WO2020052648A1 - Formes cristallines d'hétéroaryl[4,3-c]pyrimidine-5-amine, et leur procédé de préparation - Google Patents

Formes cristallines d'hétéroaryl[4,3-c]pyrimidine-5-amine, et leur procédé de préparation Download PDF

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WO2020052648A1
WO2020052648A1 PCT/CN2019/105682 CN2019105682W WO2020052648A1 WO 2020052648 A1 WO2020052648 A1 WO 2020052648A1 CN 2019105682 W CN2019105682 W CN 2019105682W WO 2020052648 A1 WO2020052648 A1 WO 2020052648A1
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compound
formula
peak
ray powder
powder diffraction
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PCT/CN2019/105682
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Chinese (zh)
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杨式波
杨俊然
杜振兴
王捷
尤凌峰
冯君
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201980044121.7A priority Critical patent/CN112334473B/zh
Publication of WO2020052648A1 publication Critical patent/WO2020052648A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • adenosine The role of adenosine is mediated by the G protein-coupled receptor family.
  • G protein-coupled receptor family At least four subtypes of adenosine receptors are currently known, classified as A1, A2a, A2b, and A3.
  • A1 and A3 receptors inhibit the activity of the enzyme adenylate cyclase
  • A2a and A2b receptors stimulate the activity of the enzyme, thereby regulating the level of cyclic AMP in cells.
  • 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.
  • 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.
  • CNS central nervous system
  • adenosine A2a receptor antagonists also have therapeutic potential as neuroprotective agents (see Jenner P. J. Neurol 2000. 24; 7Supp 12: 1143-50).
  • 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.
  • 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.
  • A2a receptor antagonists can also be used in the treatment of tumors.
  • adenosine A1 receptor 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.
  • the A1 receptor can reduce free fatty acids and triglycerides and participate in regulating blood sugar.
  • Adenosine receptor A3 (as described by Gessi et al., Pharmacol. Ther.
  • 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.
  • 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.
  • 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.
  • 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 2 ⁇ of 4.985, 10.167, 15.393, 26.651, and 27.364.
  • the X-ray powder diffraction pattern of the Form A has characteristic peaks at diffraction angles 2 ⁇ of 4.985, 10.167, 15.393, 26.651, 27.364, 30.581, and 31.154.
  • the X-ray powder diffraction pattern of the crystal form A has a diffraction angle 2 ⁇ 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 2 ⁇ of 7.953, 11.138, 13.618, 16.256, 17.985, 18.949, 20.588, 21.924, 22.853 There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the Form B has characteristic peaks at diffraction angles 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the B crystal form has a diffraction angle 2 ⁇ 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 2 ⁇ of 12.285, 12.836, 14.372, 14.755, 17.813, 18.557, 20.665, 21.668, 23.153 There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2 ⁇ 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. .
  • the X-ray powder diffraction pattern of the crystal form C has a diffraction angle 2 ⁇ 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 2 ⁇ of 6.084, 7.308, 12.665, 15.285, 16.459, 20.481, 25.514. .
  • the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at diffraction angles 2 ⁇ 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. .
  • the X-ray powder diffraction pattern of the D crystal form has a diffraction angle 2 ⁇ 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 2 ⁇ of 7.054, 11.059, 11.521, 14.993, 22.653, 22.994, 24.548. .
  • the X-ray powder diffraction pattern of the E form has a diffraction angle 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the E form at a diffraction angle 2 ⁇ 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 2 ⁇ of 6.822, 8.156, 8.903, 10.334, 14.521, 16.270, 20.985, 24.239, 25.044 There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the F crystal form has a diffraction angle 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the F crystal form has a diffraction angle 2 ⁇ 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 2 ⁇ of 6.706, 7.865, and 16.373.
  • the X-ray powder diffraction pattern of the G crystal form has characteristic peaks at diffraction angles 2 ⁇ of 6.706, 7.865, 16.373, 21.764, 23.986, 25.692, 27.524, 32.236.
  • the X-ray powder diffraction pattern of the G crystal form has characteristic peaks at diffraction angles 2 ⁇ 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 2 ⁇ of 5.938, 6.514, 8.860, 11.414, 18.259, 19.298, 21.426, 23.438, 25.296 There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the H crystal form has characteristic peaks at diffraction angles 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the H crystal form has a diffraction angle 2 ⁇ 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 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the J form has a diffraction angle 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the J form has a diffraction angle 2 ⁇ 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 2 ⁇ of 6.803, 10.699, 11.277, 16.478, 18.414, 21.039, 23.619, 28.333 Characteristic peaks.
  • the X-ray powder diffraction pattern of the K form has characteristic peaks at diffraction angles 2 ⁇ 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. .
  • the X-ray powder diffraction pattern of the K-type crystal has a diffraction angle 2 ⁇ 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 2 ⁇ of 6.805, 11.278, 16.518, 18.364, 19.550, 20.620, 21.261, 23.604, 28.262 There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the L crystal form has a diffraction angle 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the L crystal form has a diffraction angle 2 ⁇ 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 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the M crystal form has a diffraction angle 2 ⁇ 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
  • a diffraction angle 2 ⁇ 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
  • the X-ray powder diffraction pattern of the M crystal form has a diffraction angle 2 ⁇ 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 2 ⁇ of 6.587, 9.559, 13.320, 17.312, 18.158, 22.641, 23.080. .
  • the X-ray powder diffraction pattern of the N crystal form has a diffraction angle 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the N crystal form has a diffraction angle 2 ⁇ 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 2 ⁇ of 7.885, 12.357, 17.921, 18.927, 20.484, 20.600, 24.062, 24.101. Characteristic peaks.
  • the X-ray powder diffraction pattern of the O crystal form has characteristic peaks at diffraction angles 2 ⁇ of 7.885, 12.357, 17.921, 18.927, 20.484, 20.600, 21.781, 22.904, 24.062, and 24.101.
  • the X-ray powder diffraction pattern of the O crystal form has a diffraction angle 2 ⁇ 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 2 ⁇ of 6.780, 10.661, 11.005, 13.537, 18.267, 20.851, 21.075, 21.835, 22.561 There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the P crystal form has characteristic peaks at diffraction angles 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the P crystal form has a diffraction angle 2 ⁇ 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.
  • 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,
  • 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
  • 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
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical preparation may further contain a suitable filler, a binder, a disintegrant, a lubricant, and the like.
  • the pharmaceutical preparations When used for parenteral administration, the pharmaceutical preparations can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the pharmaceutical composition When prepared as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • 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.
  • the pharmaceutical preparations When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like.
  • the pharmaceutical preparation When used for pulmonary administration, the pharmaceutical preparation can be made into an inhaler or a spray.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • ketoone 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.
  • 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.
  • 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-K ⁇ 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 “2 ⁇ or 2 ⁇ angle” in the present invention refers to a diffraction angle, ⁇ is a Bragg angle, and the unit is ° or degree.
  • the error range of the 2 ⁇ can be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • 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;
  • 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. 8 is a TGA diagram of a compound of formula I in the form of B crystal
  • FIG. 9 is a DVS hygroscopic spectrum of a compound of formula I in the form of Form B;
  • 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. 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. 14 is a DVS hygroscopic spectrum chart of the compound of the 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. 18 is a DSC chart of a compound of formula I in the D crystal form
  • FIG. 19 is a TGA diagram of a compound of Formula I in the D crystalline form
  • FIG. 20 is a DVS hygroscopic spectrum chart of a compound of formula I in the D crystal form
  • 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;
  • 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. 24 is a TGA diagram of a compound of formula I in the form of E-form
  • 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. 29 is a DSC chart of a compound of formula I in the G crystalline form
  • 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. 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. 37 is an XRPD pattern of the compound of formula I in the form of K crystal form
  • FIG. 38 is a DSC chart of a compound of formula I in the form of a K crystal form
  • FIG. 39 is a TGA diagram of a compound of formula I in the form of K crystal form.
  • FIG. 40 is an XRPD pattern of the compound of formula I in the L crystal form
  • FIG. 41 is a DSC chart of a compound of formula I in the L crystal form
  • FIG. 44 is a DSC chart of a compound of formula I in the M crystalline form
  • FIG. 45 is a TGA diagram of a compound of formula I in the form of M crystal form
  • 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
  • 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.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS).
  • NMR shift ( ⁇ ) 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) Methylsilane
  • MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).
  • 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-K ⁇ rays Scanning mode: ⁇ / 2 ⁇ , 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 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 dynamic moisture adsorption: The detection adopts SMS DVS Advantage. At 25 °C, 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.
  • 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%).
  • 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%).
  • 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.
  • CHO-K1 / A 2a R cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 800 ⁇ g / mL bleomycin.
  • 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.
  • test compounds were incubated at room temperature for 30 minutes. Add 2.5 ⁇ L of 4 ⁇ concentration of ethyl carbazole in a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M 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.
  • 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.
  • 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.
  • 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 ⁇ M, 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 ⁇ L of diluted cAMP-d2 to each well, and add 12.5 ⁇ L 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.
  • CHO-K1 / A 3 R was cultured in DMEM / F12 medium containing 10% fetal bovine serum and 10 ⁇ g / 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.
  • 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 ⁇ L of diluted cAMP-d2 to each well, and then add 12.5 ⁇ L 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.
  • 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 ⁇ L of cell suspension to each well in a 384-well plate, 2.5 ⁇ L of 4 ⁇ prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M Rolipram, and 2.7 U / mL adenosine deaminase.
  • test compounds were incubated at room temperature for 30 minutes. Add 2.5 ⁇ L of 4 ⁇ concentration ethylcarbazole (Torcis, 4 ⁇ concentration) prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M 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 ⁇ M. Intracellular cAMP concentration was measured using the cAMP Dynamic 2 kit.
  • 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.
  • mice 4 C57 mice, female, 12/12 hours light / dark adjustment, temperature 24 ⁇ 3 °C 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.
  • 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.
  • 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 % ).
  • 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
  • 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).
  • 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 °C 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.
  • 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.
  • 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.
  • 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).
  • 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 °C 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 °C 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of formula I (10 mg) was added to 40 ⁇ L 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 °C 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • the exothermic peak is 256.23 ° C.
  • the TGA spectrum is shown in Figure 33.
  • 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
  • Peak 1 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
  • 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.
  • 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
  • the second exothermic peak is 262.28 ° C; 42.
  • 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
  • the exothermic peak is 258.26 ° C.
  • the TGA spectrum is shown in Figure 45.
  • 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 27.7
  • 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
  • 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
  • the second exothermic peak is The peak value is 251.61 ° C
  • the TGA spectrum is shown in Figure 48.
  • 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
  • DVS characterization The sample at 25 °C 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention concerne des formes cristallines d'un composé hétéroaryl[4,3-c]pyrimidine-5-amine tel que représenté dans la formule (I), et son procédé de préparation, les formes cristallines étant spécifiquement des formes cristallines A, B, C, D, E, F, G, H, J, K, L, M, N, O et P. Les formes cristallines ont une bonne stabilité de forme cristalline, et conviennent particulièrement à un usage clinique.
PCT/CN2019/105682 2018-09-14 2019-09-12 Formes cristallines d'hétéroaryl[4,3-c]pyrimidine-5-amine, et leur procédé de préparation WO2020052648A1 (fr)

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WO2018166493A1 (fr) * 2017-03-16 2018-09-20 江苏恒瑞医药股份有限公司 Dérivé d'hétéroaryl[4,3-c]pyrimidine-5-amine, son procédé de préparation et ses utilisations médicales

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