angles: 4.15±0.2°, 5.62±0.2°, 6.42±0.2°, 8.28±0.2°, 8.69±0.2°, 11.34±0.2°, 12.86±0.2°, 15.79±0.2°, 16.01±0.2°, 16.87±0.2°, 17.49±0.2°, 18.87±0.2°, 19.69±0.2°, 20.12±0.2°, 20.72±0.2°, 20.96±0.2°, 25.31±0.2°, 27.89±0.2°, 34.15±0.2°.

[0019] As a preferred technical solution, the salt is phosphate crystal form A, and phosphate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 1-1; or

[0020] The salt is phosphate crystal form B, which has an X-ray powder diffraction pattern substantially as shown in Figures 1-2; or

[0021] The salt is phosphate crystal form C, which has an X-ray powder diffraction pattern substantially as shown in Figures 1-3.

[0022] As a preferred technical solution, the salt is phosphate crystal form A, and the molar ratio of the compound shown in formula (I) to phosphoric acid in phosphate crystal form A is 1:(0.33~3); more preferably, the molar ratio of the compound shown in formula (I) to phosphoric acid is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; more preferably, the molar ratio of the compound shown in formula (I) to phosphoric acid is 1:1; or

[0023] The salt is phosphate crystal form B, wherein the molar ratio of the compound shown in formula (I) to phosphoric acid in phosphate crystal form B is 1:(0.33-3); preferably, the molar ratio of the compound shown in formula (I) to phosphoric acid is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; more preferably, the molar ratio of the compound shown in formula (I) to phosphoric acid is 1:1; or

[0024] The salt is phosphate crystal form C, wherein the molar ratio of the compound shown in formula (I) to phosphoric acid in phosphate crystal form C is 1:(0.33-3); preferably, the molar ratio of the compound shown in formula (I) to phosphoric acid is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; more preferably, the molar ratio of the compound shown in formula (I) to phosphoric acid is 1:1.

[0025] As a preferred technical solution, the salt is phosphate crystal form A, which has a weight loss of 3.4±0.2% at 100℃; or the salt is phosphate crystal form B, which has a weight loss of 2.0±0.2% at 100℃; or the salt is phosphate crystal form C, which has a weight loss of 2.6±0.2% at 60℃ and a weight loss of 1.2±0.2% at 120℃.

[0026] As a preferred technical solution, the salt is phosphate crystal form A, which has a TGA diagram substantially as shown in Figure 2-1; or the salt is phosphate crystal form B, which has a TGA diagram substantially as shown in Figure 2-2; or the salt is phosphate crystal form C, which has a TGA diagram substantially as shown in Figure 2-3.

[0027] As a preferred technical solution, the salt is phosphate crystal form A, which has a DSC diagram substantially as shown in Figure 3-1; or the salt is phosphate crystal form B, which has a DSC diagram substantially as shown in Figure 3-2; or the salt is phosphate crystal form C, which has a DSC diagram substantially as shown in Figure 3-3.

[0028] The present invention also provides a method for preparing the phosphate of compound I, comprising the following steps: adding (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine and an alcohol solvent or water to a reaction vessel, heating, stirring to dissolve, adding an aqueous solution of phosphoric acid dropwise to the filtrate, cooling to allow crystallization after the addition is complete, stirring, filtering, and drying the filter cake by blowing air.

[0029] As a preferred technical solution, the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, ethylene glycol, isobutanol, n-butanol, and neopentyl alcohol.

[0030] As a preferred technical solution, the alcohol solvent is selected from isopropanol, ethanol and water.

[0031] As a preferred technical solution, the solvent volume for dissolving (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine is 5.0 to 30.0 v / w, where v = volume of solvent used (ml) and w = mass of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine (g); the solvent volume for dissolving phosphoric acid is 0 to 5 v / w, where v = volume of solvent used (ml) and w = mass of phosphoric acid (g).

[0032] As a preferred technical solution, the temperature in the phosphate preparation method is raised to 20-100℃.

[0033] As a preferred technical solution, the temperature in the phosphate preparation method is lowered to 0-40℃.

[0034] As a preferred technical solution, the temperature in the phosphate preparation method is lowered to 20±5℃.

[0035] As a preferred technical solution, the filter cake drying temperature in the phosphate preparation method is 40-80℃.

[0036] As a preferred technical solution, the filter cake drying temperature in the phosphate preparation method is 60±10℃.

[0037] As a preferred technical solution, the amount of phosphoric acid used in the phosphate preparation method is 1.0 to 3.0 molar equivalents of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine, preferably 1.5 to 2.5 molar equivalents, and more preferably 1.7 molar equivalents.

[0038] The present invention also provides a pharmaceutical composition comprising the phosphate described in any of the preceding claims and pharmaceutically acceptable excipients thereof.

[0039] The present invention also provides the use of the phosphate of compound I in the preparation of medicaments for treating diseases or conditions mediated by connector-associated kinase 1 activity.

[0040] As a preferred technical solution, the disease or symptom is selected from Alzheimer's disease, bipolar disorder, pain, Parkinson's disease, and schizophrenia.

[0041] Furthermore, the pain is selected from peripheral neuropathic pain.

[0042] Furthermore, the peripheral neuropathic pain is selected from diabetic peripheral neuropathy and postherpetic neuralgia.

[0043] Definitions and general terms

[0044] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0045] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0046] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this invention include, but are not limited to, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, etc. DMF stands for N,N-dimethylformamide, DMSO is dimethyl sulfoxide, and NMP is N-methylpyrrolidone.

[0047] Crystalline or amorphous forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0048] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

[0049] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature under programmed control by continuously heating or cooling. The height of the endothermic peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plots provided in the accompanying drawings. However, DSC spectra can be subject to experimental error; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in the DSC should not be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±3° for the endothermic peaks.

[0050] Differential scanning calorimetry (DSC) can also be used to detect and analyze whether there is crystal transformation or mixed crystal phenomenon in the crystal form.

[0051] Solids with the same chemical composition often form isomers, or polymorphs, with different crystal structures under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase polymorphism. When temperature and pressure conditions change, these polymorphs can transform into each other; this phenomenon is called crystal form transformation. Due to crystal form transformation, the mechanical, electrical, and magnetic properties of the crystal undergo significant changes. When the temperature of the crystal form transformation is within a measurable range, this transformation process can be observed on a differential scanning calorimeter (DSC) chart. The DSC chart is characterized by an exothermic peak reflecting this transformation process, along with two or more endothermic peaks, which are characteristic endothermic peaks of the different crystal forms before and after the transformation.

[0052] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. Based on the instrument used in this experiment, there is an error tolerance of ±0.1% for the mass change.

[0053] Raman spectroscopy is a spectroscopic technique used to study the vibrational modes, rotational modes, and other low-frequency modes of molecules within a system. Different spatial structures of the same molecule (different crystalline or amorphous forms) exhibit different Raman activities; therefore, Raman spectroscopy can be used to determine and identify crystalline or amorphous forms. The peak positions in Raman spectra are primarily related to the structure of the substance and are relatively insensitive to experimental details, while peak intensities depend on factors such as sample preparation and instrumentation. Therefore, the characteristic of the crystalline or amorphous forms described in this invention lies in the Raman spectra with characteristic peak positions, which are essentially as shown in the Raman spectra provided in the accompanying drawings. However, Raman spectroscopy can be subject to experimental errors; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the numerical values ​​of the peak positions or peak intensities in the Raman spectra described herein should not be considered absolute. Based on the instrumentation used in this experiment, there is an error tolerance of ±2 cm⁻¹ for the absorption peaks.

[0054] In different spatial structures of the same molecule, the bond lengths and bond angles of certain chemical bonds may differ, resulting in different vibrational-rotational transition energy levels. Consequently, certain key characteristics of the corresponding infrared spectra, such as absorption band frequencies, peak shapes, peak positions, and peak intensities, will also vary. Therefore, infrared spectroscopy can be used for the study of drug polymorphism. The crystalline or amorphous characteristics of this invention are manifested in Fourier transform infrared (FT-IR) spectra with characteristic peak positions, which are essentially as shown in the FT-IR spectra provided in the accompanying drawings. However, FT-IR spectra can be subject to experimental errors; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak intensities described in the FT-IR spectra cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±2 cm⁻¹ for the absorption peaks.

[0055] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0056] The term “basically as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are shown in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum.

[0057] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0058] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0059] The pharmaceutical compositions of the present invention are characterized by an acid addition salt, a crystal form, and a pharmaceutically acceptable carrier of the compound represented by formula (I). The amount of the acid addition salt or crystal form of the compound in the pharmaceutical compositions of the present invention is sufficient to effectively treat AAK1-related diseases.

[0060] The crystalline form A of compound I phosphate is the most stable form of this salt discovered: after storage at 40°C and 75% relative humidity for up to 6 months, its form, morphology, and impurity content remained unchanged; after storage at 25°C and 60% relative humidity for up to 9 months, its form, morphology, and impurity content also remained unchanged. Furthermore, the crystalline form A of compound I phosphate exhibits particularly good pharmacokinetics, showing unexpected advantages compared to the phosphate crystal form of compound I, as well as the free base and trihydrochloride salt of compound I. It has higher in vivo exposure, is more suitable for formulation development, and has greater clinical application value.

[0061] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0062] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0063] Figure 1-1 is an XRPD diagram of phosphate crystal form A according to an embodiment of the present invention;

[0064] Figures 1-2 are XRPD diagrams of phosphate crystal form B according to an embodiment of the present invention;

[0065] Figures 1-3 are XRPD diagrams of phosphate crystal form C according to an embodiment of the present invention;

[0066] Figure 2-1 is a TGA diagram of phosphate crystal form A according to an embodiment of the present invention;

[0067] Figure 2-2 is a TGA diagram of phosphate crystal form B according to an embodiment of the present invention;

[0068] Figures 2-3 are TGA diagrams of phosphate crystal form C according to an embodiment of the present invention;

[0069] Figure 3-1 is a DSC diagram of phosphate crystal form A according to an embodiment of the present invention;

[0070] Figure 3-2 is a DSC diagram of phosphate crystal form B according to an embodiment of the present invention;

[0071] Figure 3-3 is a DSC diagram of phosphate crystal form C according to an embodiment of the present invention. Detailed Implementation

[0072] To better understand the content of this invention, the technical solution of this invention will be further described below with reference to specific embodiments. However, the specific implementation methods do not imply any limitation on this invention.

[0073] The (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine and its trihydrochloride used in the examples were prepared with reference to patent CN118772152A.

[0074] Test conditions of the instruments used in the experiment:

[0075] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR), mass spectrometry (MS), infrared absorption spectroscopy (IR), and ultraviolet absorption spectroscopy (UV). NMR shifts (δ) were expressed in terms of 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a BRUKER AVANCE NEO 600 nuclear magnetic resonance spectrometer, with deuterated methanol (CD3OD) as the solvent.

[0076] MS measurements were performed using an Agilent 6230 time-of-flight mass spectrometer.

[0077] IR measurements were performed using a Bruker TENSOR 27 infrared spectrometer.

[0078] UV measurements were performed using a Shimadzu UV-2600i ultraviolet spectrophotometer, with wavelengths ranging from 190 nm to 500 nm.

[0079] High performance liquid chromatography (HPLC) analysis was performed using a Thermo Scientific Ultimte 3000VWD / DAD, Shimadzu LC-2030VWD, and Shimadzu LC-2050C DAD HPLC system.

[0080] Moisture content was determined using a Metrohm 870KF Karl Fischer moisture analyzer.

[0081] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from chemical raw material pharmaceutical companies such as Anhui Zesheng Technology Co., Ltd., Nanjing Mingcheng Aikon Pharmaceutical Biotechnology Co., Ltd., Nanjing Yilan Biotechnology Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., and Shanghai Haohong Biopharmaceutical Technology Co., Ltd.

[0082] This invention is the result of extensive research and experimentation aimed at discovering thermodynamically and chemically stable pharmaceutically acceptable salts and their crystal forms of the AAK1 inhibitor (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine.

[0083] Example 1: Preparation of the free base of compound I, namely (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine

[0084] Step 1: Add 5-fluoro-1H-pyrrolo[2,3-b]pyridine (600 mg, 4.4 mmol, 1.0 eq) and potassium hydroxide (616.0 mg, 11.0 mmol, 2.5 eq) to N,N-dimethylformamide (5 mL). Slowly add iodine (586.7 mg, 4.62 mmol, 1.05 eq) dissolved in N,N-dimethylformamide (5 mL) to the system and react for 45 minutes. Add potassium hydroxide (616.0 mg, 11.0 mmol, 2.5 eq) and continue reacting for 5 minutes. Then, slowly add p-toluenesulfonyl chloride (1.76 g, 9.24 mmol, 2.1 eq) dissolved in N,N-dimethylformamide (3 mL) to the system and react at room temperature for 3 hours. After the reaction was complete, the system was poured into water (50 mL), stirred for 10 minutes, and then filtered directly. The filter cake was washed with water (20 mL) and ethyl acetate (20 mL) and dried to obtain a yellow solid product, 5-fluoro-3-iodo-1-p-toluenesulfonyl-1H-pyrrole[2,3-b]pyridine (957 mg, 69.75%).

[0085] Step 2: 6-Bromo-3-fluoropyridinaldehyde (20 g, 98.04 mmol, 1.0 eq) was dissolved in ultradry dichloromethane (200 mL). Diethylaminosulfur trifluoride (27.2 mL, 196.08 mmol, 2.0 eq) was added dropwise to the system at -20 °C, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the system was quenched in cold saturated sodium bicarbonate aqueous solution (200 mL), and dichloromethane (200 mL) was added for extraction and separation. The organic phase was collected and washed twice with water (250 mL), dried and concentrated to obtain a red solid. The solid was then decolorized with silica gel in a vacuum filtration funnel to obtain white crystalline 6-bromo-2-(difluoromethyl)-3-fluoropyridinium (19.0 g, yield 85.75%). LCMS (TOF MS ES+) m / z [M+H]+: 225.94. 1 H NMR (400MHz, DMSO) δ7.97 (d, J = 6.7Hz, 2H), 7.33–6.78 (m, 1H).

[0086] Step 3: Add compound (S)-2-amino-2,4-dimethylpentane-1-ol (17.74 g, 135 mmol, 1 eq) to tetrahydrofuran (450 mL), followed by potassium tert-butoxide (37.87 g, 337.5 mmol, 2.5 eq) and 6-bromo-2-(difluoromethyl)-3-fluoropyridine (36.61 g, 162 mmol, 1.2 eq), and react at 93 °C for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and purified by normal-phase column chromatography (dichloromethane:methanol = 95:5), followed by purification by reverse-phase column chromatography. The target product eluted when the ratio of acetonitrile to water (1‰ formic acid) was 13:87. Concentration yielded a pale yellow oily product (S)-1-{[6-bromo-2-(difluoromethyl)pyridin-3-yl]oxy}-2,4-dimethylpentane-2-amine (11.80 g, 25.88%). LCMS (TOF MS ES+) m / z [M+H]+: 337 / 339. 1 H NMR (400MHz, DMSO) δ7.79(d,J=8.8Hz,1H),7.66(d,J=8.9Hz,1H),7.16(t,J=53.4Hz,1H),3.81( s,2H),1.79(m,J=12.7,6.3Hz,1H),1.38-1.34(m,2H),1.10(s,3H),0.92(m,J=8.4,6.6Hz,6H).

[0087] Step 4: Compound (S)-1-{[6-bromo-2-(difluoromethyl)pyridin-3-yl]oxy}-2,4-dimethylpentane-2-amine (450 mg, 1.35 mmol, 1.0 eq) and pinacol bis(borate) (405 mg, 1.59 mmol, 1.2 eq) were dissolved in 1,4-dioxane (15.0 mL), followed by the addition of potassium acetate (393 mg, 4.02 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (58.5 mg, 0.08 mmol, 0.06 eq). The reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered to obtain the crude product filtrate (S)-{5-[(2-amino-2,4-dimethylpentyl)oxy]-6-(difluoromethyl)pyridin-2-yl}boric acid (4.8 mL). Then, 5-fluoro-3-iodo-1-p-toluenesulfonyl-1H-pyrrole[2,3-b]pyridine (588 mg, 1.35 mmol, 1.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (99.0 mg, 0.135 mmol, 0.1 eq) and sodium carbonate (426 mg, 4.02 mmol, 3.0 eq) were added to the above solution, and the reaction was carried out at 90 °C for 4 hours under nitrogen protection. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated and purified by normal-phase column chromatography (dichloromethane:methanol = 15:1) to give a brown solid product (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]oxy}-2,4-dimethylpentane-2-amine (260.7 mg, 35.75%). 1 H NMR (400MHz, DMSO) δ8.81(s,1H),8.71(dd,J=9.3,2.9Hz,1H),8.48(dd,J=2.9,1.2H z,1H),8.34(d,J=8.8Hz,1H),8.04(d,J=8.4Hz,2H),7.78(d,J=8.9Hz,1H),7.50-7.1 7(m,3H),3.95(s,2H),2.37(s,3H),1.82(dt,J=12.7,6.3Hz,1H),1.43-1.39(m,2H) ,1.33(d,J=9.8Hz,1H),1.22-1.17(m,1H),1.14(s,3H),0.94(dd,J=8.7,6.6Hz,6H).

[0088] Step 5: Add (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]oxy}-2,4-dimethylpentane-2-amine (476 mg, 1.21 mmol, 1.0 eq) to a hydrogen chloride-dioxane solution (3 mL, 4.0 mol / L) and react at 60 °C for 16 hours. After the reaction was complete, the mixture was directly filtered. The filter cake was washed with a mixed solvent (petroleum ether: ethyl acetate = 5:1, 20 mL) to remove excess impurities. The filter cake was collected and dried under reduced pressure to give the final product (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]oxy}-2,4-dimethylpentane-2-amine trihydrochloride (246 mg, yield 40.46%). LCMS (TOF MS ES+) m / z [M+H] + :393.19. 1 H NMR (400MHz, DMSO) δ12.22(d,J=2.9Hz,1H),8.59(dd,J=9.9,2.9Hz,1H),8.39(d,J=2.9Hz,4H),8.29(dd,J=2.9,1.5Hz,1H),8.09(d,J=8.9Hz,1H) ,7.81-7.46(m,2H),4.25-4.13(m,2H),1.86-1.72(m,2H),1.62(dd,J=14 .0,5.3Hz,1H),1.39(s,3H),0.96(d,J=6.5Hz,3H),0.91(d,J=6.4Hz,3H).

[0089] Step 6: Dissolve (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]oxy}-2,4-dimethylpentane-2-amine trihydrochloride (100 mg, 0.2 mmol, 1.0 eq) in tetrahydrofuran (1 mL), then add the solution to a solution of sodium hydroxide (24 mg, 0.6 mmol, 3 eq) in water (1 mL), and react at room temperature for 1 hour. After the reaction is complete, directly prepare the isolated white solid (S)-1-{[2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]oxy}-2,4-dimethylpentane-2-amine (31.7 mg, yield 40.56%). LCMS(TOF MS ES+)m / z[M+H]+:393.19.

[0090] Example 2: Preparation of crystal form A of compound I phosphate

[0091] 3.0 g of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine prepared in Example 1, 18 mL of ethanol, and 6 mL of water were added to the reaction flask. The mixture was heated to 70±5 °C and stirred for 1 h. 1.5 g of an aqueous solution of phosphoric acid was added dropwise to the filtrate. The mixture was then cooled to 20±5 °C and stirred for 2 h. After filtration, the filter cake was dried by forced air at 60±10 °C to obtain 2.7 g of a pale yellow crystalline powder, with a yield of 90%.

[0092] Example 3: Preparation of crystal form B of compound I phosphate

[0093] 3.0 g of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine prepared in Example 1 and 30 mL of water were added to a reaction flask. The mixture was heated to 95±5 °C and stirred for 1 h. 1.5 g of an aqueous solution of phosphoric acid was added dropwise to the filtrate. The mixture was then cooled to 20±5 °C and stirred for 2 h. After filtration, the filter cake was dried by forced air at 60±10 °C to obtain 2.8 g of white crystalline powder, with a yield of 93.3%.

[0094] Example 4: Preparation of crystal form C of compound I phosphate

[0095] 3.0 g of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine prepared in Example 1 and 30 mL of isopropanol were added to a reaction flask. The mixture was heated to 70±5 °C and stirred for 1 h. 1.5 g of an aqueous solution of phosphoric acid was added dropwise to the filtrate. After the addition was complete, the mixture was cooled to 20±5 °C and stirred for 2 h. The mixture was filtered, and the filter cake was dried by forced air at 60±10 °C to obtain 3.6 g of a yellow-green crystalline powder, with a yield of 96.7%.

[0096] The XRPD diagrams of phosphate crystal forms A, B, and C of compound I are shown in Figures 1-1, 1-2, and 1-3, respectively. The XRPD data of phosphate crystal forms A, B, and C are shown in Tables 1, 2, and 3, respectively.

[0097] The TGA and DSC results for phosphate crystal form A are shown in Figures 2-1 and 3-1. The TGA results show a 3.40% weight loss when the sample is heated to 100℃; the DSC results show two endothermic peaks at 123.36℃ (peak temperature) and 189.74℃ (peak temperature). HPLC results indicate that the molar ratio of phosphoric acid to compound I in the sample is 1.0:1, and no residual solvent was observed in the sample.

[0098] The TGA and DSC results for phosphate crystal form B are shown in Figures 2-2 and 3-2. The TGA results show a 2.01% weight loss when the sample is heated to 100℃; the DSC results show four endothermic peaks at 243.6℃ (peak temperature), 222.8℃ (peak temperature), 196.1℃ (peak temperature), and 180.6℃ (peak temperature); the HPLC results show that the molar ratio of phosphoric acid to compound I in the sample is 1.0:1, and no residual solvent was found in the sample.

[0099] The TGA and DSC results for phosphate crystal form C are shown in Figures 2-3 and 3-3. The TGA results show a 2.57% weight loss when heated to 60℃ and a 1.15% weight loss when heated to 120℃. The DSC results show multiple endothermic peaks at 238.8℃, 221.5℃, 199.06℃, and 167.5℃. The HPLC results indicate that the molar ratio of phosphoric acid to compound I in the sample is 1.0:1, and a small amount of residual solvent is present in the sample.

[0100] Table 1. XRPD data of phosphate crystal form A of compound I.

[0101] Table 2. XRPD data for phosphate crystal form B of compound I.

[0102] Table 3. XRPD data for phosphate crystal form C of compound I.

[0103] Experiment Example 1: Solubility Test

[0104] The solubility of the phosphates (crystal forms A, B, and C) of compound I obtained in the examples, as well as the trihydrochloride salt of compound I, in water / solvent was determined using the following methods:

[0105] Take a finely powdered sample and place it in a certain volume of water or solvent at 25℃±2℃. Shake vigorously for 30 seconds every 5 minutes. Observe the dissolution within 30 minutes. If no solute particles or droplets are visible to the naked eye, it is considered completely dissolved. The solubility is described as follows:

[0106] Easily soluble: 1g of the compound can dissolve in 1ml to less than 10ml of solvent;

[0107] Dissolution: 1g of the compound can dissolve in 10ml to less than 30ml of solvent;

[0108] Slightly soluble: 1g of the compound can dissolve in 30ml to less than 100ml of solvent;

[0109] Slightly soluble: 1g of the compound can dissolve in 100ml to less than 1000ml of solvent;

[0110] Very slight solubility: 1g of the compound can dissolve in 1000ml to less than 10000ml of solvent.

[0111] The measurement results are shown in Table 4.

[0112] Table 4. Solubility determination results in different solvents

[0113] Solubility tests show that the phosphate crystal forms A, B, and C of compound I of the present invention have significantly higher solubility in water compared to the trihydrochloride salt or free base of compound I.

[0114] Experimental Example 2: Hygroscopicity Test

[0115] The hygroscopicity of the free base, trihydrochloride, and phosphate crystal forms A, B, and C of compound I prepared in the examples was investigated using the following methods:

[0116] Take a dry, stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm), and place it in a suitable constant temperature desiccator at 25℃±1℃ (with a saturated ammonium chloride solution at the bottom) one day before the test, and accurately weigh it (m1); take an appropriate amount of the test sample, spread it evenly in the weighing bottle, with a sample thickness of about 1 mm, and accurately weigh it (m2); leave the weighing bottle open and place it under the constant temperature and humidity conditions mentioned above for 24 hours, along with the bottle cap; close the weighing bottle cap and accurately weigh it (m3), the weight gain percentage (%) = (m3-m2) / (m2-m1)×100%.

[0117] The measurement results are shown in Table 5.

[0118] Table 5. Results of hygroscopicity test

[0119] The results show that the hygroscopicity of various crystal forms of phosphate of compound I of the present invention is significantly lower than that of the trihydrochloride and free base of compound I, and the hygroscopicity is even lower than that of the trihydrochloride and free base of compound I. Therefore, the improvement in hygroscopicity of phosphate crystal forms A, B, and C of compound I of the present invention represents a significant advancement.

[0120] Experiment Example 3: Stability Investigation Experiment of Influencing Factors

[0121] Chemical stability tests were conducted on various salts and crystal forms of Compound I obtained in the examples. The specific method is as follows: Each salt and crystal form of Compound I was placed under high temperature (40℃, 60℃), high humidity at room temperature (75%RH, 92.5%RH), and light at room temperature (5000lx) conditions for 30 days. Samples were taken at 0 days, 10 days, and 30 days to detect relevant substances. The test results are shown in Table 4.

[0122] Table 6 Results of the stability test on influencing factors

[0123] The results showed that, after being placed under various conditions for 30 days, the chemical stability of the three crystal forms A, B, and C of the phosphate of compound I of the present invention was significantly better than that of the trihydrochloride and free base of compound I, the impurity content was significantly reduced, and no crystal form transformation occurred.

[0124] Experiment Example 4: Accelerated Stability Experiment

[0125] The phosphate A and B crystal forms of compound I, as well as the free base of the trihydrochloride salt, were placed under accelerated conditions (40℃±2℃, 75% RH±5% RH) for 6 months. Samples were taken at 0, 1, 2, 3 and 6 months to detect related substances, moisture, content and isomers. The test results are shown in Table 7.

[0126] Table 7. Results of accelerated stability tests (40℃±2℃, 75% RH±5% RH)

[0127] Experimental results show that after being stored at 40℃±2℃ / 75%RH±5%RH for 6 months, all the tested indicators showed no significant changes, indicating good physical and chemical stability, and no crystal transformation occurred.

[0128] Experiment Example 5: Long-term stability test

[0129] The phosphate A and B crystal forms of compound I, as well as the free base of the trihydrochloride salt, were placed under long-term conditions (25℃±2℃, 60% RH±5% RH) for 9 months. Samples were taken at 0, 3, 6 and 9 months to detect related substances, moisture, content and isomers. The results are shown in Table 8.

[0130] Table 8. Results of long-term stability test (25℃±2℃, 60% RH±5% RH)

[0131] Experimental results show that the various crystal forms of the phosphate of compound I provided by this invention, after being placed at 25℃±2℃ / 60%RH±5%RH for 9 months, showed no significant changes in any of the tested indicators, indicating good physical and chemical stability. Furthermore, no crystal form transformation occurred, and the stability was significantly improved compared to hydrochloride and free alkali.

[0132] Experiment Example 6: Rat Pharmacokinetic Experiment

[0133] Experimental Objective: The purpose of this experiment is to test the pharmacokinetics of the compound in SD rats.

[0134] Background and Principle: Non-clinical pharmacokinetic studies utilize in vivo, in vitro, and human in vitro research methods to reveal the dynamic changes of drugs in vivo, obtain basic pharmacokinetic parameters, and elucidate the processes and characteristics of drug absorption, distribution, metabolism, and excretion. Non-clinical pharmacokinetic studies play a crucial role in the evaluation of new drug research and development. In pharmacodynamic and toxicological evaluations, drug or active metabolite concentration data and their related pharmacokinetic parameters are the basis for generating, determining, or elucidating the magnitude of efficacy or toxicity, providing evidence of the drug's effects on target organs (efficacy or toxicity).

[0135] Specific experimental procedure:

[0136] (1) Preparation of test sample: solvent: 40% PEG300, 15% Tween 80, 10% ethanol, 35% water, prepared on the day of administration;

[0137] (2) Experimental animals: 12 male SD rats, SPF grade;

[0138] (3) Experimental design:

[0139] Note: * Animals should be fasted overnight (10-14 hours) before administration, and fed 4 hours after administration.

[0140] (4) Administration method: Weigh the patient before administration and calculate the dosage based on body weight. Administer via intravenous, gavage, or oral administration.

[0141] (5) Blood collection time points: IV: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h after drug administration; PO: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h. Blood was collected via the jugular vein, with approximately 0.2mL of each sample collected. K2-EDTA was used for anticoagulation, and the samples were placed on ice after collection.

[0142] (6) Plasma sample processing: After blood samples are collected, they are placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6800g, 6 minutes, 2-8℃). Plasma samples are stored in a -80℃ refrigerator before analysis.

[0143] (7) Data analysis: Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 based on blood drug concentration data at different time points, providing parameters such as AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, and T1 / 2, as well as their average values ​​and standard deviations.

[0144] The experimental results are shown in Table 9 below:

[0145] Table 9. Results of Pharmacokinetic Studies

[0146] The results showed that the phosphate crystal forms A and B of compound I had better pharmacokinetic characteristics in rats compared with the free base and trihydrochloride, especially the higher in vivo exposure of phosphate crystal form A, which has higher clinical development value.

Claims

1. A phosphate of the compound (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine, of formula (I) 2. The phosphate according to claim 1, wherein, The salt is phosphate crystal form A, characterized in that the X-ray powder diffraction pattern of phosphate crystal form A has diffraction peaks at the following 2θ angles: 4.25±0.2°, 5.60±0.2°, 20.94±0.2°; or The salt is phosphate crystal form B, characterized in that the X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at the following 2θ angles: 7.88±0.2°, 15.69±0.2°, 18.96±0.2°, 20.43±0.2°; or The salt is phosphate crystal form C, characterized in that the X-ray powder diffraction pattern of the phosphate crystal form C has diffraction peaks at the following 2θ angles: 4.15±0.2°, 5.62±0.2°, 6.42±0.2°, 19.69±0.2°.

3. The phosphate according to claim 1, wherein, The salt is phosphate crystal form A, characterized in that the X-ray powder diffraction pattern of phosphate crystal form A has diffraction peaks at the following 2θ angles: 4.25±0.2°, 5.60±0.2°, 11.32±0.2°, 15.78±0.2°, 17.46±0.2°, 18.85±0.2°, 19.16±0.2°, 20.94±0.2°, 25.35±0.2°; or The salt is phosphate crystal form B, characterized in that the X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at the following 2θ angles: 7.88±0.2°, 13.62±0.2°, 15.69±0.2°, 17.12±0.2°, 18.96±0.2°, 20.43±0.2°, 23.63±0.2°, 25.26±0.2°; or The salt is phosphate crystal form C, characterized in that the X-ray powder diffraction pattern of the phosphate crystal form C has diffraction peaks at the following 2θ angles: 4.15±0.2°, 5.62±0.2°, 6.42±0.2°, 8.28±0.2°, 19.69±0.2°, 20.96±0.2°.

4. The phosphate according to claim 1, wherein, The salt is phosphate crystal form A, characterized in that the X-ray powder diffraction pattern of phosphate crystal form A has diffraction peaks at the following 2θ angles: 4.25±0.2°, 5.60±0.2°, 11.32±0.2°, 14.03±0.2°, 15.78±0.2°, 17.46±0.2°, 18.85±0.2°, 19.16±0.2°, 20.06±0.2°, 20.94±0.2°, 23.54±0.2°, 25.35±0.2°, 26.34±0.2°, 27.73±0.2°, 31.58±0.2°; or The salt is phosphate crystal form B, characterized in that the X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at the following 2θ angles: 7.88±0.2°, 13.07±0.2°, 13.62±0.2°, 14.92±0.2°, 15.24±0.2°, 15.69±0.2°, 17.12±0.2°, 18.96±0.2°, 20.43±0.2°, 23.63±0.2°, 24.38±0.2°, 25.26±0.2°, 26.22±0.2°, 28.45±0.2°; or The salt is phosphate crystal form C, characterized in that the X-ray powder diffraction pattern of the phosphate crystal form C has diffraction peaks at the following 2θ angles: 4.15±0.2°, 5.62±0.2°, 6.42±0.2°, 8.28±0.2°, 8.69±0.2°, 11.34±0.2°, 12.86±0.2°, 15.79±0.2°, 16.01±0.2°, 16.87±0.2°, 17.49±0.2°, 18.87±0.2°, 19.69±0.2°, 20.12±0.2°, 20.72±0.2°, 20.96±0.2°, 25.31±0.2°, 27.89±0.2°, 34.15±0.2°.

5. The phosphate according to claim 1, wherein, The salt is phosphate crystal form A, characterized in that phosphate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 1-1; or The salt is phosphate crystal form B, characterized in that phosphate crystal form B has an X-ray powder diffraction pattern substantially as shown in Figures 1-2; or The salt is phosphate crystal form C, characterized in that the phosphate crystal form C has an X-ray powder diffraction pattern substantially as shown in Figures 1-3.

6. The phosphate according to claim 1, wherein, The salt is phosphate crystal form A, characterized in that the molar ratio of the compound represented by formula (I) to phosphoric acid in phosphate crystal form A is 1:(0.33-3); preferably, the molar ratio of the compound represented by formula (I) to phosphoric acid is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; more preferably, the molar ratio of the compound represented by formula (I) to phosphoric acid is 1:1; or The salt is phosphate crystal form B, characterized in that the molar ratio of the compound represented by formula (I) to phosphoric acid in phosphate crystal form B is 1:(0.33-3); preferably, the molar ratio of the compound represented by formula (I) to phosphoric acid is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; more preferably, the molar ratio of the compound represented by formula (I) to phosphoric acid is 1:1; or The salt is phosphate crystal form C, characterized in that the molar ratio of the compound shown in formula (I) to phosphoric acid in phosphate crystal form C is 1:(0.33~3); preferably, the molar ratio of the compound shown in formula (I) to phosphoric acid is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; more preferably, the molar ratio of the compound shown in formula (I) to phosphoric acid is 1:

1.

7. The phosphate according to claim 1, wherein, The salt is phosphate crystal form A, characterized in that phosphate crystal form A has a weight loss of 3.4±0.2% at 100℃; or the salt is phosphate crystal form B, characterized in that phosphate crystal form B has a weight loss of 2.0±0.2% at 100℃; or the salt is phosphate crystal form C, characterized in that phosphate crystal form C has a weight loss of 2.6±0.2% at 60℃ and a weight loss of 1.2±0.2% at 120℃.

8. The phosphate according to claim 1, wherein, The salt is a phosphate crystal form A, characterized in that the phosphate crystal form A has a TGA diagram substantially as shown in FIG2-1; or the salt is a phosphate crystal form B, characterized in that the phosphate crystal form B has a TGA diagram substantially as shown in FIG2-2; or the salt is a phosphate crystal form C, characterized in that the phosphate crystal form C has a TGA diagram substantially as shown in FIG2-3.

9. The phosphate according to claim 1, wherein, The salt is a phosphate crystal form A, characterized in that the phosphate crystal form A has a DSC diagram substantially as shown in FIG3-1; or the salt is a phosphate crystal form B, characterized in that the phosphate crystal form B has a DSC diagram substantially as shown in FIG3-2; or the salt is a phosphate crystal form C, characterized in that the phosphate crystal form C has a DSC diagram substantially as shown in FIG3-3.

10. The method for preparing the phosphate according to claim 1, comprising the following steps: adding (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine and an alcohol solvent or water to a reaction flask, heating, stirring to dissolve, adding an aqueous solution of phosphoric acid dropwise to the filtrate, cooling to allow crystallization after the addition is complete, stirring, filtering, and drying the filter cake by blowing air.

11. The method for preparing phosphate according to claim 10, characterized in that, The alcohol solvent is selected from one or a mixture of more than one of methanol, ethanol, isopropanol, ethylene glycol, isobutanol, n-butanol, and neopentyl alcohol.

12. The method for preparing phosphate according to claim 11, characterized in that, The alcohol solvent is selected from isopropanol, ethanol and water.

13. The method for preparing phosphate according to any one of claims 10-12, characterized in that, The solvent volume for dissolving (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine is 5.0–30.0 v / w, where v = volume of solvent used in ml and w = mass of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine in g; the solvent volume for dissolving phosphoric acid is 0–5 v / w, where v = volume of solvent used in ml and w = mass of phosphoric acid in g.

14. The method for preparing phosphate according to any one of claims 10-13, characterized in that, Heat to 20-100℃.

15. The method for preparing phosphate according to any one of claims 10-14, characterized in that, The temperature is lowered to 0–40℃, preferably 20±5℃.

16. The method for preparing phosphate according to any one of claims 10-15, characterized in that, The filter cake is dried at a temperature of 40–80°C, preferably 60±10°C.

17. The method for preparing phosphate according to any one of claims 10-16, characterized in that, The amount of phosphoric acid used is 1.0 to 3.0 molar equivalents of (S)-1-((2-(difluoromethyl)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine, preferably 1.5 to 2.5 molar equivalents, and more preferably 1.7 molar equivalents.

18. A pharmaceutical composition, characterized in that, It comprises the phosphate as described in any one of claims 1 to 9 and pharmaceutically acceptable excipients thereof.

19. Use of the phosphate of claim 1 in the preparation of a medicament for treating diseases or conditions mediated by connectin-associated kinase 1 activity, wherein the diseases or conditions are preferably Alzheimer's disease, bipolar disorder, pain, Parkinson's disease, or schizophrenia, and wherein the pain is preferably peripheral neuropathic pain, more preferably diabetic peripheral neuropathy or postherpetic neuralgia.

Images