WO2020052648A1 - Heteroaryl[4,3-c]pyrimidine-5-amine derivative crystalline forms, and preparation method therefor - Google Patents

Abstract

Crystalline forms of a heteroaryl[4,3-c]pyrimidine-5-amine compound as shown in formula (I), and a preparation method therefor, the crystalline forms specifically being crystalline forms A, B, C, D, E, F, G, H, J, K, L, M, N, O and P. The crystalline forms have good crystalline form stability, and are better for clinical use.

Description

Crystal form of heteroaryl [4,3-c] pyrimidine-5-amine derivatives and preparation method thereof

This application claims priority from Chinese patent application CN201811071438.3 with a filing date of September 14, 2018. This application cites the full text of the aforementioned Chinese patent application.

Technical field

The invention belongs to the field of medicinal chemistry and relates to 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4 ] A, B, C, D, E, F, G, H, J, K, L, M, N, O, P crystalline forms of triazolo [4,3-c] pyrimidin-5-amine and preparation thereof method.

Background technique

Adenosine is a naturally occurring purine nucleoside and is an endogenous regulator of many physiological functions. It plays an important role in the regulation of the functions of the cardiovascular system, central nervous system, respiratory system, kidneys, fats and platelets.

The role of adenosine is mediated by the G protein-coupled receptor family. At least four subtypes of adenosine receptors are currently known, classified as A1, A2a, A2b, and A3. Among them, A1 and A3 receptors inhibit the activity of the enzyme adenylate cyclase, and A2a and A2b receptors stimulate the activity of the enzyme, thereby regulating the level of cyclic AMP in cells. Through these receptors, adenosine regulates a wide range of physiological functions.

A2a receptor (A2aR) is widely distributed in the body, mainly expressed in the striatum in the central nervous system, and also expressed in peripheral, heart, liver, lung, kidney and other tissues. Several preclinical studies have shown that adenosine A2a receptor antagonists have amazing effects on the treatment of neurodegenerative diseases, mainly Parkinson's disease, Huntington's disease or Alzheimer's disease (Trends in Neurosci. 2006, 29 (11), 647 -654; Expert Opinion on Therapeutic Patents, 2007, 17, 979-991, etc.). It can also be used to treat other central nervous system (CNS) related diseases such as depression, hyperactivity syndrome, sleep disorders and anxiety (Clin. Neuropharmacol. 2010, 33, 55-60; J. Neurosci. 2010, 30 ( 48), 16284-16292; Parkinsonisn Relat. Disord. 2010, 16 (6), 423-426; and references in it: Mov. Disorders, 2010, 25 (2), S305). In addition, adenosine A2a receptor antagonists also have therapeutic potential as neuroprotective agents (see Jenner P. J. Neurol 2000. 24; 7Supp 12: 1143-50).

Recent studies have shown that activation of adenosine A2a receptors can play an important role in immunological regulation during ischemic hypoxia, inflammation, trauma, transplantation and many other pathological processes, which may be related to A2a receptors in T cells, B cells, and single cells. Nuclear macrophages, neutrophils and other immune cells have higher expression levels. In addition, the activation of A2a receptors can promote the body's immune tolerance, and is closely involved in the formation of tumor cells' "escape" or "immunosuppression", creating favorable conditions for the development of tumors. Lokshin and colleagues (Cancer Res. 2006 Aug1; 66 (15): 7758-65) confirmed that activation of A2a receptors on natural killer cells can increase cAMP and activate PKA to inhibit the killing of tumor cells by natural killer cells. Other studies have shown that the activation of A2a receptors can promote the proliferation of tumor cells such as melanoma A375 cells, fibroblasts NIH3T3 cells, and pheochromocytoma PC12 cells, which may be related to the activation of A2a receptors on T cells to inhibit T Cell activation and proliferation are related to tumor cell adhesion and cytotoxic effects on tumor cells; mice with A2a receptor gene knockout can enhance the anti-tumor immune effect of CD8 + T cells and significantly inhibit tumor proliferation. Therefore, A2a receptor antagonists can also be used in the treatment of tumors.

Although compounds that have significant biological activity on a variety of adenosine receptor subtypes can have therapeutic effects, they can cause unwanted side effects. For example, when adenosine A1 receptor is in tissue ischemia / hypoxia, in the central, circulatory, digestive system, and skeletal muscle, when cells are in a hypoxic and hypoxic stress environment, extracellularly aggregated adenosine activates the cell through The A1 receptor on the membrane activates the corresponding protective mechanism, thereby increasing the tolerance of cells to hypoxia and hypoxia. The A1 receptor on immune cells can promote cellular immune response in a hypoxic environment. In addition, the A1 receptor can reduce free fatty acids and triglycerides and participate in regulating blood sugar. Therefore, the continued blockade of the A1 receptor may cause various adverse reactions in the body tissue (Chinese Pharmacological Bulletin, 2008, 24 (5), 573-576). If reported in the literature, in animal models, blocking A1 receptors will produce adverse reactions such as anxiety and awakening (Basic & Clinical & Pharmaceutical & ToLcology, 2011, 109 (3), 203-7). Adenosine receptor A3 (as described by Gessi et al., Pharmacol. Ther. 117 (1), 2008, 123-140) adenosine released during myocardial ischemia plays a strong protective role in the heart, A3 receptor Continuous blockade may increase the likelihood of complications caused by any pre-existing or developing ischemic heart disease, such as angina pectoris or heart failure.

Many compounds have been developed as A _2a receptor antagonists for the treatment of many diseases, as described in WO2007116106, WO2009080197, WO2011159302, WO2011095625, WO2014101373, WO2015031221.

An application with the application number PCT / CN2018 / 079086 (filing date March 15, 2018) provides an adenosine A _2a receptor antagonist, the structure of which is shown below:

The entire contents of that application are incorporated herein.

The crystalline form as a medicinal active ingredient often affects the chemical stability of the drug. Differences in crystallization conditions and storage conditions may cause changes in the crystalline structure of the compound, sometimes accompanied by the generation of other forms. In general, amorphous pharmaceutical products do not have a regular crystalline structure and often have other defects, such as poor product stability, fine crystallisation, difficult filtration, easy agglomeration, and poor fluidity. Polymorphic forms of drugs have different requirements for product storage, production, and scale-up. Therefore, it is necessary to deeply study the crystal form of the compound of the formula I and improve various aspects of the properties of the compound of the formula I.

Summary of the Invention

The invention provides the A-form, B-form, C-form, D-form, E-form, F-form, G-form, H-form, J-form, K-form, L-form of the compound of formula I. , M crystal form, N crystal form, O crystal form, P crystal form and preparation method thereof, the crystal form of the present invention has good crystal form stability.

The present invention provides a form A of a compound of formula I, which is characterized in that the X-ray powder diffraction pattern of the form A has characteristic peaks at diffraction angles 2θ of 4.985, 10.167, 15.393, 26.651, and 27.364.

Further, the X-ray powder diffraction pattern of the Form A has characteristic peaks at diffraction angles 2θ of 4.985, 10.167, 15.393, 26.651, 27.364, 30.581, and 31.154.

Furthermore, the X-ray powder diffraction pattern of the crystal form A has a diffraction angle 2θ of 4.985, 10.167, 10.698, 12.693, 13.528, 15.393, 16.605, 20.170, 20.580, 21.382, 22.678, 23.612, 24.048, 24.704, There are characteristic peaks at 25.227, 25.880, 26.651, 27.364, 30.559, 30.581, 31.154, and 32.527.

The present invention provides a Form B of a compound of Formula I, which is characterized in that the X-ray powder diffraction pattern of Form B has a diffraction angle 2θ of 7.953, 11.138, 13.618, 16.256, 17.985, 18.949, 20.588, 21.924, 22.853 There are characteristic peaks everywhere.

Further, the X-ray powder diffraction pattern of the Form B has characteristic peaks at diffraction angles 2θ of 7.953, 11.138, 11.976, 13.618, 16.256, 17.985, 18.949, 20.207, 20.588, 21.924, 22.853, and 24.285.

Furthermore, the X-ray powder diffraction pattern of the B crystal form has a diffraction angle 2θ of 7.953, 9.549, 11.138, 11.976, 13.618, 16.256, 17.985, 18.949, 20.207, 20.588, 21.924, 22.853, 24.285, 25.227, There are characteristic peaks at 27.587, 28.628, 30.525, 32.645, and 34.100.

The present invention provides a crystal form C of a compound of formula I, characterized in that the X-ray powder diffraction pattern of the crystal form C has a diffraction angle 2θ of 12.285, 12.836, 14.372, 14.755, 17.813, 18.557, 20.665, 21.668, 23.153 There are characteristic peaks everywhere.

Further, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2θ of 12.285, 12.836, 14.372, 14.755, 17.813, 18.557, 19.463, 20.665, 21.668, 23.153, 24.996, 27.028, 28.824. .

Further, the X-ray powder diffraction pattern of the crystal form C has a diffraction angle 2θ of 6.386, 6.437, 7.901, 9.405, 10.112, 12.285, 12.836, 14.372, 14.755, 15.810, 16.309, 17.355, 17.813, 18.557, There are characteristic peaks at 19.463, 20.665, 21.668, 23.153, 23.645, 24.996, 27.028, 27.722, 28.824, 30.557, 31.233, 32.127.

The present invention provides a D-form of a compound of formula I, which is characterized in that the X-ray powder diffraction pattern of the D-form has a characteristic peak at a diffraction angle 2θ of 6.084, 7.308, 12.665, 15.285, 16.459, 20.481, 25.514. .

Further, the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at diffraction angles 2θ of 6.084, 7.308, 10.195, 12.665, 15.285, 16.354, 16.459, 18.266, 20.481, 21.083, 21.800, 22.699, 25.514. .

Furthermore, the X-ray powder diffraction pattern of the D crystal form has a diffraction angle 2θ of 6.084, 7.308, 10.195, 12.665, 15.285, 16.354, 16.459, 18.266, 19.607, 20.481, 21.083, 21.800, 22.699, 24.387, There are characteristic peaks at 25.514, 26.160, 27.327, 28.471, 29.227, 30.202, and 31.219.

The invention provides a crystal form E of a compound of formula I, which is characterized in that the X-ray powder diffraction pattern of the crystal form E has characteristic peaks at a diffraction angle 2θ of 7.054, 11.059, 11.521, 14.993, 22.653, 22.994, 24.548. .

Further, the X-ray powder diffraction pattern of the E form has a diffraction angle 2θ of 7.054, 8.944, 11.059, 11.521, 13.813, 14.993, 16.313, 17.852, 19.208, 19.811, 21.265, 22.653, 22.994, 24.548. Characteristic peaks.

Further, the X-ray powder diffraction pattern of the E form, at a diffraction angle 2θ of 7.054, 7.244, 8.944, 11.059, 11.521, 13.813, 14.993, 16.313, 17.852, 19.208, 19.811, 21.265, 22.653, 22.994, There are characteristic peaks at 23.921, 24.548, 25.382, 25.878, 26.521, 29.300, 30.832, and 32.474.

The invention provides an F-form of a compound of formula I, characterized in that the X-ray powder diffraction pattern of the F-form has a diffraction angle 2θ of 6.822, 8.156, 8.903, 10.334, 14.521, 16.270, 20.985, 24.239, 25.044 There are characteristic peaks everywhere.

Further, the X-ray powder diffraction pattern of the F crystal form has a diffraction angle 2θ of 6.822, 8.156, 8.903, 10.334, 11.266, 12.306, 12.959, 14.521, 15.044, 16.270, 18.314, 20.985, 23.526, 24.239, 25.044 There are characteristic peaks at 25.615, 29.804.

Furthermore, the X-ray powder diffraction pattern of the F crystal form has a diffraction angle 2θ of 6.822, 8.156, 8.903, 10.334, 11.266, 12.306, 12.959, 14.521, 15.044, 16.270, 18.314, 19.501, 20.985, 21.684, There are characteristic peaks at 22.176, 22.889, 23.526, 24.239, 25.044, 25.615, 26.686, 27.536, 28.383, 29.804, 31.013.

The present invention provides a crystal form G of a compound of formula I, which is characterized in that the X-ray powder diffraction pattern of crystal form G has characteristic peaks at diffraction angles 2θ of 6.706, 7.865, and 16.373.

Further, the X-ray powder diffraction pattern of the G crystal form has characteristic peaks at diffraction angles 2θ of 6.706, 7.865, 16.373, 21.764, 23.986, 25.692, 27.524, 32.236.

Further, the X-ray powder diffraction pattern of the G crystal form has characteristic peaks at diffraction angles 2θ of 6.304, 6.706, 7.865, 11.064, 12.286, 16.373, 18.840, 21.764, 23.986, 25.692, 27.524, 32.236.

The present invention provides an H crystal form of a compound of formula I, characterized in that the X-ray powder diffraction pattern of the H crystal form has a diffraction angle 2θ of 5.938, 6.514, 8.860, 11.414, 18.259, 19.298, 21.426, 23.438, 25.296 There are characteristic peaks everywhere.

Further, the X-ray powder diffraction pattern of the H crystal form has characteristic peaks at diffraction angles 2θ of 5.938, 6.514, 8.860, 11.414, 13.931, 17.582, 18.259, 19.298, 21.426, 22.612, 23.438, 25.296.

Furthermore, the X-ray powder diffraction pattern of the H crystal form has a diffraction angle 2θ of 4.695, 5.938, 6.514, 8.860, 11.414, 13.931, 14.565, 15.555, 16.703, 17.582, 18.259, 19.298, 21.426, 22.612, There are characteristic peaks at 23.438, 24.418, 25.296, 27.101, 28.338, 29.103, 30.645, 31.480, and 33.604.

The present invention provides a J-form of a compound of formula I, which is characterized in that the X-ray powder diffraction pattern of the J-form has a diffraction angle 2θ of 6.938, 11.345, 15.342, 16.132, 16.716, 18.589, 19.726, 20.878, 21.233 There are characteristic peaks at 23.948, 26.167 and 28.431.

Further, the X-ray powder diffraction pattern of the J form has a diffraction angle 2θ of 6.938, 10.293, 10.620, 11.345, 15.342, 16.132, 16.716, 17.922, 18.589, 19.726, 20.878, 21.233, 23.626, 23.948, 25.108 There are characteristic peaks at 26.167, 27.448, 28.004, 28.431, 28.737, and 32.933.

Furthermore, the X-ray powder diffraction pattern of the J form has a diffraction angle 2θ of 6.938, 10.293, 10.620, 11.345, 15.342, 16.132, 16.716, 17.922, 18.589, 19.726, 20.878, 21.233, 22.090, 22.933, There are characteristic peaks at 23.626, 23.948, 25.108, 26.167, 27.448, 28.004, 28.431, 28.737, 29.779, 31.136, 31.880, 32.933, 34.164, 36.879, 38.004.

The present invention provides a K form of a compound of formula I, which is characterized in that the X-ray powder diffraction pattern of the K form has a diffraction angle 2θ of 6.803, 10.699, 11.277, 16.478, 18.414, 21.039, 23.619, 28.333 Characteristic peaks.

Further, the X-ray powder diffraction pattern of the K form has characteristic peaks at diffraction angles 2θ of 6.803, 10.315, 10.699, 11.277, 12.346, 16.478, 18.414, 19.520, 21.039, 23.619, 25.718, 27.752, 28.333. .

Furthermore, the X-ray powder diffraction pattern of the K-type crystal has a diffraction angle 2θ of 6.803, 10.315, 10.699, 11.277, 12.346, 12.867, 16.478, 18.414, 19.520, 21.039, 21.813, 22.860, 23.619, 25.075, There are characteristic peaks at 25.718, 27.193, 27.752, 28.333, 32.384, 33.853.

The present invention provides an L crystal form of a compound of Formula I, which is characterized in that the X-ray powder diffraction pattern of the L crystal form has a diffraction angle 2θ of 6.805, 11.278, 16.518, 18.364, 19.550, 20.620, 21.261, 23.604, 28.262 There are characteristic peaks everywhere.

Further, the X-ray powder diffraction pattern of the L crystal form has a diffraction angle 2θ of 6.805, 10.158, 10.682, 11.278, 16.040, 16.518, 18.364, 19.550, 20.620, 21.261, 21.725, 23.604, 25.761, 27.805, 28.262 There are characteristic peaks at 28.396, 32.388.

Furthermore, the X-ray powder diffraction pattern of the L crystal form has a diffraction angle 2θ of 6.805, 10.158, 10.682, 11.278, 15.195, 16.040, 16.518, 18.364, 19.550, 20.620, 21.261, 21.725, 22.537, 23.604, There are characteristic peaks at 24.573, 25.761, 27.057, 27.805, 28.262, 28.396, 30.822, 32.388, 33.835, 36.218, 37.261.

The present invention provides a crystal form M of a compound of formula I, characterized in that the X-ray powder diffraction pattern of crystal form M has a diffraction angle 2θ of 8.419, 9.906, 16.265, 17.061, 17.785, 19.525, 19.798, 22.686, 25.456 There are characteristic peaks at 26.512.

Further, the X-ray powder diffraction pattern of the M crystal form has a diffraction angle 2θ of 8.419, 9.906, 10.344, 13.686, 14.097, 14.968, 16.265, 17.061, 17.785, 19.525, 19.798, 21.236, 21.979, 22.686, 25.078 There are characteristic peaks at 25.456, 26.030, 26.512, 27.759, 29.273, and 30.360.

Further, the X-ray powder diffraction pattern of the M crystal form has a diffraction angle 2θ of 7.757, 8.419, 9.906, 10.344, 12.359, 13.686, 14.097, 14.968, 16.265, 17.061, 17.785, 19.525, 19.798, 21.236, There are characteristic peaks at 21.979, 22.686, 23.743, 25.078, 25.456, 26.030, 26.512, 26.948, 27.759, 28.561, 29.273, 29.942, 30.360, 31.845, 33.805, 35.071, 35.595, 37.904, 45.322.

The present invention provides an N crystal form of a compound of formula I, characterized in that the X-ray powder diffraction pattern of the N crystal form has characteristic peaks at diffraction angles 2θ of 6.587, 9.559, 13.320, 17.312, 18.158, 22.641, 23.080. .

Further, the X-ray powder diffraction pattern of the N crystal form has a diffraction angle 2θ of 6.587, 7.640, 9.559, 11.023, 12.134, 13.320, 17.312, 18.158, 20.615, 21.491, 21.747, 22.641, 23.080, 24.143, 25.075 There are characteristic peaks everywhere.

Furthermore, the X-ray powder diffraction pattern of the N crystal form has a diffraction angle 2θ of 6.587, 7.640, 9.559, 11.023, 12.134, 13.320, 16.862, 17.312, 18.158, 21.491, 21.747, 22.641, 23.080, 24.143, There are characteristic peaks at 25.075, 26.498, 27.046, 27.848, 29.291, 31.331.

The present invention provides an O crystal form of a compound of formula I, which is characterized in that the X-ray powder diffraction pattern of the O crystal form has a diffraction angle 2θ of 7.885, 12.357, 17.921, 18.927, 20.484, 20.600, 24.062, 24.101. Characteristic peaks.

Further, the X-ray powder diffraction pattern of the O crystal form has characteristic peaks at diffraction angles 2θ of 7.885, 12.357, 17.921, 18.927, 20.484, 20.600, 21.781, 22.904, 24.062, and 24.101.

Furthermore, the X-ray powder diffraction pattern of the O crystal form has a diffraction angle 2θ of 7.261, 7.885, 9.411, 11.113, 12.357, 13.632, 14.386, 17.108, 17.921, 18.927, 20.484, 20.600, 21.781, 22.904, There are characteristic peaks at 24.062, 24.101, and 28.940.

The invention provides a P crystal form of a compound of formula I, which is characterized in that the X-ray powder diffraction pattern of the P crystal form has a diffraction angle 2θ of 6.780, 10.661, 11.005, 13.537, 18.267, 20.851, 21.075, 21.835, 22.561 There are characteristic peaks everywhere.

Further, the X-ray powder diffraction pattern of the P crystal form has characteristic peaks at diffraction angles 2θ of 6.780, 10.661, 11.005, 13.537, 18.267, 19.461, 20.851, 21.075, 21.835, 22.561, 24.714, 26.661.

Furthermore, the X-ray powder diffraction pattern of the P crystal form has a diffraction angle 2θ of 6.780, 10.661, 11.005, 11.939, 13.537, 15.077, 16.456, 18.267, 19.158, 19.461, 20.851, 21.075, 21.835, 22.561, There are characteristic peaks at 23.195, 24.119, 24.714, 25.726, 26.661, 27.337, 27.960, 28.372, 30.430, 32.498, 33.749, 36.142.

The invention also relates to Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L The preparation method of the M form, the M form, the N form, the O form, and the P form includes: taking a certain amount of a compound of formula I, adding an appropriate amount of a solvent, crystallizing, filtering, and drying to obtain a form A of the compound of formula I Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L, Form M, Form N, Form O Crystal or P crystal.

Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L, Form M Type, N-type, O-type, P-type crystalline solvents selected from hydrocarbon solvents, ether solvents, alcohol solvents, ester solvents, ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents One or more of solvents, water and dimethyl sulfoxide. The hydrocarbon solvents include, but are not limited to, cyclohexane, n-heptane, and para-xylene; the ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, or 1 , 4-dioxane; the alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol; the ester solvents include, but are not limited to, ethyl acetate, Isopropyl acetate or butyl acetate; the ketone solvents include, but are not limited to, acetone, acetophenone, and 4-methyl-2-pentanone; the nitrile solvents include, but are not limited to, acetonitrile and propionitrile; Halogenated hydrocarbon solvents include, but are not limited to, methyl chloride, dichloromethane, 1,2-dichloroethane, chloroform, or carbon tetrachloride; the nitrogen-containing solvents include, but are not limited to, nitromethane, N, N-dichloromethane Methylformamide, N, N-dimethylacetamide.

Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L, Form M The crystallization method of the N-type, N-type, O-type, and P-type crystals is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or adding seed crystals to induce crystallization.

The present invention also relates to a method for preparing a form A of a compound of formula I, which comprises: taking a certain amount of a compound of formula I, adding an appropriate amount of a solvent, crystallizing, filtering, and drying to obtain the form A of a compound of formula I. The solvent is selected from one or more of acetone, dichloromethane, methanol, and water. The A-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or adding seed crystals to induce crystallization.

The invention also relates to a method for preparing a form A of a compound of formula I, which comprises: taking a certain amount of a compound of formula I, dissolving it by adding an appropriate amount of acetone, and crystallizing by evaporation of a solvent at room temperature to obtain a form A. The invention also relates to a method for preparing a form A of a compound of formula I, which comprises: taking a certain amount of a compound of formula I, adding an appropriate amount of a mixed solvent of dichloromethane and methanol, the solid is not completely dissolved, and concentrated under reduced pressure to obtain a form A. The invention also relates to a method for preparing a form A of a compound of the formula I, which comprises: taking a certain amount of the form B of a compound of the formula I, crystallizing in water to obtain the form A.

The invention also relates to a method for preparing the B-form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the B-form of the compound of the formula I. The solvent is selected from one or more of acetone, dichloromethane, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane, n-propanol, and water. The B-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.

The invention also relates to a method for preparing the B-form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of a mixed solvent of dichloromethane and methanol, completely dissolving the solid, and concentrating under reduced pressure to obtain the B-form. The invention also relates to a preparation method of the B-form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of isopropanol, tetrahydrofuran, dichloromethane or 1,2-dichloroethane, raising and lowering the temperature and room temperature Crystallize with stirring to obtain Form B. The invention also relates to a method for preparing the B crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of dichloromethane, 1,2-dichloroethane or n-propanol, and crystallizing by slurrying at room temperature to obtain B crystal form. The invention also relates to a method for preparing the B-form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of acetone or acetone / water solubilization, and crystallizing by volatile solvents at room temperature to obtain the B-form. The invention also relates to a method for preparing Form B of a compound of Formula I, which comprises: taking a certain amount of Form B of a compound of Formula I and adding an appropriate amount of tetrahydrofuran, isopropanol, 1,4-dioxane, dichloromethane or acetone , Crystallize by slurrying at room temperature to obtain Form B.

The invention also relates to a method for preparing the crystal form C of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the crystal form C of the compound of the formula I. The solvent is selected from acetonitrile, acetone, dichloromethane, methanol, ethyl acetate, ethanol, isopropanol, isopropyl ether, 4-methyl-2-pentanone, methyl tert-butyl ether, dimethylene One or more of sulfone, isoamyl alcohol, n-heptane, butyl acetate, cyclohexane, water. The C-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.

The invention also relates to a method for preparing the crystal form C of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I and adding an appropriate amount of acetonitrile, ethyl acetate, ethanol, water, methyl tert-butyl ether, isoamyl alcohol, ethyl acetate Ester / n-heptane, methanol / water or cyclohexane, the temperature was raised and lowered, and the crystals were stirred at room temperature to obtain the C-form. The invention also relates to a method for preparing the crystal form C of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of methylene chloride / methanol, dimethyl sulfoxide or water / methanol, stirring and dissolving, and volatilizing the solvent at room temperature. Crystallize to obtain Form C. The invention also relates to a method for preparing the crystal form C of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of ethanol, methanol or isopropanol, raising and lowering the temperature, adding water to continue stirring, and lowering the temperature to room temperature, stirring and crystallizing to obtain C crystal form. The invention also relates to a method for preparing the C crystal form of the compound of formula I, which comprises: taking a certain amount of the compound of formula I, adding an appropriate amount of ethyl acetate, raising and lowering the temperature, adding n-heptane to continue stirring, and lowering the temperature to room temperature to stir and crystallize to obtain C Crystal form. The invention also relates to a method for preparing the crystal form C of the compound of formula I, which comprises: taking a certain amount of the compound of formula I and adding an appropriate amount of water, isopropanol, methyl tert-butyl ether, acetonitrile, isoamyl alcohol, ethyl acetate / N-heptane, 4-methyl-2-pentanone, butyl acetate or cyclohexane were crystallized by slurrying at room temperature to obtain Form C. The invention also relates to a method for preparing the crystal form C of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of ethyl acetate, slowly dissolving at room temperature, and crystallizing by evaporation of the solvent at room temperature to obtain the crystal form C. The present invention also relates to a method for preparing Form C of a compound of Formula I, which comprises: taking a certain amount of Form B of a compound of Formula I, adding an appropriate amount of isopropyl ether, ethyl acetate, ethanol, 4-methyl-2-pentanone, Acetonitrile or water was crystallized by beating at room temperature to obtain Form C. The invention also relates to a method for preparing the crystal form C of the compound of the formula I, which comprises: taking a certain amount of the compound G of the formula I and mixing the crystals, adding an appropriate amount of ethanol / water or butyl acetate, and crystallizing by crystallizing at room temperature to obtain the crystal form C.

The invention also relates to a method for preparing the D-form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the D-form of the compound of the formula I. The solvent is isopropyl acetate. The D-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.

The invention also relates to a method for preparing the D crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of isopropyl acetate, and slurping and crystallizing at room temperature to obtain the D crystal form. The invention also relates to a method for preparing a D-form of a compound of formula I, which comprises: taking a certain amount of a compound of formula I, adding an appropriate amount of isopropyl acetate, raising and lowering the temperature, and stirring and crystallizing at room temperature to obtain the D-form.

The invention also relates to a method for preparing the E-form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the E-form of the compound of the formula I. The solvent is selected from acetonitrile and nitromethane. The E-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or adding seed crystals to induce crystallization.

The invention also relates to a method for preparing an E crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of acetonitrile or nitromethane, and slurping and crystallizing at room temperature to obtain the E crystal form. The present invention also relates to a method for preparing the E crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of nitromethane, raising and lowering the temperature, and stirring and crystallizing at room temperature to obtain the E crystal form.

The invention also relates to a method for preparing the F-form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the F-form of the compound of the formula I. The solvent is 4-methyl-2-pentanone. The F-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.

The invention also relates to a method for preparing the F crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of 4-methyl-2-pentanone, and crystallizing at room temperature to obtain the F crystal form.

The invention also relates to a method for preparing the G crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the G crystal form of the compound of the formula I. The solvent is isopropanol. The G-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.

The invention also relates to a method for preparing the G crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of isopropyl alcohol, heating up to dissolution, adding a certain amount of the crystal form C, stirring the insoluble solution, and reducing it to Crystallize by stirring at room temperature to obtain G crystal form.

The invention also relates to a method for preparing the H crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering and drying to obtain the H crystal form of the compound of the formula I. The solvent is selected from one or more of 2-butanone, ethanol, propylene glycol methyl ether, water, ethyl acetate, acetonitrile, methanol, N, N-dimethylformamide. The H-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.

The invention also relates to a method for preparing the H crystal form of the compound of formula I, which comprises: taking a certain amount of the compound of formula I and adding an appropriate amount of 2-butanone, ethanol, propylene glycol methyl ether, water / ethanol, ethyl acetate / ethanol or N, N-dimethylformamide was dissolved and the solvent was crystallized from the volatile solvent at room temperature to obtain the H crystal form. The invention also relates to a method for preparing the H crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of ethanol, raising and lowering the temperature, and stirring and crystallizing at room temperature to obtain the H crystal form.

The invention also relates to a method for preparing the J crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering and drying to obtain the J crystal form of the compound of the formula I. The solvent is para-xylene. The J-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.

The invention also relates to a method for preparing the J crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of p-xylene, and slurping and crystallizing at room temperature to obtain the J crystal form. The invention also relates to a method for preparing the J crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of p-xylene, raising and lowering the temperature, and stirring and crystallizing at room temperature to obtain the J crystal form.

The invention also relates to a method for preparing the K crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the K crystal form of the compound of the formula I. The solvent is n-heptane. The K-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.

The invention also relates to a method for preparing the K crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of n-heptane, and slurping and crystallizing at room temperature to obtain the K crystal form. The invention also relates to a method for preparing a K-form of a compound of formula I, which comprises: taking a certain amount of a compound of formula I, adding an appropriate amount of n-heptane, raising and lowering the temperature, and stirring and crystallizing at room temperature to obtain a K-form.

The invention also relates to a method for preparing the L crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the L crystal form of the compound of the formula I. The solvent is selected from the group consisting of 1,4-dioxane and tetrahydrofuran. The L-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.

The invention also relates to a method for preparing the L crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of 1,4-dioxane or tetrahydrofuran, and crystallizing at room temperature to obtain the L crystal form. The invention also relates to a method for preparing the L crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of 1,4-dioxane or tetrahydrofuran, raising and lowering the temperature, and stirring and crystallizing at room temperature to obtain the L crystal form . The invention also relates to a method for preparing the L crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, dissolving it by adding an appropriate amount of tetrahydrofuran, and crystallizing by evaporation of the solvent at room temperature to obtain the L crystal form.

The invention also relates to a method for preparing the M crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the M crystal form of the compound of the formula I. The solvent is methanol. The M-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or seed crystal induction.

The invention also relates to a method for preparing the M crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, dissolving it by adding an appropriate amount of methanol, and crystallizing by evaporation of the solvent at room temperature to obtain the M crystal form.

The invention also relates to a method for preparing the N crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the N crystal form of the compound of the formula I. The solvent is nitromethane. The N-type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or seeding to induce crystallization.

The invention also relates to a method for preparing the N crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of nitromethane, and slurping and crystallizing at room temperature to obtain the N crystal form.

The invention also relates to a method for preparing the O crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the O crystal form of the compound of the formula I. The solvent is selected from the group consisting of isopropanol, n-propanol, and acetone. The O crystal type crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or adding seed crystals to induce crystallization.

The invention also relates to a method for preparing the O crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of isopropyl alcohol, dissolving it at room temperature, filtering the solution, and crystallizing the filtrate by evaporation of the solvent at room temperature to obtain the O crystal form. The invention also relates to a method for preparing an O crystal form of a compound of formula I, which comprises: taking a certain amount of a compound of formula I, dissolving it by adding an appropriate amount of n-propanol, and crystallizing by volatilizing a solvent at room temperature to obtain an O crystal form. The invention also relates to a method for preparing the O crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of acetone, raising and lowering the temperature to room temperature, filtering the solution, and crystallizing the solvent by evaporation of the solvent at room temperature to obtain the O crystal form. .

The invention also relates to a method for preparing the P crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of solvent, crystallizing, filtering, and drying to obtain the P crystal form of the compound of the formula I. The solvent is 4-methyl-2-pentanone. The P-type crystallizing method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals to induce crystallization.

The invention also relates to a method for preparing the P crystal form of the compound of the formula I, which comprises: taking a certain amount of the compound of the formula I, adding an appropriate amount of 4-methyl-2-pentanone, and crystallizing at room temperature to obtain the P crystal form.

The present invention also relates to a compound including Formula I, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L A pharmaceutical composition of Form M, Form M, Form N, Form O or Form P and optionally one or more pharmaceutically acceptable carriers and / or diluents. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, the present invention comprises a compound of Formula I, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, L-form, M-form, N-form, O-form or P-form pharmaceutical preparations can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections) Liquid, sterile powder for injection and concentrated solution for injection), suppositories, inhalants or sprays.

In addition, the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be made into an oral preparation, such as an oral solid preparation, such as tablets, capsules, pills, granules, etc .; or an oral liquid preparation, such as an oral solution, orally mixed Suspensions, syrups, etc. When formulated into an oral preparation, the pharmaceutical preparation may further contain a suitable filler, a binder, a disintegrant, a lubricant, and the like. When used for parenteral administration, the pharmaceutical preparations can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When prepared as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field. When an injection is formulated, an additional agent may not be added to the pharmaceutical preparation, or a suitable additional agent may be added according to the properties of the drug. When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparation can be made into an inhaler or a spray. In certain embodiments, the compound of Formula I of the present invention, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K Form, Form L, Form M, Form N, Form O, or Form P are present in a pharmaceutical composition or medicament in a therapeutically and / or prophylactically effective amount. In certain embodiments, the compound of Formula I according to the present invention, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, The K-form, L-form, M-form, N-form, O-form or P-form is present in a pharmaceutical composition or a medicament in the form of a unit dose.

The present invention further relates to a method for preparing a pharmaceutical composition, comprising making a compound of Formula I selected from the group consisting of Form A, Form B, Form C, Form D, Form E, Form F, and Form G of the compound of the present invention. Form H, Form J, Form K, Form L, Form M, Form N, Form O, or Form P and at least one pharmaceutically acceptable form A carrier, diluent or excipient is mixed.

The present invention further relates to the compound of Formula I Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L The use of crystalline, M, N, O, or P form in the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the A2a receptor. The present invention further relates to the compound of Formula I Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L Form, Form M, Form N, Form O, Form P, or a pharmaceutical composition comprising the aforementioned forms in the preparation of a treatment selected from the group consisting of tumors, depression, cognitive disorders, neurodegenerative disorders, attention-related Application of medicines for diseases such as disorders, extrapyramid syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behavior. The tumor described in the present invention is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma , Sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder Cancer, gallbladder cancer, bile duct cancer, chorionic epithelial cancer, and pediatric tumors; lung cancer is preferred. The neurodegenerative disorders described in the present invention are selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzberg Second's disease, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, spinal muscular atrophy.

Detailed description of the invention

In the specification and claims of this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, in order to better understand the present invention, the definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided in this application are not consistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in this application shall prevail.

The “ether solvent” in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, tetrahydrofuran, ether, and propylene glycol methyl ether , Methyl tert-butyl ether, isopropyl ether, or 1,4-dioxane.

The "alcoholic solvent" in the present invention refers to a group derived by replacing one or more hydrogen atoms on a "C1-6 alkyl" with one or more "hydroxy", and the "hydroxy" and "C1- "6alkyl" is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.

The “ester solvent” in the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms. Specific examples include, but are not limited to, acetic acid Ethyl, isopropyl or butyl acetate.

The "ketone solvent" in the present invention refers to a compound in which a carbonyl group (-C (O)-) is connected to two hydrocarbon groups, and ketones can be classified into fatty ketones, alicyclic ketones, aromatic ketones, Specific examples of saturated ketones and unsaturated ketones include, but are not limited to, acetone, acetophenone, and 4-methyl-2-pentanone.

The "nitrile solvent" in the present invention refers to a group derived from the substitution of one or more "cyano" groups with one or more hydrogen atoms on a "C1-6 alkyl group". The "cyano group" and " "C1-6 alkyl" is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.

The “halogenated hydrocarbon solvent” in the present invention refers to a group derived by replacing one or more hydrogen atoms on the “C1-6 alkyl” with one or more “halogen atoms”, and the “halogen atom” And "C1-6 alkyl" are as defined above, and specific examples include, but are not limited to, methyl chloride, methylene chloride, chloroform, or carbon tetrachloride.

The "X-ray powder diffraction pattern or XRPD" in the present invention is obtained by Cu-Kα ray diffraction.

The “differential scanning calorimetry or DSC” in the present invention refers to measuring the temperature difference and heat flow difference between the sample and the reference during the temperature rising or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. Change to get the phase transition information of the sample.

The “2θ or 2θ angle” in the present invention refers to a diffraction angle, θ is a Bragg angle, and the unit is ° or degree. The error range of the 2θ can be ± 0.3, ± 0.2, or ± 0.1.

The beneficial effects of the invention

8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo provided by the present invention [4,3-c] pyrimidin-5-amine (compound of formula I) Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, J-form, K-form, L-form, M-form, N-form, O-form and P-form have more advantages in solubility, stability and hygroscopicity, and are more suitable for drug development and bioavailability It can meet the medicinal requirements of production, transportation and storage. The production process is stable, repeatable and controllable, and it can be adapted to industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an XRPD pattern of a compound of the formula I in the form of Form A;

FIG. 2 is a DSC chart of a compound of formula I in the form of Form A;

Figure 3 is a TGA diagram of a compound of formula I in the form of Form A;

4 is a DVS hygroscopic spectrum of a compound of formula I in the form of A form;

5 is a comparison chart of XRPD before and after DVS detection of a compound of formula I in the form of Form A;

FIG. 6 is an XRPD pattern of the compound of formula I in the B-form;

FIG. 7 is a DSC chart of the compound of formula I in the form of the B-form; FIG.

FIG. 8 is a TGA diagram of a compound of formula I in the form of B crystal; FIG.

FIG. 9 is a DVS hygroscopic spectrum of a compound of formula I in the form of Form B; FIG.

FIG. 10 is a comparison chart of XRPD before and after DVS detection of the compound of formula I in the B-form;

FIG. 11 is an XRPD pattern of the compound of formula I in the form of C crystal form; FIG.

FIG. 12 is a DSC chart of a compound of formula I in the form of C crystal;

FIG. 13 is a TGA diagram of a compound of formula I in the form of C crystal form; FIG.

FIG. 14 is a DVS hygroscopic spectrum chart of the compound of the formula I in the form of C form; FIG.

15 is a comparison chart of XRPD before and after DVS detection of a compound of formula I in the form of C form;

16 is an ellipsoidal diagram of the X-single crystal diffraction molecular structure of the compound of the formula I in the form of the C form;

FIG. 17 is an XRPD pattern of the compound of the formula I in the D crystalline form; FIG.

FIG. 18 is a DSC chart of a compound of formula I in the D crystal form; FIG.

FIG. 19 is a TGA diagram of a compound of Formula I in the D crystalline form; FIG.

FIG. 20 is a DVS hygroscopic spectrum chart of a compound of formula I in the D crystal form; FIG.

FIG. 21 is a comparison chart of XRPD before and after DVS detection of the compound of formula I in the form of D form; FIG.

Figure 22 is an XRPD pattern of the compound of formula I in the form of the E form;

FIG. 23 is a DSC chart of a compound of formula I in the form of the E-form; FIG.

FIG. 24 is a TGA diagram of a compound of formula I in the form of E-form; FIG.

FIG. 25 is an XRPD pattern of a compound of formula I in the F-form;

FIG. 26 is a DSC chart of a compound of Formula I in the F-form;

FIG. 27 is a TGA diagram of a compound of formula I in the F-form;

FIG. 28 is an XRPD pattern of a compound of formula I in the G crystalline form; FIG.

FIG. 29 is a DSC chart of a compound of formula I in the G crystalline form; FIG.

FIG. 30 is a TGA diagram of a compound of formula I in the form of a G crystal;

FIG. 31 is an XRPD pattern of the compound of the formula I in the H crystal form; FIG.

FIG. 32 is a DSC chart of a compound of formula I in the form of H;

FIG. 33 is a TGA diagram of a compound of formula I in the form of H;

Figure 34 is an XRPD pattern of the compound of formula I in the J-form;

FIG. 35 is a DSC chart of a compound of formula I in the J-form;

FIG. 36 is a TGA diagram of a compound of formula I in the form of a J-form; FIG.

FIG. 37 is an XRPD pattern of the compound of formula I in the form of K crystal form; FIG.

FIG. 38 is a DSC chart of a compound of formula I in the form of a K crystal form; FIG.

FIG. 39 is a TGA diagram of a compound of formula I in the form of K crystal form; FIG.

FIG. 40 is an XRPD pattern of the compound of formula I in the L crystal form; FIG.

FIG. 41 is a DSC chart of a compound of formula I in the L crystal form; FIG.

42 is a TGA diagram of a compound of formula I in the L crystal form;

43 is an XRPD pattern of the compound of formula I in the form of M crystal;

FIG. 44 is a DSC chart of a compound of formula I in the M crystalline form; FIG.

FIG. 45 is a TGA diagram of a compound of formula I in the form of M crystal form; FIG.

Figure 46 is an XRPD pattern of the compound of formula I in the N crystalline form;

Figure 47 is a DSC chart of the compound of formula I in the N crystalline form;

Figure 48 is a TGA diagram of a compound of formula I in the N crystalline form;

Figure 49 is an XRPD pattern of the compound of formula I in the form of O crystal;

Figure 50 is a DSC chart of the compound of formula I in the form of O crystal;

FIG. 51 is a TGA diagram of a compound of formula I in the form of O crystal; FIG.

52 is a DVS hygroscopic spectrum of a compound of Formula I in the form of O crystal;

53 is a comparison chart of XRPD before and after DVS detection of the compound of formula I in the form of O crystal;

Figure 54 is an XRPD pattern of the compound of formula I in the form of a P crystal;

Figure 55 is a DSC chart of a compound of formula I in the form of a P crystal;

Figure 56 is a TGA diagram of a compound of formula I in the form of a P crystal;

FIG. 57 is a comparison chart of XRPD before and after the test of influencing factors of the compound of the formula I in the B-form form;

Fig. 58 is a comparison chart of XRPD before and after the test of the influencing factors of the compound of formula I in the form of C form.

detailed description

The present invention will be explained in more detail with reference to the following embodiments. The embodiments of the present invention are only used to explain the technical solution of the present invention, and the essence and scope of the present invention are not limited thereto.

The present invention will be explained in more detail with reference to the following embodiments. The embodiments of the present invention are only used to explain the technical solution of the present invention, and do not limit the essence and scope of the present invention.

Test conditions of the instrument used in the experiment:

The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was four. Methylsilane (TMS).

MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

For HPLC measurement, an Agilent 1200 DAD high-pressure liquid chromatography (Agilent SB C18 250 × 4.6 mm column) and a Thermo Dionex Ultimate 3000 high-pressure liquid chromatography (Kromasil 100-5-C18 200 × 4.6 mm column) were used.

扫描方式：θ/2θ，扫描范围：5-48°。 XRPD is X-ray powder diffraction detection: The measurement is performed using a BRUKER D8 X-ray diffractometer. The specific collection information: Cu anode (40kV, 40mA), Cu-Kα rays

Scanning mode: θ / 2θ, scanning range: 5-48 °.

DSC is differential scanning calorimetry: The measurement uses a METTLER TOLEDO DSC 3+ differential scanning calorimeter, with a heating rate of 10 ° C / min, and the specific temperature range refers to the corresponding map (mostly 25-300 or 25-350 ° C), nitrogen purging The speed is 50 mL / min.

TGA is thermogravimetric analysis: The test uses a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10 ° C / min, the specific range of temperature refers to the corresponding map (mostly 25-300 ° C), and a nitrogen purge rate of 20mL / min.

DVS is dynamic moisture adsorption: The detection adopts SMS DVS Advantage. At 25 ℃, the humidity change is 50% -95% -0% -95% -50%, and the step is 10% (the last step is 5%) (the specific range of humidity) Based on the corresponding map, most of the methods are listed here.) The judgment criterion is dM / dT not greater than 0.002.

Preparation Example of Compound of Formula I (Method for Preparation of Example 20 in Application No. PCT / CN2018 / 079086) 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- ( 2,4-difluorophenyl)-[1,2,4] triazolo [4,3-c] pyrimidin-5-amine 1 (i.e.

Compound of formula I)

first step

4-chloro-6- (2,4-difluorophenyl) pyrimidin-2-amine 1c

Under argon atmosphere, compound 1a (11g, 63.72mmol, Shaoyuan Technology Shanghai Co., Ltd.), (2,4-difluorophenyl) boric acid 1b (10.06g, 63.72mmol, Shanghai Shuya Technology Co., Ltd.), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (4.66 g, 6.37 mmol) and potassium carbonate (26.42 g, 191.17 mmol) were added to 500 mL of 1,4-dioxane and In a mixed solvent of water (V / V = 4: 1), the reaction was stirred at 90 ° C for 2 hours. The reaction solution was filtered, and the filtrate was separated. The aqueous phase was extracted with ethyl acetate (200 mL × 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography using eluent system A (dichloromethane / methanol system). Thus, the title compound 1c was obtained (14.04 g, yield: 91.19%).

MS m / z (ESI): 242.3 [M + 1]

Second step

5-bromo-4-chloro-6- (2,4-difluorophenyl) pyrimidine-2-amine 1d

Compound 1c (14.04 g, 58.11 mmol) was dissolved in 300 mL of N, N-dimethylformamide, N-bromosuccinimide (11.38 g, 63.92 mmol) was added, and the reaction was stirred for 1 hour. The reaction solution was poured into 1 L of water, stirred for 30 minutes, filtered, and the filter cake was collected and dried under vacuum to obtain the crude title compound 1d (16 g). The product was directly subjected to the next reaction without purification.

MS m / z (ESI): 320.0 [M + 1]

third step

5-bromo-4- (2,4-difluorophenyl) -6-hydrazinopyrimidin-2-amine 1e

The crude compound 1d (16 g, 49.92 mmol) was dissolved in 250 mL of ethanol, 50 mL of 85% hydrazine hydrate was added, and the reaction was stirred for 17 hours. The reaction solution was filtered, and the filter cake was washed with ethanol (20 mL × 2) and n-hexane (20 mL × 2) in this order, and the filter cake was dried to obtain the title compound 1e (12 g, yield: 76.05%).

MS m / z (ESI): 316.0 [M + 1]

the fourth step

8-bromo-7- (2,4-difluorophenyl)-[1,2,4] triazolo [4,3-c] pyrimidin-5-amine 1f

Compound 1e (4 g, 12.65 mmol) and (tri) ethyl orthoformate (2.25 g, 15.18 mmol) were dissolved in 50 mL of ethanol, and the reaction was stirred under reflux for 2 hours. The reaction was stopped, cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The obtained residue was slurried with 5 mL of ethanol for 0.5 hours, filtered, and the filter cake was washed with anhydrous ether (10 mL x 2). The filter cake was dried to obtain the title compound 1f (3.85 g, Yield: 93.37%).

MS m / z (ESI): 326.2 [M + 1]

the fifth step

8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4,3 -c] pyrimidin-5-amine 1

Under an argon atmosphere, 2- (difluoromethyl) -6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2- 1) pyridine (247.56 mg, 919.96 μmol, prepared by the method disclosed in the patent application "WO2011095625A1"), compound 1f (200 mg, 613.31 μmol), [1,1'-bis (diphenylphosphino) dicene Iron] Palladium dichloride (44.88 mg, 61.33 μmol) and potassium carbonate (254.29 mg, 1.84 mmol) were added to 12 mL of a mixed solvent of 1,4-dioxane and water (V / V = 5: 1), and heated Stir to 90 ° C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified with a CombiFlash rapid preparation device using eluent system A (dichloromethane / methanol system). : Ammonium bicarbonate, water, acetonitrile) to obtain the title compound 1, which is the compound of formula I (26 mg, yield: 11.98%).

MS m / z (ESI): 389.5 [M + 1]

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.44 (brs, 2H), 7.54 (s, 1H), 7.40-7.18 (m, 4H), 6.96-6.69 (m, 1H ), 2.44 (s, 3H).

Test examples of biological activity of compounds of formula I (partial test examples with application number PCT / CN2018 / 079086)

The compounds of formula Ⅰ the adenosine A _2a receptor _{(adenosine A 2a receptor, A 2a} R) cAMP signaling pathway, A _2b adenosine receptor _{(adenosine A 2b receptor, A 2b} R) cAMP signaling pathway, adenosine A ₁ receptors (adenosine A ₁ receptor, A ₁ R) cAMP signaling pathway and adenosine A ₃ receptor (adenosine A ₃ receptor, A ₃ R) cAMP signaling pathway inhibitory activity.

Adenosine A _2a receptor

CHO-K1 / A _2a R cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 800 μg / mL bleomycin. When cell separation experiments using buffer cells were digested with balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin and resuspend the cells counted, and adjusted to a cell density of 10 ⁶ / mL. Add 5 μL of cell suspension to each well in a 384-well plate, 2.5 μL of 4 × prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM Rolipram, and 2.7 U / mL adenosine deaminase. Concentrations of test compounds were incubated at room temperature for 30 minutes. Add 2.5 μL of 4 × concentration of ethyl carbazole in a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM rolipram and 2.7 U / mL adenosine deaminase in each well, and incubate at room temperature. 30 minutes. The final compound concentration was 10,000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, 0.001024 nM, and the final ethylcarbazole concentration was 20 nM. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-Cryptate with cAMP lysis buffer at a ratio of 1: 4. Add 5 μL of diluted cAMP-d2 to each well, and add 5 μL of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark. The HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC ₅₀ values.

Adenosine A ₁ receptor

CHO-K1 / A ₁ R was cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1 mg / mL G418. During the experiment, the cells were digested with cell isolation buffer, and then the cells were resuspended and counted with a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 × 10 ⁵ cells / mL. Add 12.5 μL of cell suspension to each well in a 384-well plate, 6.25 μL of 4 prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM Rolipram, and 2.7 U / mL adenosine deaminase. × concentration of the test compound and incubated at room temperature for 30 minutes. Add 6.25 μL of 4 × concentration of forskolin and N6-cycline in a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM rolipram and 2.7 U / mL adenosine deaminase in each well. Amyl adenosine, incubated for 30 minutes at room temperature. The final compound concentrations were: 100,000, 10,000, 1000, 100, 10, 1, 0.1 and 0 nM, the final concentration of forskolin was 10 μM, and the final concentration of CPA was 10 nM. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptic compound with cAMP lysis buffer at a ratio of 1: 4. Add 12.5 μL of diluted cAMP-d2 to each well, and add 12.5 μL of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark. The HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC ₅₀ values.

Adenosine A ₃ receptor

CHO-K1 / A ₃ R was cultured in DMEM / F12 medium containing 10% fetal bovine serum and 10 μg / mL puromycin. During the experiment, cells were digested with cell isolation buffer, and the cells were resuspended and counted with a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 × 10 ⁵ / mL. Add 12.5 μL of cell suspension to each well in a 384-well plate, 6.25 μL of 4 prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM Rolipram, and 2.7 U / mL adenosine deaminase. × concentration of the test compound and incubated at room temperature for 30 minutes. Add another 6.25 μL of 4 × concentration of forskolin and 2Cl-IB in a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM rolipram and 2.7 U / mL adenosine deaminase. -MECA, incubate at room temperature for 30 minutes. The final compound concentrations were: 100,000, 10,000, 1000, 100, 10, 1, 0.1 and 0 nM, the final concentration of forskolin was 10 μM, and the final concentration of 2Cl-IB-MECA was 5 nM. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptic compound with cAMP lysis buffer at a ratio of 1: 4. Add 12.5 μL of diluted cAMP-d2 to each well, and then add 12.5 μL of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark. The HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC ₅₀ values.

A _2b adenosine receptor _{(adenosine A 2b receptor, A 2b} R)

CHO-K1 / A _2b R was cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1 mg / mL G418. When cell separation experiments using buffer cells were digested with balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin and resuspend the cells counted, and adjusted to a cell density of 10 ⁶ / mL. Add 5 μL of cell suspension to each well in a 384-well plate, 2.5 μL of 4 × prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM Rolipram, and 2.7 U / mL adenosine deaminase. Concentrations of test compounds were incubated at room temperature for 30 minutes. Add 2.5 μL of 4 × concentration ethylcarbazole (Torcis, 4 × concentration) prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μM rolipram, and 2.7 U / mL adenosine deaminase to each well. 1691/10), incubate at room temperature for 30 minutes. The final compound concentration was 100,000, 10,000, 1000, 100, 10, 1, 0.1, and 0 nM, and the final ethylcarbazole concentration was 1 μM. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptic compound with cAMP lysis buffer at a ratio of 1: 4. Add 5 μL of diluted cAMP-d2 to each well, and then add 5 μL of diluted anti-cAMP-Eu-cryptic compound, and incubate for 1 hour at room temperature in the dark. The HTRF signal value was read using a PHERAstar multifunctional microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC ₅₀ values.

Table 1. Inhibitory activities of compounds of formula I on A _2a R, A ₁ R and A ₃ R

Table 2. Inhibitory activities of compounds of formula I on A _2a R and A _2b R

Measurement of the brain permeability of compounds of formula Ⅰ in mice

Experimental animal operation: 4 C57 mice, female, 12/12 hours light / dark adjustment, temperature 24 ± 3 ℃ constant temperature, 50-60% humidity, free to eat and drink. After fasting overnight, they were administered orally. The dose was 20 mg / kg. The administration group was sacrificed after 0.5 h of blood collection (blood collection volume 0.5 ml). The blood samples were placed in heparinized test tubes, centrifuged at 3500 rpm for 10 min to separate plasma, and recorded as plasma 1. Stored at -80 ° C. After the animals were sacrificed, physiological saline was perfused, and excess blood was removed from the brain tissue. The brain tissue was taken out, and the remaining blood was blotted with filter paper, which was recorded as brain tissue 1, and stored at -80 ° C. Another 3 animals were taken from blank plasma and brain tissue 2 and treated in the same way as the administration group.

Plasma protein binding equilibrium dialysis process:

1) Sample preparation

Dissolve the drug compound to 20 mM with DMSO to obtain stock solution I; transfer an appropriate amount of stock solution I and dilute with methanol to obtain 200 μM diluted stock solution II; transfer 10 μL of stock solution II to a 1.5 mL Eppendorf tube, add 990 μL blank plasma, and mix A 2 μM plasma sample 2 (DMSO content ≦ 0.2%) was obtained and used to determine the plasma protein binding rate at this concentration. Take the 50 μL of the prepared plasma sample, record it as T ₀ , and store it in a -4 ° C refrigerator for testing.

2) Experimental process

Take the RED device and insert the balanced dialysis tube into the 96-well bottom plate. Take 300 μL of the above-prepared plasma sample 2 containing the analyte and the corresponding blank plasma sample, and place them in the red labeled plasma chamber. Take 500 μL of a pH 7.4 phosphate buffered saline solution and place it in another red-labeled buffer chamber side by side (buffer chamber). According to the above method, each sample has a concentration of 2 samples. The 96-well plate was covered with a sealing tape, and the entire bottom plate was placed in a thermal mixer, and equilibrated at 37 ° C for 4 h at a speed of 400 rpm. After incubation, remove the 96-well bottom plate device from the thermomixer to complete equilibrium dialysis. Take 25 μL of equilibrated plasma sample or dialysate sample, add 25 μL of the corresponding unbalanced blank drug-free blank phosphate buffer solution or blank plasma without drug, add 200 μL of internal standard (prepared by acetonitrile), and vortex for 5 min After centrifugation for 10 min (4000 rpm), the supernatant was taken for LC / MS / MS analysis. To sample T ₀ without incubation, the LC / MS / MS method established above was used to determine the total peak area ratio of the plasma chamber and the free chamber (buffer chamber) to the chromatographic peak of the internal standard to calculate the free percentage (f _{u plasma} % ).

Brain tissue protein-binding equilibrium dialysis process: blank brain tissue 2 was prepared into a blank brain homogenate with pH 7.4PBS according to the dilution factor = 11, and the compound was added to prepare a 2 μM brain homogenate. The LC / MS / MS method was used to determine the ratio of the peak area of the total drug (brain homo chamber) and free drug (buffer chamber) to the chromatographic peak of the internal standard to calculate the free percentage (f _{u brain hom} %).

Brain permeability test data calculation method:

1) The established LC / MS / MS method was used to determine the drug concentration in plasma 1 and brain tissue 0.5 h after administration of mice, respectively, and this is the total concentration (C _{total, p} and C _{total, b} );

2) The RED Device Inserts were used to measure the protein binding rate of the compounds in mouse plasma and brain tissues by equilibrium dialysis to calculate the free percentages (f _{u plasma} %, f _{u brain} %);

Percent free plasma (f _{u plasma} %) = C _buffer / C _plasma × 100%;

Free percentage of brain homogenate (f _{u brain hom} %) = C _buffer / C _{brain hom} × 100%;

Free percentage of brain tissue (f _{u brain} %) = f _{u brain hom} / (Df- (Df-1) × f _{u brain hom} ) × 100%; here Df = 11

3) Calculate the blood-brain permeability index Kp-unbound using the following formula.

Table 3. Blood-brain permeability index of compounds of formula I

Compound Blood brain permeability index (Kp-unbound) Formula I 0.015

Example 1 Preparation of Form A

The compound of formula I (17 mg) was added to 1.5 mL of acetone, stirred to dissolve, and slowly evaporated at room temperature until most of the solvent was evaporated. The solid was collected and dried under vacuum to give the product (10 mg). After X-ray powder diffraction detection, the product was defined as Form A, and the XRPD spectrum is shown in Figure 1. The DSC spectrum is shown in Figure 2. The endothermic peak is 247.16 ° C and the exothermic peak is 250.40 ° C. The TGA spectrum is shown in Figure 3.

DVS characterization: The sample at 25 ℃ is between 20.0% RH and 80.0% RH. As the humidity increases, the water absorption also increases, the weight change is 0.1259%, and the moisture gain is less than 0.2%. Or almost non-hygroscopic. Under normal storage conditions (ie, humidity of 60% at 25 ° C), water absorption is about 0.1134%; under accelerated test conditions (ie, humidity of 70%), water absorption is about 0.1299%; under extreme conditions (ie, humidity of 90%), water absorption is about 0.2097 %. The crystal form did not change before and after DVS detection. The DVS hygroscopic spectrum is shown in Figure 4, and the X-ray powder diffraction comparison spectrum before and after DVS detection is shown in Figure 5.

Table 4. Characteristic peaks of Form A

Example 2 Preparation of Form A

The crude compound of formula I (12 g) synthesized according to the method of Comparative Example 1 was purified by combiflash (mobile phase: DCM: MeOH gradient eluent), and the eluent was concentrated under reduced pressure. The obtained solid was transferred using a mixed solvent of DCM and MeOH. The solid was not completely dissolved in a small single-necked bottle, and concentrated under reduced pressure to obtain the product (1.42 g). After X-ray powder diffraction detection, the product was in Form A.

Example 3 Preparation of Form A

The crystal form (50 mg) of the compound B of formula I was added to 0.5 mL of water and slurried for 72 hours at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (40 mg). After X-ray powder diffraction detection, the product was in Form A.

Example 4 Preparation of Form B

The crude compound of formula I (21 g) synthesized by the method of Comparative Example 1 was purified by combiflash (mobile phase: DCM: MeOH gradient eluent), and the eluent was concentrated under reduced pressure. The obtained solid was mixed with DCM and MeOH The solvent was transferred to a small single-necked flask, the solid was completely dissolved, and concentrated under reduced pressure to obtain the product (2.68 g). After X-ray powder diffraction detection, the product was defined as Form B, and the XRPD spectrum is shown in Figure 6. The DSC spectrum is shown in Fig. 7, the first exothermic peak is 219.39 ° C, the endothermic peak is: 256.51 ° C, and the second exothermic peak is 259.65 ° C; the TGA spectrum is shown in Fig. 8.

DVS characterization: The sample at 25 ℃ is between 20.0% RH and 80.0% RH. As the humidity increases, the water absorption also increases, the weight change is 0.1747%, and the moisture gain is less than 0.2%. Or almost non-hygroscopic. Under normal storage conditions (ie, humidity of 60% at 25 ° C), water absorption is about 0.1771%; under accelerated test conditions (ie, humidity of 70%), water absorption is about 0.2044%; under extreme conditions (ie, humidity of 90%), water absorption is about 0.2948 %. The crystal form did not change before and after DVS detection. The DVS hygroscopic spectrum is shown in Figure 9 and the X-ray powder diffraction comparison spectrum before and after DVS detection is shown in Figure 10.

Table 5.Characteristic peaks of Form B

Serial number 2-Theta d (A) I% Peak 1 7.953 11.10848 100.0 Peak 2 9.549 9.25504 8.7 Peak 3 11.138 7.93782 61.6 Peak 4 11.976 7.38404 15.1 Peak 5 13.618 6.49707 53.9 Peak 6 16.256 5.44825 61.8 Peak 7 17.985 4.92824 97.1 Peak 8 18.949 4.67963 41.5 Peak 9 20.207 4.39110 31.5 Peak 10 20.588 4.31062 49.0 Peak 11 21.924 4.05081 45.6 Peak 12 22.853 3.88818 34.1 Peak 13 24.285 3.66203 17.1 Peak 14 25.227 3.52743 13.8 Peak 15 27.587 3.23082 13.6 Peak 16 28.628 3.11567 11.1 Peak 17 30.525 2.92620 12.4 Peak 18 32.645 2.74085 11.1 Peak 19 34.100 2.62717 2.0

Example 5 Preparation of Form B

The compound of formula I (50 mg) was added to 1.5 mL of isopropanol, the temperature was raised to 80 ° C., the solution was stirred, the stirring was continued for 30 minutes, and the temperature was slowly lowered to room temperature, and the room temperature was stirred for 16 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (33.9 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 6 Preparation of Form B

The compound of formula I (50 mg) was added to 1.5 mL of tetrahydrofuran, the temperature was raised to 66 ° C, the solution was stirred, the stirring was continued for 30 minutes, the temperature was slowly lowered to room temperature, and the room temperature was stirred for 16 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (32.2 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 7 Preparation of Form B

The crystal form B (40 mg) of the compound of formula I was added to 0.5 mL of tetrahydrofuran and slurried for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (31.8 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 8 Preparation of Form B

Add the compound of formula I (10 mg) to 0.5 mL of dichloromethane, heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, stir at room temperature for 2 days . The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (6.5 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 9 Preparation of Form B

The compound of formula I (100 mg) was added to 3 mL of dichloromethane and beaten at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (78 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 10 Preparation of Form B

The compound of formula I (10 mg) was added to 1 mL of 1,2-dichloroethane and slurried at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (6.8 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 11 Preparation of Form B

Add the compound of formula I (10mg) to 0.5mL of 1,2-dichloroethane, heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, room temperature Stir for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (7.0 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 12 Preparation of Form B

The compound of formula I (50 mg) was added to 0.5 mL of n-propanol and beaten for 3 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (33 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 13 Preparation of Form B

The compound of formula I (10 mg) was added to 0.6 mL of acetone, stirred to dissolve, and crystallized slowly at room temperature to obtain the product (9.0 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 14 Preparation of Form B

The compound of formula I (10 mg) was added to 0.2 mL of 10% water / acetone, stirred to dissolve, and crystallized slowly at room temperature to obtain the product (8.6 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 15 Preparation of Form B

Form B (40 mg) of compound B of formula I was added to 1 mL of isopropanol and beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (25.6 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 16 Preparation of Form B

Form B (40 mg) of compound B of formula I was added to 1 mL of 1,4-dioxane and beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (34.3 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 17 Preparation of Form B

Form B (40 mg) of compound B of formula I was added to 1.5 mL of dichloromethane and beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (37.2 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 18 Preparation of Form B

Form B of the compound of formula I (40 mg) was added to 1 mL of acetone, and beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (19.6 mg). The product was in the B-form by X-ray powder diffraction detection.

Example 19 Preparation of Form C

The compound of formula I (50 mg) was added to 1.5 mL of acetonitrile, the temperature was raised to 80 ° C., the solution was stirred, and the stirring was continued for 30 minutes, and then slowly lowered to room temperature, and the room temperature was stirred for 16 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (32.4 mg). After X-ray powder diffraction detection, the product was defined as the crystal form C, and the XRPD spectrum is shown in FIG. 11. The DSC spectrum is shown in Fig. 12, and the endothermic peak value is 250.92 ° C, and the exothermic peak value is 253.18 ° C. The TGA spectrum is shown in Fig. 13.

DVS characterization: The sample at 25 ℃ is between 20.0% RH and 80.0% RH. As the humidity increases, the water absorption also increases, the weight change is 0.1222%, and the moisture gain is less than 0.2%. Or almost non-hygroscopic. Under normal storage conditions (ie, humidity of 60% at 25 ° C), water absorption is about 0.1147%; under accelerated test conditions (ie, humidity of 70%), water absorption is about 0.1243%; under extreme conditions (ie, humidity of 90%), water absorption is about 0.2238 %. The crystal form did not change before and after DVS detection. The DVS hygroscopic spectrum is shown in Figure 14, and the X-ray powder diffraction spectrum before and after DVS detection is shown in Figure 15.

Table 6.Characteristic peaks of Form C

Serial number 2-Theta d (A) I% Peak 1 6.386 13.83038 5.5 Peak 2 6.437 13.71932 6.4 Peak 3 7.901 11.18140 10.9 Peak 4 9.405 9.39615 4.2 Peak 5 10.112 8.74024 5.2 Peak 6 12.285 7.19879 100.0 Peak 7 12.836 6.89121 31.9 Peak 8 14.372 6.15795 17.8 Peak 9 14.755 5.99911 11.0 Peak 10 15.810 5.60087 7.8 Peak 11 16.309 5.43078 12.5 Peak 12 17.355 5.10550 10.6 Peak 13 17.813 4.97547 18.1 Peak 14 18.557 4.77744 26.0 Peak 15 19.463 4.55718 8.7 Peak 16 20.665 4.29463 43.7 Peak 17 21.668 4.09817 19.9 Peak 18 23.153 3.83851 47.1 Peak 19 23.645 3.75976 11.8 Peak 20 24.996 3.55946 10.9 Peak 21 27.028 3.29635 13.8 Peak 22 27.722 3.21540 6.0 Peak 23 28.824 3.09492 10.7 Peak 24 30.557 2.92321 4.0

Peak 25 31.233 2.86149 3.9 Peak 26 32.127 2.78382 3.4

Example 20 Preparation of C Form

The compound of formula I (17 mg) was added to a mixed solvent of 0.5 mL of dichloromethane and methanol (V: V = 1: 1), and the solution was stirred to dissolve, and a solid was gradually evaporated at room temperature. Take a part of the sample to detect the single crystal, and the ellipsoid diagram of the molecular three-dimensional structure is shown in Fig. 16;

Example 21 Preparation of Form C

The compound of formula I (100 mg) was added to 2 mL of ethyl acetate, the temperature was raised to 70 ° C., and the mixture was stirred for 30 minutes. The solution was dissolved first, and then a solid precipitated out. The temperature was slowly reduced to room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (43.9 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 22 Preparation of Form C

The compound of formula I (100 mg) was added to 1 mL of ethanol, the temperature was raised to 70 ° C., and the solution was stirred, and 2 mL of water was added dropwise. After a slight turbid stirring, the solution was dissolved again, and the temperature was slowly reduced to room temperature, followed by stirring at room temperature for 1 hour. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (68.4 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 23 Preparation of Form C

Add the compound of formula I (200mg) to 2mL of methanol, heat to reflux, stir to dissolve, dropwise add 1.5mL of water, turbidity begins to appear, continue to stir undissolved, continue to stir for 30 minutes under reflux, slowly drop to room temperature, room temperature Stir for 16 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (125 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 24 Preparation of Form C

The compound of formula I (200 mg) was added to 4 mL of isopropanol, heated to reflux, stirred to dissolve, and 5 mL of water was added dropwise, and no turbidity occurred. Continue stirring for 30 minutes at reflux, slowly drop to room temperature, and stir at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (96 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 25 Preparation of C crystal form

Add the compound of formula I (200 mg) to 2.4 mL of ethanol, warm to reflux, stir to dissolve, add 4 mL of water dropwise, turbidity appears, continue to stir undissolved, continue to stir for 30 minutes under reflux, slowly drop to room temperature, and stir at room temperature 16 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (158 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 26 Preparation of C crystal form

Add the compound of formula I (200 mg) to 8 mL of ethyl acetate, warm to reflux, stir to dissolve, add 4 mL of n-heptane dropwise, turbidity appears, continue to stir undissolved, continue to stir for 30 minutes under reflux, and slowly drop to room temperature And stirred at room temperature for 2 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (135 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 27 Preparation of Form C

The crude compound of formula I (200 mg) was added to 1.4 mL of ethanol, the temperature was raised to reflux, and the solution was stirred. The solution was stirred for 30 minutes under reflux, slowly dropped to room temperature, and stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (85 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 28 Preparation of Form C

The compound of formula I (10 mg) was added to 1 mL of water and slurried at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (6.1 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 29 Preparation of Form C

The compound of formula I (10 mg) was added to 0.5 mL of water, the temperature was raised to 50 ° C. and insoluble, and stirring was continued for 30 minutes, and then slowly lowered to room temperature, and then raised to 50 ° C. for half an hour, slowly lowered to room temperature, and beaten at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (6.9 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 30 Preparation of C Form

The compound of formula I (50 mg) was added to 0.5 mL of isopropanol and beaten for 3 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (32 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 31 Preparation of Form C

The compound of Formula I (10 mg) was added to 1 mL of ethyl acetate, and most of the compounds were dissolved. After being slurried at room temperature for 2 days, the compounds were dissolved and slowly crystallized to obtain the product (8.5 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 32 Preparation of C crystal form

The compound of formula I (100 mg) was added to 2 mL of ethyl acetate, and the temperature was raised to 50 ° C. and insoluble, and stirring was continued for 30 minutes, and then slowly lowered to room temperature, and then raised to 50 ° C. for half an hour, slowly lowered to room temperature, and beaten at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (62 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 33 Preparation of Form C

The compound of formula I (10 mg) was added to 1 mL of methyl tert-butyl ether, and slurried for 2 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (6.0 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 34 Preparation of Form C

Add the compound of formula I (10mg) to 0.5mL methyl tert-butyl ether, insoluble at 50 ° C, continue to stir for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, beat at room temperature 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (5.5 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 35 Preparation of Form C

The compound of formula I (50 mg) was added to 1 mL of acetonitrile and beaten for 2 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (31 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 36 Preparation of Form C

The compound of formula I (10 mg) was added to 40 μL of dimethyl sulfoxide to dissolve, and crystallized slowly at room temperature. Centrifuge and collect the solid to give the product (4.2 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 37 Preparation of Form C

The compound of formula I (10 mg) was added to 1 mL of isoamyl alcohol and beaten for 2 days at room temperature. Centrifuged and collected the solid to give the product (5.2 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 38 Preparation of Form C

The compound of formula I (10 mg) was added to 0.5 mL of isoamyl alcohol, and the temperature was raised to 50 ° C. and insoluble, and stirring was continued for 30 minutes, and then slowly lowered to room temperature, and then raised to 50 ° C. for half an hour, slowly lowered to room temperature, and beaten at room temperature for 2 days. Centrifuge and collect the solid to give the product (5.0 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 39 Preparation of Form C

The compound of formula I (10 mg) was added to 0.3 mL of 10% water / methanol to dissolve, and the crystals were slowly evaporated at room temperature. Centrifuged and collected the solid to give the product (5.3 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 40 Preparation of Form C

The compound of formula I (10 mg) was added to 1 mL of ethyl acetate / n-heptane (1: 1), and slurried for 2 days at room temperature. Centrifuge and collect the solid to give the product (5.1 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 41 Preparation of Form C

Add the compound of formula I (10 mg) to 0.5 mL of ethyl acetate / n-heptane (1: 1), heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly Reduce to room temperature and beat at room temperature for 2 days. Centrifuge and collect the solid to give the product (4.5 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 42 Preparation of Form C

The compound of formula I (50 mg) was added to 1 mL of 4-methyl-2-pentanone and beaten for 3 days at room temperature. Centrifuge and collect the solid to give the product (31 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 43 Preparation of Form C

The compound of formula I (10 mg) was added to 1 mL of methanol / water (1: 1) and beaten at room temperature for 2 days. Centrifuge and collect the solid to give the product (5.4 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 44 Preparation of Form C

Add the compound of formula I (10mg) to 0.5mL of methanol / water (1: 1), heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature Beat for 2 days at room temperature. Centrifuge and collect the solid to give the product (4.9 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 45 Preparation of Form C

The compound of formula I (10 mg) was added to 0.5 mL of butyl acetate, and the mixture was beaten at room temperature for 2 days. It was centrifuged and the solid was collected to give the product (5.7 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 46 Preparation of C crystalline form

The compound of formula I (10 mg) was added to 1 mL of cyclohexane, and slurried for 2 days at room temperature. Centrifuge and collect the solid to give the product (6.7 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 47 Preparation of Form C

The compound of formula I (10 mg) was added to 0.5 mL of cyclohexane, and the temperature was raised to 50 ° C. and insoluble, and stirring was continued for 30 minutes, and then slowly lowered to room temperature, and then raised to 50 ° C. for half an hour, slowly lowered to room temperature, and beaten at room temperature for 2 days. Centrifuge and collect the solid to give the product (4.2 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 48 Preparation of Form C

Form B (40 mg) of compound I of formula I was added to 1.5 mL of isopropyl ether and beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (12 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 49 Preparation of C Form

The crystal form (40 mg) of compound B of formula I was added to 0.5 mL of ethyl acetate, and the mixture was beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (27.6 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 50 Preparation of crystal form

The crystal form B (40 mg) of the compound of formula I was added to 0.5 mL of ethanol, and the mixture was beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (16.3 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 51 Preparation of crystal form

Form C of the compound of formula I (400 mg) was added to 10 mL of 4-methyl-2-pentanone and slurried at room temperature for 3.5 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (290 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 52 Preparation of Form C

Form B (40 mg) of compound B of formula I was added to 0.5 mL of acetonitrile and slurried at room temperature for 3.5 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (26 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 53 Preparation of Form C

Form C of compound I (100 mg) was added to 1 mL of water and beaten for 3 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (80 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 54 Preparation of C crystalline form

The compound G and C mixed crystals of formula I (50 mg) were added to a mixed solvent of 1 mL of ethanol and water (V: V = 1: 1), and slurried for 2 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (38 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 55 Preparation of Form C

The compound G and C mixed crystals (50 mg) of formula I were added to 2.5 mL of butyl acetate, and the mixture was beaten at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (35 mg). After X-ray powder diffraction detection, the product was in the C form.

Example 56 Preparation of D crystal form

The compound of formula I (40 mg) was added to 1 mL of isopropyl acetate, and beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (39.3 mg). After X-ray powder diffraction detection, the product was defined as the D crystal form, and the XRPD spectrum is shown in FIG. 17. The DSC spectrum is shown in Figure 18. The first endothermic peak is 77.43 ° C, the second endothermic peak is 125.41 ° C, the first exothermic peak is 217.56 ° C, the third endothermic peak is: 254.09 ° C, and the second endothermic peak is 256.87 ° C; TGA spectrum is shown in Figure 19.

DVS characterization: The sample at 25 ℃ is between 20.0% RH and 80.0% RH. As the humidity increases, the water absorption also increases, the weight change is 0.666%, and the moisture gain is less than 2% but not less than 0.2 %, The sample is slightly hygroscopic. Under normal storage conditions (ie, humidity of 25 ° C 60%), water absorption is about 0.556%; under accelerated test conditions (ie, humidity 70%), water absorption is about 0.703%; under extreme conditions (ie humidity 90%), water absorption is about 1.063 %. The crystal form did not change after DVS detection. The DVS spectrum is shown in Figure 20, and the X-ray powder diffraction comparison spectrum before and after DVS detection is shown in Figure 21.

Table 7.Characteristic peaks of Form D

Example 57 Preparation of D crystal form

Add the compound of formula I (10mg) to 0.5mL of isopropyl acetate, heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, beat at room temperature for 2 days . The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (5.8 mg). The product was in the D-form by X-ray powder diffraction detection.

Example 58 Preparation of crystalline form

The compound of formula I (40 mg) was added to 0.5 mL of acetonitrile and beaten for 4 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (29.7 mg). After X-ray powder diffraction detection, the product was defined as the E form, and the XRPD spectrum is shown in FIG. 22. The DSC detection spectrum is shown in Figure 23. The first endothermic peak is 126.27 ° C, the second endothermic peak is 254.49 ° C, and the exothermic peak is 257.82 ° C. The TGA spectrum is shown in Figure 24.

Table 8.Characteristic peaks of Form E

Serial number 2-Theta d (A) I% Peak 1 7.054 12.52094 13.1 Peak 2 7.244 12.19278 6.9 Peak 3 8.944 9.87882 10.3 Peak 4 11.059 7.99440 12.2 Peak 5 11.521 7.67441 26.2 Peak 6 13.813 6.40596 6.0 Peak 7 14.993 5.90407 100.0 Peak 8 16.313 5.42944 6.2 Peak 9 17.852 4.96472 7.6 Peak 10 19.208 4.61704 3.3 Peak 11 19.811 4.47791 3.8 Peak 12 21.265 4.17496 3.8 Peak 13 22.653 3.92210 12.9 Peak 14 22.994 3.86475 13.2 Peak 15 23.921 3.71707 6.6 Peak 16 24.548 3.62340 19.6 Peak 17 25.382 3.50627 8.8 Peak 18 25.878 3.44015 5.7 Peak 19 26.521 3.35816 3.0 Peak 20 29.300 3.04572 4.0 Peak 21 30.832 2.89778 3.0 Peak 22 32.474 2.75486 4.7

Example 59 Preparation of crystalline form

The compound of formula I (10 mg) was added to 1 mL of nitromethane and beaten for 2 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (5.9 mg). The product was in the E-form by X-ray powder diffraction detection.

Example 60 Preparation of E crystal form

The compound of formula I (10 mg) was added to 0.5 mL of nitromethane, and the temperature was raised to 50 ° C. and insoluble, and stirring was continued for 30 minutes, and then slowly lowered to room temperature, and then raised to 50 ° C. for half an hour, slowly lowered to room temperature, and beaten at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (5.9 mg). The product was in the E-form by X-ray powder diffraction detection.

Example 61 Preparation of crystalline form

The compound of formula I (40 mg) was added to 1 mL of 4-methyl-2-pentanone and beaten at room temperature for 4 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (29.9 mg). After X-ray powder diffraction detection, the product was defined as the F crystal form, and the XRPD spectrum is shown in FIG. 25. The DSC spectrum is shown in Figure 26, the first endothermic peak is 157.22 ° C, the first exothermic peak is 161.994 ° C, the second endothermic peak is 249.50 ° C, and the second exothermic peak is 253.58 ° C; 27.

Table 9.Characteristic peaks of Form F

Example 62 Preparation of G crystal form

The crude compound of formula I (6.67 g) was added to 67 mL of isopropanol, and the temperature was raised to reflux, and the stirring was continued for 1 hour under reflux. The reaction solution was dissolved, and 67 mg of seed crystal (C form) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filter cake was rinsed with 6 mL of isopropanol. The filter cake was collected and dried under vacuum to obtain the product (3.13 g). After X-ray powder diffraction detection, the product was defined as the G crystal form, and the XRPD spectrum is shown in FIG. 28. The DSC spectrum is shown in Figure 29, the first exothermic peak is 195.54 ° C, the second exothermic peak is 260.97 ° C, and the endothermic peak is 258.74 ° C; the TGA spectrum is shown in Figure 30.

Table 10.Characteristic peaks of Form G

Serial number 2-Theta d (A) I% Peak 1 6.304 14.00907 5.6 Peak 2 6.706 13.16938 100.0 Peak 3 7.865 11.23188 33.5 Peak 4 11.064 7.99034 1.1 Peak 5 12.286 7.19865 2.4 Peak 6 16.373 5.40949 7.3 Peak 7 18.840 4.70636 1.8 Peak 8 21.764 4.08023 2.1 Peak 9 23.986 3.70705 3.2 Peak 10 25.692 3.46468 2.8 Peak 11 27.524 3.23810 1.8 Peak 12 32.236 2.77469 1.9

Example 63 Preparation of Form H

About 100 mg of the compound of formula I was dissolved by adding 2.5 ml of 2-butanone, and the product was obtained by slowly evaporating and crystallizing at room temperature. After X-ray powder diffraction detection, the product was defined as the H crystal form, and the XRPD spectrum is shown in FIG. 31. The DSC spectrum is shown in Figure 32. The first endothermic peak is 106.90 ° C, the second endothermic peak is 253.57 ° C, and the exothermic peak is 256.23 ° C. The TGA spectrum is shown in Figure 33.

Table 11.Characteristic peaks of crystal

Serial number 2-Theta d (A) I% Peak 1 4.695 18.80622 3.8 Peak 2 5.938 14.87203 80.8 Peak 3 6.514 13.55902 88.7 Peak 4 8.860 9.97321 78.1 Peak 5 11.414 7.74654 17.8 Peak 6 13.931 6.35195 13.2 Peak 7 14.565 6.07660 9.2 Peak 8 15.555 5.69210 7.1 Peak 9 16.703 5.30333 3.6 Peak 10 17.582 5.04024 12.4 Peak 11 18.259 4.85496 15.5 Peak 12 19.298 4.59565 22.4 Peak 13 21.426 4.14377 100.0 Peak 14 22.612 3.92913 11.6 Peak 15 23.438 3.79255 38.4 Peak 16 24.418 3.64252 11.0 Peak 17 25.296 3.51805 24.7 Peak 18 27.101 3.28762 7.0 Peak 19 28.338 3.14690 4.8 Peak 20 29.103 3.06591 6.2 Peak 21 30.645 2.91499 9.9 Peak 22 31.480 2.83961 3.6 Peak 23 33.604 2.66482 1.4

Example 64 Preparation of Form H

About 10 mg of the compound of formula I was dissolved by adding 0.5 ml of ethanol, and the product was obtained by slowly evaporating and crystallizing at room temperature. The product was in the H crystal form by X-ray powder diffraction.

Example 65 Preparation of H crystal form

Add about 20 mg of the compound of formula I, add 0.6 ml of ethanol, heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, and beat at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. The product was in the H crystal form by X-ray powder diffraction.

Example 66 Preparation of Form H

About 10 mg of the compound of formula I was dissolved by adding 0.1 ml of propylene glycol methyl ether, and the product was obtained by slowly evaporating and crystallizing at room temperature. The product was in the H crystal form by X-ray powder diffraction.

Example 67 Preparation of H crystal form

About 10 mg of the compound of formula I was dissolved by adding 7% water / ethanol 0.4 ml, and the crystals were slowly evaporated at room temperature to obtain the product. The product was in the H crystal form by X-ray powder diffraction.

Example 68 Preparation of Form H

About 10 mg of the compound of formula I was dissolved by adding 0.25 ml of ethyl acetate / ethanol (1: 1), and the product was obtained by slowly evaporating and crystallizing at room temperature. The product was in the H crystal form by X-ray powder diffraction.

Example 69 Preparation of H crystal form

About 10 mg of the compound of formula I was dissolved by adding 0.1 ml of acetonitrile / methanol (1: 1), and the product was obtained by slowly evaporating and crystallization at room temperature. The product was in the H crystal form by X-ray powder diffraction.

Example 70 Preparation of Form H

About 10 mg of the compound of formula I was dissolved by adding 20 μL of N, N-dimethylformamide, and the product was obtained by slowly evaporating and crystallization at room temperature. The product was in the H crystal form by X-ray powder diffraction.

Example 71 Preparation of J crystal form

About 100 mg of the compound of formula I was added with 3 mL of para-xylene, slurried for 2 days at room temperature, centrifuged, and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was defined as the J-form, and the XRPD spectrum is shown in Figure 34. The DSC spectrum is shown in Figure 35, the first endothermic peak is 175.35 ° C, the second endothermic peak is 257.04 ° C, and the exothermic peak is 259.80 ° C; the TGA spectrum is shown in Figure 36.

Table 12.Characteristic peaks of Form J

Serial number 2-Theta d (A) I% Peak 1 6.938 12.73100 100.0 Peak 2 10.293 8.58755 17.0 Peak 3 10.620 8.32325 9.2 Peak 4 11.345 7.79324 40.1 Peak 5 15.342 5.77066 27.2 Peak 6 16.132 5.48994 37.9 Peak 7 16.716 5.29925 93.4 Peak 8 17.922 4.94545 13.8 Peak 9 18.589 4.76947 70.7 Peak 10 19.726 4.49703 50.2 Peak 11 20.878 4.25140 48.7 Peak 12 21.233 4.18108 54.5 Peak 13 22.090 4.02070 1.7 Peak 14 22.933 3.87483 12.1 Peak 15 23.626 3.76272 15.9 Peak 16 23.948 3.71290 58.5 Peak 17 25.108 3.54386 17.2 Peak 18 26.167 3.40286 23.2 Peak 19 27.448 3.24690 16.6 Peak 20 28.004 3.18364 20.5 Peak 21 28.431 3.13684 25.4 Peak 22 28.737 3.10410 32.1 Peak 23 29.779 2.99782 5.7 Peak 24 31.136 2.87015 6.8 Peak 25 31.880 2.80489 3.2 Peak 26 32.933 2.71758 12.5 Peak 27 34.164 2.62239 8.4 Peak 28 36.879 2.43532 4.1

Peak 29 38.004 2.36575 1.2

Example 72 Preparation of J crystal form

Add about 10 mg of the compound of formula I, add 0.5 ml of para-xylene, heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, and beat at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. The product was in the J-form by X-ray powder diffraction detection.

Example 73 Preparation of Crystal Form K

About 100 mg of the compound of formula I was added insoluble in 3 mL of n-heptane, slurried for 2 days at room temperature, centrifuged, and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was defined as the K crystal form, and the XRPD spectrum is shown in FIG. 37. The DSC spectrum is shown in Figure 38, the first endothermic peak is 104.06 ° C, the second endothermic peak is 254.89 ° C, and the exothermic peak is 257.21 ° C; the TGA spectrum is shown in Figure 39.

Table 13.Characteristic peaks of Form K

Example 74 Preparation of Crystal Form K

Add about 10 mg of the compound of formula I, add 0.5 ml of n-heptane, heat to 50 ° C and insoluble, continue to stir for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, and beat at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. The product was in the K crystal form by X-ray powder diffraction.

Example 75 Preparation of L crystal form

About 50 mg of the compound of formula I was added insoluble 1.5 ml of 1,4-dioxane, beaten at room temperature for 2 days, centrifuged, and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was defined as the L crystal form, and the XRPD spectrum is shown in FIG. 40. The DSC spectrum is shown in Figure 41. The first endothermic peak is 138.95 ° C, the first exothermic peak is 206.73 ° C, the second endothermic peak is 259.47 ° C, and the second exothermic peak is 262.28 ° C; 42.

Table 14.Characteristic peaks of L form

Example 76 Preparation of L crystal form

About 10 mg of the compound of formula I was added to 1.5 ml of tetrahydrofuran, and the solution was stirred to dissolve, and the solvent was crystallized slowly at room temperature to obtain the product. The product was found to be in the L crystal form by X-ray powder diffraction.

Example 77 Preparation of L crystal form

Add about 100 mg of the compound of formula I, add 3 mL of tetrahydrofuran, heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, and beat at room temperature for 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. The product was found to be in the L crystal form by X-ray powder diffraction.

Example 78 Preparation of L crystal form

Add about 10 mg of the compound of formula I, add 0.5 mL of 1,4-dioxane, heat to 50 ° C and insoluble, continue stirring for 30 minutes, slowly drop to room temperature, and then warm to 50 ° C for half an hour, slowly drop to room temperature, beat at room temperature 2 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. The product was found to be in the L crystal form by X-ray powder diffraction.

Example 79 Preparation of M crystal form

About 100 mg of the compound of formula I was dissolved by adding 1.5 mL of methanol, and the product was obtained by slowly evaporating and crystallizing at room temperature. After X-ray powder diffraction detection, the product was defined as the M crystal form, and the XRPD spectrum is shown in Figure 43. The DSC spectrum is shown in Figure 44. The first endothermic peak is 89.61 ° C, the second endothermic peak is 254.62 ° C, and the exothermic peak is 258.26 ° C. The TGA spectrum is shown in Figure 45.

Table 15.Characteristic peaks of M form

Serial number 2-Theta d (A) I% Peak 1 7.757 11.38871 3.2 Peak 2 8.419 10.49365 63.0 Peak 3 9.906 8.92186 19.7 Peak 4 10.344 8.54536 6.2 Peak 5 12.359 7.15611 4.0 Peak 6 13.686 6.46515 7.8 Peak 7 14.097 6.27755 7.7 Peak 8 14.968 5.91422 6.6 Peak 9 16.265 5.44537 13.0 Peak 10 17.061 5.19289 100.0 Peak 11 17.785 4.98328 15.2 Peak 12 19.525 4.54274 21.7 Peak 13 19.798 4.48068 20.9 Peak 14 21.236 4.18059 11.8 Peak 15 21.979 4.04091 10.6 Peak 16 22.686 3.91642 39.9 Peak 17 23.743 3.74442 4.9 Peak 18 25.078 3.54813 12.4 Peak 19 25.456 3.49618 17.4 Peak 20 26.030 3.42038 10.5 Peak 21 26.512 3.35933 20.8 Peak 22 26.948 3.30592 2.9 Peak 23 27.759 3.21116 8.2 Peak 24 28.561 3.12283 1.3 Peak 25 29.273 3.04840 12.2 Peak 26 29.942 2.98182 6.9 Peak 27 30.360 2.94177 13.4 Peak 28 31.845 2.80782 2.8 Peak 29 33.805 2.64940 2.0

Peak 30 35.071 2.55659 7.1 Peak 31 35.595 2.52020 4.2 Peak 32 37.904 2.37177 1.5 Peak 33 45.322 1.99935 4.8

Example 80 Preparation of N Crystal Form

About 100 mg of the compound of formula I was added to 3 mL of nitromethane, and slurried for 2 days at room temperature. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was defined as the N crystal form, and the XRPD spectrum is shown in Figure 46. The DSC spectrum is shown in Figure 47. The first endothermic peak is 106.07 ° C, the second endothermic peak is 162.39 ° C, the first exothermic peak is 170.48 ° C, the third endothermic peak is 249.21 ° C, and the second exothermic peak is The peak value is 251.61 ° C; the TGA spectrum is shown in Figure 48.

Table 16.Characteristic peaks of N form

Serial number 2-Theta d (A) I% Peak 1 6.587 13.40890 34.4 Peak 2 7.640 11.56169 3.4 Peak 3 9.559 9.24506 6.9 Peak 4 11.023 8.01981 5.0 Peak 5 12.134 7.28815 4.9 Peak 6 13.320 6.64174 100.0 Peak 7 16.862 5.25366 2.1 Peak 8 17.312 5.11830 8.3 Peak 9 18.158 4.88161 7.6 Peak 10 20.615 4.30494 2.4 Peak 11 21.491 4.13155 3.3 Peak 12 21.747 4.08346 4.2 Peak 13 22.641 3.92421 10.7 Peak 14 23.080 3.85054 9.6 Peak 15 24.143 3.68332 5.0 Peak 16 25.075 3.54849 7.3 Peak 17 26.498 3.36104 2.9 Peak 18 27.046 3.29418 2.6

Peak 19 27.848 3.20114 1.7 Peak 20 29.291 3.04666 2.0 Peak 21 31.331 2.85276 2.0

Example 81 Preparation of crystalline form

About 10 mg of the compound of formula I was added with 1 mL of isopropanol, and most of them were dissolved. After being slurried at room temperature for 2 days, the solution was dissolved, and the solvent was crystallized slowly to obtain the product. After X-ray powder diffraction detection, the product was defined as the O crystal form, and the XRPD spectrum is shown in Fig. 49. The DSC spectrum is shown in Figure 50. The first exothermic peak is 195.29 ° C, the endothermic peak is 258.71 ° C, and the second exothermic peak is 260.52 ° C. The TGA spectrum is shown in Figure 51.

DVS characterization: The sample at 25 ℃ is between 20.0% RH and 80.0% RH. As the humidity increases, the water absorption also increases, the weight change is 0.1255%, and the moisture gain is less than 0.2%. Or almost non-hygroscopic. Under normal storage conditions (that is, 25 ° C humidity 60%), water absorption is about 0.1076%; under accelerated test conditions (that is, 70% humidity), water absorption is about 0.1350%; under extreme conditions (that is, 90% humidity), water absorption is about 0.2271 %. The crystal form did not change after DVS detection. The DVS spectrum is shown in Figure 52, and the X-ray powder diffraction comparison spectrum before and after DVS detection is shown in Figure 53.

Table 17.Characteristic peaks of Form O

Example 82 Preparation of O crystal form

About 10 mg of the compound of formula I was added with 0.6 mL of n-propanol, and the solution was stirred and dissolved, and the crystal was slowly evaporated at room temperature to obtain the product. After X-ray powder diffraction detection, the product was in the O crystal form.

Example 83 Preparation of O crystal form

About 20 mg of the compound of formula I was added with 1.2 mL of acetone, the temperature was raised to 50 ° C., and the solution was stirred and slowly cooled to room temperature. The solution was filtered, and the filtrate was collected. The crystal was slowly evaporated and crystallized at room temperature to obtain the product. After X-ray powder diffraction detection, the product was in the O crystal form.

Example 84 Preparation of P crystal form

About 150 mg of the compound B of formula I was added to 3 mL of 4-methyl-2-pentanone, and beaten at room temperature for 4 days. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was defined as the P crystal form, and the XRPD spectrum is shown in Figure 54. The DSC spectrum is shown in Figure 55. The first endothermic peak is 121.49 ° C, the second endothermic peak is 254.40 ° C, and the exothermic peak is 256.84 ° C. The TGA spectrum is shown in Figure 56.

Table 18.Characteristic peaks of P form

Example 85 A-type, B-type and C-type mixed crystal slurry experiments

Form A (7.2 mg), Form B (7.3 mg) and Form C (7.3 mg) of the compound represented by Formula I were added to 0.6 mL of dioxane, and the mixture was beaten at room temperature for 140 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. The product was in the B-form by X-ray powder diffraction detection.

Example 86 A-type, B-type and C-type mixed crystal slurry experiments

Form A (8.2 mg), Form B (7.1 mg), and Form C (8.1 mg) of the compound represented by Formula I were added to 0.75 mL of tetrahydrofuran and slurried at room temperature for 140 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. The product was in the B-form by X-ray powder diffraction detection.

Example 87 A, B, and C mixed crystal slurry experiments

Form A (8.7 mg), Form B (8.1 mg), and Form C (8.2 mg) of the compound represented by Formula I were added to 1 mL of 4-methyl-2-pentanone and slurried at room temperature for 140 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was in the C form.

Example 88: A, B and C mixed crystal slurry experiments

Form A (8.4 mg), Form B (6.8 mg), and Form C (7.4 mg) of the compound represented by Formula I were added to 0.5 mL of acetonitrile and slurried at room temperature for 140 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was in the C form.

Example 89: A, B and C mixed crystal slurry experiments

Form A (7.5 mg), Form B (7.6 mg) and Form C (8.8 mg) of the compound represented by Formula I were added to 0.6 mL of ethyl acetate, and the mixture was slurried at room temperature for 140 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was in the C form.

Example 90 A-type, B-type and C-type mixed crystal slurry experiments

Form A (7.6 mg), Form B (7.3 mg), and Form C (7.3 mg) of the compound represented by Formula I were added to 1 mL of isopropyl alcohol, and the mixture was beaten at room temperature for 140 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was in the C form.

Example 91 Mixed A-, B- and C-crystal slurry experiments

Form A (8.1 mg), Form B (8.3 mg), and Form C (7.8 mg) of the compound represented by Formula I were added to 1 mL of isopropyl acetate, and the mixture was beaten at room temperature for 140 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product. The product was in the D-form by X-ray powder diffraction detection.

Experiment of Influencing Factors in Example 92

Place the samples of Form B and Form C of the compound of Formula I in an open flat, and examine the stability of the samples under heating (40 ° C, 60 ° C), light (4500 Lux), and high humidity (RH75%, RH90%) The sampling period is 30 days.

Experimental results:

Table 19. Experimental results of factors affecting Form B and Form C of the compound of formula I

NA means not available.

Experimental results:

According to the experimental results of the influencing factors in Table 19, under the conditions of light, high temperature 40 ° C, high temperature 60 ° C, high humidity 75%, and high humidity 90%, the physical and chemical stability of Form C is better than that of Form B for 30 days. Crystal form. The comparison of X-ray powder diffraction before and after the experiment of the influence factors of the crystal form B is shown in FIG. 57, and the comparison of the X-ray powder diffraction before and after the experiment of the influence factors of the crystal form B is shown in FIG. 58.

Example 93 Long-term Accelerated Stability Experiment of C Form

Form C of the compound of Formula I was subjected to a long-term (25 ° C, 60% RH), accelerated (40 ° C, 75% RH) stability study for 6 months.

Table 20: Results of long-term accelerated stability of Form C of the compound of Formula I:

The long-term accelerated stability test results from Table 20 show that the crystal form C is stable for 6 months under long-term (25 ° C, 60% RH) and accelerated (40 ° C, 75% RH) conditions, and the re-testing of the crystal form has not changed.

Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are merely examples, and that various changes or modifications may be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (25)

Compound of Formula I 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [ The crystal form A of 4,3-c] pyrimidin-5-amine is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ of 4.985, 10.167, 15.393, 26.651, 27.364,

Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, B-form of 3-c] pyrimidin-5-amine, characterized in that its X-ray powder diffraction pattern has characteristics at 2θ of 7.953, 11.138, 13.618, 16.256, 17.985, 18.949, 20.588, 21.924, 22.853 peak. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, 3-c] Form C of pyrimidine-5-amine, which is characterized in its X-ray powder diffraction pattern at 2θ of 12.285, 12.836, 14.372, 14.755, 17.813, 18.557, 20.665, 21.668, 23.153 peak. The crystal form C according to claim 3, wherein in the X-ray powder diffraction pattern, 2θ is 12.285, 12.836, 14.372, 14.755, 17.813, 18.557, 19.463, 20.665, 21.668, 23.153, 24.996, 27.028 There are characteristic peaks at 28.824. The crystal form C according to claim 3, wherein in the X-ray powder diffraction pattern, 2θ is 6.386, 6.437, 7.901, 9.405, 10.112, 12.285, 12.836, 14.372, 14.755, 15.810, 16.309, 17.355 There are characteristic peaks at 17.813, 18.557, 19.463, 20.665, 21.668, 23.153, 23.645, 24.996, 27.028, 27.722, 28.824, 30.557, 31.233, 32.127. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, 3-c] Pyrimidin-5-amine D crystal form, characterized in that in its X-ray powder diffraction pattern, there are characteristic peaks at 2θ of 6.084, 7.308, 12.665, 15.285, 16.459, 20.481, 25.514. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, 3-c] Pyrimidin-5-amine in the E-form, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ of 7.054, 11.059, 11.521, 14.993, 22.653, 22.994, 24.548. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, F-form of 3-c] pyrimidin-5-amine, characterized in that its X-ray powder diffraction pattern has characteristics at 2θ of 6.822, 8.156, 8.903, 10.334, 14.521, 16.270, 20.985, 24.239, 25.044 peak. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, The G crystal form of 3-c] pyrimidin-5-amine is characterized in that the X-ray powder diffraction pattern has characteristic peaks at 2θ of 6.706, 7.865, and 16.373. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, H-form of 3-c] pyrimidin-5-amine, characterized in that its X-ray powder diffraction pattern has characteristics at 2θ of 5.938, 6.514, 8.860, 11.414, 18.259, 19.298, 21.426, 23.438, 25.296 peak. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, 3-c] J-form of pyrimidine-5-amine, characterized in that in its X-ray powder diffraction pattern, 2θ is 6.938, 11.345, 15.342, 16.132, 16.716, 18.589, 19.726, 20.878, 21.233, 23.948, There are characteristic peaks at 26.167 and 28.431. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, The K-form of 3-c] pyrimidin-5-amine is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ of 6.803, 10.699, 11.277, 16.478, 18.414, 21.039, 23.619, 28.333. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, L-form of 3-c] pyrimidin-5-amine, characterized in that its X-ray powder diffraction pattern has characteristics at 2θ of 6.805, 11.278, 16.518, 18.364, 19.550, 20.620, 21.261, 23.604, 28.262 peak. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, 3-c] M crystal form of pyrimidine-5-amine, characterized in that in its X-ray powder diffraction pattern, 2θ is 8.419, 9.906, 16.265, 17.061, 17.785, 19.525, 19.798, 22.686, 25.456, 26.512 There are characteristic peaks. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, The N-type form of 3-c] pyrimidin-5-amine is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ of 6.587, 9.559, 13.320, 17.312, 18.158, 22.641, 23.080. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, The 3-crystalline form O of pyrimidine-5-amine is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ of 7.885, 12.357, 17.921, 18.927, 20.484, 20.600, 24.062, and 24.101. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[1,2,4] triazolo [4, 3-c] P form of pyrimidine-5-amine, characterized in that its X-ray powder diffraction pattern has characteristics at 2θ of 6.780, 10.661, 11.005, 13.537, 18.267, 20.851, 21.075, 21.835, 22.561 peak. The crystal form according to any one of claims 1 to 17, wherein the error range of the 2θ value is ± 0.2. Compound 8- (2- (difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl)-[ A, B, C, D, E, F, G, H, J, K, L, M, N, O or 1,2,4] triazolo [4,3-c] pyrimidin-5-amine or The preparation method of the P crystal form includes: taking a certain amount of a compound of formula I, adding an appropriate amount of a solvent, crystallizing, filtering, and drying to obtain the A crystal form, B crystal form, C crystal form, D crystal form, E Form, Form F, Form G, Form H, Form J, Form K, Form L, Form M, Form N, Form O, or Form P. A pharmaceutical composition, characterized in that it contains at least one crystalline form according to any one of claims 1-18, and further comprises one or more pharmaceutically acceptable carriers, diluents or excipients . A method for preparing a pharmaceutical composition, characterized in that it mixes at least one crystalline form according to any one of claims 1 to 18 with at least one pharmaceutically acceptable carrier, diluent or excipient . Use of the crystalline form according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 20 for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the A2a receptor. The crystalline form according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 20 in the preparation of a treatment selected from the group consisting of tumors, depression, cognitive disorders, neurodegenerative disorders, attention-related disorders, Use of medicines for diseases of one or more of extrapyramid syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behavior . The use according to claim 23, wherein the tumor is selected from the group consisting of melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, Neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, One or more of ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, chorionic epithelial cancer, and pediatric tumor. Use according to claim 23, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform One or more of encephalopathy, Creutzfeldt-Jakob disease, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, and spinal muscular atrophy.

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