WO2019206154A1 - Cdk4/6抑制剂及其药学上可接受的盐和多晶型物及其应用 - Google Patents

Cdk4/6抑制剂及其药学上可接受的盐和多晶型物及其应用 Download PDF

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WO2019206154A1
WO2019206154A1 PCT/CN2019/083970 CN2019083970W WO2019206154A1 WO 2019206154 A1 WO2019206154 A1 WO 2019206154A1 CN 2019083970 W CN2019083970 W CN 2019083970W WO 2019206154 A1 WO2019206154 A1 WO 2019206154A1
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ray powder
compound
diffraction pattern
powder diffraction
formula
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江涛涛
李金晶
赵双妮
姚霞
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Priority to US17/050,392 priority Critical patent/US20210214358A1/en
Priority to CN201980006359.0A priority patent/CN111566101B/zh
Priority to JP2021508052A priority patent/JP2021521282A/ja
Priority to EP19792044.0A priority patent/EP3786161A4/en
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    • 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
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention belongs to the field of medical technology, and in particular to a CDK4/6 inhibitor, and pharmaceutically acceptable salts and polymorphs thereof, and the use thereof, the inhibitor is 2-cyclopropyl-N- (5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-3-isopropyl-3,8-dihydroimidazo[4',5',4,5 Cyclopentadien[1,2-d]pyrimidine-5-amine.
  • CDK is a type of serine/threonine protein kinase that has kinase activity only when it binds to cyclins and plays a key role in the initiation of cell cycle and regulation of transformation in various periods.
  • CDK4/6 is an important regulatory protein of the cell cycle, which phosphorylates the tumor suppressor protein Rb and releases the E2F transcription factor, allowing cells to pass through the G1/S detection point of the cell cycle, and the cell cycle can continue.
  • CDK4 single knockout mice have diabetes signs and cell defects
  • CDK6 single knockout mice have mild anemia symptoms due to defects in hematopoietic cell proliferation
  • CDK4 and CDK6 (CDK4/6) double knockouts make hematopoietic precursor cells Impaired proliferative capacity, leading to double knockout of mouse embryonic death.
  • Superactivation of the CDK4/6-cyclin D/Rb signaling pathway is commonly found in tumor cells. Under the stimulation of various mitotic signals inside and outside the cell, cyclin D is highly expressed, regulates the interaction between CDK4/6 protein and cyclin D, and promotes the localization and kinase activity of CDK4/6.
  • Activated CDK4/6 inhibits the activity of Rb tumor suppressor protein by phosphorylation, dissociates the Rb-E2F complex, releases free E2F into the nucleus, regulates protein transcription, and initiates cell cycle progression.
  • Superactivation of CDK4 is often found in epithelial malignancies, whereas superactivation of CDK6 is often found in stromal cell tumors such as sarcomas and hematological cancers. Construction of a breast cancer-bearing mouse model revealed that wild-type nude mice all formed tumors, while CDK4 knockout nude mice were completely unable to form tumors.
  • CDK4 siRNA interfered with the expression of CDK4, and it was found that the tumor growth of nude mice was significantly inhibited.
  • Selective CDK4/6 inhibitors can induce G1 arrest in cells, thereby increasing the tolerance of hematopoietic stem/progenitor cells to DNA damaging agents such as IR, and effectively reducing various hematopoietic toxicities caused by radiation, including myelosuppression and susceptibility. Neutrophilic leukopenia, leukopenia, anemia, etc.
  • CDK4 can inhibit the growth of tumor cells, while CDK6 is highly expressed in the blood system, and its function is to regulate the growth of hematopoietic cells.
  • the inhibition of CDK6 may cause hematological toxicity, such as neutrophils. Reduce, red blood cell reduction, etc.
  • Palbociclib has the same inhibition on both CDK4 and CDK6, with enzyme activities of 10 nm and 10 nm, respectively, and its toxicity should be related to this.
  • Abemaciclib inhibits CDK4 more strongly than CDK6; weak CDK6 inhibitors cause low hematologic toxicity. Since the homology of CDK4 and CDK6 is very high, about 70%, the development of selective CDK4/6 inhibitors, especially CDK4 inhibitors, is a big challenge.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, hydrobromide, phosphate, methanesulfonate, maleate, L-tartrate, Citrate, fumarate, formate.
  • the polymorph of the pharmaceutically acceptable salt of the compound of formula X or the compound of formula X and a pharmaceutically acceptable salt thereof is in the form of an anhydrous form, a hydrate form or a solvate.
  • the pharmaceutically acceptable salt is selected from the group consisting of: maleate, hydrochloride, formate.
  • the pharmaceutically acceptable salt is a maleate salt
  • the molar ratio of maleic acid to the compound of formula X is (0.8-2.1):1, preferably (1.1-1.2):1.
  • the pharmaceutically acceptable salt is a hydrochloride salt
  • the molar ratio of hydrochloric acid to the compound of the formula X is (0.8-2.1):1, preferably (1.1-1.2):1.
  • the polymorph is a Form A crystal of the compound maleate of the formula X, ie, Form A, the X-ray powder diffraction pattern of which has a diffraction angle 2 ⁇ (°) of the lower group A1. Peaks: 4.47 ⁇ 0.2, 8.93 ⁇ 0.2, 13.41 ⁇ 0.2, 13.98 ⁇ 0.2, 15.77 ⁇ 0.2, 16.52 ⁇ 0.2, 17.18 ⁇ 0.2, 18.06 ⁇ 0.2, 18.61 ⁇ 0.2, 19.16 ⁇ 0.2, 21.50 ⁇ 0.2, 22.26 ⁇ 0.2, 23.43 ⁇ 0.2, 23.84 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form A further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group A2: 14.97 ⁇ 0.2, 15.95 ⁇ 0.2, 20.27 ⁇ 0.2, 20.90 ⁇ 0.2, 24.08 ⁇ 0.2, 24.83 ⁇ 0.2, 26.20 ⁇ 0.2, 30.38 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form A further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group A3: 10.42 ⁇ 0.2, 11.11 ⁇ 0.2, 12.78 ⁇ 0.2, 21.96 ⁇ 0.2, 22.77 ⁇ 0.2, 27.03 ⁇ 0.2, 27.88 ⁇ 0.2, 28.60 ⁇ 0.2, 29.06 ⁇ 0.2, 31.64 ⁇ 0.2, 32.29 ⁇ 0.2, 35.91 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form A is selected from 6 or more or all of Groups A1, A2, and A3 (eg, 6, 7, 8, 9, 10, 11) , 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of Form A has a peak at a 2 ⁇ (°) value shown in Table A1, and the relative intensities of the respective peaks are as shown in Table A1:
  • the X-ray powder diffraction pattern of Form A is substantially characterized as in Figure 1.
  • the molar ratio of maleic acid to the compound of formula X in the crystalline form A is (0.8-2.1):1, preferably (1.0-1.2):1, more preferably 1.2:1. .
  • the crystalline form A is in anhydrous form.
  • the Form A also has one or more characteristics selected from the group consisting of:
  • the onset temperature is 193 ⁇ 2 ° C; preferably, the differential scanning calorimetry analysis pattern is substantially characterized by Figure 2;
  • the crystalline form A has a melting point of 193 to 211 ° C, preferably 205 to 207 ° C.
  • the polymorph is a B-1 type crystal of the hydrochloride salt of the compound of the formula X, that is, the crystal form B-1, and the X-ray powder diffraction pattern thereof is in the diffraction angle of the lower group B-1-1.
  • the 2 ⁇ (°) value has peaks: 4.93 ⁇ 0.2, 6.78 ⁇ 0.2, 8.04 ⁇ 0.2, 9.82 ⁇ 0.2, 12.46 ⁇ 0.2, 14.75 ⁇ 0.2, 15.32 ⁇ 0.2, 21.17 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form B-1 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group B-1-2: 10.63 ⁇ 0.2, 14.48 ⁇ 0.2, 15.78 ⁇ 0.2, 22.21 ⁇ 0.2, 23.19 ⁇ 0.2, 23.56 ⁇ 0.2, 27.42 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form B-1 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group B-1-3: 6.30 ⁇ 0.2, 11.09 ⁇ 0.2, 11.69 ⁇ 0.2, 17.46 ⁇ 0.2, 18.80 ⁇ 0.2, 20.32 ⁇ 0.2, 28.32 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form B-1 is selected from 6 or more of Groups B-1-1, B-1-2, and B-1-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystal form B-1 has a peak at a 2 ⁇ (°) value shown in Table (B-1), and the relative intensity of each peak is as shown in Table (B-1). Shown as follows:
  • the X-ray powder diffraction pattern of Form B-1 is substantially characterized as in Figure 4.
  • the molar ratio of hydrochloric acid to the compound of the formula X in the crystalline form B-1 is (0.8-2.1):1, preferably (1.0-1.2):1, more preferably 1.2:1. .
  • the crystalline form B-1 further has one or more characteristics selected from the group consisting of:
  • the onset temperature is 240 ⁇ 2 ° C and 263 ⁇ 2 ° C; preferably, the differential scanning calorimetry analysis pattern is substantially characterized as in Figure 5;
  • thermogravimetric analysis maps are substantially characterized as shown in Figure 6;
  • the crystal form B-1 has a weight loss of about 7.4% at 50 ° C to 90 ° C. According to the calculation, it should be the reason why the HCl in the compound is removed, and the compound is unstable at a high temperature (above 50 ° C);
  • the polymorph is a B-2 type crystal of the hydrochloride salt of the compound of the formula X, that is, the crystal form B-2, and the X-ray powder diffraction pattern thereof is in the diffraction angle of the lower group B-2-1.
  • peaks at 2 ⁇ (°) values 4.56 ⁇ 0.2, 11.41 ⁇ 0.2, and 13.60 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form B-2 further comprises peaks at the diffraction angle 2 ⁇ (°) of the lower group B-2-2: 5.72 ⁇ 0.2, 9.06 ⁇ 0.2, 17.72 ⁇ 0.2, 22.92 ⁇ 0.2, 23.71 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form B-2 is selected from 6 or more or all of Group B-2-1, B-2-2 (eg, 6, 7 , 8 , etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystal form B-2 has a peak at a 2 ⁇ (°) value shown in Table (B-2), and the relative intensity of each peak is as shown in Table (B-2). Shown as follows:
  • the X-ray powder diffraction pattern of Form B-2 is substantially characterized as in Figure 7.
  • the polymorph is a B-3 type crystal of the hydrochloride salt of the compound of formula X, ie, Form B-3, the X-ray powder diffraction pattern of which is in the diffraction angle of the lower group B-3-1. There are peaks at 2 ⁇ (°) values: 5.03 ⁇ 0.2, 9.97 ⁇ 0.2, and 14.96 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form B-3 further includes peaks at a diffraction angle 2 ⁇ (°) of the lower group B-3-2: 11.98 ⁇ 0.2, 17.07 ⁇ 0.2, 25.00 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form B-3 further comprises a peak at a diffraction angle 2 ⁇ (°) of 2 or more lower groups B-3-3: 12.59 ⁇ 0.2, 16.06 ⁇ 0.2, 16.64 ⁇ 0.2, 18.07 ⁇ 0.2, 20.05 ⁇ 0.2, 21.05 ⁇ 0.2, 21.98 ⁇ 0.2, 22.40 ⁇ 0.2, 23.50 ⁇ 0.2, 24.04 ⁇ 0.2, 25.90 ⁇ 0.2, 27.03 ⁇ 0.2, 30.12 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form B-3 is selected from 6 or more selected from the group B-3-1, B-3-2, and B-3-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystalline form B-3 has a peak at a 2 ⁇ (°) value shown in Table (B-3), and the relative intensities of the respective peaks are shown in Table (B-3). Shown as follows:
  • the X-ray powder diffraction pattern of Form B-3 is substantially characterized as in Figure 8.
  • the polymorph is a C-1 type crystal of a sulfate of the compound of the formula X, that is, a crystal form C-1, and an X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of the lower group C-1-1.
  • the (°) value has peaks: 9.13 ⁇ 0.2, 9.71 ⁇ 0.2, 10.50 ⁇ 0.2, 11.19 ⁇ 0.2, 13.72 ⁇ 0.2, 13.94 ⁇ 0.2, 15.70 ⁇ 0.2, 16.79 ⁇ 0.2, 22.46 ⁇ 0.2, 23.87 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form C-1 further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group consisting of C-1-2: 4.60 ⁇ 0.2, 12.35 ⁇ 0.2, 15.26 ⁇ 0.2, 18.23 ⁇ 0.2, 19.40 ⁇ 0.2, 25.56 ⁇ 0.2, 26.11 ⁇ 0.2, 27.68 ⁇ 0.2, 28.43 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form C-1 further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group consisting of C-1-3: 14.78 ⁇ 0.2, 21.50 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form C-1 is selected from 6 or more selected from the group consisting of C-1-1, C-1-2, and C-1-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystalline form C-1 has a peak at a 2 ⁇ (°) value shown in Table (C-1), and the relative intensity of each peak is shown in Table (C-1). Shown as follows:
  • the X-ray powder diffraction pattern of Form C-1 is substantially characterized as in Figure 9.
  • the polymorph is a C-2 type crystal of the sulfate of the compound of the formula X, that is, the crystal form C-2, and the X-ray powder diffraction pattern thereof has a diffraction angle 2 ⁇ of the lower group C-2-1.
  • the (°) value has peaks: 10.47 ⁇ 0.2, 14.78 ⁇ 0.2, 15.72 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form C-2 further includes peaks at a diffraction angle 2 ⁇ (°) value of the lower group C-2-2: 5.29 ⁇ 0.2, 19.36 ⁇ 0.2, 19.75 ⁇ 0.2, 20.58 ⁇ 0.2, 21.96 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form C-2 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group C-2-3: 7.21 ⁇ 0.2, 9.74 ⁇ 0.2, 11.37 ⁇ 0.2, 12.25 ⁇ 0.2, 16.34 ⁇ 0.2, 16.67 ⁇ 0.2, 17.14 ⁇ 0.2, 18.89 ⁇ 0.2, 21.30 ⁇ 0.2, 22.40 ⁇ 0.2, 23.28 ⁇ 0.2, 23.75 ⁇ 0.2, 24.59 ⁇ 0.2, 26.73 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form C-2 is selected from 6 or more selected from the group consisting of Groups C-2-1, C-2-2, and C-2-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystalline form C-2 has a peak at a 2 ⁇ (°) value shown in Table (C-2), and the relative intensities of the respective peaks are shown in Table (C-2). Shown as follows:
  • the X-ray powder diffraction pattern of Form C-2 is substantially characterized as in Figure 10.
  • the polymorph is a D-type crystal of the hydrobromide salt of the compound of formula X, ie, Form D, the X-ray powder diffraction pattern of which has a diffraction angle 2 ⁇ (°) of the lower group D1. Peaks: 7.99 ⁇ 0.2, 9.74 ⁇ 0.2, 10.53 ⁇ 0.2, 12.37 ⁇ 0.2, 14.64 ⁇ 0.2, 15.21 ⁇ 0.2, 21.04 ⁇ 0.2, 22.11 ⁇ 0.2, 23.03 ⁇ 0.2, 23.38 ⁇ 0.2, 24.45 ⁇ 0.2, 27.22 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form D further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group D2: 14.42 ⁇ 0.2, 15.76 ⁇ 0.2, 17.30 ⁇ 0.2, 18.09 ⁇ 0.2, 18.74 ⁇ 0.2, 20.29 ⁇ 0.2, 26.48 ⁇ 0.2, 28.10 ⁇ 0.2, 28.74 ⁇ 0.2, 29.86 ⁇ 0.2, 30.64 ⁇ 0.2, 31.11 ⁇ 0.2, 32.11 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form D further comprises a peak at a diffraction angle 2 ⁇ (°) selected from the group D3: 29.09 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form D is selected from 6 or more or all of Groups D1, D2, and D3 (eg, 6, 7, 8, 9, 10, 11) , 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the Form D has a peak at a 2 ⁇ (°) value shown in Table D1, and the relative intensities of the respective peaks are as shown in Table D1:
  • the X-ray powder diffraction pattern of Form D is substantially characterized as in Figure 11.
  • the polymorph is an E-type crystal of the compound L-tartrate of the formula X, that is, the crystal form E, and the X-ray powder diffraction pattern thereof has a diffraction angle 2 ⁇ (°) value of the lower group E1. Peaks: 6.43 ⁇ 0.2, 10.02 ⁇ 0.2, 11.63 ⁇ 0.2, 16.07 ⁇ 0.2, 19.33 ⁇ 0.2, 22.59 ⁇ 0.2, 25.88 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form E further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group E2: 7.46 ⁇ 0.2, 10.69 ⁇ 0.2, 12.88 ⁇ 0.2, 16.76 ⁇ 0.2, 20.42 ⁇ 0.2, 25.13 ⁇ 0.2, 26.52 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form E is at 6 or more or all selected from Groups E1, E2 (eg, 6, 7, 8, 9, 10, 11, 12) , 13, 14, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the Form E has a peak at a 2 ⁇ (°) value shown in Table E1, and the relative intensities of the respective peaks are as shown in Table E1:
  • the X-ray powder diffraction pattern of Form E is substantially as characterized in FIG.
  • the polymorph is a Form F crystal of the compound phosphate of Formula X, ie, Form F, the X-ray powder diffraction pattern having a peak at a diffraction angle 2 ⁇ (°) of the lower group F1: 12.03 ⁇ 0.2, 17.26 ⁇ 0.2, 19.65 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form F further comprises peaks at diffraction angle 2[Theta] ([deg.]) values of the lower group F2: 5.99 ⁇ 0.2, 18.20 ⁇ 0.2, 21.01 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form F further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group F3: 8.59 ⁇ 0.2, 13.41 ⁇ 0.2, 13.69 ⁇ 0.2, 14.21 ⁇ 0.2, 15.57 ⁇ 0.2, 19.15 ⁇ 0.2, 20.34 ⁇ 0.2, 21.70 ⁇ 0.2, 21.99 ⁇ 0.2, 22.98 ⁇ 0.2, 23.59 ⁇ 0.2, 25.01 ⁇ 0.2, 25.52 ⁇ 0.2, 26.74 ⁇ 0.2, 34.64 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form F is selected from 6 or more or all of Groups F1, F2, and F3 (eg, 6, 7, 8, 9, 10, 11) , 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the Form F has a peak at a 2 ⁇ (°) value shown in Table F1, and the relative intensity of each peak is as shown in Table F1:
  • the X-ray powder diffraction pattern of Form F is substantially characterized as in Figure 13.
  • the polymorph is a G-type crystal of the citrate salt of the compound of formula X, ie, Form G, and the X-ray powder diffraction pattern has a peak at a diffraction angle 2 ⁇ (°) of the lower group G1. : 9.13 ⁇ 0.2, 10.13 ⁇ 0.2, 11.06 ⁇ 0.2, 12.38 ⁇ 0.2, 13.04 ⁇ 0.2, 14.07 ⁇ 0.2, 14.72 ⁇ 0.2, 15.33 ⁇ 0.2, 19.16 ⁇ 0.2, 20.31 ⁇ 0.2, 24.83 ⁇ 0.2, 28.04 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form G further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group G2: 6.05 ⁇ 0.2, 16.25 ⁇ 0.2, 17.18 ⁇ 0.2, 18.31 ⁇ 0.2, 20.58 ⁇ 0.2, 22.29 ⁇ 0.2, 23.26 ⁇ 0.2, 24.35 ⁇ 0.2, 26.06 ⁇ 0.2, 27.67 ⁇ 0.2, 29.77 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form G further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group G3: 8.48 ⁇ 0.2, 13.43 ⁇ 0.2, 19.74 ⁇ 0.2, 20.92 ⁇ 0.2, 26.66 ⁇ 0.2, 30.85 ⁇ 0.2, 32.75 ⁇ 0.2, 34.21 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form G is selected from 6 or more or all of the groups G1, G2, and G3 (eg, 6, 7, 8, 9, 10, 11) , 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the Form G has a peak at a 2 ⁇ (°) value shown in Table G1, and the relative intensities of the respective peaks are as shown in Table G1:
  • the X-ray powder diffraction pattern of Form G is substantially characterized as in Figure 14.
  • the polymorph is a H-1 type crystal of the compound of the formula X fumarate, that is, the crystal form H-1, and the X-ray powder diffraction pattern thereof is diffracted in the lower group H-1-1.
  • the angle 2 ⁇ (°) has peaks: 5.37 ⁇ 0.2, 10.74 ⁇ 0.2, 17.67 ⁇ 0.2, 19.08 ⁇ 0.2, 19.35 ⁇ 0.2, 20.11 ⁇ 0.2, 21.25 ⁇ 0.2, 22.84 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form H-1 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group H-1-2: 8.83 ⁇ 0.2, 11.60 ⁇ 0.2, 12.33 ⁇ 0.2, 13.57 ⁇ 0.2, 15.38 ⁇ 0.2, 16.06 ⁇ 0.2, 16.56 ⁇ 0.2, 17.08 ⁇ 0.2, 18.41 ⁇ 0.2, 19.66 ⁇ 0.2, 21.74 ⁇ 0.2, 23.59 ⁇ 0.2, 24.19 ⁇ 0.2, 29.98 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form H-1 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group H-1-3: 12.03 ⁇ 0.2, 14.47 ⁇ 0.2, 17.33 ⁇ 0.2, 25.56 ⁇ 0.2, 26.49 ⁇ 0.2, 28.56 ⁇ 0.2, 29.10 ⁇ 0.2, 33.12 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form H-1 is selected from 6 or more selected from the group consisting of H-1-1, H-1-2, and H-1-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystal form H-1 has a peak at a 2 ⁇ (°) value shown in Table (H-1), and the relative intensity of each peak is shown in Table (H-1). Shown as follows:
  • the X-ray powder diffraction pattern of Form H-1 is substantially characterized as in Figure 15.
  • the polymorph is a H-2 type crystal of the compound of the formula X fumarate, ie, Form H-2, and the X-ray powder diffraction pattern is diffracted in the lower group H-2-1.
  • the angle 2 ⁇ (°) has peaks: 5.69 ⁇ 0.2, 11.67 ⁇ 0.2, 14.39 ⁇ 0.2, 21.15 ⁇ 0.2, 23.49 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form H-2 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group H-2-2: 17.06 ⁇ 0.2, 17.33 ⁇ 0.2, 17.56 ⁇ 0.2, 18.05 ⁇ 0.2, 18.81 ⁇ 0.2, 21.80 ⁇ 0.2, 22.68 ⁇ 0.2, 23.74 ⁇ 0.2, 25.97 ⁇ 0.2, 29.48 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form H-2 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group H-2-3: 7.16 ⁇ 0.2, 9.43 ⁇ 0.2, 14.86 ⁇ 0.2, 19.95 ⁇ 0.2, 20.51 ⁇ 0.2, 24.41 ⁇ 0.2, 24.90 ⁇ 0.2, 28.70 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form H-2 is selected from 6 or more selected from the group consisting of H-2, H-2-2, and H-2-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the Form H-2 has a peak at a 2 ⁇ (°) value shown in Table (H-2), and the relative intensity of each peak is shown in Table (H-2). Shown as follows:
  • the X-ray powder diffraction pattern of Form H-2 is substantially characterized as in Figure 16.
  • the polymorph is a J-type crystal of the methanesulfonate salt of the compound of the formula X, that is, the crystal form J, and the X-ray powder diffraction pattern thereof has a diffraction angle 2 ⁇ (°) value of the lower group J1. Peaks: 10.64 ⁇ 0.2, 18.70 ⁇ 0.2, 20.55 ⁇ 0.2, 20.86 ⁇ 0.2, 21.58 ⁇ 0.2, 22.16 ⁇ 0.2, 23.05 ⁇ 0.2, 24.39 ⁇ 0.2, 24.75 ⁇ 0.2, 27.18 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form J further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group J2: 4.87 ⁇ 0.2, 8.06 ⁇ 0.2, 9.13 ⁇ 0.2, 9.77 ⁇ 0.2, 12.51 ⁇ 0.2, 13.89 ⁇ 0.2, 14.69 ⁇ 0.2, 15.81 ⁇ 0.2, 16.10 ⁇ 0.2, 17.22 ⁇ 0.2, 17.98 ⁇ 0.2, 19.31 ⁇ 0.2, 19.75 ⁇ 0.2, 20.23 ⁇ 0.2, 23.98 ⁇ 0.2, 25.97 ⁇ 0.2, 27.43 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form J further comprises a peak at a diffraction angle 2 ⁇ (°) selected from the group J3: 6.93 ⁇ 0.2, 16.62 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form J is selected from 6 or more or all of Groups J1, J2, and J3 (eg, 6, 7, 8, 9, 10, 11) , 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the Form J has peaks at a value of 2 ⁇ (°) shown in Table J1, and the relative intensities of the respective peaks are as shown in Table J1:
  • the X-ray powder diffraction pattern of Form J is substantially characterized as in Figure 17.
  • the polymorph is a K-1 type crystal of the formic acid salt of the compound of the formula X, ie, the crystalline form K-1, and the X-ray powder diffraction pattern thereof is in the diffraction angle of the lower group K-1-1.
  • the X-ray powder diffraction pattern of Form K-1 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group K-1-2: 10.98 ⁇ 0.2, 11.21 ⁇ 0.2, 13.32 ⁇ 0.2, 15.17 ⁇ 0.2, 15.65 ⁇ 0.2, 16.96 ⁇ 0.2, 21.33 ⁇ 0.2, 24.15 ⁇ 0.2, 27.96 ⁇ 0.2, 28.19 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-1 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group K-1-3: 16.19 ⁇ 0.2, 16.70 ⁇ 0.2, 17.49 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-1 is selected from 6 or more selected from the group consisting of K-1-1, K-1-2, and K-1-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the Form K-1 has a peak at a 2 ⁇ (°) value shown in Table (K-1), and the relative intensity of each peak is shown in Table (K-1). Shown as follows:
  • the X-ray powder diffraction pattern of Form K-1 is substantially characterized as in Figure 18.
  • the polymorph is a K-2 type crystal of the formic acid salt of the compound of the formula X, that is, the crystalline form K-2, and the X-ray powder diffraction pattern thereof is in the diffraction angle of the lower group K-2-1.
  • the 2 ⁇ (°) value has peaks: 5.23 ⁇ 0.2, 17.05 ⁇ 0.2, 17.31 ⁇ 0.2, 21.28 ⁇ 0.2, 22.50 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-2 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group K-2-2: 10.53 ⁇ 0.2, 12.33 ⁇ 0.2, 12.75 ⁇ 0.2, 13.99 ⁇ 0.2, 15.54 ⁇ 0.2, 16.44 ⁇ 0.2, 18.23 ⁇ 0.2, 19.47 ⁇ 0.2, 22.93 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-2 further comprises a peak at a diffraction angle 2 ⁇ (°) value of the lower group K-2-3: 19.86 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-2 is selected from 6 or more selected from the group K-2-1, K-2-2, and K-2-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystalline form K-2 has a peak at a 2 ⁇ (°) value shown in Table (K-2), and the relative intensity of each peak is shown in Table (K-2). Shown as follows:
  • the X-ray powder diffraction pattern of Form K-2 is substantially characterized as in Figure 19.
  • the polymorph is a K-3 type crystal of the formic acid salt of the compound of the formula X, that is, the crystalline form K-3, and the X-ray powder diffraction pattern thereof is in the diffraction angle of the lower group K-3-1.
  • peaks at 2 ⁇ (°) values 4.51 ⁇ 0.2, 5.27 ⁇ 0.2, and 13.76 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-3 further comprises a peak at a diffraction angle 2 ⁇ (°) of the following group K-3-2: 9.17 ⁇ 0.2, 13.28 ⁇ 0.2, 15.77 ⁇ 0.2, 23.91 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-3 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group K-3-3: 11.25 ⁇ 0.2, 12.36 ⁇ 0.2, 14.93 ⁇ 0.2, 16.46 ⁇ 0.2, 17.11 ⁇ 0.2, 18.45 ⁇ 0.2, 21.11 ⁇ 0.2, 22.09 ⁇ 0.2, 23.04 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-3 is at 6 or more or all selected from the group consisting of K-3-1, K-3- and K-3-3 (such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 etc.) has a peak at a 2 ⁇ (°) value.
  • the X-ray powder diffraction pattern of the crystalline form K-3 has a peak at a 2 ⁇ (°) value shown in Table (K-3) 1, and the relative intensity of each peak is as shown in the table (K-3). ) shown:
  • the X-ray powder diffraction pattern of Form K-3 is substantially characterized as in Figure 20.
  • the polymorph is a K-4 type crystal of the formic acid salt of the compound of the formula X, that is, the crystalline form K-4, and the X-ray powder diffraction pattern thereof is in the diffraction angle of the lower group K-4-1.
  • the 2 ⁇ (°) value has peaks: 13.26 ⁇ 0.2, 15.04 ⁇ 0.2, 16.18 ⁇ 0.2, 19.09 ⁇ 0.2, 21.54 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-4 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group K-4-2: 9.69 ⁇ 0.2, 16.35 ⁇ 0.2, 16.86 ⁇ 0.2, 19.46 ⁇ 0.2, 20.85 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-4 further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group K-4-3: 11.2 ⁇ 0.2, 12.03 ⁇ 0.2, 14.00 ⁇ 0.2, 17.13 ⁇ 0.2, 19.66 ⁇ 0.2, 20.38 ⁇ 0.2, 21.83 ⁇ 0.2, 22.12 ⁇ 0.2, 22.58 ⁇ 0.2, 23.40 ⁇ 0.2, 26.21 ⁇ 0.2, 27.44 ⁇ 0.2, 28.08 ⁇ 0.2, 29.39 ⁇ 0.2, 30.34 ⁇ 0.2, 33.14 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form K-4 is in 6 or more selected from the group K-4-1, K-4-2, and K-4-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of the crystalline form K-4 has a peak at a 2 ⁇ (°) value shown in Table (K-4), and the relative intensity of each peak is shown in Table (K-4). Shown as follows:
  • the X-ray powder diffraction pattern of Form K-4 is substantially characterized as in Figure 21.
  • the polymorph is Form I of the compound of Formula X, and its X-ray powder diffraction pattern has a peak at a diffraction angle 2 ⁇ (°) of Group I-1: 6.20 ⁇ 0.2, 6.68 ⁇ 0.2, 13.42 ⁇ 0.2, 21.31 ⁇ 0.2, 22.56 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form I further comprises a peak at 2 or more diffraction angles 2 ⁇ (°) selected from the group I-2: 5.28 ⁇ 0.2, 8.53 ⁇ 0.2, 10.54 ⁇ 0.2, 15.56 ⁇ 0.2, 18.12 ⁇ 0.2, 20.29 ⁇ 0.2, 24.99 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form I further comprises a peak at two or more diffraction angles 2 ⁇ (°) selected from the group I-3: 12.34 ⁇ 0.2, 14.80 ⁇ 0.2, 16.35 ⁇ 0.2, 17.17 ⁇ 0.2, 26.40 ⁇ 0.2, 27.86 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form I is selected from 6 or more or all of Groups I-1, I-2, and I-3 (eg, 6, 7, 8) , 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of Form I has a peak at the 2 ⁇ (°) value shown in Table I1, and the relative intensities of the respective peaks are as shown in Table I1:
  • the X-ray powder diffraction pattern of Form I is substantially characterized as in Figure 22.
  • Form I further has one or more characteristics selected from the group consisting of:
  • the initial temperature is 80 ⁇ 2 ° C and 189 ⁇ 2 ° C; preferably, the differential scanning calorimetry analysis pattern is substantially characterized as shown in FIG. 23;
  • the crystalline form I has a melting point of from 189 to 197 ° C, preferably from 199 to 201 ° C.
  • the polymorph is Form II of the compound of Formula X, and its X-ray powder diffraction pattern has peaks at a diffraction angle 2 ⁇ (°) of Group II-1: 13.27 ⁇ 0.2, 15.03 ⁇ 0.2, 16.20 ⁇ 0.2, 19.09 ⁇ 0.2, 21.56 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form II further comprises a peak at 2 or more diffraction angles 2 ⁇ (°) selected from the group II-2: 9.71 ⁇ 0.2, 11.21 ⁇ 0.2, 14.01 ⁇ 0.2, 16.35 ⁇ 0.2, 19.46 ⁇ 0.2, 19.69 ⁇ 0.2, 20.86 ⁇ 0.2, 22.56 ⁇ 0.2, 26.24 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form II further comprises a peak at 2 or more diffraction angles 2 ⁇ (°) selected from the group II-3: 11.98 ⁇ 0.2, 15.89 ⁇ 0.2, 16.86 ⁇ 0.2, 20.39 ⁇ 0.2, 21.15 ⁇ 0.2, 21.83 ⁇ 0.2, 23.09 ⁇ 0.2, 27.43 ⁇ 0.2, 28.08 ⁇ 0.2, 29.43 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form II is selected from 6 or more or all of Groups II-1, II-2, and II-3 (eg, 6, 7, 8) , 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of Form II has peaks at the 2 ⁇ (°) values shown in Table II1, and the relative intensities of the respective peaks are as shown in Table II1:
  • the X-ray powder diffraction pattern of Form II is substantially characterized as in Figure 25.
  • the polymorph is Form III of the compound of Formula X, and the X-ray powder diffraction pattern has a peak at a diffraction angle 2 ⁇ (°) of Group III-1: 5.23 ⁇ 0.2, 17.02 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form III further comprises a peak at a diffraction angle 2 ⁇ (°) of Group III-2: 12.32 ⁇ 0.2, 12.74 ⁇ 0.2, 15.57 ⁇ 0.2, 16.41 ⁇ 0.2, 16.72 ⁇ 0.2, 17.34 ⁇ 0.2, 18.21 ⁇ 0.2, 19.50 ⁇ 0.2, 21.29 ⁇ 0.2, 22.06 ⁇ 0.2, 22.49 ⁇ 0.2, 22.94 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form III further comprises a peak at two or more diffraction angles 2 ⁇ (°) selected from the group III-3: 10.51 ⁇ 0.2, 14.01 ⁇ 0.2, 19.07 ⁇ 0.2, 19.84 ⁇ 0.2, 23.73 ⁇ 0.2, 24.25 ⁇ 0.2, 28.49 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form III is in 6 or more or all selected from Groups III-1, III-2, and III-3 (eg, 6, 7, 8) , 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of Form III has peaks at the 2 ⁇ (°) values shown in Table III1, and the relative intensities of the respective peaks are as shown in Table III1:
  • the X-ray powder diffraction pattern of Form III is substantially characterized as in Figure 26.
  • the polymorph is Form IV of the compound of Formula X, and its X-ray powder diffraction pattern has a peak at a diffraction angle 2 ⁇ (°) of Group IV-1: 5.25 ⁇ 0.2, 11.94 ⁇ 0.2, 12.23 ⁇ 0.2, 14.42 ⁇ 0.2, 16.65 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form IV further comprises a peak at 2 or more diffraction angles 2 ⁇ (°) selected from the group IV-2: 5.60 ⁇ 0.2, 15.97 ⁇ 0.2, 17.45 ⁇ 0.2, 17.96 ⁇ 0.2, 18.81 ⁇ 0.2, 19.35 ⁇ 0.2, 20.58 ⁇ 0.2, 21.00 ⁇ 0.2, 22.17 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form IV further comprises a peak at 2 or more diffraction angles 2 ⁇ (°) selected from the group IV-3: 8.13 ⁇ 0.2, 11.25 ⁇ 0.2, 13.17 ⁇ 0.2, 17.02 ⁇ 0.2, 22.78 ⁇ 0.2, 23.94 ⁇ 0.2.
  • the X-ray powder diffraction pattern of Form IV is selected from 6 or more or all of Groups IV-1, IV-2, and IV-3 (eg, 6, 7, 8) , 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at 2 ⁇ (°) values.
  • the X-ray powder diffraction pattern of Form IV has peaks at 2 ⁇ (°) values shown in Table IV1, and the relative intensities of the respective peaks are as shown in Table IV1:
  • the X-ray powder diffraction pattern of Form IV is substantially characterized as in Figure 27.
  • the compound of the formula X formed by the step (1) or the step (2) or a pharmaceutically acceptable salt thereof is subjected to crystallization treatment to obtain a polymorph.
  • the solvent is selected from the group consisting of acetonitrile, 50% acetonitrile / 50% water, methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl t-butyl. Ether, tetrahydrofuran, n-heptane, dimethyl sulfoxide, preferably acetone, ethanol, ethyl acetate, 50% acetonitrile / 50% water.
  • the method includes any of the following sub-methods:
  • the polymorph is a type A crystal of the compound maleate of the formula X, ie, Form A, and in the step (3) comprises: in a solvent, in the presence of maleic acid, the formula X The compound is subjected to a crystallization treatment to form Form A.
  • the solvent is selected from the group consisting of water, 50% acetone / 50% water, acetone, acetonitrile, ethyl acetate, ethanol, isopropanol, 50% acetonitrile / 50 % water, methanol or tetrahydrofuran, preferably, the organic solvent is acetone, ethanol, ethyl acetate, 50% acetonitrile / 50% water or 50% acetone / 50% water, acetonitrile, isopropanol, tetrahydrofuran.
  • the molar ratio of maleic acid to the compound of formula X in step (A) is (1 to 2):1, preferably (1.0 to 1.2):1.
  • the crystallization treatment is slow volatilization, slow cooling, or suspension shaking.
  • the crystallization treatment temperature is 0-100 ° C, preferably 25-80 ° C.
  • the crystallization treatment time is from 0.5 to 24 hours.
  • the polymorph is a B-1 type crystal of the hydrochloride salt of the compound of the formula X, that is, the crystal form B-1, and in the step (3) includes: in a solvent, in the presence of hydrochloric acid, The compound of the formula X is subjected to a crystallization treatment to form a crystal form B-1.
  • the solvent is selected from the group consisting of water, 50% acetone/50% water, acetone, acetonitrile, ethyl acetate, ethanol, isopropanol, 50% acetonitrile. /50% water, methanol or tetrahydrofuran, preferably, the organic solvent is acetone, ethanol, methanol, ethyl acetate, acetonitrile, isopropanol or tetrahydrofuran.
  • the molar ratio of hydrochloric acid to the compound of the formula X in the step (B-1) is (1 to 2):1, preferably (1.0 to 1.2):1.
  • the crystallization treatment is slow volatilization, slow cooling, or suspension shaking.
  • the crystallization treatment temperature is 0-100 ° C, preferably 25-80 ° C.
  • the crystallization treatment time is from 0.5 to 24 hours.
  • the polymorph is a B-2 type crystal of the hydrochloride salt of the compound of the formula X, that is, the crystal form B-2, and includes in the step (3): in the solvent, the crystal form B-1 Crystallization treatment is carried out to form Form B-2.
  • the solvent is acetonitrile.
  • the molar ratio of hydrochloric acid to the compound of the formula X in the step (B-2) is (1 to 2):1, preferably (1.0 to 1.2):1.
  • the crystallization treatment is a slow cooling.
  • the crystallization treatment temperature is 0 to 60 °C.
  • the crystallization treatment time is 2-3 days.
  • the polymorph is a B-3 type crystal of the hydrochloride salt of the compound of the formula X, that is, the crystal form B-3, and includes in the step (3): in the solvent, the crystal form B-1 Crystallization treatment is carried out to form crystal form B-3.
  • the solvent is acetone.
  • the molar ratio of hydrochloric acid to the compound of the formula X in the step (B-3) is (1 to 2):1, preferably (1.0 to 1.2):1.
  • the crystallization treatment is a slow cooling.
  • the crystallization treatment temperature is 0 to 60 °C.
  • the crystallization treatment time is 2-3 days.
  • the polymorph is a C-1 type crystal of a sulfate of the compound of the formula X, that is, a crystal form C-1, and includes in the step (3): a solvent, in the presence of sulfuric acid, a pair
  • the X compound is subjected to a crystallization treatment to form a crystal form C-1.
  • the solvent is ethanol or acetone.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • the polymorph is a C-2 type crystal of a sulfate of the compound of the formula X, that is, a crystal form C-2, and includes in the step (3): in a solvent, in the presence of sulfuric acid, a pair
  • the X compound is subjected to a crystallization treatment to form a crystal form C-2.
  • the solvent is ethyl acetate.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • Step (3) the polymorph is a Form D crystal of the hydrobromide salt of the compound of Formula X, ie Form D, and in Step (3) comprises: in a solvent, in the presence of hydrobromic acid, a compound of Formula X A crystallization treatment is performed to form a crystal form D.
  • the solvent is ethyl acetate.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • step (3) comprises: in a solvent, in the presence of L-tartaric acid, a compound of formula X A crystallization treatment is performed to form a crystal form E.
  • the solvent is acetone.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is from 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • the polymorph is a Form F crystal of the compound phosphate of the formula X, ie, Form F, and in the step (3) comprises: crystallizing the compound of the formula X in the presence of phosphoric acid in a solvent, Thereby, the crystal form F is formed.
  • the solvent is acetone.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is from 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • the polymorph is a G-type crystal of the citrate salt of the compound of the formula X, ie, Form G, and in the step (3) comprises: crystallization of the compound of the formula X in the presence of citric acid in a solvent Processing to form Form G.
  • the solvent is acetone.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • the polymorph is a H-1 type crystal of the compound of the formula X fumarate, ie, Form H-1, and in the step (3) includes: in the solvent, in the presence of fumaric acid Next, the compound of the formula X is subjected to a crystallization treatment to form a crystal form H-1.
  • the solvent is acetone.
  • the crystallization treatment mode is slow volatilization.
  • the crystallization treatment temperature is 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • the polymorph is a H-2 type crystal of the compound of the formula X fumarate, ie, Form H-2, and in the step (3) includes: in the solvent, in the presence of fumaric acid Next, the compound of the formula X is subjected to a crystallization treatment to form a crystal form H-2.
  • the solvent is ethanol or ethyl acetate.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • the polymorph is a J-type crystal of the methanesulfonate salt of the compound of the formula X, ie, Form J, and in the step (3) comprises: a compound of the formula X in the presence of methanesulfonic acid in a solvent A crystallization treatment is performed to form a crystal form J.
  • the solvent is ethanol, acetone, 50% acetonitrile / 50% water, or ethyl acetate.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is 0 to 60 °C. It is preferably 4 to 50 °C.
  • the crystallization treatment time is from 1 hour to 3 days.
  • the polymorph is a K-1 type crystal of the formic acid salt of the compound of the formula X, ie, the crystalline form K-1, and comprises in the step (3): in a solvent, in the presence of formic acid,
  • the compound of the formula X is subjected to a crystallization treatment to form a crystal form K-1.
  • the solvent is ethyl acetate, tetrahydrofuran, methanol, isopropanol or ethanol.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is 0 to 80 °C.
  • the crystallization treatment time is from 1 hour to 5 days.
  • the polymorph is a K-2 type crystal of the formic acid salt of the compound of the formula X, ie, the crystalline form K-2, and includes in the step (3): in the solvent, the crystalline form K-1 A crystallization treatment is performed to form a crystal form K-2.
  • the solvent is acetonitrile or acetone.
  • the crystallization treatment is slow volatilization.
  • the crystallization treatment temperature is 0 to 80 °C.
  • the crystallization treatment time is from 1 hour to 5 days.
  • the polymorph is a K-3 type crystal of the formic acid compound of the formula X, that is, the crystal form K-3, and includes in the step (3): in the solvent, the crystal form K-1 Crystallization treatment is carried out to form crystal form K-3.
  • the solvent is acetonitrile.
  • the crystallization treatment is a slow cooling.
  • the crystallization treatment temperature is 0 to 80 °C.
  • the crystallization treatment time is from 1 hour to 5 days.
  • the polymorph is a K-4 type crystal of the formic acid compound of the formula X, ie, the crystalline form K-4, and in the step (3) includes: in the solvent, the crystalline form K-1 Crystallization treatment is carried out to form crystal form K-4.
  • the solvent is acetone.
  • the crystallization treatment is a slow cooling.
  • the crystallization treatment temperature is 0 to 80 °C.
  • the crystallization treatment time is from 1 hour to 5 days.
  • Step (3) comprises: crystallizing the compound of Formula X in a solvent to form Form I.
  • the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, butanol, acetone, acetonitrile, tetrahydrofuran, propylene glycol, ethyl acetate, and A.
  • the solvent is selected from the group consisting of water, acetonitrile, 50% acetonitrile / 50% water, methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl uncle Butyl ether, tetrahydrofuran, n-heptane, dimethyl sulfoxide.
  • the crystallization mode is slow volatilization.
  • step (I) in the step (I), 5 to 30 ° C, preferably 10 to 20 ° C.
  • the crystallization treatment time is from 1 to 10 days, preferably from 4 to 8 days.
  • the polymorph is a crystal form II of the formula X, and in the step (3), the compound of the formula X is subjected to a crystallization treatment in a solvent to form a crystal form II.
  • the solvent is selected from the group consisting of 50% acetonitrile/50% water, water, methanol, ethanol, propanol, isopropanol, butanol, acetone, acetonitrile, Tetrahydrofuran, propylene glycol, ethyl acetate, methyl isobutyl ketone, isopropyl acetate, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether, dimethyl sulfoxide, toluene, N, N-di Methyl acetamide, N-methylpyrrolidone, or a mixture thereof.
  • Preference is given to isopropanol, ethanol, ethyl acetate, acetone, acetonitrile, or 50% acetonitrile/50% water.
  • the crystallization mode is slow volatilization.
  • step (II) in the step (II), 0 to 60 ° C, preferably 5 to 40 ° C.
  • the crystallization treatment time is from 0.5 hours to 10 days.
  • the polymorph is a crystal form III of the formula X, and in the step (3), the compound of the formula X is subjected to a crystallization treatment in a solvent to form a crystal form III.
  • the solvent is selected from the group consisting of water, n-heptane, methanol, ethanol, propanol, isopropanol, butanol, acetone, acetonitrile, tetrahydrofuran, propylene glycol, acetic acid.
  • Preference is given to methyl tert-butyl ether or n-heptane.
  • the crystallization mode is slow volatilization.
  • step (III) in the step (III), 0 to 60 ° C, preferably 5 to 40 ° C.
  • the crystallization treatment time is from 0.5 hours to 10 days.
  • Step (3) comprises: crystallizing the compound of Formula X in a solvent to form Form IV.
  • the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, butanol, acetone, acetonitrile, tetrahydrofuran, propylene glycol, ethyl acetate, and A.
  • the crystallization mode is slow volatilization.
  • step (IV) in the step (IV), 0 to 60 ° C, preferably 5 to 40 ° C.
  • the crystallization treatment time is from 0.5 hours to 10 days.
  • a third aspect of the invention provides a pharmaceutical composition comprising:
  • a fourth aspect of the invention provides a polymorph of a pharmaceutically acceptable salt of a compound of formula X, or a compound of formula X, or a pharmaceutically acceptable salt thereof, according to the first aspect of the invention, or a third aspect of the invention
  • a pharmaceutical composition for the preparation of a medicament for treating a disease or condition selected from the group consisting of cancer, abnormal cell proliferative diseases, infections, inflammatory conditions, autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, A hematopoietic toxic disease caused by radiation, or a combination thereof.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, Glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, true Polycythemia, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor.
  • the radiation-induced hematopoietic toxic diseases include, but are not limited to, myelosuppression, neutropenia, leukopenia, anemia.
  • a fifth aspect of the invention provides a method of inhibiting the activity of CDK4 and/or CDK6 comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula X according to the first aspect of the invention, or a compound of formula X Or a polymorph of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention.
  • a sixth aspect of the invention provides a method for treating abnormal cell proliferative diseases, infection (eg, viral infections such as herpes, HIV, fungal infections, etc.) inflammatory conditions (eg, rheumatoid arthritis, osteoarthritis, etc.), autoimmunity Sexual diseases (eg psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis) Or a method of a neurodegenerative disease (eg, Alzheimer's disease, Parkinson's disease, etc.) comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula X according to the first aspect of the invention, Or a polymorph of a compound of formula X or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect
  • a seventh aspect of the invention provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula X according to the first aspect of the invention, or a compound of formula X or a pharmaceutically acceptable compound thereof A polymorph of a salt, or a pharmaceutical composition according to the third aspect of the invention, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, astrocytic gelatin having malignancy) Glioma, oligodendroglioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg non-small cell lung cancer, small Cell lung cancer, primary or metastatic squamous cell carcinoma, etc., kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma
  • Figure 31 14-day XRD pattern of Form A at 60 °C
  • Figure 32 32-day XRD pattern of Form A at 60 °C
  • crystal of the present invention As used herein, “crystal of the present invention”, “crystal form of the present invention”, “polymorph of the present invention” and the like are used interchangeably.
  • the compound of the formula X is 2-cyclopropyl-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-3-isopropyl-3 , 8-dihydroimidazo[4',5',4,5]cyclopenta[1,2-d]pyrimidin-5-amine, which has high inhibitory activity against CDK4 and CDK6,
  • the inhibitory activities of CDK1 and CDK2 are weak and have obvious 4 and 6 selectivity.
  • the invention also includes polymorphic forms of a pharmaceutically acceptable salt of a compound of formula X, or a compound of formula X, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, hydrobromide, phosphate, methanesulfonate, maleate (maleate). ), L-tartrate, citrate (citrate), fumarate (fumarate), formate.
  • the solid does not exist in an amorphous form or in a crystalline form.
  • the molecules are positioned within the three-dimensional lattice lattice.
  • polymorphism When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattices (this property is called "polymorphism"), forming crystals with different crystalline forms, and these various crystalline forms are It is called "polymorph”.
  • Different polymorphs of a given substance may differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, bulk mode, flowability, and/or solid state stability.
  • the solubility limit of the compound of interest can be exceeded by operating the solution to complete production-scale crystallization. This can be done in a number of ways, for example by dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods. The solubility of the compound of interest can be lowered by adding an antisolvent or a solvent having a low solubility in the compound or a mixture of such a solvent. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
  • solution stirring means that a solution of the compound of the formula X and the corresponding acid or the corresponding acid is mixed in a suitable solvent to form a turbid liquid, or the compound of the formula X is mixed with a suitable solvent to form a turbid liquid, followed by stirring.
  • a suitable solvent can be water or an organic solvent.
  • slow volatilization refers to a method in which a solution of a compound of the formula X or a solution containing a compound of the formula X and a corresponding acid is slowly volatilized at a certain temperature to obtain a crystal.
  • the "anti-solvent addition” according to the present invention is a method of decomposing a crystal by adding another suitable solvent to a solution of the compound of the formula X.
  • salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Similarly, in the final desired form of the medium having less solubility than the reactants, the completion of the synthesis reaction allows the final product to crystallize directly.
  • optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed.
  • many crystallization methods use a combination of the above strategies.
  • One embodiment is to dissolve the compound of interest in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
  • room temperature generally refers to 4-30 ° C, preferably 20 ⁇ 5 ° C.
  • polymorph of the invention includes a polymorph of a compound of formula X, or a pharmaceutically acceptable salt thereof (such as a hydrochloride, a maleate), or a mixture of its various solvates, Also included are different polymorphs of the same salt or solvate.
  • Polymorphs of the compound of formula X and “polymorph of the free base of the compound of formula X” are used interchangeably.
  • Preferred polymorphs of the invention include, but are not limited to:
  • Methods for determining X-ray powder diffraction of crystalline forms are known in the art.
  • an X-ray powder diffractometer is used to acquire a spectrum using a copper radiation target at a scanning speed of 2° per minute.
  • the polymorph of the compound of the formula X of the present invention or a pharmaceutically acceptable salt thereof has a specific crystal form and has a specific characteristic peak in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • DSC differential calorimetric scanning analysis
  • a compound of formula X of the present invention can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • the above carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or suspension with the above carriers.
  • compositions of the present invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • the "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the present invention provides a polymorph of a pharmaceutically acceptable salt of a compound of formula X according to the first aspect of the invention, or a compound of formula X or a pharmaceutically acceptable salt thereof, for use in the preparation of a CDK4/6 inhibitor or in the treatment of CDK4/6 The application of drugs for related diseases.
  • the CDK4/6 related disease is cancer, abnormal cell proliferative disease, infection, inflammatory condition, autoimmune disease, cardiovascular disease, neurodegenerative disease, hematopoietic disease caused by radiation, or a combination thereof.
  • the cancer is breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, Neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, Thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor, or any combination thereof.
  • the breast cancer is an HR-positive, HER2-negative advanced breast cancer.
  • terapéuticaally effective amount refers to an amount that is functional or active to a human and/or animal and that is acceptable to humans and/or animals.
  • pharmaceutically acceptable carrier means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating or auxiliary formulation or any type of excipient that is compatible with the patient, most Preferably, it is a mammal, more preferably a human, which is suitable for delivering the active agent to a target of interest without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing, or alleviating one or more symptoms of the disease or condition to some extent.
  • the therapeutically effective amount of the pharmaceutically acceptable salt of the compound of the formula X or the polymorph of the compound of the formula X or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention or the pharmaceutical composition is preferably 0.1 mg- 5g/kg (body weight).
  • the present inventors have found that 2-cyclopropyl-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-3-isopropyl-3,8-di
  • the hydrogenimidazo[4',5',4,5]cyclopenta[1,2-d]pyrimidin-5-amine free base polymorphs and salts also have good physicochemical properties and outstanding
  • the relevant pharmacological activity is an ideal CDK4/6 inhibitor.
  • the structure and purity of the compound are determined by nuclear magnetic resonance ( 1 H NMR) and mass spectrometry (LC-MS).
  • 1 H NMR Bruker AVANCE-400 nuclear magnetic instrument, internal standard is tetramethylsilane (TMS).
  • LC-MS Agilent 1200 HPLC System, 6140 MS LC/MS (purchased from Agilent), column Waters X-Bridge, 150 x 4.6 mm, 3.5 ⁇ m.
  • Preparative High Performance Liquid Chromatography pre-HPLC: Waters PHW007, column XBridge C18, 4.6*150 mm, 3.5 um.
  • ISCO Combiflash-Rf75 or Rf200 automatic column analyzer Use ISCO Combiflash-Rf75 or Rf200 automatic column analyzer, Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
  • the specifications for the board are 0.4mm-0.5mm.
  • silica gel Yantai Huanghai silica gel 200-300 mesh silica gel is generally used as a carrier.
  • the basic alumina column is generally prepared by using FCP200-300 mesh basic alumina as a carrier.
  • the reactions were all carried out under a nitrogen or argon atmosphere.
  • the solution means an aqueous solution.
  • DMF means dimethylformamide
  • DMSO means dimethyl sulfoxide
  • THF means tetrahydrofuran
  • DIEA means N,N-diisopropylethylamine
  • EA means ethyl acetate
  • PE means petroleum ether.
  • BINAP stands for (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl
  • NBS stands for N-bromosuccinimide
  • NCS stands for N-chlorosuccinimide
  • Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium
  • Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • Acetonitrile ACN methanol MeOH, ethanol EtOH, isopropanol IPA, acetone ACE, ethyl acetate EA, methyl tert-butyl ether MTBE, tetrahydrofuran THF, water H 2 O, 50% acetonitrile 50% ACN, dicyclohexyl [3 ,6-Dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine Brettphos.
  • room temperature refers to about 20 ⁇ 5 °C.
  • the powder X-ray diffraction pattern of the above crystal form is obtained by a D8 ADVANCE X-ray powder diffraction analyzer by a method known in the art.
  • the instrument test conditions are shown in the following table:
  • the position of each peak is determined by 2 ⁇ (°). It will be appreciated that different instruments and/or conditions may result in slightly different data being produced, with varying positions and relative intensities of the peaks. The intensity division of the peaks only reflects the approximate size of the peaks at each location.
  • each crystal form has a diffraction peak having the highest peak height as a base peak, and its relative intensity is defined as 100%, and as a peak of I 0 (the crystal form I has a 2 ⁇ (°) value of 6.68,
  • the peak of the 2 ⁇ (°) value of the crystal form II is 15.03
  • the peak of the crystal form III having a 2 ⁇ (°) value of 5.23 is the base peak
  • the peak of the crystal form IV having a 2 ⁇ (°) value of 5.25 is the base peak.
  • the peak of the crystal form A having a 2 ⁇ (°) value of 18.06 is the base peak
  • the crystal form B-1 having a 2 ⁇ (°) value of 14.75 is the base peak
  • the crystal form B-2 having the 2 ⁇ (°) value of 4.56 is the base peak
  • the peak of the crystal form B-3 has a 2 ⁇ (°) value of 14.96
  • the peak of the crystal form C-1 has a 2 ⁇ (°) value of 13.72.
  • the crystal form C-2 The peak with a 2 ⁇ (°) value of 10.47 is the base peak, the peak of the crystal form D with a 2 ⁇ (°) value of 21.04 is the base peak, and the peak of the crystal form E with a 2 ⁇ (°) value of 19.33 is the base peak, and the crystal form F
  • the peak of the 2 ⁇ (°) value of 12.03 is the base peak
  • the peak of the crystal form G having a 2 ⁇ (°) value of 10.13 is the base peak
  • the peak of the crystal form H-1 having a 2 ⁇ (°) value of 22.84 is the base peak.
  • the peak of the 2 ⁇ (°) value of the crystal form H-2 is 11.67
  • the peak of the crystal form J having a 2 ⁇ (°) value of 10.64 is the base peak
  • the 2 ⁇ (°) value of the crystal form K-1 is 12.08.
  • the peak is the base peak
  • the 2 ⁇ (°) value of the crystal form K-2 is 5.23.
  • the base peak, the K 2 has a 2 ⁇ (°) value of 5.27 as the base peak
  • the crystal form K-4 has a 2 ⁇ (°) value of 15.04 as the base peak)
  • the other peaks have their peak heights.
  • the ratio of the peak height of the base peak as its relative intensity I, I 0 , and the relative intensity of each peak are defined as follows:
  • the salt of the present invention or its crystal form determines the acid-base molar ratio by HPLC/IC or 1 H NMR.
  • High Performance Liquid Chromatography In the present invention, high performance liquid chromatography (HPLC) was performed on an Agilent 1260 HPLC.
  • TGA and DSC spectra were acquired on a TA Q500/5000 thermogravimetric analyzer and a TA Q200/2000 differential scanning calorimeter, respectively.
  • the instrument test conditions are shown in the following table:
  • Dynamic moisture adsorption (DVS) curve acquired on DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25 ° C was corrected with the deliquescent point of LiCl, Mg(NO 3 ) 2 and KCl. The instrument test conditions are shown in the following table:
  • Step 1 Compound 1-1 (50 g, 0.51 mol) was dissolved in 500 ml of ethanol, and the compound p-toluenesulfonic acid was added and refluxed for 48 h. After the reaction mixture was cooled to room temperature, the mixture was evaporated, evaporated, evaporated. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to remove most solvent and filtered over Celite. The filtrate was concentrated under reduced pressure to give Compound 1-2 (62 g). MS m/z (ESI): 127 [M+H] +
  • Step 2 Compound 1-2 (62 g, 0.51 mol) was dissolved in methylene chloride (hexane), and NBS (100 g, 0.56 mol) was added portionwise at 5-10 ° C, and the reaction mixture was stirred at room temperature for 16 h. The organic layer was concentrated under reduced pressure and dichloromethane was evaporated. EtOAc m. MS m/z (ESI): 206 [M+H] +
  • Step 3 Compound 1-3 (446 g, 2.175 mol) was dissolved in DMF (3 L). Compound 1-4 (263.2 g, 2.175 mol), potassium carbonate (870 g, 6.30 mol), and the reaction mixture was stirred at 100 ° C for 2 h. . The reaction was quenched with saturated ammonium chloride solution. 162 [M + H] +: After the solvent was purified by chromatography, the crude product was purified by column removed, beating with ethyl acetate, to give the compound 1a (195g, yield 55%), MS m / z (ESI) under reduced pressure.
  • Step 1 Compound 1a (10 g, 0.062 mol) was dissolved in DMF (100 ml), sodium hydrogen (3 g, 0.075 mol) was added portionwise at 5-10 ° C, and the reaction mixture was stirred at 5 ° C for 1 h, slowly adding iodine. The isopropanol (7.5 ml, 0.75 mol) was stirred at 60 ° C for 4 h. The solvent was removed by concentration under reduced pressure, the crude product was purified by column chromatography to give compound 2-1 (2.5g), MS m / z (ESI): 204 [M + H] +.
  • Step 2 Compound 2-1 (30 g, 0.147 mol), compound 2-2 (130 ml, 0.632 mol) was stirred at 110 ° C for 4 h, and the reaction mixture was concentrated under reduced pressure to give 2-3 (40 g). .
  • Step 3 Compound 2-3 (40 g, 0.147 mol), 2-4 (140.4 g, 1.47 mol), and sodium ethoxide (100 g, 1.47 mol) were dissolved in ethanol and sealed at 120 ° C for 36 h. After the reaction mixture was cooled to room temperature, the insoluble solid was removed by filtration, and the filtrate was concentrated and purified by column chromatography to afford compound 2a (25 g, yield 67%), MS m/z (ESI): 256 [M+H] + .
  • the obtained powder was subjected to XRD measurement, and its powder X-ray diffraction pattern showed no significant characteristic peak and was in an amorphous form.
  • Solvent Compound X formate Crystal form Solid form acetone Heating and dissolving, cooling does not precipitate; slow volatilization Form K-2 White powder Acetonitrile Heating and dissolving, cooling does not precipitate; slow volatilization Form K-2 White powder Ethyl acetate Heating and dissolving, cooling does not precipitate; slow volatilization Form K-1 White to pale yellow powder Ethanol Completely dissolved; slowly volatilized Form K-1 White to pale yellow powder Isopropanol Completely dissolved; slowly volatilized Form K-1 White to pale yellow powder Methanol Completely dissolved; slowly volatilized Form K-1 White to pale yellow powder Tetrahydrofuran Completely dissolved; slowly volatilized Form K-1 White to pale yellow powder
  • the free base of the compound of the formula X obtained in the method of Example 1 was beaten with diethylene glycol diethyl ether at room temperature for 4 h, filtered, and the filter cake was washed with acetone, and the filter cake was further slurried with diethylene glycol diethyl ether at room temperature overnight, filtered, and the filter cake was acetone. It is washed and dried to obtain a white powder.
  • the X-ray diffraction pattern of the obtained powder is shown in Fig. 22 (the 2 ⁇ angle has been indicated), and the melting point is 199-120 ° C, which is defined herein as the free base crystal form I of the compound of the formula X.
  • Solvent Solvent addition amount ml Solution state Crystallization mode Crystal form Eye 11 Heating becomes clarified Slow volatilization Form II 50% acetonitrile 0.4 clarify Slow volatilization Form II Ethanol 0.2 clarify Slow volatilization Form II Isopropanol 0.5 clarify Slow volatilization Form II acetone 2 clarify Slow volatilization Form II Ethyl acetate 1 clarify Slow volatilization Form II Methyl tert-butyl ether 5 clarify Slow volatilization Crystal form III Tetrahydrofuran 0.1 clarify Slow volatilization Form IV N-heptane 5 turbid Suspended, dried Crystal form III
  • the content and related substances were measured by HPLC, and XRD was measured to determine the stability of the crystal form.
  • Form B-1 will decompose and deacidify at temperatures above 40 °C, and will not be included in the experiment at 60 °C.
  • Form A has no significant change in content and related substances at 60 ° C, and its chemical properties are stable.
  • the crystal form A and the crystal form B-1 were accelerated under 28 days, the characteristic peak of the XRD pattern did not change, and the crystal form was stable (Fig. 29, 30).
  • Form A weigh about 5 mg of Form A, Form B-1, and Form K-1 in a centrifuge tube, and add 200 ⁇ L of H 2 O, 0.1 M HCl, pH 4.5, pH 6.8, and pH 7.4, respectively.
  • the medium and 7 kinds of organic solvents such as acetone, acetonitrile, ethyl acetate, ethanol, methanol, isopropanol and tetrahydrofuran are sonicated to dissolve, and the compound in the partial centrifuge tube is completely dissolved, and then 5 mg to 10 mg is continuously added to make the solution turbid;
  • Form K-1 is a clear solution in four organic solvents of acetonitrile, ethanol, isopropanol and methanol and the above five aqueous media;
  • Form B-1 is a clear solution in acetone and methanol;
  • Form I has a relatively high solubility in 50% acetonitrile, methanol, ethanol, isopropanol, ethyl acetate and tetrahydrofuran, in acetonitrile, acetone, n-heptane and dimethyl sulfoxide.
  • Crystalline K-1 has a relatively high solubility in organic solvents and aqueous media, reaching 11 to 45 mg/ml;
  • Form B-1 has a relatively high solubility in methanol, ethanol and acetone, and solubility in acetonitrile, isopropanol, tetrahydrofuran and ethyl acetate is relatively small, and the solubility in aqueous medium is relatively large, exceeding 25 mg/ml;
  • Form A has a high solubility in methanol and ethanol; solubility in other organic solvents is small, and solubility in aqueous medium is relatively large, exceeding 11 mg/ml; in summary, crystal form K-1 is most soluble Well, Form B-2 and Form A are second, and Form I has the worst solubility.
  • Form I The DVS test results of Form I, Form A, Form B-1 and Form K-1 are shown in Figure 33-36, respectively.
  • Form I The moisture absorption weight gain is 8.84%, which is hygroscopic; the crystal form A moisture absorption weight gain is 0.613%, slightly hygroscopic; the crystal form B-1 moisture absorption gain 6.88, with hygroscopicity.
  • Form K-1 has a hygroscopic weight gain of 30.74% at 80% humidity, so this compound is a highly hygroscopic drug.
  • CDK1, CCNB1 and CDK9, CCNT were purchased from BPS; CDK2, CCNA1, CDK4, CCND1 and CDK6, CCND1 were purchased from Invitrogen; CDK4, CycD3 and CDK6, CycD3 were purchased from Carna.
  • Adenosine triphosphate (ATP) was purchased from Life tech.
  • the substrate Ulight-4EBP1 and the corresponding detection antibody were purchased from Perkinelmer.
  • the detection system uses Perkinelmer's LANCEUltra system.
  • the test compound was diluted at a gradient of 1:3 and then added to the reaction plate and an appropriate amount of recombinant enzyme was added. Subsequently, a buffer containing a predetermined concentration of ATP, Ulight-4EBP1 premix [50 mM HEPES pH 7.5, 10 mM MgCl2, 3 mM MnCl2, 1 mM EGTA, 0.01% Tween-20, 1 mM TCEP] was added, and the kinase reaction was started at room temperature.
  • a buffer containing a predetermined concentration of ATP, Ulight-4EBP1 premix [50 mM HEPES pH 7.5, 10 mM MgCl2, 3 mM MnCl2, 1 mM EGTA, 0.01% Tween-20, 1 mM TCEP] was added, and the kinase reaction was started at room temperature.
  • the compound of the formula X has a strong inhibitory activity against CDK4 and CDK6, and has a weak inhibitory activity against CDK1 and CDK2, and has a selective inhibitory activity against CDK4/6.
  • Comparative Compound 1 specific structure is shown below, and can be found in WO2012010704 Example I-44, although it has strong inhibitory activity against CDK4 and CDK6, the inhibition of CDK1 and CDK2 is also strong, and CDK4/6 is not shown. The choice of inhibitory activity.
  • Test animals healthy adult male Sprague-Dawley rats (body weight 210-230 g, 12 animals, fasted overnight, fed 4 hours after administration), supplied by Slack Company; preparation of oral solution: Weigh 40.14 mg of compound P-53 In a clean tube, 36.479 mL of 0.5% HPC-H (TCI, E6ZQA) acetate buffer (pH 4.5) was added to the tube and the tube was vortexed for 1-2 minutes. Sonicate for 20-25 minutes and stir for 20-25 minutes.
  • HPC-H TCI, E6ZQA
  • SD rats were intragastrically administered (10 mg/kg (10 mL/kg)); samples were taken at 4 time points at 0.5, 1, 2, and 4 hours after administration. Only plasma samples were collected continuously, brain tissue and cerebrospinal fluid were Collected at each time point.
  • Blood sample collection Animals were manually controlled and approximately 150 [mu]L of blood was collected through the tail vein at time points into tubes containing K2EDTA. Within 15 minutes, blood samples were placed on wet ice and centrifuged (2000 g, 5 min under 4 °C) to obtain plasma samples.
  • Brain tissue collection Make an incision in the middle of the animal's scalp and then contract the skin. Use a small bone knife and a rongeur to move the skull behind your head. Use a spatula to remove the brain and rinse with cold saline. Place the brain in a spiral tube and store the tube at -70 °C until analysis.
  • Cerebrospinal fluid collection In the case of deep anesthesia of the animal, air is euthanized in the tail vein. Using the occipital bone and the atlas as a symbol, the cerebrospinal fluid was collected by directly piercing the cisterna magna with a butterfly needle. During the collection process, a piece of white paper is placed over the needle as a background to monitor the color change of the sample. In the observation of the color change, the PE tube is quickly closed above the color change and cut over the clamped portion to draw a clean sample into the syringe.
  • Plasma, brain and cerebrospinal fluid samples are temporarily stored in dry ice and then transferred to a cold storage at -80 °C for long-term storage.
  • Glipizide was used as the internal standard in SD rat plasma and brain, and LCMSMS-002 (API-4000, triple quadrupole) was used for testing and analysis. Take 30 ⁇ L of plasma sample and brain tissue sample, add 200 ⁇ L of acetonitrile containing 100 ng/mL internal standard (Glipizide), mix and vortex for 10 min, centrifuge at 5800 rpm for 10 min, then take 2 ⁇ L of the supernatant after centrifugation for LC. - MS/MS analysis.
  • the compound of formula X can cross the blood-brain barrier and be well distributed into the brain, with better brain permeability.
  • Tablets of Form A were prepared from the following components:
  • the crystal form A and the starch are mixed and sieved, and then uniformly mixed with the other components described above, and directly compressed.
  • Capsules of Form I were prepared from the following components:
  • the crystalline form I and the starch are mixed and sieved, and then uniformly mixed with the other components described above, and filled into ordinary transparent capsules.

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Abstract

本发明提供了一种CDK4/6抑制剂及其药学上可接受的盐和多晶型物及其应用。具体地，本发明提供了2-环丙基-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-3-异丙基-3，8-二氢咪唑并[4'，5'，4，5]环戊二烯并[1，2-d]嘧啶-5-胺及其药学上可接受盐的多晶型物及其应用。此外，本发明开公开了还该化合物的药物组合物及其应用。

Description

CDK4/6抑制剂及其药学上可接受的盐和多晶型物及其应用 技术领域
本发明属于医药技术领域，具体地说，本发明涉及一种CDK4/6抑制剂及其药学上可接受的盐和多晶型物及其应用，该抑制剂为2-环丙基-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-3-异丙基-3，8-二氢咪唑并[4′，5′，4，5]环戊二烯并[1，2-d]嘧啶-5-胺。
背景技术
CDK是一类丝氨酸/苏氨酸蛋白激酶，只有与周期蛋白结合后才有激酶活性，在细胞周期的启动和各个时期的转换调节中起关键作用。CDK4/6是细胞周期的重要调节蛋白，可磷酸化抑癌基因蛋白Rb，释放E2F转录因子，使细胞顺利通过细胞周期G1/S检测点，细胞周期得以继续。CDK4单基因敲除老鼠存在糖尿病征和细胞缺陷，CDK6单基因敲除老鼠因造血细胞增值缺陷导致轻微的贫血症状，而CDK4和CDK6(CDK4/6)双基因敲除则会使造血前体细胞增殖能力受损，导致双敲除老鼠胚胎晚期的死亡。在肿瘤细胞中，普遍发现CDK4/6-cyclin D/Rb信号通路的超活化。在胞内外各种有丝分裂信号刺激下，cyclin D高表达，调节CDK4/6蛋白与cyclin D的相互作用，促进CDK4/6的定位和激酶活性。激活的CDK4/6通过磷酸化抑制Rb肿瘤抑制蛋白的活性，使Rb-E2F复合物解离，释放游离的E2F入核，调节蛋白转录，启动细胞周期的进行。在上皮细胞恶性肿瘤中常发现CDK4的超活化，而间质细胞肿瘤如肉瘤和血液性癌症中常发现CDK6的超活化。构建乳腺癌荷瘤鼠模型发现，野生型裸鼠全部成瘤，而CDK4敲除裸鼠完全无法成瘤；而用anti-CDK4 siRNA干扰CDK4的表达，则发现裸鼠的肿瘤生长显著受抑制。选择性CDK4/6抑制剂可以诱导细胞G1期阻滞，进而提高造血干/祖细胞对DNA损伤剂，如IR的耐受性，有效减少由辐射引起的各种造血毒性，包括骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血等。
近几年各大公司已分别鉴定发现了一系列选择性抑制CDK4和CDK6的抑制剂，用于治疗癌症、心血管障碍及炎症等疾病。如Pfizer的palbociclib、Eli Lilly的Abemaciclib等，此外国内的多家企业也有专利公开，选择性抑制CDK4和CDK6的专利申请包括WO2014183520、WO2015101293、WO2015180642、WO2016014904和WO2016015597等。尽管目前这些小分子CDK抑制剂在临床上具有一定的优势，但也有其自身的缺点，如palbociclib具有较大的中性粒细胞毒性。一般认为，对于CDK4的抑制就可以抑制肿瘤细胞的生长，而CDK6在血液系统高表达，功能为调控造血细胞等的生长，对CDK6的抑制可能会造成血液学方面的毒性，如中性粒细胞减少，红细胞减少等。Palbociclib对CDK4和CDK6都有相同的抑制，酶活性分别是10nm和10nm，其毒性应当和此相关。而Abemaciclib对于CDK4的抑制要强于CDK6的抑制；弱的CDK6抑制剂造成了低的血液学方面的毒性。由于CDK4和CDK6的同源性非常高，有约70％，因此开发选择性的CDK4/6抑制剂，特别是CDK4抑制剂是一个很大的挑战。
此外，晚期肿瘤患者有相当一部分会出现脑转移，这在肺癌、乳腺癌、黑色素瘤中尤为突出，这部分患者运用现有的治疗方法效果很差，主要是由于大部分药物不能进入血脑屏障，因此若能开发具有独特的药代动力学特征，能够有效透过血脑屏障，针对目前临床有重大需求的脑肿瘤或脑转移的肿瘤患者有显著药效的选择性CDK4/6抑制剂，将具有重要的临床意义和广阔的市场前景。为了达到更好的肿瘤治疗效果的目的，更好的满足市场需求，我们希望能开发出新一代的高效低毒的选择性CDK4和CDK6抑制剂。本发明在前述工作的基础上开发了CDK4/6抑制剂的多种盐型和晶型，有助于进一步的药物开发。
发明内容
本发明的目的在于提供一种CDK4/6抑制剂的药学上可接受的盐及其多晶型及其应用。
在本发明的第一方面，提供了一种式X化合物药学上可接受的盐或式X化合物及其药学上可接受盐的多晶型物：
Figure PCTCN2019083970-appb-000001
在另一优选例中，所述药学上可接受的盐选自下组：盐酸盐、硫酸盐、氢溴酸盐、磷酸盐、甲磺酸盐、马来酸盐、L-酒石酸盐、柠檬酸盐、富马酸盐、甲酸盐。
在另一优选例中，所述式X化合物药学上可接受的盐或式X化合物及其药学上可接受盐的多晶型物为无水形式、水合物形式或溶剂合物形式。
在另一优选例中，所述药学上可接受的盐选自：马来酸盐、盐酸盐、甲酸盐。
在另一优选例中，所述药学上可接受盐为马来酸盐，并且马来酸与式X化合物的摩尔比为(0.8-2.1)∶1，较佳地(1.1-1.2)∶1。
在另一优选例中，所述药学上可接受盐为盐酸盐，并且盐酸与式X化合物的摩尔比为(0.8-2.1)∶1，较佳地(1.1-1.2)∶1。
在另一优选例中，所述多晶型物为式X化合物马来酸盐的A型结晶，即晶型A，其X射线粉末衍射图在下组A1的衍射角2θ(°)值处具有峰：4.47±0.2、8.93±0.2、13.41±0.2、13.98±0.2、15.77±0.2、16.52±0.2、17.18±0.2、18.06±0.2、18.61±0.2、19.16±0.2、21.50±0.2、22.26±0.2、23.43±0.2、23.84±0.2。
在另一优选例中，所述晶型A的X射线粉末衍射图还包含在2个或2个以上选自下组A2的衍射角2θ(°)值处的峰：14.97±0.2、15.95±0.2、20.27±0.2、20.90±0.2、24.08±0.2、24.83±0.2、26.20±0.2、30.38±0.2。
在另一优选例中，所述晶型A的X射线粉末衍射图还包含在2个或2个以上选自下组A3的衍射角2θ(°)值处的峰：10.42±0.2、11.11±0.2、12.78±0.2、21.96±0.2、22.77±0.2、27.03±0.2、27.88±0.2、28.60±0.2、29.06±0.2、31.64±0.2、32.29±0.2、35.91±0.2。
在另一优选例中，所述晶型A的X射线粉末衍射图在选自组A1、A2和A3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型A的X射线粉末衍射图在表A1所示的2θ(°)值处具有峰，各峰相对强度如表A1所示：
表A1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
4.47 VS 8.93 S 10.42 W
11.11 W 12.78 W 13.41 VS
13.98 S 14.97 22 15.77 S
15.95 M 16.52 S 17.18 S
18.06 VS 18.61 VS 19.16 S
20.27 M 20.90 M 21.50 S
21.96 W 22.26 VS 22.77 W
23.43 VS 23.84 S 24.08 M
24.83 M 26.20 M 27.03 W
27.88 W 28.60 W 29.06 W
30.38 M 31.64 W 32.29 W
35.91 W        
在另一优选例中，所述晶型A的X射线粉末衍射图基本如图1所表征。
在另一优选例中，所述晶型A中，马来酸与式X化合物的摩尔比为(0.8-2.1)∶1，较佳地(1.0-1.2)∶1，更佳地1.2∶1。
在另一优选例中，所述晶型A为无水形式。
在另一优选例中，所述晶型A还具有选自下组的一个或多个特征：
(i)差示扫描量热分析图谱中，起始温度为193±2℃；较佳地，其差示扫描量热法分析图谱基本如图2所表征；
(ii)热重分析图谱基本如图3所表征；
(iii)所述的晶型A的熔点为193-211℃，较佳地为205-207℃。
在另一优选例中，所述多晶型物为式X化合物盐酸盐的B-1型结晶，即晶型B-1，其X射线粉末衍射图在下组B-1-1的衍射角2θ(°)值处具有峰：4.93±0.2、6.78±0.2、8.04±0.2、9.82±0.2、12.46±0.2、14.75±0.2、15.32±0.2、21.17±0.2。
在另一优选例中，所述晶型B-1的X射线粉末衍射图还包含在2个或2个以上选自下组B-1-2的衍射角2θ(°)值处的峰：10.63±0.2、14.48±0.2、15.78±0.2、22.21±0.2、23.19±0.2、23.56±0.2、27.42±0.2。
在另一优选例中，所述晶型B-1的X射线粉末衍射图还包含在2个或2个以上选自下组B-1-3的衍射角2θ(°)值处的峰：6.30±0.2、11.09±0.2、11.69±0.2、17.46±0.2、18.80±0.2、20.32±0.2、28.32±0.2。
在另一优选例中，所述晶型B-1的X射线粉末衍射图在选自组B-1-1、B-1-2和B-1-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型B-1的X射线粉末衍射图在表(B-1)所示的2θ(°)值处具有峰，各峰相对强度如表(B-1)所示：
表(B-1)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
4.93 VS 6.30 W 6.78 S
8.04 VS 9.82 VS 10.63 M
11.09 W 11.69 W 12.46 VS
14.48 M 14.75 VS 15.32 VS
15.78 M 17.46 W 18.80 W
20.32 W 21.17 VS 22.21 M
23.19 M 23.56 M 27.42 M
28.32 W        
在另一优选例中，所述晶型B-1的X射线粉末衍射图基本如图4所表征。
在另一优选例中，所述晶型B-1中，盐酸与式X化合物的摩尔比为(0.8-2.1)∶1，较佳地(1.0-1.2)∶1， 更佳地1.2∶1。
在另一优选例中，所述晶型B-1还具有选自下组的一个或多个特征：
(i)差示扫描量热分析图谱中，起始温度为240±2℃和263±2℃；较佳地，其差示扫描量热法分析图谱基本如图5所表征；
(ii)热重分析图谱基本如图6所表征；
(iii)晶型B-1在50℃-90℃条件下，失重为7.4％左右，根据计算应该是化合物中HCl脱去的原因，此化合物在高温下(高于50℃)不稳定；
在另一优选例中，所述多晶型物为式X化合物盐酸盐的B-2型结晶，即晶型B-2，其X射线粉末衍射图在下组B-2-1的衍射角2θ(°)值处具有峰：4.56±0.2、11.41±0.2、13.60±0.2。
在另一优选例中，所述晶型B-2的X射线粉末衍射图还包含在下组B-2-2的衍射角2θ(°)值处的峰：5.72±0.2、9.06±0.2、17.72±0.2、22.92±0.2、23.71±0.2。
在另一优选例中，所述晶型B-2的X射线粉末衍射图在选自组B-2-1、B-2-2中的6个或更多个或全部(如6、7、8等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型B-2的X射线粉末衍射图在表(B-2)所示的2θ(°)值处具有峰，各峰相对强度如表(B-2)所示：
表(B-2)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
4.56 VS 5.72 M 9.06 M
11.41 S 13.60 S 17.72 M
22.92 M 23.71 M    
在另一优选例中，所述晶型B-2的X射线粉末衍射图基本如图7所表征。
在另一优选例中，所述多晶型物为式X化合物盐酸盐的B-3型结晶，即晶型B-3，其X射线粉末衍射图在下组B-3-1的衍射角2θ(°)值处具有峰：5.03±0.2、9.97±0.2、14.96±0.2。
在另一优选例中，所述晶型B-3的X射线粉末衍射图还包括在下组B-3-2的衍射角2θ(°)值处的峰：11.98±0.2、17.07±0.2、25.00±0.2。
在另一优选例中，所述晶型B-3的X射线粉末衍射图还包括在2个或2个以上下组B-3-3的衍射角2θ(°)值处的峰：12.59±0.2、16.06±0.2、16.64±0.2、18.07±0.2、20.05±0.2、21.05±0.2、21.98±0.2、22.40±0.2、23.50±0.2、24.04±0.2、25.90±0.2、27.03±0.2、30.12±0.2。
在另一优选例中，所述晶型B-3的X射线粉末衍射图在选自组B-3-1、B-3-2和B-3-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型B-3的X射线粉末衍射图在表(B-3)所示的2θ(°)值处具有峰，各峰相对强度如表(B-3)所示：
表(B-3)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.03 VS 9.97 VS 11.98 M
12.59 W 14.96 VS 16.06 W
16.64 W 17.07 M 18.07 W
20.05 W 21.05 W 21.98 W
22.40 W 23.50 W 24.04 W
25.00 M 25.90 W 27.03 W
30.12 W        
在另一优选例中，所述晶型B-3的X射线粉末衍射图基本如图8所表征。
在另一优选例中，所述多晶型物为式X化合物硫酸盐的C-1型结晶，即晶型C-1，其X射线粉末衍射图在下组C-1-1的衍射角2θ(°)值处具有峰：9.13±0.2、9.71±0.2、10.50±0.2、11.19±0.2、13.72±0.2、13.94±0.2、15.70±0.2、16.79±0.2、22.46±0.2、23.87±0.2。
在另一优选例中，所述晶型C-1的X射线粉末衍射图还包含在2个或2个以上选自下组C-1-2的衍射角2θ(°)值处的峰：4.60±0.2、12.35±0.2、15.26±0.2、18.23±0.2、19.40±0.2、25.56±0.2、26.11±0.2、27.68±0.2、28.43±0.2。
在另一优选例中，所述晶型C-1的X射线粉末衍射图还包含在2个或2个以上选自下组C-1-3的衍射角2θ(°)值处的峰：14.78±0.2、21.50±0.2。
在另一优选例中，所述晶型C-1的X射线粉末衍射图在选自组C-1-1、C-1-2和C-1-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型C-1的X射线粉末衍射图在表(C-1)所示的2θ(°)值处具有峰，各峰相对强度如表(C-1)所示：
表(C-1)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
4.60 M 9.13 S 9.71 S
10.50 S 11.19 S 12.35 M
13.72 VS 13.94 S 14.78 W
15.26 M 15.70 S 16.79 S
18.23 M 19.40 M 21.50 W
22.46 VS 23.87 S 25.56 M
26.11 M 27.68 M 28.43 M
在另一优选例中，所述晶型C-1的X射线粉末衍射图基本如图9所表征。
在另一优选例中，所述多晶型物为式X化合物硫酸盐的C-2型结晶，即晶型C-2，其X射线粉末衍射图在下组C-2-1的衍射角2θ(°)值处具有峰：10.47±0.2、14.78±0.2、15.72±0.2。
在另一优选例中，所述晶型C-2的X射线粉末衍射图还包括在下组C-2-2的衍射角2θ(°)值处的峰：5.29±0.2、19.36±0.2、19.75±0.2、20.58±0.2、21.96±0.2。
在另一优选例中，所述晶型C-2的X射线粉末衍射图还包含在2个或2个以上选自下组C-2-3的衍射角2θ(°)值处的峰：7.21±0.2、9.74±0.2、11.37±0.2、12.25±0.2、16.34±0.2、16.67±0.2、17.14±0.2、18.89±0.2、21.30±0.2、22.40±0.2、23.28±0.2、23.75±0.2、24.59±0.2、26.73±0.2。
在另一优选例中，所述晶型C-2的X射线粉末衍射图在选自组C-2-1、C-2-2和C-2-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型C-2的X射线粉末衍射图在表(C-2)所示的2θ(°)值处具有峰，各峰相对强度如表(C-2)所示：
表(C-2)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.29 M 7.21 W 9.74 W
10.47 VS 11.37 W 12.25 W
14.78 S 15.72 S 16.34 W
16.67 W 17.14 W 18.89 W
19.36 M 19.75 M 20.58 M
21.30 W 21.96 M 22.40 W
23.28 W 23.75 W 24.59 W
26.73 W        
在另一优选例中，所述晶型C-2的X射线粉末衍射图基本如图10所表征。
在另一优选例中，所述多晶型物为式X化合物氢溴酸盐的D型结晶，即晶型D，其X射线粉末衍射图在下组D1的衍射角2θ(°)值处具有峰：7.99±0.2、9.74±0.2、10.53±0.2、12.37±0.2、14.64±0.2、15.21±0.2、21.04±0.2、22.11±0.2、23.03±0.2、23.38±0.2、24.45±0.2、27.22±0.2。
在另一优选例中，所述晶型D的X射线粉末衍射图还包含在2个或2个以上选自下组D2的衍射角2θ(°)值处的峰：14.42±0.2、15.76±0.2、17.30±0.2、18.09±0.2、18.74±0.2、20.29±0.2、26.48±0.2、28.10±0.2、28.74±0.2、29.86±0.2、30.64±0.2、31.11±0.2、32.11±0.2。
在另一优选例中，所述晶型D的X射线粉末衍射图还包含在选自下组D3的衍射角2θ(°)值处的峰：29.09±0.2。
在另一优选例中，所述晶型D的X射线粉末衍射图在选自组D1、D2和D3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型D的X射线粉末衍射图在表D1所示的2θ(°)值处具有峰，各峰相对强度如表D1所示：
表D1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
7.99 S 9.74 S 10.53 S
12.37 VS 14.42 M 14.64 S
15.21 S 15.76 M 17.30 M
18.09 M 18.74 M 20.29 M
21.04 VS 22.11 S 23.03 S
23.38 S 24.45 S 26.48 M
27.22 VS 28.10 M 28.74 M
29.09 W 29.86 M 30.64 M
31.11 M 32.11 M    
在另一优选例中，所述晶型D的X射线粉末衍射图基本如图11所表征。
在另一优选例中，所述多晶型物为式X化合物L-酒石酸盐的E型结晶，即晶型E，其X射线粉末衍射图在下组E1的衍射角2θ(°)值处具有峰：6.43±0.2、10.02±0.2、11.63±0.2、16.07±0.2、19.33±0.2、22.59±0.2、25.88±0.2。
在另一优选例中，所述晶型E的X射线粉末衍射图还包含在2个或2个以上选自下组E2的衍射角2θ(°)值处的峰：7.46±0.2、10.69±0.2、12.88±0.2、16.76±0.2、20.42±0.2、25.13±0.2、26.52±0.2。
在另一优选例中，所述晶型E的X射线粉末衍射图在选自组E1、E2中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型E的X射线粉末衍射图在表E1所示的2θ(°)值处具有峰，各峰相对强度如表E1所示：
表E1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
6.43 VS 7.46 M 10.02 S
10.69 M 11.63 S 12.88 M
16.07 S 16.76 M 19.33 VS
20.42 M 22.59 S 25.13 M
25.88 S 26.52 M    
在另一优选例中，所述晶型E的X射线粉末衍射图基本如图12所表征。
在另一优选例中，所述多晶型物为式X化合物磷酸盐的F型结晶，即晶型F，其X射线粉末衍射图在下组F1的衍射角2θ(°)值处具有峰：12.03±0.2、17.26±0.2、19.65±0.2。
在另一优选例中，所述晶型F的X射线粉末衍射图还包含下组F2的衍射角2θ(°)值处的峰：5.99±0.2、18.20±0.2、21.01±0.2。
在另一优选例中，所述晶型F的X射线粉末衍射图还包含在2个或2个以上选自下组F3的衍射角2θ(°)值处的峰：8.59±0.2、13.41±0.2、13.69±0.2、14.21±0.2、15.57±0.2、19.15±0.2、20.34±0.2、21.70±0.2、21.99±0.2、22.98±0.2、23.59±0.2、25.01±0.2、25.52±0.2、26.74±0.2、34.64±0.2。
在另一优选例中，所述晶型F的X射线粉末衍射图在选自组F1、F2和F3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型F的X射线粉末衍射图在表F1所示的2θ(°)值处具有峰，各峰相对强度如表F1所示：
表F1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.99 M 8.59 W 12.03 VS
13.41 W 13.69 W 14.21 W
15.57 W 17.26 S 18.20 M
19.15 W 19.65 S 20.34 W
21.01 M 21.70 W 21.99 W
22.98 W 23.59 W 25.01 W
25.52 W 26.74 W 34.64 W
在另一优选例中，所述晶型F的X射线粉末衍射图基本如图13所表征。
在另一优选例中，所述多晶型物为式X化合物柠檬酸盐的G型结晶，即晶型G，其X射线粉末衍射图在下组G1的衍射角2θ(°)值处具有峰：9.13±0.2、10.13±0.2、11.06±0.2、12.38±0.2、13.04±0.2、14.07±0.2、14.72±0.2、15.33±0.2、19.16±0.2、20.31±0.2、24.83±0.2、28.04±0.2。
在另一优选例中，所述晶型G的X射线粉末衍射图还包含在2个或2个以上选自下组G2的衍射角2θ(°)值处的峰：6.05±0.2、16.25±0.2、17.18±0.2、18.31±0.2、20.58±0.2、22.29±0.2、23.26±0.2、24.35±0.2、26.06±0.2、27.67±0.2、29.77±0.2。
在另一优选例中，所述晶型G的X射线粉末衍射图还包含在2个或2个以上选自下组G3的衍射角2θ(°)值处的峰：8.48±0.2、13.43±0.2、19.74±0.2、20.92±0.2、26.66±0.2、30.85±0.2、32.75±0.2、34.21±0.2。
在另一优选例中，所述晶型G的X射线粉末衍射图在选自组G1、G2和G3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型G的X射线粉末衍射图在表G1所示的2θ(°)值处具有峰，各峰相对强度如表G1所示：
表G1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
6.05 M 8.48 W 9.13 S
10.13 VS 11.06 VS 12.38 S
13.04 S 13.43 W 14.07 S
14.72 VS 15.33 VS 16.25 M
17.18 M 18.31 M 19.16 S
19.74 W 20.31 S 20.58 M
20.92 W 22.29 M 23.26 M
24.35 M 24.83 S 26.06 M
26.66 W 27.67 M 28.04 S
29.77 M 30.85 W 32.75 W
34.21 W        
在另一优选例中，所述晶型G的X射线粉末衍射图基本如图14所表征。
在另一优选例中，所述多晶型物为式X化合物富马酸盐的H-1型结晶，即晶型H-1，其X射线粉末衍射图在下组H-1-1的衍射角2θ(°)值处具有峰：5.37±0.2、10.74±0.2、17.67±0.2、19.08±0.2、19.35±0.2、20.11±0.2、21.25±0.2、22.84±0.2。
在另一优选例中，所述晶型H-1的X射线粉末衍射图还包含在2个或2个以上选自下组H-1-2的衍射角2θ(°)值处的峰：8.83±0.2、11.60±0.2、12.33±0.2、13.57±0.2、15.38±0.2、16.06±0.2、16.56±0.2、17.08±0.2、18.41±0.2、19.66±0.2、21.74±0.2、23.59±0.2、24.19±0.2、29.98±0.2。
在另一优选例中，所述晶型H-1的X射线粉末衍射图还包含在2个或2个以上选自下组H-1-3的衍射角2θ(°)值处的峰：12.03±0.2、14.47±0.2、17.33±0.2、25.56±0.2、26.49±0.2、28.56±0.2、29.10±0.2、33.12±0.2。
在另一优选例中，所述晶型H-1的X射线粉末衍射图在选自组H-1-1、H-1-2和H-1-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型H-1的X射线粉末衍射图在表(H-1)所示的2θ(°)值处具有峰，各峰相对强度如表(H-1)所示：
表(H-1)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.37 S 8.83 M 10.74 VS
11.60 M 12.03 W 12.33 M
13.57 M 14.47 W 15.38 M
16.06 M 16.56 M 17.08 M
17.33 W 17.67 S 18.41 M
19.08 S 19.35 S 19.66 M
20.11 S 21.25 VS 21.74 M
22.84 VS 23.59 M 24.19 M
25.56 W 26.49 W 28.56 W
29.10 W 29.98 M 33.12 W
在另一优选例中，所述晶型H-1的X射线粉末衍射图基本如图15所表征。
在另一优选例中，所述多晶型物为式X化合物富马酸盐的H-2型结晶，即晶型H-2，其X射线粉末衍射图在下组H-2-1的衍射角2θ(°)值处具有峰：5.69±0.2、11.67±0.2、14.39±0.2、21.15±0.2、23.49±0.2。
在另一优选例中，所述晶型H-2的X射线粉末衍射图还包含在2个或2个以上选自下组H-2-2的衍射角2θ(°)值处的峰：17.06±0.2、17.33±0.2、17.56±0.2、18.05±0.2、18.81±0.2、21.80±0.2、22.68±0.2、23.74±0.2、25.97±0.2、29.48±0.2。
在另一优选例中，所述晶型H-2的X射线粉末衍射图还包含在2个或2个以上选自下组H-2-3的衍射角2θ(°)值处的峰：7.16±0.2、9.43±0.2、14.86±0.2、19.95±0.2、20.51±0.2、24.41±0.2、24.90±0.2、28.70±0.2。
在另一优选例中，所述晶型H-2的X射线粉末衍射图在选自组H-2-1、H-2-2和H-2-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型H-2的X射线粉末衍射图在表(H-2)所示的2θ(°)值处具有峰，各峰相对强度如表(H-2)所示：
表(H-2)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.69 S 7.16 W 9.43 W
11.67 VS 14.39 S 14.86 W
17.06 M 17.33 M 17.56 M
18.05 M 18.81 M 19.95 W
20.51 W 21.15 S 21.80 M
22.68 M 23.49 S 23.74 M
24.41 W 24.90 W 25.97 M
28.70 W 29.48 M    
在另一优选例中，所述晶型H-2的X射线粉末衍射图基本如图16所表征。
在另一优选例中，所述多晶型物为式X化合物甲磺酸盐的J型结晶，即晶型J，其X射线粉末衍射图在下组J1的衍射角2θ(°)值处具有峰：10.64±0.2、18.70±0.2、20.55±0.2、20.86±0.2、21.58±0.2、22.16±0.2、23.05±0.2、24.39±0.2、24.75±0.2、27.18±0.2。
在另一优选例中，所述晶型J的X射线粉末衍射图还包含在2个或2个以上选自下组J2的衍射角2θ(°)值处的峰：4.87±0.2、8.06±0.2、9.13±0.2、9.77±0.2、12.51±0.2、13.89±0.2、14.69±0.2、15.81±0.2、16.10±0.2、17.22±0.2、17.98±0.2、19.31±0.2、19.75±0.2、20.23±0.2、23.98±0.2、25.97±0.2、27.43±0.2。
在另一优选例中，所述晶型J的X射线粉末衍射图还包含在选自下组J3的衍射角2θ(°)值处的峰：6.93±0.2、16.62±0.2。
在另一优选例中，所述晶型J的X射线粉末衍射图在选自组J1、J2和J3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型J的X射线粉末衍射图在表J1所示的2θ(°)值处具有峰，各峰相对强度如表J1所示：
表J1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
4.87 M 6.93 W 8.06 M
9.13 M 9.77 M 10.64 VS
12.51 M 13.89 M 14.69 M
15.81 M 16.10 M 16.62 W
17.22 M 17.98 M 18.70 S
19.31 M 19.75 M 20.23 M
20.55 VS 20.86 VS 21.58 VS
22.16 S 23.05 S 23.98 M
24.39 S 24.75 S 25.97 M
27.18 S 27.43 M    
在另一优选例中，所述晶型J的X射线粉末衍射图基本如图17所表征。
在另一优选例中，所述多晶型物为式X化合物甲酸盐的K-1型结晶，即晶型K-1，其X射线粉末衍射图在下组K-1-1的衍射角2θ(°)值处具有峰：4.80±0.2、8.43±0.2、9.63±0.2、9.88±0.2、12.08±0.2、13.87±0.2、14.63±0.2、18.02±0.2、19.44±0.2、20.05±0.2、20.64±0.2、22.47±0.2、23.68±0.2。
在另一优选例中，所述晶型K-1的X射线粉末衍射图还包含在2个或2个以上选自下组K-1-2的衍射角2θ(°)值处的峰：10.98±0.2、11.21±0.2、13.32±0.2、15.17±0.2、15.65±0.2、16.96±0.2、21.33±0.2、24.15±0.2、27.96±0.2、28.19±0.2。
在另一优选例中，所述晶型K-1的X射线粉末衍射图还包含在2个或2个以上选自下组K-1-3的衍射角2θ(°)值处的峰：16.19±0.2、16.70±0.2、17.49±0.2。
在另一优选例中，所述晶型K-1的X射线粉末衍射图在选自组K-1-1、K-1-2和K-1-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型K-1的X射线粉末衍射图在表(K-1)所示的2θ(°)值处具有峰，各峰相对强度如表(K-1)所示：
表(K-1)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
4.80 VS 8.43 S 9.63 S
9.88 S 10.98 M 11.21 M
12.08 VS 13.32 M 13.87 S
14.63 S 15.17 M 15.65 M
16.19 W 16.70 W 16.96 M
17.49 W 18.02 S 19.44 S
20.05 S 20.64 S 21.33 M
22.47 VS 23.68 S 24.15 M
27.96 M 28.19 M    
在另一优选例中，所述晶型K-1的X射线粉末衍射图基本如图18所表征。
在另一优选例中，所述多晶型物为式X化合物甲酸盐的K-2型结晶，即晶型K-2，其X射线粉末衍射图在下组K-2-1的衍射角2θ(°)值处具有峰：5.23±0.2、17.05±0.2、17.31±0.2、21.28±0.2、22.50±0.2。
在另一优选例中，所述晶型K-2的X射线粉末衍射图还包含在2个或2个以上选自下组K-2-2的衍射角2θ(°)值处的峰：10.53±0.2、12.33±0.2、12.75±0.2、13.99±0.2、15.54±0.2、16.44±0.2、18.23±0.2、19.47±0.2、22.93±0.2。
在另一优选例中，所述晶型K-2的X射线粉末衍射图还包含在下组K-2-3的衍射角2θ(°)值处的峰：19.86±0.2。
在另一优选例中，所述晶型K-2的X射线粉末衍射图在选自组K-2-1、K-2-2和K-2-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型K-2的X射线粉末衍射图在表(K-2)所示的2θ(°)值处具有峰，各峰相对强度如表(K-2)所示：
表(K-2)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.23 VS 10.53 M 12.33 M
12.75 M 13.99 M 15.54 M
16.44 M 17.05 VS 17.31 S
18.23 M 19.47 M 19.86 W
21.28 VS 22.50 S 22.93 M
在另一优选例中，所述晶型K-2的X射线粉末衍射图基本如图19所表征。
在另一优选例中，所述多晶型物为式X化合物甲酸盐的K-3型结晶，即晶型K-3，其X射线粉末衍射图在下组K-3-1的衍射角2θ(°)值处具有峰：4.51±0.2、5.27±0.2、13.76±0.2。
在另一优选例中，所述晶型K-3的X射线粉末衍射图还包含下组K-3-2的衍射角2θ(°)值处的峰：9.17±0.2、13.28±0.2、15.77±0.2、23.91±0.2。
在另一优选例中，所述晶型K-3的X射线粉末衍射图还包含在2个或2个以上选自下组K-3-3的衍射角2θ(°)值处的峰：11.25±0.2、12.36±0.2、14.93±0.2、16.46±0.2、17.11±0.2、18.45±0.2、21.11±0.2、22.09±0.2、23.04±0.2。
在另一优选例中，所述晶型K-3的X射线粉末衍射图在选自组K-3-1、K-3-和K-3-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型K-3的X射线粉末衍射图在表(K-3)1所示的2θ(°)值处具有峰，各峰相对强度如表(K-3)所示：
表(K-3)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
4.51 VS 5.27 VS 9.17 M
11.25 W 12.36 W 13.28 M
13.76 S 14.93 W 15.77 M
16.46 W 17.11 W 18.45 W
21.11 W 22.09 W 23.04 W
23.91 M        
在另一优选例中，所述晶型K-3的X射线粉末衍射图基本如图20所表征。
在另一优选例中，所述多晶型物为式X化合物甲酸盐的K-4型结晶，即晶型K-4，其X射线粉末衍射图在下组K-4-1的衍射角2θ(°)值处具有峰：13.26±0.2、15.04±0.2、16.18±0.2、19.09±0.2、21.54±0.2。
在另一优选例中，所述晶型K-4的X射线粉末衍射图还包含在2个或2个以上选自下组K-4-2的衍射角2θ(°)值处的峰：9.69±0.2、16.35±0.2、16.86±0.2、19.46±0.2、20.85±0.2。
在另一优选例中，所述晶型K-4的X射线粉末衍射图还包含在2个或2个以上选自下组K-4-3的衍射角 2θ(°)值处的峰：11.2±0.2、12.03±0.2、14.00±0.2、17.13±0.2、19.66±0.2、20.38±0.2、21.83±0.2、22.12±0.2、22.58±0.2、23.40±0.2、26.21±0.2、27.44±0.2、28.08±0.2、29.39±0.2、30.34±0.2、33.14±0.2。
在另一优选例中，所述晶型K-4的X射线粉末衍射图在选自组K-4-1、K-4-2和K-4-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型K-4的X射线粉末衍射图在表(K-4)所示的2θ(°)值处具有峰，各峰相对强度如表(K-4)所示：
表(K-4)
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
9.69 M 11.2 W 12.03 W
13.26 S 14.00 W 15.04 VS
16.18 S 16.35 M 16.86 M
17.13 W 19.09 S 19.46 M
19.66 W 20.38 W 20.85 M
21.54 S 21.83 W 22.12 W
22.58 W 23.40 W 26.21 W
27.44 W 28.08 W 29.39 W
30.34 W 33.14 W    
在另一优选例中，所述晶型K-4的X射线粉末衍射图基本如图21所表征。
在另一优选例中，所述多晶型物为式X化合物的晶型I，其X射线粉末衍射图在组I-1的衍射角2θ(°)值处具有峰：6.20±0.2、6.68±0.2、13.42±0.2、21.31±0.2、22.56±0.2。
在另一优选例中，所述晶型I的X射线粉末衍射图还包含在2个或2个以上选自下组I-2的衍射角2θ(°)值处的峰：5.28±0.2、8.53±0.2、10.54±0.2、15.56±0.2、18.12±0.2、20.29±0.2、24.99±0.2。
在另一优选例中，所述晶型I的X射线粉末衍射图还包含在2个或2个以上选自下组I-3的衍射角2θ(°)值处的峰：12.34±0.2、14.80±0.2、16.35±0.2、17.17±0.2、26.40±0.2、27.86±0.2。
在另一优选例中，所述晶型I的X射线粉末衍射图在选自组I-1、I-2和I-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型I的X射线粉末衍射图在表I1所示的2θ(°)值处具有峰，各峰相对强度如表I1所示：
表I1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.28 M 6.20 S 6.68 VS
8.53 M 10.54 M 12.34 W
13.42 S 14.80 W 15.56 M
16.35 W 17.17 W 18.12 M
20.29 M 21.31 S 22.56 S
24.99 M 26.40 W 27.86 W
在另一优选例中，所述晶型I的X射线粉末衍射图基本如图22所表征。
在另一优选例中，所述晶型I还具有选自下组的一个或多个特征：
(i)差示扫描量热法分析图谱中，起始温度为80±2℃和189±2℃；较佳地，其差示扫描量热法分析图谱基本如图23所表征；
(ii)热重分析图谱如图24所表征；
(iii)所述晶型I的熔点为189-197℃，较佳地为199-201℃。
在另一优选例中，所述多晶型物为式X化合物的晶型II，其X射线粉末衍射图在组II-1的衍射角2θ(°)值处具有峰：13.27±0.2、15.03±0.2、16.20±0.2、19.09±0.2、21.56±0.2。
在另一优选例中，所述晶型II的X射线粉末衍射图还包含在2个或2个以上选自下组II-2的衍射角2θ(°)值处的峰：9.71±0.2、11.21±0.2、14.01±0.2、16.35±0.2、19.46±0.2、19.69±0.2、20.86±0.2、22.56±0.2、26.24±0.2。
在另一优选例中，所述晶型II的X射线粉末衍射图还包含在2个或2个以上选自下组II-3的衍射角2θ(°)值处的峰：11.98±0.2、15.89±0.2、16.86±0.2、20.39±0.2、21.15±0.2、21.83±0.2、23.09±0.2、27.43±0.2、28.08±0.2、29.43±0.2。
在另一优选例中，所述晶型II的X射线粉末衍射图在选自组II-1、II-2和II-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型II的X射线粉末衍射图在表II1所示的2θ(°)值处具有峰，各峰相对强度如表II1所示：
表II1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
9.71 M 11.21 M 11.98 W
13.27 S 14.01 M 15.03 VS
15.89 W 16.20 S 16.35 M
16.86 W 19.09 S 19.46 M
19.69 M 20.39 W 20.86 M
21.15 W 21.56 S 21.83 W
22.56 M 23.09 W 26.24 M
27.43 W 28.08 W 29.43 W
在另一优选例中，所述晶型II的X射线粉末衍射图基本如图25所表征。
在另一优选例中，所述多晶型物为式X化合物的晶型III，其X射线粉末衍射图在组III-1的衍射角2θ(°)值处具有峰：5.23±0.2、17.02±0.2。
在另一优选例中，所述晶型III的X射线粉末衍射图还包含组III-2的衍射角2θ(°)值处的峰：12.32±0.2、12.74±0.2、15.57±0.2、16.41±0.2、16.72±0.2、17.34±0.2、18.21±0.2、19.50±0.2、21.29±0.2、22.06±0.2、22.49±0.2、22.94±0.2。
在另一优选例中，所述晶型III的X射线粉末衍射图还包含在2个或2个以上选自下组III-3的衍射角2θ(°)值处的峰：10.51±0.2、14.01±0.2、19.07±0.2、19.84±0.2、23.73±0.2、24.25±0.2、28.49±0.2。
在另一优选例中，所述晶型III的X射线粉末衍射图在选自组III-1、III-2和III-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型III的X射线粉末衍射图在表III1所示的2θ(°)值处具有峰，各峰相对强度如表III1所示：
表III1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.23 VS 10.51 W 12.32 M
12.74 M 14.01 W 15.57 M
16.41 M 16.72 M 17.02 S
17.34 M 18.21 M 19.07 W
19.50 M 19.84 W 21.29 M
22.06 M 22.49 M 22.94 M
23.73 W 24.25 W 28.49 W
在另一优选例中，所述晶型III的X射线粉末衍射图基本如图26所表征。
在另一优选例中，所述多晶型物为式X化合物的晶型IV，其X射线粉末衍射图在组IV-1的衍射角2θ(°)值处具有峰：5.25±0.2、11.94±0.2、12.23±0.2、14.42±0.2、16.65±0.2。
在另一优选例中，所述晶型IV的X射线粉末衍射图还包含在2个或2个以上选自下组IV-2的衍射角2θ(°)值处的峰：5.60±0.2、15.97±0.2、17.45±0.2、17.96±0.2、18.81±0.2、19.35±0.2、20.58±0.2、21.00±0.2、22.17±0.2。
在另一优选例中，所述晶型IV的X射线粉末衍射图还包含在2个或2个以上选自下组IV-3的衍射角2θ(°)值处的峰：8.13±0.2、11.25±0.2、13.17±0.2、17.02±0.2、22.78±0.2、23.94±0.2。
在另一优选例中，所述晶型IV的X射线粉末衍射图在选自组IV-1、IV-2和IV-3中的6个或更多个或全部(如6、7、8、9、10、11、12、13、14、15等)的2θ(°)值处具有峰。
在另一优选例中，所述晶型IV的X射线粉末衍射图在表IV1所示的2θ(°)值处具有峰，各峰相对强度如表IV1所示：
表IV1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.25 VS 5.60 M 8.13 W
11.25 W 11.94 S 12.23 S
13.17 W 14.42 S 15.97 M
16.65 S 17.02 W 17.45 M
17.96 M 18.81 M 19.35 M
20.58 M 21.00 M 22.17 M
22.78 W 23.94 W    
在另一优选例中，所述晶型IV的X射线粉末衍射图基本如图27所表征。
在本发明的第二方面，提供了一种制备本发明第一方面所述的式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物的方法，包括步骤：
(1)在溶剂中，将化合物2a与化合物3a进行反应，从而形成式X化合物；和
Figure PCTCN2019083970-appb-000002
(2)任选地将式X化合物与酸进行成盐反应，从而形成药学上可接受的盐；
(3)任选地将步骤(1)或步骤(2)所形成的式X化合物或其药学上可接受的盐进行结晶处理，从而获得多晶型物。
在另一优选例中，步骤(2)中，所述溶剂选自下组：乙腈、50％乙腈/50％水、甲醇、乙醇、异丙醇、丙酮、 乙酸乙酯、甲基叔丁基醚、四氢呋喃、正庚烷、二甲基亚砜，优选为丙酮、乙醇、乙酸乙酯、50％乙腈/50％水。
在另一优优选例中，所述方法包括以下子方法中任一子方法：
(A)所述多晶型物为式X化合物马来酸盐的A型结晶，即晶型A，并且在步骤(3)中包括：在溶剂中，在马来酸存在下，对式X化合物进行结晶处理，从而形成晶型A。
在另一优选例中，步骤(A)中，所述溶剂选自下组：水、50％丙酮/50％水、丙酮、乙腈、乙酸乙酯、乙醇、异丙醇、50％乙腈/50％水、甲醇或四氢呋喃，较佳地，所述有机溶剂为丙酮、乙醇、乙酸乙酯、50％乙腈/50％水或50％丙酮/50％水、乙腈、异丙醇、四氢呋喃。
在另一优选例中，步骤(A)中，马来酸与式X化合物的摩尔比为(1～2)∶1，较佳地为(1.0～1.2)∶1。
在另一优选例中，步骤(A)中，结晶处理方式为缓慢挥发、缓慢降温或混悬振摇。
在另一优选例中，步骤(A)中，结晶处理温度为0-100℃，较佳地为25-80℃。
在另一优选例中，步骤(A)中，结晶处理时间为0.5-24小时。
(B-1)所述多晶型物为式X化合物盐酸盐的B-1型结晶，即晶型B-1，并且在步骤(3)中包括：溶剂中，在盐酸存在下，对式X化合物进行结晶处理，从而形成晶型B-1。
在另一优选例中，步骤(B-1)中，所述溶剂选自下组：水、50％丙酮/50％水、丙酮、乙腈、乙酸乙酯、乙醇、异丙醇、50％乙腈/50％水、甲醇或四氢呋喃，较佳地，所述有机溶剂为丙酮、乙醇、甲醇、乙酸乙酯、乙腈、异丙醇、四氢呋喃。
在另一优选例中，步骤(B-1)中，盐酸与式X化合物的摩尔比为(1～2)∶1，较佳地为(1.0～1.2)∶1。
在另一优选例中，步骤(B-1)中，结晶处理方式为缓慢挥发、缓慢降温或混悬振摇。
在另一优选例中，步骤(B-1)中，结晶处理温度为0-100℃，较佳地为25-80℃。
在另一优选例中，步骤(B-1)中，结晶处理时间为0.5-24小时。
(B-2)所述多晶型物为式X化合物盐酸盐的B-2型结晶，即晶型B-2，并且在步骤(3)中包括：溶剂中，对晶型B-1进行结晶处理，从而形成晶型B-2。
在另一优选例中，步骤(B-2)中，所述溶剂为乙腈。
在另一优选例中，步骤(B-2)中，盐酸与式X化合物的摩尔比为(1～2)∶1，较佳地为(1.0～1.2)∶1。
在另一优选例中，步骤(B-2)中，结晶处理方式为缓慢降温。
在另一优选例中，步骤(B-2)中，结晶处理温度为0-60℃。
在另一优选例中，步骤(B-2)中，结晶处理时间为2-3天。
(B-3)所述多晶型物为式X化合物盐酸盐的B-3型结晶，即晶型B-3，并且在步骤(3)中包括：溶剂中，对晶型B-1进行结晶处理，从而形成晶型B-3。
在另一优选例中，步骤(B-3)中，所述溶剂为丙酮。
在另一优选例中，步骤(B-3)中，盐酸与式X化合物的摩尔比为(1～2)∶1，较佳地为(1.0～1.2)∶1。
在另一优选例中，步骤(B-3)中，结晶处理方式为缓慢降温。
在另一优选例中，步骤(B-3)中，结晶处理温度为0-60℃。
在另一优选例中，步骤(B-3)中，结晶处理时间为2-3天。
(C-1)所述多晶型物为式X化合物硫酸盐的C-1型结晶，即晶型C-1，并且在步骤(3)中包括：溶剂中，在硫酸存在下，对式X化合物进行结晶处理，从而形成晶型C-1。
在另一优选例中，步骤(C-1)中，所述溶剂为乙醇或丙酮。
在另一优选例中，步骤(C-1)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(C-1)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(C-1)中，结晶处理时间为1小时-3天。
(C-2)所述多晶型物为式X化合物硫酸盐的C-2型结晶，即晶型C-2，并且在步骤(3)中包括：溶剂中，在硫酸存在下，对式X化合物进行结晶处理，从而形成晶型C-2。
在另一优选例中，步骤(C-2)中，所述溶剂为乙酸乙酯。
在另一优选例中，步骤(C-2)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(C-2)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(C-2)中，结晶处理时间为1小时-3天。
(D)所述多晶型物为式X化合物氢溴酸盐的D型结晶，即晶型D，并且在步骤(3)中包括：溶剂中，在氢溴酸存在下，对式X化合物进行结晶处理，从而形成晶型D。
在另一优选例中，步骤(D)中，所述溶剂为乙酸乙酯。
在另一优选例中，步骤(D)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(D)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(D)中，结晶处理时间为1小时-3天。
(E)所述多晶型物为式X化合物L-酒石酸盐的E型结晶，即晶型E，并且在步骤(3)中包括：溶剂中，在L-酒石酸存在下，对式X化合物进行结晶处理，从而形成晶型E。
在另一优选例中，步骤(E)中，所述溶剂为丙酮。
在另一优选例中，步骤(E)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(E)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(E)中，结晶处理时间为1小时-3天。
(F)所述多晶型物为式X化合物磷酸盐的F型结晶，即晶型F，并且在步骤(3)中包括：溶剂中，在磷酸存在下，对式X化合物进行结晶处理，从而形成晶型F。
在另一优选例中，步骤(F)中，所述溶剂为丙酮。
在另一优选例中，步骤(F)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(F)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(F)中，结晶处理时间为1小时-3天。
(G)所述多晶型物为式X化合物柠檬酸盐的G型结晶，即晶型G，并且在步骤(3)中包括：溶剂中，在柠檬酸存在下，对式X化合物进行结晶处理，从而形成晶型G。
在另一优选例中，步骤(G)中，所述溶剂为丙酮。
在另一优选例中，步骤(G)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(G)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(G)中，结晶处理时间为1小时-3天。
(H-1)所述多晶型物为式X化合物富马酸盐的H-1型结晶，即晶型H-1，并且在步骤(3)中包括：溶剂中，在富马酸存在下，对式X化合物进行结晶处理，从而形成晶型H-1。
在另一优选例中，步骤(H-1)中，所述溶剂为丙酮。
在另一优选例中，步骤(H-1)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(H-1)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(H-1)中，结晶处理时间为1小时-3天。
(H-2)所述多晶型物为式X化合物富马酸盐的H-2型结晶，即晶型H-2，并且在步骤(3)中包括：溶剂中，在富马酸存在下，对式X化合物进行结晶处理，从而形成晶型H-2。
在另一优选例中，步骤(H-2)中，所述溶剂为乙醇或乙酸乙酯。
在另一优选例中，步骤(H-2)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(H-2)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(H-2)中，结晶处理时间为1小时-3天。
(J)所述多晶型物为式X化合物甲磺酸盐的J型结晶，即晶型J，并且在步骤(3)中包括：溶剂中，在甲磺酸存在下，对式X化合物进行结晶处理，从而形成晶型J。
在另一优选例中，步骤(J)中，所述溶剂为乙醇、丙酮、50％乙腈/50％水、或乙酸乙酯。
在另一优选例中，步骤(J)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(J)中，结晶处理温度为0-60℃。优选为4-50℃。
在另一优选例中，步骤(J)中，结晶处理时间为1小时-3天。
(K-1)所述多晶型物为式X化合物甲酸盐的K-1型结晶，即晶型K-1，并且在步骤(3)中包括：溶剂中，在甲酸存在下，对式X化合物进行结晶处理，从而形成晶型K-1。
在另一优选例中，步骤(K-1)中，所述溶剂为乙酸乙酯、四氢呋喃、甲醇、异丙醇或乙醇。
在另一优选例中，步骤(K-1)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(K-1)中，结晶处理温度为0-80℃。
在另一优选例中，步骤(K-1)中，结晶处理时间为1小时-5天。
(K-2)所述多晶型物为式X化合物甲酸盐的K-2型结晶，即晶型K-2，并且在步骤(3)中包括：溶剂中，对晶型K-1进行结晶处理，从而形成晶型K-2。
在另一优选例中，步骤(K-2)中，所述溶剂为乙腈或丙酮。
在另一优选例中，步骤(K-2)中，结晶处理方式为缓慢挥发。
在另一优选例中，步骤(K-2)中，结晶处理温度为0-80℃。
在另一优选例中，步骤(K-2)中，结晶处理时间为1小时-5天。
(K-3)所述多晶型物为式X化合物甲酸盐的K-3型结晶，即晶型K-3，并且在步骤(3)中包括：溶剂中，对晶型K-1进行结晶处理，从而形成晶型K-3。
在另一优选例中，步骤(K-3)中，所述溶剂为乙腈。
在另一优选例中，步骤(K-3)中，结晶处理方式为缓慢降温。
在另一优选例中，步骤(K-3)中，结晶处理温度为0-80℃。
在另一优选例中，步骤(K-3)中，结晶处理时间为1小时-5天。
(K-4)所述多晶型物为式X化合物甲酸盐的K-4型结晶，即晶型K-4，并且在步骤(3)中包括：溶剂中，对晶型K-1进行结晶处理，从而形成晶型K-4。
在另一优选例中，步骤(K-4)中，所述溶剂为丙酮。
在另一优选例中，步骤(K-4)中，结晶处理方式为缓慢降温。
在另一优选例中，步骤(K-4)中，结晶处理温度为0-80℃。
在另一优选例中，步骤(K-4)中，结晶处理时间为1小时-5天。
(I)所述多晶型物为式X化合的晶型I，并且在步骤(3)中包括：在溶剂中，对式X化合物进行结晶处理， 从而形成晶型I。
在另一优选例中，步骤(I)中，所述溶剂选自下组：水、甲醇、乙醇、丙醇、异丙醇、丁醇、丙酮、乙腈、四氢呋喃、丙二醇、乙酸乙酯、甲基异丁基酮、乙酸异丙酯、2-甲基四氢呋喃、二氯甲烷、甲基叔丁基醚、二甲基亚砜、甲苯、N，N-二甲基乙酰胺、N-甲基吡咯烷酮，或其混合。
在另一优选例中，步骤(I)中，所述溶剂选自下组：水、乙腈、50％乙腈/50％水、甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、甲基叔丁基醚、四氢呋喃、正庚烷、二甲基亚砜。
在另一优选例中，步骤(I)中，结晶方式为缓慢挥发。
在另一优选例中，步骤(I)中，5-30℃，较佳地为10-20℃。
在另一优选例中，步骤(I)中，结晶处理时间为1-10天，较佳地为4-8天。
(II)所述多晶型物为式X化合的晶型II，并且在步骤(3)中包括：在溶剂中，对式X化合物进行结晶处理，从而形成晶型II。
在另一优选例中，步骤(II)中，所述溶剂选自下组：50％乙睛/50％水、水、甲醇、乙醇、丙醇、异丙醇、丁醇、丙酮、乙腈、四氢呋喃、丙二醇、乙酸乙酯、甲基异丁基酮、乙酸异丙酯、2-甲基四氢呋喃、二氯甲烷、甲基叔丁基醚、二甲基亚砜、甲苯、N，N-二甲基乙酰胺、N-甲基吡咯烷酮，或其混合。优选为异丙醇、乙醇、乙酸乙酯、丙酮、乙睛、或50％乙睛/50％水。
在另一优选例中，步骤(II)中，结晶方式为缓慢挥发。
在另一优选例中，步骤(II)中，0-60℃，较佳地为5-40℃。
在另一优选例中，步骤(II)中，结晶处理时间为0.5小时-10天。
(III)所述多晶型物为式X化合的晶型III，并且在步骤(3)中包括：在溶剂中，对式X化合物进行结晶处理，从而形成晶型III。
在另一优选例中，步骤(III)中，所述溶剂选自下组：水、正庚烷、甲醇、乙醇、丙醇、异丙醇、丁醇、丙酮、乙腈、四氢呋喃、丙二醇、乙酸乙酯、甲基异丁基酮、乙酸异丙酯、2-甲基四氢呋喃、二氯甲烷、甲基叔丁基醚、二甲基亚砜、甲苯、N，N-二甲基乙酰胺、N-甲基吡咯烷酮，或其混合。优选甲基叔丁基醚或正庚烷。
在另一优选例中，步骤(III)中，结晶方式为缓慢挥发。
在另一优选例中，步骤(III)中，0-60℃，较佳地为5-40℃。
在另一优选例中，步骤(III)中，结晶处理时间为0.5小时-10天。
(IV)所述多晶型物为式X化合的晶型IV，并且在步骤(3)中包括：在溶剂中，对式X化合物进行结晶处理，从而形成晶型IV。
在另一优选例中，步骤(IV)中，所述溶剂选自下组：水、甲醇、乙醇、丙醇、异丙醇、丁醇、丙酮、乙腈、四氢呋喃、丙二醇、乙酸乙酯、甲基异丁基酮、乙酸异丙酯、2-甲基四氢呋喃、二氯甲烷、甲基叔丁基醚、二甲基亚砜、甲苯、N，N-二甲基乙酰胺、N-甲基吡咯烷酮，或其混合。优选为四氢呋喃。
在另一优选例中，步骤(IV)中，结晶方式为缓慢挥发。
在另一优选例中，步骤(IV)中，0-60℃，较佳地为5-40℃。
在另一优选例中，步骤(IV)中，结晶处理时间为0.5小时-10天。
本发明第三方面提供了一种药物组合物，所述药物组合物包括：
(a)本发明第一方面中任一所述的式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物；以及(b)药学可接受的载体。
本发明第四方面提供了如本发明第一方面所述的式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物、或如本发明第三方面所述药物组合物在制备治疗疾病或病症的药物中的应用，所述疾病或病症选自癌症、异常细胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病、神经变性疾病、由辐射引起的造血毒性疾病，或其组合。
在另一优选例中，所述的癌症选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
在另一优选例中，所述的辐射引起的造血毒性疾病包括但不限于骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血。
本发明第五方面提供了一种抑制CDK4和/或CDK6活性的方法，其包括给予所需患者治疗有效量的本发明第一方面所述的式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物，或如本发明第三方面所述药物组合物。
本发明第六方面提供了一种治疗异常细胞增殖性疾病、感染(例如病毒感染，如疱疹、HIV、真菌感染等)炎性病症(例如类风湿性关节炎、骨关节炎等)、自身免疫性疾病(例如牛皮癣、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎等)、心血管疾病(例如心肌梗塞、中风、动脉粥样硬化、手术后血管狭窄、再狭窄等)或神经变性疾病(例如阿尔茨海默氏病、帕金森病等)的方法，其包括给予所需患者治疗有效量的本发明第一方面所述的式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物，或如本发明第三方面所述药物组合物，其中所述的异常细胞增殖性疾病可以是癌症。
本发明第七方面提供了一种治疗癌症的方法，其包括给予所需患者治疗有效量的本发明第一方面所述的式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物，或如本发明第三方面所述药物组合物，其中所述癌症选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤(例如具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌(例如子宫颈癌、子宫内膜癌等)、头颈肿瘤(例如上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例如尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1晶型A的X射线粉末衍射图谱
图2晶型A的差示扫描量热分析图谱
图3晶型A的热重分析图谱
图4晶体B-1的X射线粉末衍射图谱
图5晶体B-1的差示扫描量热分析图谱
图6晶体B-1的热重分析分析图谱
图7晶型B-2的X射线粉末衍射图谱
图8晶型B-3的X射线粉末衍射图谱
图9晶型C-1的X射线粉末衍射图谱
图10晶型C-2的X射线粉末衍射图谱
图11晶型D的X射线粉末衍射图谱
图12晶型E的X射线粉末衍射图谱
图13晶型F的X射线粉末衍射图谱
图14晶型G的X射线粉末衍射图谱
图15晶型H-1的X射线粉末衍射图谱
图16晶型H-2的X射线粉末衍射图谱
图17晶型J的X射线粉末衍射图谱
图18晶型K-1的X射线粉末衍射图谱
图19晶型K-2的X射线粉末衍射图谱
图20晶型K-3的X射线粉末衍射图谱
图21晶型K-4的X射线粉末衍射图谱
图22晶型I的X射线粉末衍射图谱
图23晶型I的差示扫描量热法分析图谱
图24晶型I的热重分析图谱
图25晶型II的X射线粉末衍射图谱
图26晶型III的X射线粉末衍射图谱
图27晶型IV的X射线粉末衍射图谱
图28晶型A的 1HNMR图谱
图29晶型B-1加速条件0天-28天XRD图谱
图30晶型A加速条件0天-28天XRD图谱
图31晶型A在60℃条件下14天XRD图谱
图32晶型A在60℃条件下32天XRD图谱
图33晶型I的DVS图谱
图34晶型A的DVS图谱
图35晶型B-1的DVS图谱
图36晶型K-1的DVS图谱
具体实施方式
发明人经过广泛而深入的研究，意外地发现了一系列式X化合物的游离碱多晶型物、盐以及盐的多晶型物，对CDK4和CDK6具有较高的抑制活性，同时对CDK1和CDK2的抑制活性较弱，具有明显的4、6选择性。研究还发现，式X化合物的一系列游离碱多晶型物、其盐以及盐的多晶型物不仅具有较好的物理化学稳定性，还具有较好的体内、体外相关药理活性，因此具有进一步开发成为药物的可能。
术语
如本发明所用，“本发明的晶体”、“本发明的晶型”、“本发明的多晶型物”等可互换使用。
式X化合物
在本发明中，式X化合物为2-环丙基-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-3-异丙基-3，8-二氢咪唑并[4′，5′，4，5]环戊二烯并[1，2-d]嘧啶-5-胺，其对CDK4和CDK6具有较高的抑制活性，同时对CDK1和CDK2的抑制活性较弱，具有明显的4、6选择性。
本发明还包括式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物。
在本发明中，所述的药学上可接受的盐选自下组：盐酸盐、硫酸盐、氢溴酸盐、磷酸盐、甲磺酸盐、马来酸盐(顺丁烯二酸盐)、L-酒石酸盐、柠檬酸盐(枸橼酸盐)、富马酸盐(反丁烯二酸盐)、甲酸盐。
多晶型物
固体不是以无定形的形式就是以结晶的形式存在。在结晶形式的情况下，分子定位于三维晶格格位内。当化合物从溶液或浆液中结晶出来时，它可以不同的空间点阵排列结晶(这种性质被称作“多晶型现象”)，形成具有不同的结晶形式的晶体，这各种结晶形式被称作“多晶型物”。给定物质的不同多晶型物可在一个或多个物理属性方面(如溶解度和溶解速率、真比重、晶形、堆积方式、流动性和/或固态稳定性)彼此不同。
结晶
可以通过操作溶液，使得感兴趣化合物的溶解度极限被超过，从而完成生产规模的结晶。这可以通过多种方法来完成，例如，在相对高的温度下溶解化合物，然后冷却溶液至饱和极限以下。或者通过沸腾、常压蒸发、真空干燥或通过其它的一些方法来减小液体体积。可通过加入抗溶剂或化合物在其中具有低的溶解度的溶剂或这样的溶剂的混合物，来降低感兴趣化合物的溶解度。另一种可选方法是调节pH值以降低溶解度。有关结晶方面的详细描述请参见Crystallization，第三版，J W Mullens，Butterworth-Heineman Ltd.，1993，ISBN 0750611294。
本发明所述的“悬浮搅拌”是指将式X化合物和相应的酸或相应酸的溶液在合适的溶剂中混合形成浑浊液，或者将式X化合物与合适的溶剂混合形成浑浊液后搅拌得到晶体的一种方法。合适的溶剂可以为水或有机溶剂。
本发明所述的“缓慢挥发”是指将式X化合物的溶液或含式X化合物和相应酸的溶液置于一定温度下缓慢挥发掉溶剂，得到晶体的一种方法。
本发明所述的“反溶剂添加”是指向式X化合物的一种溶液中加入另一种合适溶剂后析出得到晶体的一种方法。
假如期望盐的形成与结晶同时发生，如果盐在反应介质中比原料溶解度小，那么加入适当的酸或碱可导致所需盐的直接结晶。同样，在最终想要的形式比反应物溶解度小的介质中，合成反应的完成可使最终产物直接结晶。
结晶的优化可包括用所需形式的晶体作为晶种接种于结晶介质中。另外，许多结晶方法使用上述策略的组合。一个实施例是在高温下将感兴趣的化合物溶解在溶剂中，随后通过受控方式加入适当体积的抗溶剂，以使体系正好在饱和水平之下。此时，可加入所需形式的晶种(并保持晶种的完整性)，将体系冷却以完成结晶。
如本文所用，术语“室温”一般指4-30℃，较佳地指20±5℃。
本发明的多晶型物
如本文所用，术语“本发明的多晶型物”包括式X化合物或其药学上可接受盐(如盐酸盐、马来酸盐)，或 其各种溶剂合物的多晶型物，还包括相同的盐或溶剂合物的不同多晶型物。
“式X化合物的多晶型物”与“式X化合物游离碱的多晶型物”可互换使用。
优选的本发明多晶型物包括(但并不限于)：
(i)晶型A、B(包括B-1、B-2、B-3)、C(包括C-1、C-2)、D、E、F、G、H(包括H-1、H-2)、J、K(包括K-1、K-2、K-3、K-4)(盐的晶型)；
(ii)晶型I、II、III、IV(式X化合物的晶型)。
在本发明中，某些晶型可以相互转化，因此本发明还提供了部分晶型相互转化的方法。
多晶型物的鉴定和性质
本发明在制备式X化合物的多晶型物后，采用如下多种方式和仪器对其性质进行了研究。
X射线粉末衍射
测定晶型的X射线粉末衍射的方法在本领域中是已知的。例如使X射线粉末衍射仪，以2°每分钟的扫描速度，采用铜辐射靶获取图谱。
本发明的式X化合物或其药学上可接受的盐的多晶型物，具有特定的晶型形态，在X-射线粉末衍射(XRPD)图中具有特定的特征峰。
示差扫描量热分析
又称“差示量热扫描分析”(DSC)，是在加热过程中，测量被测物质与参比物之间的能量差与温度之间关系的一种技术。DSC图谱上的峰位置、形状和峰数目与物质的性质有关，故可以定性地用来鉴定物质。本领域常用该方法来检测物质的相变温度、玻璃化转变温度、反应热等多种参数。
式X化合物的药物组合物及其应用
通常，本发明式X化合物或其药学可接受的盐可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
本发明提供了本发明第一方面所述的式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物可用于制备CDK4/6抑制剂或治疗CDK4/6相关疾病的药物中的应用。
作为优选，所述CDK4/6相关疾病为癌症、异常细胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病、神经变性疾病、由辐射引起的造血毒性疾病，或其组合。
作为优选，所述癌症为乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤，或它们的任何组合。
作为优选，所述乳腺癌是HR-阳性、HER2-阴性晚期乳腺癌。
如本文所用，“治疗有效量”是指可对人和/或动物产生功能或活性的且可被人和/或动物所接受的量。
如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
本发明的药物组合物或所述药用组合物中含有的式X化合物药学上可接受盐、或式X化合物或其药学上可接受盐的多晶型物的治疗有效量优选为0.1mg-5g/kg(体重)。
本发明的主要优点在于：
本发明人发现，2-环丙基-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-3-异丙基-3，8-二氢咪唑并[4′，5′，4，5]环戊二烯并[1，2-d]嘧啶-5-胺游离碱多晶型物以及盐也具有较好的物理化学性质和突出的相关药理活性，是理想的CDK4/6抑制剂。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
试剂与仪器
本发明中，化合物的结构和纯度通过核磁共振( 1HNMR)和、或液质联用质谱(LC-MS)来确定。 1HNMR：BrukerAVANCE-400核磁仪，内标为四甲基硅烷(TMS)。LC-MS：Agilent 1200 HPLC System、6140MS液质联用质谱仪(购自安捷伦)，柱子WatersX-Bridge，150×4.6mm，3.5μm。制备高效液相色谱(pre-HPLC)：用Waters PHW007，柱子XBridge C18，4.6*150mm，3.5um。
采用ISCO Combiflash-Rf75或Rf200型自动过柱仪，Agela 4g、12g、20g、40g、80g、120g一次性硅胶柱。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)，检测反应使用的硅胶板采用的规格是0.15mm-0.2mm，薄层色谱法分离纯化产品使用的硅胶板采用的规格是0.4mm-0.5mm。硅胶一般使用烟台黄海硅胶200-300目硅胶为载体。碱性氧化铝柱一般使用国药层析用FCP200-300目碱性氧化铝为载体。
实施例中无特殊说明，反应均在氮气或氩气氛下进行。实施例中无特殊说明，溶液是指水溶液。
如本文所用，DMF表示二甲基甲酰胺，DMSO表示二甲基亚砜，THF表示四氢呋喃，DIEA表示N，N-二异丙基乙胺，EA表示乙酸乙酯，PE表示石油醚。BINAP表示(2R，3S)-2，2’-双二苯膦基-1，1’-联萘，NBS表示N-溴代丁二酰亚胺，NCS表示N-氯代丁二酰亚胺，Pd2(dba)3表示三(二亚苄基丙酮)二钯，Pd(dppf)Cl2表示[1，1’-双(二苯基磷)二茂铁]二氯化钯。
乙腈ACN，甲醇MeOH，乙醇EtOH，异丙醇IPA，丙酮ACE，乙酸乙酯EA，甲基叔丁基醚MTBE，四氢呋喃THF，水H 2O，50％乙腈50％ACN，二环己基[3，6-二甲氧基-2′，4′，6′-三异丙基[1，1′-联苯]-2-基]膦Brettphos。
如本文所用，室温指的是约20±5℃。
通用方法
X射线粉末衍射：本发明中，上述晶型的粉末X衍射图谱是通过本领域的已知方法，使用D8 ADVANCE X射线粉末衍射分析仪获得。仪器测试条件如下表所示：
Figure PCTCN2019083970-appb-000003
在粉末X衍射图中，各峰的位置由2θ(°)确定。可以理解，不同的仪器和、或条件可导致产生的数据会略有不同，各峰的位置和相对强度会有变化。峰的强度划分仅仅反映了各位置上峰的近似大小。在本发明中，各晶型均以其峰高最高的衍射峰作为基峰，定义其相对强度为100％，作为I 0(晶型I的2θ(°)值为6.68的峰为基峰，晶型II的2θ(°)值为15.03的峰为基峰，晶型III的2θ(°)值为5.23的峰为基峰，晶型IV的2θ(°)值为5.25的峰为基峰，晶型A的2θ(°)值为18.06的峰为基峰，晶型B-1的2θ(°)值为14.75的峰为基峰，晶型B-2的2θ(°)值为4.56的峰为基峰，晶型B-3的2θ(°)值为14.96的峰为基峰，晶型C-1的2θ(°)值为13.72的峰为基峰，晶型C-2的2θ(°)值为10.47的峰为基峰，晶型D的2θ(°)值为21.04的峰为基峰，晶型E的2θ(°)值为19.33的峰为基峰，晶型F的2θ(°)值为12.03的峰为基峰，晶型G的2θ(°)值为10.13的峰为基峰，晶型H-1的2θ(°)值为22.84的峰为基峰，晶型H-2的2θ(°)值为11.67的峰为基峰，晶型J的2θ(°)值为10.64的峰为基峰，晶型K-1的2θ(°)值为12.08的峰为基峰，晶型K-2的2θ(°)值为5.23的峰为基峰，晶型K-3的2θ(°)值为5.27的峰为基峰，晶型K-4的2θ(°)值为15.04的峰为基峰)，其它各峰以其峰高与基峰峰高的比值作为其相对强度I、I 0，各峰相对强度的划分定义如下表所示：
相对强度I/I 0(％) 定义
50～100 VS(很强)
25～50 S(强)
10～25 M(中等)
1～10 W(弱)
本发明的盐或其晶型通过HPLC/IC或 1H NMR确定酸碱摩尔比。
高效液相色谱：本发明中，高效液相色谱(HPLC)在Agilent1260 HPLC上采集。
TGA和DSC图谱：TGA和DSC图谱分别在TA Q500/5000热重分析仪和TA Q200/2000差示扫描量热仪上采集。仪器测试条件如下表所示：
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铂金盘，敞开 铝盘，压盖
温度范围 室温-设定温度 25℃-设定温度
扫描速率(℃、分钟) 10 10
保护气体 氮气 氮气
动态水分吸附(DVS)曲线：在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl，Mg(NO 3) 2和KCl的潮解点校正。仪器测试条件如下表所示：
Figure PCTCN2019083970-appb-000004
可以理解的是，使用与上述仪器作用相同的其他类型的仪器或使用不同与本发明中使用的测试条件时，可能会得到另外的数值，因此，所引用的数值不应视为绝对的数值。
由于仪器的误差或操作人员的区别，本领域技术人员能理解，以上用于表征晶体的物理性质的参数可能有微小的差别，所以上述的参数仅用于辅助表征本发明提供的多晶型物，而不能视为是对本发明的多晶型物的限制。
中间体制备
化合物1a的制备
Figure PCTCN2019083970-appb-000005
步骤1：将化合物1-1(50g，0.51mol)溶于500ml乙醇，加入化合物对甲苯磺酸，回流48h。反应液冷却至室温后，减压浓缩，除去溶剂，再加入500ml乙醇，继续回流18h。反应液冷却至室温后，减压浓缩，除去大部分溶剂后用硅藻土过滤，滤饼用乙醇洗涤。滤液减压浓缩后得到化合物1-2(62g)，直接用于下一步反应。MS m/z(ESI)：127[M+H] +
步骤2：将化合物1-2(62g，0.51mol)溶于600ml二氯甲烷，在5-10℃下分批加入NBS(100g，0.56mol)，反应液在室温下搅拌16h。减压浓缩，除去二氯甲烷，粗品中加入600ml甲基叔丁基醚，搅拌，过滤，滤液浓缩后得到化合物1-3(95g)，直接用于下一步反应。MS m/z(ESI)：206[M+H] +
步骤3：将化合物1-3(446g，2.175mol)溶于DMF(3L)加入化合物1-4(263.2g，2.175mol)，碳酸钾(870g，6.30mol)，反应液在100℃下搅拌2h。用饱和氯化铵溶液淬灭反应。减压除去溶剂，粗品经柱层析纯化后，用乙酸乙酯打浆，得到化合物1a(195g，收率55％)，MS m/z(ESI)：162[M+H] +。
化合物2a的制备
Figure PCTCN2019083970-appb-000006
步骤1：将化合物1a(10g，0.062mol)溶于DMF(100ml)，在5-10℃下分批加入钠氢(3g，0.075mol)，反 应液在5℃下搅拌1h，慢慢加入碘代异丙烷(7.5ml，0.75mol)，反应液在60℃搅拌4h。减压浓缩除去溶剂，粗品经柱层析纯化得化合物2-1(2.5g)，MS m/z(ESI)：204[M+H] +。
步骤2：将化合物2-1(30g，0.147mol)、化合物2-2(130ml，0.632mol)于110℃搅拌4h，反应液减压浓缩得2-3(40g)，直接用于下一步反应。MS m/z(ESI)：260[M+H] +。
步骤3：将化合物2-3(40g，0.147mol)，2-4(140.4g，1.47mol)，和乙醇钠(100g，1.47mol)溶于乙醇中120℃下封管搅拌36h。反应液冷却至室温后，过滤除去不溶固体，滤液浓缩，经柱层析纯化得化合物2a(25g，收率67％)，MS m/z(ESI)：256[M+H] +。
化合物3a的制备
Figure PCTCN2019083970-appb-000007
将化合物3-1(142g，0.877mol)，化合物3-2(100g，0.877mol)和碳酸钾(242g，1.754mol)溶于乙醇，反应液在60℃搅拌24h，反应液冷却至室温后过滤除去不溶固体，滤液减压浓缩，经柱层析纯化得化合物3a(59g，收率97％)，MS m/z(ESI)：240[M+H] +。
实施例1式X化合物的制备
Figure PCTCN2019083970-appb-000008
将化合物2a(1.5g，5.9mmol)，3a(1.83g，7.6mmol)，碳酸铯(3.81g，11.7mmol)，醋酸钯(66mg，0.3mmol)，Brettphos(0.16g，0.3mmol)溶于二甘醇二乙醚中，在氮气保护下150℃搅拌过夜。反应液冷却至室温后，用甲醇淬灭反应，用硅藻土过滤除去不溶固体，浓缩滤液，粗品经Pre-HPLC酸法制备(流动相中的酸为甲酸)得到淡黄色式X化合物甲酸盐粉末(1.8g，收率69％)，MS m/z(ESI)：459[M+H] +， 1H NMR(400MHz，DMSO)δ9.44(s，1H)，8.35-8.32(m，2H)，8.18-8.16(m，2H)，7.68(dd，1H)，4.95-4.92(m，1H)，3.44(d，4H)，2.49-2.39(m，8H)，2.35-2.34(m，2H)，2.32-2.30(m，1H)，1.68(d，6H)，1.04-0.94(m，7H)。将所得粉末送XRD检测，其粉末X衍射图显示无明显特征峰，为无定形形式。将所得式X化合物甲酸盐通过Pre-HPLC(NH 3H 2O-NH 4HCO 3)转化为游离碱形式，得到1.38g式X化合物游离碱，为白色固体。
实施例2式X化合物晶型A的制备
将800mg按实施例1方法得到的式X化合物游离碱溶于30ml丙酮，超声使其完全分散；加入2100μL马来酸(浓度1M)，酸碱摩尔比1.2∶1，40℃下磁力搅拌4h。将反应混悬液经真空泵抽滤，润洗，于40℃烘箱内烘干，得到类白色至黄色粉末，收率：87.57％。所得结晶的粉末X衍射图如图1所示(2θ角已标出)， 1HMR如图28所示，酸碱摩尔比为1.2∶1，熔点206℃。在本申请中定义为晶型A。
实施例3式X化合物晶型A的制备
分别取15mg按实施例1方法得到的式X化合物游离碱于样品瓶中，分别加入1-3ml乙醇、丙酮、乙酸乙酯或50％乙腈使化合物完全溶解，加入1M马来酸0.039ml，加入搅拌子密封样品瓶，置于50℃水浴中反应4h，使化合物与酸反应。取出样品瓶，冷却至室温后置于4℃冰箱过夜，得到乙醇、丙酮或乙酸乙酯的混浊液离心弃上清液，沉淀挥干；50％乙腈盐溶液置于通风橱中缓慢挥干，得到类白色至黄色粉末，所得结晶的粉末X衍射图如图1所示(2θ角已标出)， 1HMR如图1A所示，酸碱摩尔比为1.2∶1，熔点206℃。在本申请中定义为晶型A。
实施例4式X化合物晶型B-1的制备
将800mg按实施例1方法得到的式X化合物游离碱溶于30ml丙酮或乙酸乙酯，超声使其完全分散；加入2100μL盐酸(浓度1M)，酸碱摩尔比1.2∶1，40℃下磁力搅拌4h。将反应混悬液经真空泵抽滤，润洗，于40℃烘箱内烘干，得到浅黄色粉末，收率：81.7％％。所得结晶的粉末X衍射图如图4所示(2θ角已标出)，酸碱摩尔比为1.2∶1。在本申请中定义为晶型B-1。
实施例5式X化合物晶型B-2的制备
取20mg式X化合物晶型B-1于15ml离心管内，加入11ml乙腈，密封置于60℃水浴锅内加热得到浑浊液，取上清液于另一离心管内，至于4℃冰箱过夜保存2-3天，取出离心，干燥，得到类白色粉末，所得结晶的粉末X衍射图如图7所示(2θ角已标出)，酸碱摩尔比为1.2∶1。在本申请中定义该晶型为晶型B-2。
实施例6式X化合物晶型B-3的制备
取20mg式X化合物晶型B-1于15ml离心管内，加入11ml丙酮，密封置于60℃水浴锅内加热溶解，将溶解的样品冷却至室温，置于4℃冰箱2-3天，取出离心，干燥得到类白色粉末，所得结晶的粉末X衍射图如图8所示(2θ角已标出)，酸碱摩尔比为1.2∶1。在本申请中定义该晶型为晶型B-3。
实施例7式X化合物晶型C-1至晶型J的制备
分别取15mg按实施例1方法得到的式X化合物游离碱于样品瓶中，加入3ml相应溶剂，使化合物完全溶解，加入一定体积和浓度的酸，加入搅拌子密封样品瓶，置于50℃水浴中反应4h，取出样品瓶，冷却至室温后与4℃冰箱过夜，将样品于离心机中离心(10000rmp，10min)，弃去上清液，沉淀于通风橱中缓慢挥干，得到相应晶体，具体溶剂、酸的浓度和体积见表1：
表1
Figure PCTCN2019083970-appb-000009
实施例9式X甲酸盐晶型K-1、K-2的制备
分别称取15mg实施例1方法得到的式X化合物甲酸盐至离心管，加入500μL溶剂，若甲酸盐完全溶解，则置于通风橱内室温挥干；若未完全溶解，则置于75℃的水浴锅中加热，若完全溶解则置于室温冷却，如有固体析出，析出固体离心去上清液挥干，无固体析出则置于通风橱室温下挥干；加热不溶解则是以25℃摇床振摇24h(速度170rpm)后离心弃上清液，剩余固体挥干。具体处理方法及所得晶型如表2所示：
表2
溶剂 式X化合物甲酸盐 晶型 固体形态
丙酮 加热溶解，降温不析出；缓慢挥发 晶型K-2 类白色粉末
乙腈 加热溶解，降温不析出；缓慢挥发 晶型K-2 类白色粉末
乙酸乙酯 加热溶解，降温不析出；缓慢挥发 晶型K-1 类白色至浅黄色粉末
乙醇 完全溶解；缓慢挥发 晶型K-1 类白色至浅黄色粉末
异丙醇 完全溶解；缓慢挥发 晶型K-1 类白色至浅黄色粉末
甲醇 完全溶解；缓慢挥发 晶型K-1 类白色至浅黄色粉末
四氢呋喃 完全溶解；缓慢挥发 晶型K-1 类白色至浅黄色粉末
实施例10式X化合物甲酸盐晶型K-3的制备
取20mg实施例1方法得到的式X化合物甲酸盐于15ml离心管中，加入6ml乙腈，密封置于60℃水浴锅内加热至样品完全溶解，将样品冷却至室温后置于4℃冰箱过夜保存，取出离心，干燥得类白色，所得结晶的粉末X衍射图如图20所示(2θ角已标出)，酸碱摩尔比为1.2∶1。在本申请中定义该晶型为K-3晶型。
实施例11式X化合物甲酸盐晶型K-4的制备
取20mg实施例1方法得到的式X化合物甲酸盐于15ml离心管中，加入6.5ml丙酮，密封置于60℃水浴锅内加热至样品完全溶解，将样品冷却至室温后置于4℃冰箱过夜保存，取出离心，干燥得类白色，所得结晶的粉末X衍射图如图21所示(2θ角已标出)，酸碱摩尔比为1.2∶1。在本申请中定义该晶型为K-4晶型。
实施例12式X化合物游离碱晶型I的制备
将实施例1方法得到的式X化合物游离碱用二甘醇二乙醚室温打浆4h，过滤，滤饼用丙酮洗涤，将滤饼再用二甘醇二乙醚室温打浆过夜，过滤，滤饼用丙酮洗涤，烘干得类白色粉末，所得粉末X衍射图如图22所示(2θ角已标出)，熔点为199-120℃，在本申请中定义为式X化合物游离碱晶型I。
实施例13式X化合物游离碱晶型II-IV的制备
称取10mg按实施例1方法得到的式X化合物游离碱于样品瓶中，逐步往瓶中加入100μL或200μL或500μL溶剂，使完全溶解或至11ml停止。将所得溶液或悬浮液置于通风橱中，缓慢挥发使其析出固体。实验结果如表3所示：
表3式X化合物游离碱晶型
溶剂 溶剂加入量ml 溶液状态 结晶方式 晶型
乙睛 11 加热变澄清 缓慢挥发 晶型II
50％乙睛 0.4 澄清 缓慢挥发 晶型II
乙醇 0.2 澄清 缓慢挥发 晶型II
异丙醇 0.5 澄清 缓慢挥发 晶型II
丙酮 2 澄清 缓慢挥发 晶型II
乙酸乙酯 1 澄清 缓慢挥发 晶型II
甲基叔丁基醚 5 澄清 缓慢挥发 晶型III
四氢呋喃 0.1 澄清 缓慢挥发 晶型IV
正庚烷 5 浑浊 混悬、挥干 晶型III
实施例14稳定性实验
1.晶型A和晶型B-1稳定性实验
(A)分别称取适量样品在室温和加速条件(40℃/75％RH)敞口放置，取时间点：0，7，14，28天；
(B)晶型A置于60℃烘箱，取时间点14，32天。
HPLC检测含量和有关物质变化，同时测XRD，考察晶型稳定性。
表4含量和有关物质结果
样品名称 含量(％) 杂质峰面积
晶型B-1(0天) 94.43 无
晶型B-1(室温，7天) 96.50 无
晶型B-1(室温，14天) 96.45 无
晶型B-1(室温，28天*) 107.12 无
晶型B-1(40℃，7天) 94.36 无
晶型B-1(40℃，14天) 95.19 无
晶型B-1(40℃，28天*) 110.05 无
晶型A(0天) 103.14 无
晶型A(室温，7天) 103.82 无
晶型A(室温，14天) 104.20 无
晶型A(室温，28天*) 116.27 无
晶型A(40℃，7天) 100.97 无
晶型A(40℃，14天) 104.46 无
晶型A(40℃，28天*) 113.75 无
晶型A(60℃，14天) 106.2 无
晶型A(60℃，32天) 104.5 无
*28天含量明显偏高，测量有误差
注：晶型B-1在高于40℃条件下会分解和脱去酸，60℃条件下不纳入实验。
晶型A和晶型B-1在室温下和加速条件下，含量无明显变化，无杂质峰出现，化学性质稳定。
晶型A在60℃条件下含量和有关物质无明显变化，化学性质稳定。
晶型A和晶型B-1经加速条件下28天，XRD图谱特征峰未发生变化，晶型稳定(如图29、30)。
在高温60℃条件下14天和32天，晶型A未发生转变，晶型稳定(如图31、32)。
实施例15溶解性实验
1)称取大概5-20mg左右的晶型I于离心管中，分别加入200μL H 2O、0.1M HCl、pH4.5、pH6.8及pH7.4介质中，介质变混浊，离心(10000rpm，10min)，取上清液，稀释100倍进液相；
2)称取大概5mg左右的晶型A、晶型B-1、晶型K-1于离心管内，分别加入200μL H 2O、0.1M HCl、pH4.5、pH6.8及pH7.4水性介质和丙酮、乙腈、乙酸乙酯、乙醇、甲醇、异丙醇及四氢呋喃7种有机溶剂中，超声使其溶解，部分离心管内化合物溶解完全后继续加入5mg-10mg左右，使其溶液变混浊；晶型K-1在乙腈、乙醇、异丙醇、甲醇四种有机溶剂和上述5种水性介质中为澄清溶液；晶型B-1在丙酮和甲醇中为澄清溶液；
3)澄清溶液稀释100倍后进液相；混浊液离心(10000rpm，10min)，取上清液，稀释10-100倍进液相。液相方法如表5所示，实验结果如表6所示：
表5
Figure PCTCN2019083970-appb-000010
Figure PCTCN2019083970-appb-000011
表6
Figure PCTCN2019083970-appb-000012
从上表可以看出，(1)晶型I在50％乙腈、甲醇、乙醇、异丙醇、乙酸乙酯及四氢呋喃中溶解度比较大，在乙腈、丙酮、正庚烷及二甲亚砜中溶解度较小，在水性介质中溶解度较小(在0.1M HCl中溶解度大)；(2)晶型K-1在有机溶剂和水性介质中溶解度都比较大，可达到11至45mg/ml；(3)晶型B-1在甲醇、乙醇及丙酮中溶解度比较大，在乙腈、异丙醇、四氢呋喃及乙酸乙酯中溶解度较小，在水性介质中溶解度均比较大，超过25mg/ml；(3)晶型A在甲醇和乙醇中溶解度较大；在其他有机溶剂中溶解度较小，在水性介质中溶解度均较大，超过11mg/ml；综上所述，晶型K-1溶解性最好，晶型B-2和晶型A次之，晶型I溶解性最差。
实施例16引湿性实验
晶型I、晶型A、晶型B-1和晶型K-1的DVS测试结果分别如图33-36所示，在25℃条件下，当湿度增加到80％RH时，晶型I吸湿增重为8.84％，具有引湿性；晶型A吸湿增重为0.613％，略有引湿性；晶型B-1吸湿增重6.88，具有引湿性。晶型K-1在80％的湿度下，吸湿增重为30.74％，所以此化合物属于极具引湿性药物。
实施例17体外激酶测试
重组CDK1、CCNB1和CDK9、CCNT购自BPS；CDK2、CCNA1、CDK4、CCND1和CDK6、CCND1购自Invitrogen；CDK4、CycD3和CDK6、CycD3购自Carna。三磷酸腺苷(ATP)购自Life tech。底物Ulight-4EBP1和对应检测抗体购自Perkinelmer。检测体系采用Perkinelmer公司的LANCEUltra系统。
激酶实验中，将待测化合物按1∶3的比例进行8个梯度点稀释后，加入反应板中并加适量的重组酶。随后加入含有预定浓度ATP、Ulight-4EBP1预混物的缓冲液[50mM HEPES pH7.5，10mM MgCl2，3mM MnCl2，1mM EGTA，0.01％Tween-20，1mM TCEP]，室温下开始激酶反应。反应适当时间后，加入预混有10mM EDTA和检测抗体的检测液，室温反应1小时后，在Tecan infinite pro上读取荧光值。IC 50通过XLfit软件中的四因素模型拟合进行计算。结果如表7所示：
表7式X化合物的体外激酶活性
Figure PCTCN2019083970-appb-000013
从上表可以看出，式X化合物对CDK4和CDK6具有较强的抑制活性，而对CDK1和CDK2的抑制活性弱，具有CDK4/6的选择抑制活性。而对比化合物1(具体结构如下所示，并可参见WO2012010704实施例I-44)虽然对CDK4和CDK6具有较强的抑制活性，但对CDK1和CDK2的抑制也很强，没有显示出CDK4/6的选择抑制活性。
Figure PCTCN2019083970-appb-000014
实施例18药代动力学和脑分布测试
实验方案：
试验动物：健康成年雄性SD大鼠(体重210-230g，12只，过夜禁食，给药后4小时喂食)，由斯莱克公司提供；口服溶液的制备：称取40.14mg化合物P-53于干净试管中，将36.479mL的0.5％HPC-H(TCI，E6ZQA)的乙酸缓冲液(PH4.5)加入试管中，涡旋试管1-2分钟。超声处理20-25分钟，搅拌20-25分钟。
给予SD大鼠灌胃给药(10mg/kg(10mL/kg))；在给药后0.5，1，2，4小时共4个时间点采样，只有血浆样品是连续采集，脑组织和脑脊液是在每个时间点采集。
血样采集：手动控制动物，通过尾静脉收集大约150μL的血液、时间点到含K2EDTA的管中。在15分钟内，血液样本被放在湿冰上，离心(2000g，5min under 4℃)，获得血浆样品。
脑组织采集：在动物头皮中间做一个切口，然后收缩皮肤。用小的骨刀和骨钳，把头骨移到脑后。用抹刀去除大脑，用冷盐水冲洗。将大脑放置在螺旋管中，然后将试管储存到-70℃，直到分析。
脑脊液采集：在动物深度麻醉的情况下，在尾静脉注射空气安乐死。以枕骨和寰椎为标志，用蝴蝶针直接刺穿了小脑延髓池来采集脑脊液。在收集的过程中，一张白色的纸作为背景放在针的上方，用来监测样品的颜色变化。在对颜色变化的观察中，在颜色变化上方快速关上PE管，并在夹紧的部位上方剪断，将干净的样品抽进注射器。
样品保存和处理：血浆、大脑和脑脊液样本将暂时保存在干冰中，然后将它们转移到-80℃的冷库中， 以长期保存。
分析方法：以SD大鼠血浆和脑为基质，Glipizide为内标，采用LCMSMS-002(API-4000，三重四级杆)进行测试分析。分别取30μL血浆样品和脑组织样品，加入200μL含100ng/mL内标(Glipizide)的乙腈，将其混合涡旋10min，在5800rpm转速下离心10min，然后取2μL离心后的上清液，进行LC-MS/MS分析。取10μL脑脊液样品，加入10μL的甲醇/水(1/1)和60μL含100ng/mL内标(Glipizide)的乙腈，将其混合涡旋5min，然后取2μL上清液进行LC-MS/MS分析。应用LC/MS/MS法测定药物浓度，在大鼠血浆、脑组织内和脑脊液内的药代动力学参数如表8所示：
表8化合物在大鼠口服给药10mg/kg后的曲线下面积
化合物 式X化合物游离碱
血浆内AUC(hr*ng/mL) 2620
脑组织内AUC(hr*ng/mL) 4944
脑脊液内AUC(hr*ng/mL) 204
从表8可以看出，式X化合物能穿越血脑屏障并且很好地分布到脑中，具有较好的脑通透性。
实施例19药物组合物
由以下组分制备晶型A的片剂：
Figure PCTCN2019083970-appb-000015
按常规方法，将晶型A、淀粉混合过筛，再与上述其它组分混合均匀，直接压片。
实施例20药物组合物
由以下组分制备晶型I的胶囊：
Figure PCTCN2019083970-appb-000016
按常规方法，将晶型I、淀粉混合过筛，再与上述其他组分混合均匀，装入普通透明胶囊。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式X化合物的药学上可接受盐及其多晶型物，
    Figure PCTCN2019083970-appb-100001
    其特征在于，所述药学上可接受盐选自：盐酸盐、硫酸盐、氢溴酸盐、磷酸盐、甲磺酸盐、马来酸盐、L-酒石酸盐、柠檬酸盐、富马酸盐和甲酸盐。
  2. 如权利要求1所述的式X化合物的药学上可接受盐及其多晶型物，其特征在于，所述药学上可接受盐选自：盐酸盐、马来酸盐和甲酸盐。
  3. 如权利要求1所述的式X化合物的药学上可接受盐及其多晶型物，其特征在于，所述多晶型物选自下组：
    式X化合物马来酸盐的A型结晶，即晶型A，其X射线粉末衍射图在下组A1的衍射角2θ(°)值处具有峰：4.47±0.2、8.93±0.2、13.41±0.2、13.98±0.2、15.77±0.2、16.52±0.2、17.18±0.2、18.06±0.2、18.61±0.2、19.16±0.2、21.50±0.2、22.26±0.2、23.43±0.2、23.84±0.2；
    式X化合物盐酸盐的B-1型结晶，即晶型B-1，其X射线粉末衍射图在下组B-1-1的衍射角2θ(°)值处具有峰：4.93±0.2、6.78±0.2、8.04±0.2、9.82±0.2、12.46±0.2、14.75±0.2、15.32±0.2、21.17±0.2；
    式X化合物盐酸盐的B-2型结晶，即晶型B-2，其X射线粉末衍射图在下组B-2-1的衍射角2θ(°)值处具有峰：4.56±0.2、11.41±0.2、13.60±0.2；
    式X化合物盐酸盐的B-3型结晶，即晶型B-3，其X射线粉末衍射图在下组B-3-1的衍射角2θ(°)值处具有峰：5.03±0.2、9.97±0.2、14.96±0.2；
    式X化合物硫酸盐的C-1型结晶，即晶型C-1，其X射线粉末衍射图在下组C-1-1的衍射角2θ(°)值处具有峰：9.13±0.2、9.71±0.2、10.50±0.2、11.19±0.2、13.72±0.2、13.94±0.2、15.70±0.2、16.79±0.2、22.46±0.2、23.87±0.2；
    式X化合物硫酸盐的C-2型结晶，即晶型C-2，其X射线粉末衍射图在下组C-2-1的衍射角2θ(°)值处具有峰：10.47±0.2、14.78±0.2、15.72±0.2；
    式X化合物氢溴酸盐的D型结晶，即晶型D，其X射线粉末衍射图在下组D1的衍射角2θ(°)值处具有峰：7.99±0.2、9.74±0.2、10.53±0.2、12.37±0.2、14.64±0.2、15.21±0.2、21.04±0.2、22.11±0.2、23.03±0.2、23.38±0.2、24.45±0.2、27.22±0.2；
    式X化合物L-酒石酸盐的E型结晶，即晶型E，其X射线粉末衍射图在下组E1的衍射角2θ(°)值处具有峰：6.43±0.2、10.02±0.2、11.63±0.2、16.07±0.2、19.33±0.2、22.59±0.2、25.88±0.2；
    式X化合物磷酸盐的F型结晶，即晶型F，其X射线粉末衍射图在下组F1的衍射角2θ(°)值处具有峰：12.03±0.2、17.26±0.2、19.65±0.2；
    式X化合物柠檬酸盐的G型结晶，即晶型G，其X射线粉末衍射图在下组G1的衍射角2θ(°)值处具有 峰：9.13±0.2、10.13±0.2、11.06±0.2、12.38±0.2、13.04±0.2、14.07±0.2、14.72±0.2、15.33±0.2、19.16±0.2、20.31±0.2、24.83±0.2、28.04±0.2；
    式X化合物富马酸盐的H-1型结晶，即晶型H-1，其X射线粉末衍射图在下组H-1-1的衍射角2θ(°)值处具有峰：5.37±0.2、10.74±0.2、17.67±0.2、19.08±0.2、19.35±0.2、20.11±0.2、21.25±0.2、22.84±0.2；
    式X化合物富马酸盐的H-2型结晶，即晶型H-2，其X射线粉末衍射图在下组H-2-1的衍射角2θ(°)值处具有峰：5.69±0.2、11.67±0.2、14.39±0.2、21.15±0.2、23.49±0.2；
    式X化合物甲磺酸盐的J型结晶，即晶型J，其X射线粉末衍射图在下组J1的衍射角2θ(°)值处具有峰：10.64±0.2、18.70±0.2、20.55±0.2、20.86±0.2、21.58±0.2、22.16±0.2、23.05±0.2、24.39±0.2、24.75±0.2、27.18±0.2；
    式X化合物甲酸盐的K-1型结晶，即晶型K-1，其X射线粉末衍射图在下组K-1-1的衍射角2θ(°)值处具有峰：4.80±0.2、8.43±0.2、9.63±0.2、9.88±0.2、12.08±0.2、13.87±0.2、14.63±0.2、18.02±0.2、19.44±0.2、20.05±0.2、20.64±0.2、22.47±0.2、23.68±0.2；
    式X化合物甲酸盐的K-2型结晶，即晶型K-2，其X射线粉末衍射图在下组K-2-1的衍射角2θ(°)值处具有峰：5.23±0.2、17.05±0.2、17.31±0.2、21.28±0.2、22.50±0.2；
    式X化合物甲酸盐的K-3型结晶，即晶型K-3，其X射线粉末衍射图在下组K-3-1的衍射角2θ(°)值处具有峰：4.51±0.2、5.27±0.2、13.76±0.2；
    式X化合物甲酸盐的K-4型结晶，即晶型K-4，其X射线粉末衍射图在下组K-4-1的衍射角2θ(°)值处具有峰：13.26±0.2、15.04±0.2、16.18±0.2、19.09±0.2、21.54±0.2；
    式X化合物的晶型I，其X射线粉末衍射图在组I-1的衍射角2θ(°)值处具有峰：6.20±0.2、6.68±0.2、13.42±0.2、21.31±0.2、22.56±0.2；
    式X化合物的晶型II，其X射线粉末衍射图在组II-1的衍射角2θ(°)值处具有峰：13.27±0.2、15.03±0.2、16.20±0.2、19.09±0.2、21.56±0.2；
    式X化合物的晶型III，其X射线粉末衍射图在组III-1的衍射角2θ(°)值处具有峰：5.23±0.2、17.02±0.2；或
    式X化合物的晶型IV，其X射线粉末衍射图在组IV-1的衍射角2θ(°)值处具有峰：5.25±0.2、11.94±0.2、12.23±0.2、14.42±0.2、16.65±0.2。
  4. 如权利要求3所述的式X化合物的药学上可接受盐及其多晶型物，其特征在于：
    所述晶型A的X射线粉末衍射图基本如图1所表征；
    所述晶型B-1的X射线粉末衍射图基本如图4所表征；
    所述晶型B-2的X射线粉末衍射图基本如图7所表征；
    所述晶型B-3的X射线粉末衍射图基本如图8所表征；
    所述晶型C-1的X射线粉末衍射图基本如图9所表征；
    所述晶型C-2的X射线粉末衍射图基本如图10所表征；
    所述晶型D的X射线粉末衍射图基本如图11所表征；
    所述晶型E的X射线粉末衍射图基本如图12所表征；
    所述晶型F的X射线粉末衍射图基本如图13所表征；
    所述晶型G的X射线粉末衍射图基本如图14所表征；
    所述晶型H-1的X射线粉末衍射图基本如图15所表征；
    所述晶型H-2的X射线粉末衍射图基本如图16所表征；
    所述晶型J的X射线粉末衍射图基本如图17所表征；
    所述晶型K-1的X射线粉末衍射图基本如图18所表征；
    所述晶型K-2的X射线粉末衍射图基本如图19所表征；
    所述晶型K-3的X射线粉末衍射图基本如图20所表征；
    所述晶型K-4的X射线粉末衍射图基本如图21所表征。
  5. 如权利要求3所述的式X化合物的药学上可接受盐及其多晶型物，其特征在于：
    所述晶型I的X射线粉末衍射图基本如图22所表征；
    所述晶型II的X射线粉末衍射图基本如图25所表征；
    所述晶型III的X射线粉末衍射图基本如图26所表征；
    所述晶型IV的X射线粉末衍射图基本如图27所表征。
  6. 一种制备式X化合物的药学上可接受盐及其多晶型物的方法，其特征在于，包括步骤：
    (1)在溶剂中，将化合物2a与化合物3a进行反应，从而形成式X化合物；和
    Figure PCTCN2019083970-appb-100002
    (2)任选地将式X化合物与酸进行成盐反应，从而形成药学上可接受的盐；
    (3)任选地将步骤(1)或步骤(2)所形成的式X化合物或其药学上可接受的盐进行结晶处理，从而获得多晶型物。
  7. 一种药物组合物，其特征在于，所述药物组合物包括：
    (a)权利要求1所述的式X化合物的药学上可接受盐及其多晶型物；以及
    (b)药学可接受的载体。
  8. 权利要求1所述的式X化合物的药学上可接受盐及其多晶型物，或权利要求7所述药物组合物在制备治疗疾病或病症的药物中的用途，所述疾病或病症选自癌症、异常细胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病、神经变性疾病、由辐射引起的造血毒性疾病，或其组合。
  9. 如权利要求8所述的用途，其特征在于，所述的癌症选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
  10. 一种抑制CDK4和/或CDK6活性的方法，其包括给予所需患者治疗有效量的权利要求1所述的式X化合物的药学上可接受盐及其多晶型物，或权利要求7所述药物组合物。
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