WO2021143922A1 - 一种溴区结构域蛋白抑制剂的晶型、盐型及其制备方法 - Google Patents

一种溴区结构域蛋白抑制剂的晶型、盐型及其制备方法 Download PDF

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WO2021143922A1
WO2021143922A1 PCT/CN2021/072651 CN2021072651W WO2021143922A1 WO 2021143922 A1 WO2021143922 A1 WO 2021143922A1 CN 2021072651 W CN2021072651 W CN 2021072651W WO 2021143922 A1 WO2021143922 A1 WO 2021143922A1
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formula
compound
crystal form
crystalline form
following
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PCT/CN2021/072651
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English (en)
French (fr)
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徐文卫
单振良
张迎亚
张国亮
戈云
张爱明
张喜全
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正大天晴药业集团股份有限公司
首药控股(北京)有限公司
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Priority to CN202180008525.8A priority Critical patent/CN114929703A/zh
Priority to US17/793,588 priority patent/US20240101551A1/en
Priority to JP2022543423A priority patent/JP2023510610A/ja
Priority to EP21742003.3A priority patent/EP4092027A4/en
Publication of WO2021143922A1 publication Critical patent/WO2021143922A1/zh

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

  • This application belongs to the field of medicinal chemistry, and specifically relates to a crystal form of a bromine domain domain protein inhibitor, a preparation method thereof, a crystal composition containing the crystal form, a pharmaceutical composition containing the crystal form or a crystal composition thereof, and them the use of.
  • This application also relates to the hydrochloride, sulfate, phosphate, and methanesulfonate salts of the above-mentioned bromine domain domain protein inhibitors, as well as their crystal forms, preparation methods, pharmaceutical compositions containing the above-mentioned salts, and uses thereof.
  • the apparent regulation of transcription genes plays an important role in the development of tumors, inflammations and metabolic diseases.
  • the acetylation of nucleosomal histone lysine N-terminal residues is particularly important for the regulation of genetic epigenes.
  • Histone acetylation is usually most related to the activation of gene transcription.
  • the recognition of histone lysine acetylation is a key step for histone acetylation to participate in epigenetic regulation.
  • Bromodomains are a class of conserved protein domains that can specifically recognize acetylated lysine (KAc) in histones, and promote chromatin remodeling factors and transcription factors by binding to acetylated lysines And other related proteins are enriched in specific gene transcription sites, changing the activity of RNAII polymerase, thereby cooperating to complete the regulation of gene expression.
  • KAc acetylated lysine
  • the BET (Bromodomain and Extra Terminal) protein consists of two interrelated bromodomain domain centers and an outer terminal domain. According to the amino acid sequence, it is divided into four proteins: Brd2, Brd3, Brd4 and BrdT, among which Brd2 ⁇ Brd4 are widely distributed In all organs of the human body.
  • BET is a type of transcriptional regulatory protein, which plays a very important role in the regulation of gene expression through its interaction with chromatin.
  • the BET protein has a two-way regulatory function of co-activation or co-inhibition for the intracellular network signal transduction pathway, such as insulin transcription, fat formation in lipid tissue, differentiation of hematopoietic system, and so on.
  • BET protein has increasingly become one of the important targets in the field of epigenetics, which has attracted great attention from major pharmaceutical companies and scientific research institutions.
  • the application provides a crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • crystal form is selected from:
  • Form I of the compound of formula (I) its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.4° ⁇ 0.2°, 14.5° ⁇ 0.2°, 17.4° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.4° ⁇ 0.2°, 24.7° ⁇ 0.2°;
  • the crystalline form A of the hydrochloride salt of the compound of formula (I), its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.8° ⁇ 0.2°, 8.4° ⁇ 0.2°, 9.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 16.8° ⁇ 0.2°;
  • the crystalline form B of the hydrochloride salt of the compound of formula (I), its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.7° ⁇ 0.2°, 9.5° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.5° ⁇ 0.2°, 17.4° ⁇ 0.2°;
  • the crystalline form C of the hydrochloride of the compound of formula (I), its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.8° ⁇ 0.2°, 9.5° ⁇ 0.2°, 12.9° ⁇ 0.2°, 20.5° ⁇ 0.2°, 24.6° ⁇ 0.2°;
  • the crystalline form D of the sulfate salt of the compound of formula (I), its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 13.5° ⁇ 0.2°, 14.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 21.2° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°;
  • the crystalline form E of the phosphate of the compound of formula (I), its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.1° ⁇ 0.2°, 10.5° ⁇ 0.2°, 19.0° ⁇ 0.2°, 21.0° ⁇ 0.2°, 22.7° ⁇ 0.2°, 24.0° ⁇ 0.2°; or
  • the crystalline form F of the methanesulfonate salt of the compound of formula (I), its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.8° ⁇ 0.2°, 10.1° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.0 ° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.8° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • Table 1 The characteristic peak positions and relative intensities of the X-ray powder diffraction pattern of crystal form I
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form I has the characteristics represented by the XRPD pattern shown in FIG. 1.
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form I has the characteristics represented by the DSC spectrum shown in FIG. 2.
  • the DSC spectrum of the crystalline form I has an endothermic peak at 275°C ⁇ 3°C.
  • the crystal form I is selected from one or more of water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide, dichloromethane Prepared in mixed solvents.
  • the crystalline form I is prepared in one or more mixed solvents selected from water, methanol, dimethyl sulfoxide, dichloromethane, and acetonitrile.
  • the crystalline form I is prepared in dimethyl sulfoxide, methanol or water.
  • the crystal form I is a mixed solvent of dimethyl sulfoxide and water, a mixed solvent of dimethyl sulfoxide and methanol, a mixed solvent of dichloromethane and methanol, or a mixed solvent of acetonitrile and water. Prepared in solvent.
  • the particle size distribution X 90 of the crystal form I is less than 30 ⁇ m. In some embodiments, the particle size distribution X 90 of the crystal form I is less than 20 ⁇ m. In some embodiments, the particle size distribution X 90 of the crystal form I is less than 15 ⁇ m. In some embodiments, the particle size distribution X 90 of the crystal form I is less than 12 ⁇ m. In some embodiments, the particle size distribution X 90 of the crystal form I is less than 10 ⁇ m. In some embodiments, the particle size distribution X 90 of the crystal form I is less than 7 ⁇ m.
  • the particle size distribution X 90 of the crystal form I is 3.0 to 14.0 ⁇ m, preferably 3.5 to 13.5 ⁇ m, more preferably 4.0 to 13.0 ⁇ m, further preferably 4.5 to 12.5 ⁇ m, still more preferably 5.0 to 12.0 ⁇ m.
  • the particle size distribution X 90 of the crystal form I is 3.5 to 8.5 ⁇ m, preferably 4.5 to 7.5 ⁇ m, more preferably 5.5 to 6.5 ⁇ m.
  • the particle size distribution X 90 of the crystal form I is 9.5 to 13.5 ⁇ m, preferably 10.5 to 12.5 ⁇ m, more preferably 11.0 to 12.0 ⁇ m.
  • the particle size distribution X 90 of the crystal form I is measured after the crystal form I has been subjected to jet pulverization.
  • the pulverization pressure of the jet pulverization is selected from 0.1 MPa to 0.7 MPa, preferably from 0.1 MPa to 0.6 MPa; or the pulverization pressure of the jet pulverization is selected from 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa , 0.5MPa, 0.6MPa, 0.7MPa or a range formed by any of the above values.
  • This application also provides a method for preparing the crystalline form I of the compound of formula (I), including:
  • the solvent I is preferably selected from one or more mixed solvents selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide, and dichloromethane, preferably from A mixed solvent of one or more of water, acetonitrile, methanol, dimethyl sulfoxide, and dichloromethane, more preferably water or dimethyl sulfoxide, and still more preferably a mixed solvent of dichloromethane and methanol.
  • the method for preparing the crystalline form I of the compound of formula (I) includes:
  • step (2) The mixture of step (1) is mixed with solvent II;
  • the solvent I and the solvent II are each independently preferably selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide or dichloromethane, preferably from water, acetonitrile, methanol , Dimethyl sulfoxide or dichloromethane, more preferably water, methanol or dimethyl sulfoxide, further preferably dichloromethane and methanol.
  • step (2) the manner in which the mixture of step (1) is mixed with solvent II includes but is not limited to: a. adding the mixture of step (1) to solvent II; b. to step (1) Add solvent II to the mixture.
  • the above-mentioned addition method is preferably dropwise.
  • the above step (2) is to add the mixture of step (1) dropwise to the solvent II at an appropriate temperature.
  • the appropriate temperature is -10 to 30°C.
  • the appropriate temperature is -5 to 10°C.
  • the appropriate temperature is 0°C.
  • This application also provides a preparation method of the crystalline form I of the compound of formula (I), including:
  • the solvent III is preferably selected from one or more mixed solvents selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, and acetone, preferably from one or more of water, acetonitrile, and methanol.
  • One or more mixed solvents are more preferably selected from water, acetonitrile/water mixed solvent, or methanol/water mixed solvent.
  • step (1) after the pharmaceutically acceptable salt of the compound of formula (I) is mixed with solvent III, the mixture is stirred for a period of time, preferably 3h-4h. In some embodiments, the stirring is performed at room temperature.
  • the method for preparing the crystalline form I of the compound of formula (I) includes:
  • step (2) The mixture of step (1) is mixed with solvent IV;
  • the solvent III and the solvent IV are each independently preferably selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate or acetone, preferably from water, acetonitrile, methanol, ethanol or isopropanol, more preferably from Water, acetonitrile or methanol.
  • step (2) the manner in which the mixture of step (1) is mixed with solvent IV includes but is not limited to: a. adding the mixture of step (1) to solvent IV; b. to step (1) Add Solvent IV to the mixture.
  • the above-mentioned addition method is preferably dropwise.
  • step (2) the mixture of step (1) is mixed with solvent IV and then crystallized. In some embodiments, the crystallization is performed at room temperature.
  • the above-mentioned pharmaceutically acceptable salt of the compound of formula (I) is selected from the hydrochloride salt of the compound of formula (I).
  • the hydrochloride salt of the compound of formula (I) is selected from crystal form A, crystal form B, or crystal form C, preferably crystal form A.
  • the application also provides a pharmaceutically acceptable salt (salt form) of the compound of formula (I), and the pharmaceutically acceptable salt is selected from the hydrochloride salt of the compound of formula (I) and the compound of formula (I). Sulfate, the phosphate of the compound of formula (I) or the methanesulfonate of the compound of formula (I).
  • this application provides the hydrochloride salt of the compound represented by formula (I):
  • This application also provides the crystalline form of the hydrochloride salt of the compound of formula (I), its preparation method and the corresponding crystalline composition.
  • the hydrochloride of the compound represented by formula (I) is a salt formed by the compound of formula (I) and hydrochloric acid at a molar ratio of 1:1.
  • the hydrochloric acid content of the hydrochloride of the compound of formula (I) is 5-10% by weight, preferably 6-9% by weight, 6-8% by weight; or the hydrochloride of the compound of formula (I)
  • the hydrochloric acid content is selected from 6.0wt%, 6.1wt%, 6.2wt%, 6.3wt%, 6.4wt%, 6.5wt%, 6.6wt%, 6.7wt%, 6.8wt%, 6.9wt%, 7.0wt%, 7.1wt%, 7.2wt%, 7.3wt%, 7.4wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9wt%, 8.0wt%, 8.1wt%, 8.2wt%, 8.3wt %, 8.4% by weight, 8.5% by weight, 8.6% by weight, 8.7% by weight, 8.8% by weight, 8.9% by weight, 9.0% by weight, or a range formed by weight,
  • the crystalline form of the hydrochloride salt of the compound of formula (I) is a hydrate, and the hydrate is selected from the group consisting of hemihydrate, monohydrate, dihydrate, trihydrate and tetrahydrate, Preferred are monohydrate, dihydrate and tetrahydrate, and more preferred are monohydrate and tetrahydrate.
  • the crystalline form of the hydrochloride salt of the compound of formula (I) is a monohydrate.
  • the crystalline form of the hydrochloride salt of the compound of formula (I) is tetrahydrate.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Table 2 The characteristic peak positions and relative intensities of the X-ray powder diffraction pattern of crystal form A
  • the X-ray powder diffraction (XRPD) pattern of the crystal form A has the characteristics represented by the XRPD pattern shown in FIG. 3.
  • the differential scanning calorimetry (DSC) chart of the crystalline form A has the characteristics represented by the DSC chart shown in FIG. 4.
  • the DSC spectrum of the crystal form A has an endothermic peak at 149.61°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystal form A has an endothermic peak at 101.14°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystal form A has an endothermic peak at 80.15°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystal form A has an endothermic peak at 62.98°C ⁇ 3°C.
  • the DSC spectrum of the crystalline form A has an absorption at 149.61°C ⁇ 3°C, and/or 101.14°C ⁇ 3°C, and/or 80.15°C ⁇ 3°C, and/or 62.98°C ⁇ 3°C. Hot peak.
  • the weight loss and moisture content described in this application all refer to wt%.
  • thermogravimetric analysis curve (TGA) profile of the crystal form A has the characteristics represented by the TGA profile shown in FIG. 5.
  • thermogravimetric analysis curve of the crystal form A has a weight loss of 2.37 ⁇ 0.2% at 119.1 ⁇ 3°C.
  • thermogravimetric analysis curve of the crystal form A has a weight loss of 2.37 ⁇ 0.2% at 119.1 ⁇ 3°C, and/or a weight loss of 16.78 ⁇ 0.2% at 258.7 ⁇ 3°C, and/or a weight loss of 494.1
  • the weight loss at ⁇ 3°C is 38.60 ⁇ 0.2%.
  • the crystal form A is prepared in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile. In some embodiments, the crystal form A is prepared from methanol, ethanol, or isopropanol. In some embodiments, the crystalline form A is prepared in methanol.
  • This application also provides a method for preparing the crystalline form A of the hydrochloride salt of the compound of formula (I), which includes the following steps:
  • the solvent A is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, preferably methanol, ethanol or isopropanol, and more preferably methanol.
  • the moisture content of the crystal form A is 5.0% to 9.0%, preferably 5.5% to 8.5%, more preferably 5.8% to 8.1%. In some embodiments, the moisture content of the crystal form A is 4.7%. In some embodiments, the moisture content of the crystal form A is 5.8%. In some embodiments, the moisture content of the crystalline form A is 6.6%. In some embodiments, the moisture content of the crystalline form A is 8.1%.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Table 3 The characteristic peak positions and relative intensities of the X-ray powder diffraction pattern of Form B
  • the X-ray powder diffraction (XRPD) pattern of the crystal form B has the characteristics represented by the XRPD pattern as shown in FIG. 6.
  • the moisture content of the crystal form B is 2.0% to 5.5%, preferably 3.0% to 5.0%, more preferably 3.6% to 4.6%. In some embodiments, the moisture content of the crystalline form B is 3.6%. In some embodiments, the moisture content of the crystalline form B is 4.6%.
  • the crystal form B is prepared by the crystal form A at 60 ⁇ 2°C.
  • This application also provides a method for preparing the crystalline form B of the hydrochloride of the compound of formula (I), which includes allowing the crystalline form A to stand at 60 ⁇ 2° C. for 30 days.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Table 4 The characteristic peak positions and relative intensities of the X-ray powder diffraction pattern of Form C
  • the X-ray powder diffraction (XRPD) pattern of the crystal form C has the characteristics represented by the XRPD pattern as shown in FIG. 7.
  • the moisture content of the crystal form C is 9.0% to 14.0%, preferably 9.5% to 13.5%, more preferably 10.0% to 13.0%. In some embodiments, the moisture content of the crystalline form C is 11.9%. In some embodiments, the moisture content of the crystalline form C is 12.2%. In some embodiments, the moisture content of the crystalline form C is 13.0%.
  • the crystal form C is prepared by the crystal form A at room temperature and a relative humidity of 92.5 ⁇ 5%.
  • This application also provides a method for preparing the crystalline form C of the hydrochloride salt of the compound of formula (I), which includes allowing the crystalline form A to stand for 30 days in an environment of room temperature and a relative humidity of 92.5 ⁇ 5%.
  • the sulfate salt of the compound of formula (I) is as shown in formula II
  • x is selected from 0.5 to 1.
  • the above-mentioned x is selected from 0.5 or 1.
  • the above-mentioned x is selected from 1.
  • the sulfuric acid content in the sulfate salt of the compound of formula (I) is 15-20% by weight, preferably 16-19% by weight, 17-19% by weight; or the sulfuric acid in the sulfate salt of the compound of formula (I)
  • the sulfuric acid content is selected from 16.1wt%, 16.2wt%, 16.3wt%, 16.4wt%, 16.5wt%, 16.6wt%, 16.7%, 16.8wt%, 16.9wt%, 17.0wt%, 17.1wt%, 17.2wt %, 17.3wt%, 17.4wt%, 17.5wt%, 17.6wt%, 17.7wt%, 17.8wt%, 17.9wt%, 18.0wt%, 18.1wt%, 18.2wt%, 18.3wt%, 18.4wt%, 18.5 wt%, 18.6 wt%, 18.7 wt%, 18.8 wt%, 18.9 wt%, 19.0
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Table 5 The characteristic peak positions and relative intensities of the X-ray powder diffraction pattern of crystal form D
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form D has the characteristics represented by the XRPD pattern as shown in FIG. 8.
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form D has the characteristics represented by the DSC spectrum as shown in FIG. 9.
  • the DSC spectrum of the crystalline form D has an exothermic peak at 262.82°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystalline form D has an exothermic peak at 272.31°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystalline form D has an exothermic peak at 272.31°C ⁇ 3°C, and/or 262.82°C ⁇ 3°C.
  • thermogravimetric analysis curve (TGA) profile of the crystal form D has the characteristics represented by the TGA profile shown in FIG. 10.
  • thermogravimetric analysis curve of the crystal form D has a weight loss of 40.74 ⁇ 0.2% at 425.0 ⁇ 3°C.
  • the crystal form D is prepared in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, and ethyl acetate. In some embodiments, the crystal form D is prepared in one or more mixed solvents selected from methanol, ethanol or isopropanol. In some embodiments, the crystalline form D is prepared in methanol.
  • This application also provides a method for preparing the crystalline form D of the sulfate salt of the compound of formula (I), including contacting the compound of formula (I) with sulfuric acid.
  • the preparation method of the above-mentioned crystal form D includes the following steps:
  • the solvent D is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, and ethyl acetate, preferably from methanol, ethanol or isopropanol, and more preferably methanol.
  • the application provides a phosphate of the compound of formula (I):
  • the phosphate of the compound of formula (I) is as shown in formula III
  • x is selected from 0.5 to 1.
  • the above-mentioned x is selected from 0.5 or 1.
  • the above-mentioned x is selected from 1.
  • the phosphoric acid content in the phosphate of the compound of formula (I) is 10-20% by weight, preferably 12-19% by weight; or the phosphoric acid content in the phosphate of the compound of formula (I) is selected from 12.1 wt%, 12.2wt%, 12.3wt%, 12.4wt%, 12.5wt%, 12.6wt%, 12.7wt%, 12.8wt%, 12.9wt%, 13.0wt%, 13.1wt%, 13.2wt%, 13.3wt% , 13.4wt%, 13.5wt%, 13.6wt%, 13.7wt%, 13.8wt%, 13.9wt%, 14.0wt%, 14.1wt%, 14.2wt%, 14.3wt%, 14.4wt%, 14.5wt%, 14.6 wt%, 14.7wt%, 14.8wt%, 14.9wt%, 15.0wt%, 15.1wt%, 15.2wt
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern of the crystal form E has the characteristics represented by the XRPD pattern as shown in FIG. 11.
  • the differential scanning calorimetry (DSC) chart of the crystal form E has the characteristics represented by the DSC chart shown in FIG. 12.
  • the DSC spectrum of the crystal form E has an endothermic peak at 171.37°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystal form E has an endothermic peak at 159.07°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystal form E has an endothermic peak at 141.12°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystal form E has an endothermic peak at 116.46°C ⁇ 3°C.
  • the DSC spectrum of the crystal form E has an absorption at 171.37°C ⁇ 3°C, and/or 159.07°C ⁇ 3°C, and/or 141.12°C ⁇ 3°C, and/or 116.46°C ⁇ 3°C. Hot peak.
  • thermogravimetric analysis curve (TGA) profile of the crystal form E has the characteristics represented by the TGA profile shown in FIG. 13.
  • thermogravimetric analysis curve of the crystal form E has a weight loss of 2.24 ⁇ 0.2% at 157.5 ⁇ 3°C.
  • thermogravimetric analysis curve of the crystal form E has a weight loss of 2.24 ⁇ 0.2% at 157.5 ⁇ 3°C, and/or a weight loss of 7.85 ⁇ 0.2% at 270.8 ⁇ 3°C, and/or a weight loss of 493.8 The weight loss at ⁇ 3°C is 27.85 ⁇ 0.2%.
  • the crystal form E is prepared in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile. In some embodiments, the crystal form E is prepared in one or more mixed solvents selected from ethyl acetate and acetonitrile. In some embodiments, the crystalline form E is prepared in acetonitrile.
  • the application also provides a method for preparing the crystalline form E of the phosphate of the compound of formula (I), including contacting the compound of formula (I) with phosphoric acid.
  • the preparation method of the above-mentioned crystal form E includes the following steps:
  • the solvent E is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, preferably ethyl acetate, acetonitrile, and more preferably acetonitrile.
  • the present application provides the mesylate salt of the compound of formula (I):
  • the methanesulfonate salt of the compound of formula (I) is as shown in formula IV
  • x is selected from 0.5 to 1.
  • the above-mentioned x is selected from 0.5 or 1.
  • the above-mentioned x is selected from 1.
  • the methanesulfonic acid content in the methanesulfonate salt of the compound of formula (I) is 10-20 wt%, preferably 12-19 wt%; or in the methanesulfonate salt of the compound of formula (I)
  • the content of methanesulfonic acid is selected from 12.1wt%, 12.2wt%, 12.3wt%, 12.4wt%, 12.5wt%, 12.6wt%, 12.7%, 12.8wt%, 12.9wt%, 13.0wt%, 13.1wt% , 13.2wt%, 13.3wt%, 13.4wt%, 13.5wt%, 13.6wt%, 13.7wt%, 13.8wt%, 13.9wt%, 14.0wt%, 14.1wt%, 14.2wt%, 14.3wt%, 14.4 wt%, 14.5wt%, 14.6wt%, 14.7wt%, 14.8wt%, 14.9w
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Table 7 The characteristic peak positions and relative intensities of the X-ray powder diffraction pattern of Form F
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form F has the characteristics represented by the XRPD pattern as shown in FIG. 14.
  • the differential scanning calorimetry (DSC) chart of the crystalline form F has the characteristics represented by the DSC chart shown in FIG. 15.
  • the DSC spectrum of the crystalline form F has an exothermic peak at 282.74°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystalline form F has an endothermic peak at 221.41°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystalline form F has an endothermic peak at 167.36°C ⁇ 3°C. In some embodiments, the DSC spectrum of the crystalline form F has an endothermic peak at 167.36°C ⁇ 3°C, and/or an endothermic peak at 221.41°C ⁇ 3°C, and/or at 282.74°C ⁇ 3°C There is an exothermic peak.
  • thermogravimetric analysis curve (TGA) pattern of the crystal form F has the characteristics represented by the TGA pattern shown in FIG. 16.
  • thermogravimetric analysis curve of the crystal form F has a weight loss of 2.80 ⁇ 0.2% at 170.2 ⁇ 3°C.
  • the thermogravimetric analysis curve of the crystal form F has a weight loss of 2.80 ⁇ 0.2% at 170.2 ⁇ 3°C, and/or a weight loss of 5.28 ⁇ 0.2% at 261.4 ⁇ 3°C, and/or a weight loss at 311.4
  • the weight loss at ⁇ 3°C is 9.21 ⁇ 0.2%, and/or the weight loss at 396.3 ⁇ 3°C is 25.22 ⁇ 0.2%, and/or the weight loss at 554.9 ⁇ 3°C is 13.88 ⁇ 0.2%.
  • the crystal form F is prepared in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile. In some embodiments, the crystal form F is prepared in one or more mixed solvents selected from ethyl acetate and acetonitrile. In some embodiments, the crystalline form F is prepared in acetonitrile.
  • This application also provides a method for preparing crystal form F, which includes contacting the compound of formula (I) with methanesulfonic acid.
  • the preparation method of the above-mentioned crystalline form F includes the following steps:
  • the solvent F is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, preferably ethyl acetate, acetonitrile, and more preferably acetonitrile.
  • the present application provides a crystalline composition comprising the above-mentioned crystal form, wherein the crystal form accounts for more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, most preferably 95%. %above.
  • the present application provides a pharmaceutical composition, which comprises the above-mentioned crystal form or a crystal composition thereof.
  • the pharmaceutical composition may also optionally include pharmaceutically acceptable carriers, excipients and/or vehicles.
  • the pharmaceutical composition of the present application may further include one or more other therapeutic agents.
  • the above-mentioned pharmaceutical composition comprises crystal form I or its crystal composition, crystal form A or its crystal composition, crystal form B or its crystal composition, crystal form C or its crystal composition, crystal Form D or its crystal composition, crystal form E or its crystal composition, or crystal form F or its crystal composition.
  • the aforementioned pharmaceutical composition comprises crystal form I, crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, or crystal form F.
  • the above-mentioned pharmaceutical composition comprises 0.0001 to 500 mg of crystal form I, crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, or crystal form F, preferably 0.001 to 250 mg Form I, Form A, Form B, Form C, Form D, Form E, or Form F, more preferably 0.005 to 100 mg of Form I, Form A, Form B, Form Form C, Form D, Form E, or Form F, most preferably 0.005 to 50 mg of Form I, Form A, Form B, Form C, Form D, Form E, or Form F.
  • the present application also provides a method for treating a disease mediated by BET protein in a mammal, comprising administering a therapeutically effective amount of the above-mentioned crystal form, or salt form, or crystal composition thereof to a mammal (preferably a human) in need of the treatment Or a pharmaceutical composition.
  • the application also provides the use of the above-mentioned crystal form, or salt form, or crystal composition or pharmaceutical composition thereof in the preparation of a medicine for the treatment of diseases mediated by the BET protein.
  • the application also provides the above-mentioned crystal form, or salt form, or crystal composition or pharmaceutical composition thereof for the treatment of diseases mediated by BET protein.
  • the application also provides the use of the above-mentioned crystal form, or salt form, or crystal composition or pharmaceutical composition thereof to treat diseases mediated by BET protein.
  • the disease mediated by the BET protein is selected from cancer.
  • the cancer is selected from solid tumors or hematological tumors. More preferably, the solid tumor is selected from breast cancer or prostate cancer. More preferably, the hematological tumor is selected from acute myeloid leukemia, multiple myeloma or diffuse large B-cell lymphoma.
  • the crystal form of this application has good stability, and shows good results under stability tests such as high humidity, high temperature or light; shows good pharmacological activity in in vivo or in vitro tests; when used as a raw material in preparations ,
  • the obtained product has good dissolution, dissolution or pharmacokinetic properties, indicating that the crystal form of the present application has good pharmaceutical properties and a higher prospect of preparing medicines.
  • the crystal form of the present application contributes to the solid form of the compound.
  • the position of the peak or the relative intensity of the peak may be different due to factors such as measuring instrument, measuring method/condition and so on.
  • the measurement error of the 2 ⁇ value may be ⁇ 0.2°. Therefore, when determining each crystal type, this error should be taken into account, and the error also belongs to the scope of this application.
  • the position of the endothermic peak of DSC may be different due to factors such as measuring instrument, measuring method/condition and so on.
  • there may be an error in the position of the endothermic peak which can be ⁇ 5°C or ⁇ 3°C. Therefore, when determining each crystal type, this error should be taken into account, and the error also belongs to the scope of this application.
  • hydrate refers to the hydration reaction between drug molecules and crystal water to form a eutectic solid state.
  • One compound molecule of the present application can be combined with one water molecule, such as a monohydrate; one compound molecule of the present application can also be combined with more than one water molecule, such as dihydrate, trihydrate, or tetrahydrate; The application compound molecule can also be combined with less than one water molecule, such as a hemihydrate.
  • the hydrates described in this application retain the bioavailability of the compounds in their non-hydrated form.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable excipients” refer to inert substances that are administered together with the active ingredients to facilitate the administration of the active ingredients, including but not limited to those acceptable for use in humans or animals (such as those approved by the State Food and Drug Administration).
  • Livestock any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, Isotonic agent, solvent or emulsifier.
  • auxiliary materials include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the crystal form described in the present application or its pharmaceutical composition include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, Intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the therapeutic dose of the compound of the present application may be determined according to, for example, the following: the specific use of the treatment, the way of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on various factors, including dosage, chemical properties (for example, hydrophobicity), and route of administration.
  • treatment means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or preparation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • the moisture content described in this application is measured in accordance with the moisture determination method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0832 First Method 1).
  • particle size distribution X 90 means the particle size corresponding to the volume cumulative distribution number in the powder sample reaching 90%.
  • the particle size distribution X 90 described in this application is measured in accordance with the light scattering method (the third method for the determination of particle size and particle size distribution in Chinese Pharmacopoeia 2020 Edition Four General Rules 0982).
  • the therapeutically effective amount of the crystal form described in the present application is from about 0.0001 to 20 mg/Kg body weight/day, for example, from 0.001 to 10 mg/Kg body weight/day.
  • the dosage frequency of the crystal form described in the present application is determined by the needs of the individual patient, for example, once or twice a day, or more times a day.
  • the administration may be intermittent, for example, where the patient receives the daily dose of the crystal form during a period of several days, and then the patient does not receive the daily dose of the crystal form during a period of several days or more.
  • the intermediate compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those of those skilled in the art.
  • Well-known equivalent alternatives, and preferred implementations include but are not limited to the examples of the present application.
  • each parameter value (including 2 ⁇ value, reaction conditions) is regarded as modified by the term "about" to reflect the measurement and other errors of each value, for example, relative to a given value, there is ⁇ 5% error.
  • Light tube voltage 40kV
  • light tube current 40mA
  • TGA Thermal Gravimetric Analyzer
  • Step D Ethyl 6-bromo-5-(2,4-difluorophenoxy)picolinate
  • Step F tert-Butyl [6-bromo-5-(2,4-difluorophenoxy)pyridin-2-yl]carbamate
  • Step I ((6-Bromo-5-(2,4-difluorophenoxy)pyridin-2-yl)imino)dimethyl- ⁇ 6 -sulfonimide
  • Step J tert-Butyl 4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate
  • Step K 6-Methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7 -Dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester
  • Step L 4- ⁇ 3-(2,4-Difluorophenoxy)-6- ⁇ [dimethyl(oxo)- ⁇ 6 -sulfinyl]amino ⁇ -pyridin-2-yl ⁇ -6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester
  • Step M 4- ⁇ 3-(2,4-Difluorophenoxy)-6- ⁇ [dimethyl(oxo)- ⁇ 6 -sulfinyl]amino ⁇ -pyridin-2-yl ⁇ -6 -Methyl-1,6-dihydro-7H-pyrrolo[23-c]pyridin-7-one
  • Test XRPD that is, crystal form I, its DSC The map is shown in Figure 2.
  • Test XRPD that is, crystal form I.
  • the hydrochloride of the compound of formula (I) used in method five to method seven is crystal form A.
  • Preparation method of crystal form A Take 100g of the compound of formula (I), add 1300ml of anhydrous methanol, add 160ml of 6mol/L hydrochloric acid, stir to dissolve, add 10g of activated carbon, decolorize for 10min, filter, and collect the filtrate. Concentrate the material to a weight of about 380g, heat the material to clear, naturally cool down and crystallize, crystallize at 0°C, filter, and dry the filter cake under reduced pressure at 50°C for more than 4 hours to obtain the product.
  • Test XRPD that is, crystal form A. With a moisture content of 5.8%, its XRPD spectrum is shown in Figure 3, its DSC spectrum is shown in Figure 4, and its TGA spectrum is shown in Figure 5. The hydrochloric acid content of the resulting product was 7.7%.
  • the preparation method of the crystal form B the crystal form A is allowed to stand for 30 days in an environment of 60 ⁇ 2° C. to obtain the product, and the XRPD is tested, that is, the crystal form B with a moisture content of 4.6%.
  • the XRPD spectrum is shown in Figure 6.
  • the preparation method of the crystal form C the crystal form A is allowed to stand for 30 days in an environment of room temperature and a relative humidity of 92.5 ⁇ 5% to obtain the product.
  • the XRPD is tested, and it is the crystal form C with a moisture content of 11.9%.
  • the XRPD pattern is shown in Figure 7.
  • test XRPD is the crystal form D. Its XRPD spectrum is shown in Figure 8, its DSC spectrum is shown in Figure 9, and its TGA spectrum is shown in Figure 10. The sulfuric acid content of the resulting product was 18.3%.
  • test XRPD is the crystal form E.
  • crystal form I In order to evaluate the solid stability of the crystal form of the present application, the stability of the influencing factors (high temperature, high humidity and light) of crystal form I, crystal form A, crystal form D, crystal form E, and crystal form F were investigated. Place the above crystal forms at high temperature (60°C ⁇ 2°C, open (weighing bottle)), high humidity (room temperature, 92.5%RH ⁇ 5%, open (weighing bottle) and with packaging) for 5 days , 10 days, 30 days, according to ICH light conditions (5500 Lux, 0.9w/m 2 , closed (weighing bottle) and packaging) for 5 days, 10 days.
  • the inner packaging material of the packaged sample is a medicinal low-density polyethylene bag
  • the outer material is a polyester/aluminum/polyethylene medicinal composite bag.
  • the samples after storage were characterized by their properties, purity (HPLC), crystal form (XRD), and moisture to detect changes in crystal form and purity; the results are shown in Tables 8-12 (" # "indicates ICH conditions).
  • the stability of its influencing factors was investigated.
  • High temperature 40°C, open mouth (weighing bottle)
  • high temperature 60°C, open mouth (weighing bottle)
  • high humidity room temperature, 75%RH, open mouth (weighing bottle)
  • high humidity room temperature, 92.5%RH, open (weighing bottle) and packaging
  • the inner packaging material of the packaged sample is a double-layer medicinal low-density polyethylene bag
  • the outer material is a polyester/aluminum/polyethylene compound bag for pharmaceutical packaging.
  • HPLC high-density polyethylene
  • XRD crystal form
  • moisture and content of the samples after being placed are determined to investigate the effects of high temperature, high humidity and light conditions on the product. The results are shown in Table 13 ("#" indicates ICH conditions).
  • the accelerated and long-term stability of the crystalline form I of the present application were investigated. They were placed under accelerated (40 ⁇ 2°C, 75%RH ⁇ 5%, with packaging) conditions for 1, 2, 3, and 6 months, and the long-term (25 ⁇ Place it for 3, 6, 9, 12, 18, 24, 36 months under the conditions of 2°C, 65%RH ⁇ 5%, with packaging.
  • the inner packaging material of the packaged sample is a double-layer medicinal low-density polyethylene bag, and the outer material is a polyester/aluminum/polyethylene compound bag for pharmaceutical packaging.
  • HPLC high-LC
  • crystal form XRD
  • moisture and content of the samples after storage were determined to investigate the stability of the product.
  • the inhibitory IC 50 value of the compound of formula (I) on the enzyme binding reaction of BRD4 (BD2) is performed by the homogeneous time-resolved fluorescence (HTRF) method.
  • the compound of formula (I) was diluted 5-fold with 100% DMSO starting from 1 mM (7 concentrations in total), and 2 ⁇ L of the compound of formula (I) at each concentration was added to 18 ⁇ L of reaction buffer (20 mM HEPES pH 7.5, Dilute in 150mM NaCl, 5mM DTT, 0.005% Tween 20 and 100 ⁇ g/mL BSA), and after mixing, take 2 ⁇ L of the compound of formula (I) at each concentration and add it to 48 ⁇ L of the above reaction buffer to dilute and mix again (formula (I) The final concentration of compound DMSO is 0.1%).
  • OptiPlate-384 purchased from PerkinElmer
  • 5 ⁇ L of GST-BRD4 (BD2, 349-460aa) (final concentration is 2nM)
  • centrifuge and mix then add 2.5 ⁇ L of Biotin -AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV peptide (final concentration of 200nM) to start the reaction (total reaction volume is 10 ⁇ L).
  • the inhibitory IC 50 value of the compound of formula (I) on the enzyme binding reaction of BRD4 (BD1) is performed by the homogeneous time-resolved fluorescence (HTRF) method.
  • the compound of formula (I) was diluted 5-fold with 100% DMSO starting from 0.2mM (7 concentrations in total), and 2 ⁇ L of the compound of formula (I) at each concentration was added to 48 ⁇ L of reaction buffer (20mM HEPES pH 7.5). , 150mM NaCl, 5mM DTT, 0.005% Tween 20 and 100 ⁇ g/ml BSA) were diluted and mixed.
  • OptiPlate-384 purchased from PerkinElmer
  • 5 ⁇ L of GST-BRD4 (BD1, 44-168aa) (final concentration is 1nM)
  • centrifuge and mix then add 2.5 ⁇ L of Biotin -AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV) short peptide (final concentration 100nM) to start the reaction (total reaction volume is 10 ⁇ L).
  • Human acute lymphoblastic leukemia cell line MV4-11 uses PRIM1640 medium plus 10% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin/streptomycin (P/S, purchased from Life) Techonology) for cultivation under 37°C and 5% CO 2 .
  • FBS fetal bovine serum
  • P/S penicillin/streptomycin
  • the compound of formula (I) was diluted 4-fold with 100% DMSO from 10 mM (9 concentrations in total), and then 2 ⁇ L of the compound of formula (I) at each concentration was added to 48 ⁇ L of PRIM1640 medium. dilution. Add 5 ⁇ L of the diluted compound of formula (I) to the paved cell suspension at each concentration. Incubate the compound of formula (I) with the cells in a cell incubator for 72 hours (3 days) and then add 35 ⁇ L of Cell-Titer Blue Reagent (purchased from Promega) was incubated again for 4 hours. The fluorescence value (excitation at 560 nm, detection at 590 nm) was then read on Flexstation III, and the data was calculated using GraphPad Prism software to obtain the IC 50 value of the compound of formula (I) inhibiting cell proliferation.
  • Kasumi-1 cells Human acute myeloblastic leukemia cell line Kasumi-1 cells use PRIM1640 medium plus 20% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin/streptomycin (P/S, purchased from Life Techonology) was cultured under 37°C and 5% CO 2 . The day before the detection of the compound of formula (I), Kasumi-1 cells were plated in a 96-well plate (purchased from Corning) at a concentration of 5000 cells/195 ⁇ L/well.
  • FBS fetal bovine serum
  • P/S penicillin/streptomycin
  • the compound of formula (I) was diluted 4-fold with 100% DMSO from 10 mM (9 concentrations in total), and then 2 ⁇ L of the compound of formula (I) at each concentration was added to 48 ⁇ L of PRIM1640 medium. dilution. Add 5 ⁇ L of the diluted compound of formula (I) to the paved cell suspension at each concentration. Incubate the compound of formula (I) with the cells in a cell incubator for 72 hours (3 days) and then add 35 ⁇ L of Cell-Titer Blue Reagent (purchased from Promega) was incubated again for 4 hours.
  • the animal pharmacokinetic experiment uses 3 healthy adult male rats, which come from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
  • the compound of formula (I) is suspended in 2% absolute ethanol, 5% Tween 80, 20% polyethylene glycol 400, 73% (5% hydroxypropyl methylcellulose in water) (V/V/V/ In V), the concentration is 1 mg/mL, the administration volume is 5 mL/kg, and the single intragastric administration is administered at a dose of 5 mg/kg.
  • the animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
  • the animals were lightly anesthetized by isoflurane, and about 0.4 mL of whole blood was collected from the orbital venous plexus with a glass blood collection tube, and placed in a heparin anticoagulation tube.
  • the sample was centrifuged at 4°C and 4200 rpm for 5 minutes.
  • the plasma was transferred to a centrifuge tube and placed Store at -80°C until analysis.
  • Plasma sample analysis uses acetonitrile protein precipitation method to extract the test compound and internal standard (warfarin or propranolol) in rat plasma, and the extract is analyzed by LC/MS/MS.
  • the measured plasma concentration-time data of individual animals were analyzed using the non-compartmental model of WinNonlin (version 5.2.1; Pharsight) software, and the pharmacokinetic parameters shown in Table 17 below were obtained: maximum (peak) plasma drug Concentration C max ; time to peak T max ; half-life T 1/2 and area under the plasma concentration-time curve extrapolated to infinite time AUC 0-inf .
  • parameter unit Compound of formula (I) t 1/2 hr 5.25 T max hr 2.67 C max ng/mL 372 AUC 0-inf hr ⁇ ng/mL 3466
  • the compound of formula (I) has good activity and good pharmacokinetic properties.
  • the particle size distribution test is carried out by referring to the third method of the determination of particle size and particle size distribution (light scattering method) in the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia. The details are as follows: Weigh 10 mg of the sample and place it in a laser scattering particle size distribution instrument. Test (trigger condition: 10s, 1%; dispersion pressure: 2.0 bar), the test results are shown in Table 18.

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Abstract

一种式（I）所示的溴区结构域蛋白抑制剂的晶型、盐型及其制备方法，以及上述晶型和盐型在制备治疗由BET蛋白介导的疾病的药物中的用途。

Description

一种溴区结构域蛋白抑制剂的晶型、盐型及其制备方法
相关申请的交叉引用
本申请要求于2020年01月19日向中国国家知识产权局提交的第202010057297.0号中国专利申请、以及于2020年01月19日向中国国家知识产权局提交的第202010060110.2号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于药物化学领域，具体涉及一种溴区结构域蛋白抑制剂的晶型、其制备方法、含有该晶型的结晶组合物、包含该晶型或其结晶组合物的药物组合物以及它们的用途。本申请还涉及上述溴区结构域蛋白抑制剂的盐酸盐、硫酸盐、磷酸盐、甲磺酸盐，以及它们的晶型、制备方法、包含上述盐的药物组合物及其用途。
背景技术
转录基因的表观调控在肿瘤、炎症及代谢类等疾病的发展过程中发挥重要作用。核小体组蛋白赖氨酸N-端残基的乙酰化对遗传表观基因的调控尤为重要。而组蛋白乙酰化通常与基因转录的活化最为相关，组蛋白赖氨酸乙酰化的识别是组蛋白乙酰化参与表观遗传调控的关键步骤。溴区结构域(Bromodomains,BRDs)是一类能够特异性识别组蛋白中乙酰化赖氨酸(KAc)的保守蛋白结构域，通过与乙酰化赖氨酸结合促使染色质重塑因子和转录因子等相关蛋白富集于特定的基因转录位点，改变RNAⅡ聚合酶的活性，从而协同完成基因表达调控。
BET(Bromodomain and Extra Terminal)蛋白包括两个相互关联的溴区结构域中心和一个外末端结构域，根据氨基酸序列不同又分为Brd2、Brd3、Brd4和BrdT四种蛋白，其中Brd2～Brd4广泛分布于人体各器官中。BET是一类转录调控蛋白，通过与染色质的相互作用对基因的表达调控起到了非常重要的作用。BET蛋白对于细胞内的网状信号传导通路具有共激活或共抑制的双向调控功能，如胰岛素的转录、脂质组织中的脂肪形成、造血系统的分化等等。近些年的研究证明，以BET蛋白为靶点的药物可以用来治疗癌症、炎症、肾病、自身免疫性疾病和抗男性生育等。因此，BET蛋白已日益成为表观遗传领域内的重要靶标之一，引起了各大制药公司和科研机构的极大关注。
发明内容
一方面，本申请提供了式(I)化合物或其药学上可接受的盐的晶型：
Figure PCTCN2021072651-appb-000001
其中，所述晶型选自：
式(I)化合物的晶型I，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.4°±0.2°、14.5°±0.2°、17.4°±0.2°、18.5°±0.2°、20.4°±0.2°、24.7°±0.2°；
式(I)化合物的盐酸盐的晶型A，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.8°±0.2°、8.4°±0.2°、9.4°±0.2°、10.2°±0.2°、16.8°±0.2°；
式(I)化合物的盐酸盐的晶型B，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.7°±0.2°、9.5°±0.2°、10.5°±0.2°、14.5°±0.2°、17.4°±0.2°；
式(I)化合物的盐酸盐的晶型C，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.8°±0.2°、9.5°±0.2°、12.9°±0.2°、20.5°±0.2°、24.6°±0.2°；
式(I)化合物的硫酸盐的晶型D，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.5°±0.2°、14.7°±0.2°、18.6°±0.2°、21.2°±0.2°、23.0°±0.2°、24.1°±0.2°；
式(I)化合物的磷酸盐的晶型E，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.1°±0.2°、10.5°±0.2°、19.0°±0.2°、21.0°±0.2°、22.7°±0.2°、24.0°±0.2°；或者
式(I)化合物的甲磺酸盐的晶型F，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.8°± 0.2°、10.1°±0.2°、17.7°±0.2°、18.0°±0.2°、24.1°±0.2°、24.8°±0.2°。
另一方面，本申请提供式(I)化合物的晶型I：
Figure PCTCN2021072651-appb-000002
所述晶型I的特征在于，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝12.4°±0.2°、14.5°±0.2°、17.4°±0.2°、18.5°±0.2°、20.4°±0.2°、24.7°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型I在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.6°±0.2°、9.3°±0.2°、12.4°±0.2°、14.5°±0.2°、16.6°±0.2°、17.4°±0.2°、18.5°±0.2°、20.0°±0.2°、20.4°±0.2°、24.7°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型I在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.6°±0.2°、9.3°±0.2°、12.4°±0.2°、14.5°±0.2°、16.6°±0.2°、17.4°±0.2°、18.5°±0.2°、20.0°±0.2°、20.4°±0.2°、21.5°±0.2°、22.5°±0.2°、23.7°±0.2°、24.7°±0.2°、25.2°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型I的X-射线粉末衍射(XRPD)图谱中，特征衍射峰的位置及相对强度如表1所示：
表1：晶型I的X-射线粉末衍射图谱的特征峰位置及相对强度
编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％)
1 6.6 20.0 12 21.5 20.9
2 9.3 16.2 13 21.8 8.1
3 12.4 63.4 14 22.5 21.8
4 14.5 100.0 15 23.3 8.0
5 14.7 27.5 16 23.7 26.4
6 15.2 10.2 17 24.7 36.7
7 16.6 21.1 18 25.2 26.9
8 17.4 32.4 19 26.9 11.1
9 18.5 99.2 20 29.3 15.5
10 20.0 25.3 21 29.7 14.8
11 20.4 45.0 22 30.3 12.5
。
在一些实施方案中，所述晶型I的X-射线粉末衍射(XRPD)图谱具有如图1所示的XRPD图谱所代表的特征。
在一些实施方案中，所述晶型I的差示扫描量热曲线(DSC)图谱具有如图2所示的DSC图谱所代表的特征。
在一些实施方案中，所述晶型I的DSC图谱在275℃±3℃处有吸热峰。
在一些实施方案中，所述晶型I是在选自水、乙腈、甲醇、乙醇、异丙醇、乙酸乙酯、丙酮、二甲基亚砜、二氯甲烷中的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型I是在选自水、甲醇、二甲基亚砜、二氯甲烷、乙腈中的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型I是在二甲基亚砜、甲醇或水中制备得到的。在一些实施方案中，所述晶型I是在二甲基亚砜和水的混合溶剂、二甲基亚砜和甲醇的混合溶剂、二氯甲烷和甲醇的混合溶剂、或乙腈和水的混合溶剂中制备得到的。
在一些实施方案中，所述晶型I的粒度分布X 90小于30μm。在一些实施方案中，所述晶型I的粒度分布X 90小于20μm。在一些实施方案中，所述晶型I的粒度分布X 90小于15μm。在一些实施方案中，所述晶型I的粒度分布X 90小于12μm。在一些实施方案中，所述晶型I的粒度分布X 90小于10μm。在一些实 施方案中，所述晶型I的粒度分布X 90小于7μm。
在一些实施方案中，所述晶型I的粒度分布X 90为3.0～14.0μm，优选为3.5～13.5μm，更优选为4.0～13.0μm，进一步优选为4.5～12.5μm，更进一步优选5.0～12.0μm。
在一些实施方案中，所述晶型I的粒度分布X 90为3.5～8.5μm，优选为4.5～7.5μm，更优选为5.5～6.5μm。
在一些实施方案中，所述晶型I的粒度分布X 90为9.5～13.5μm，优选为10.5～12.5μm，更优选为11.0～12.0μm。
在一些实施方案中，所述晶型I的粒度分布X 90是在晶型I经过气流粉碎后测定的。在一些实施方案中，所述气流粉碎的粉碎压力选自0.1MPa～0.7MPa，优选自0.1MPa～0.6MPa；或者所述气流粉碎的粉碎压力选自0.1MPa、0.2MPa、0.3MPa、0.4MPa、0.5MPa、0.6MPa、0.7MPa或者由任选上述值形成的范围。
本申请还提供式(I)化合物的晶型I的制备方法，包括：
(1)将式(I)化合物与溶剂I混合；
(2)过滤，干燥；
其中，所述溶剂I优选选自水、乙腈、甲醇、乙醇、异丙醇、乙酸乙酯、丙酮、二甲基亚砜、二氯甲烷中的一种或一种以上的混合溶剂，优选自水、乙腈、甲醇、二甲基亚砜、二氯甲烷中的一种或一种以上的混合溶剂，更优选自水或二甲基亚砜，进一步优选二氯甲烷和甲醇的混合溶剂。
在一些实施方案中，上述式(I)化合物的晶型I的制备方法包括：
(1)将式(I)化合物与溶剂I混合；
(2)步骤(1)的混合物与溶剂II混合；
(3)过滤，干燥；
其中，所述溶剂I和溶剂II各自独立地优选选自水、乙腈、甲醇、乙醇、异丙醇、乙酸乙酯、丙酮、二甲基亚砜或二氯甲烷，优选自水、乙腈、甲醇、二甲基亚砜或二氯甲烷，更优选自水、甲醇或二甲基亚砜，进一步优选二氯甲烷和甲醇。
在一些实施方案中，步骤(2)中，步骤(1)的混合物与溶剂II混合的方式包括但不限于：a.向溶剂II中加入步骤(1)的混合物；b.向步骤(1)的混合物中加入溶剂II。在一些实施方案中，上述加入方式优选滴加。
在一些实施方案中，上述步骤(2)是在适当温度下，向溶剂II中滴加步骤(1)的混合物。在一些实施方案中，所述适当温度是-10到30℃。在一些实施方案中，所述适当温度是-5到10℃。在一些实施方案中，所述适当温度是0℃。
本申请还提供了式(I)化合物的晶型I的制备方法，包括：
(1)将式(I)化合物的药学上可接受的盐与溶剂III混合；
(2)过滤，干燥；
其中，所述溶剂III优选选自水、乙腈、甲醇、乙醇、异丙醇、乙酸乙酯、丙酮中的一种或一种以上的混合溶剂，优选自水、乙腈、甲醇中的一种或一种以上的混合溶剂，更优选自水、乙腈/水混合溶剂、或甲醇/水混合溶剂。
在一些实施方案中，步骤(1)中，式(I)化合物的药学上可接受的盐与溶剂III混合后，搅拌一段时间、优选3h-4h。在一些实施方案中，所述搅拌在室温下进行。
在一些实施方案中，上述式(I)化合物的晶型I的制备方法包括：
(1)将式(I)化合物的药学上可接受的盐与溶剂III混合；
(2)步骤(1)的混合物与溶剂IV混合；
(3)过滤，干燥；
其中，所述溶剂III和溶剂IV各自独立地优选选自水、乙腈、甲醇、乙醇、异丙醇、乙酸乙酯或丙酮，优选自水、乙腈、甲醇、乙醇或异丙醇，更优选自水、乙腈或甲醇。
在一些实施方案中，步骤(2)中，步骤(1)的混合物与溶剂IV混合的方式包括但不限于：a.向溶剂IV中加入步骤(1)的混合物；b.向步骤(1)的混合物中加入溶剂IV。在一些实施方案中，上述加入方式优选滴加。
在一些实施方案中，步骤(2)中，步骤(1)的混合物与溶剂IV混合后，析晶。在一些实施方案中， 所述析晶在室温下进行。
在一些实施方案中，上述式(I)化合物的药学上可接受的盐选自式(I)化合物的盐酸盐。在一些实施方案中，上述式(I)化合物的盐酸盐选自晶型A、晶型B、或晶型C，优选为晶型A。
本申请还提供了所述式(I)化合物的药学上可接受的盐(盐型)，所述药学上可接受的盐选自式(I)化合物的盐酸盐、式(I)化合物的硫酸盐、式(I)化合物的磷酸盐或式(I)化合物的甲磺酸盐。
再一方面，本申请提供式(I)所示化合物的盐酸盐：
Figure PCTCN2021072651-appb-000003
本申请还提供了式(I)化合物的盐酸盐的晶型及其制备方法和相应的结晶组合物。
在一些实施方案中，所述式(I)所示化合物的盐酸盐为所述式(I)化合物与盐酸按1:1的摩尔比形成的盐。
在一些实施方案中，所述式(I)化合物的盐酸盐中的盐酸含量是5～10wt％，优选6～9wt％、6～8wt％；或者所述式(I)化合物的盐酸盐中的盐酸含量选自6.0wt％、6.1wt％、6.2wt％、6.3wt％、6.4wt％、6.5wt％、6.6wt％、6.7wt％、6.8wt％、6.9wt％、7.0wt％、7.1wt％、7.2wt％、7.3wt％、7.4wt％、7.5wt％、7.6wt％、7.7wt％、7.8wt％、7.9wt％、8.0wt％、8.1wt％、8.2wt％、8.3wt％、8.4wt％、8.5wt％、8.6wt％、8.7wt％、8.8wt％、8.9wt％、9.0wt％或者由任选上述值形成的范围。
在一些实施方案中，所述式(I)化合物的盐酸盐的晶型为水合物，所述水合物选自半水合物、一水合物、二水合物、三水合物和四水合物，优选为一水合物、二水合物和四水合物，更优选为一水合物和四水合物。
在一些实施方案中，所述式(I)化合物的盐酸盐的晶型为一水合物。
在一些实施方案中，所述式(I)化合物的盐酸盐的晶型为四水合物。
本申请提供了式(I)化合物的盐酸盐的晶型A，其特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.8°±0.2°、8.4°±0.2°、9.4°±0.2°、10.2°±0.2°、16.8°±0.2°的衍射峰。
在一些实施方案中，所述晶型A的特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.8°±0.2°、8.4°±0.2°、9.4°±0.2°、10.2°±0.2°、14.4°±0.2°、16.8°±0.2°、20.5°±0.2°、24.7°±0.2°的衍射峰。
在一些实施方案中，所述晶型A的特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.8°±0.2°、8.4°±0.2°、9.4°±0.2°、10.2°±0.2°、14.4°±0.2°、16.8°±0.2°、19.2°±0.2°、20.5°±0.2°、21.7°±0.2°、23.3°±0.2°、24.7°±0.2°的衍射峰。
在一些实施方案中，所述晶型A的X-射线粉末衍射(XRPD)图谱中，特征衍射峰的位置及相对强度如表2所示：
表2：晶型A的X-射线粉末衍射图谱的特征峰位置及相对强度
编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％)
1 6.8 45.2 7 19.2 4.8
2 8.4 100.0 8 20.5 10.6
3 9.4 13.6 9 21.7 4.2
4 10.2 21.5 10 23.3 3.5
5 14.4 5.4 11 24.7 7.0
6 16.8 33.5 12    
。
在一些实施方案中，所述晶型A的X-射线粉末衍射(XRPD)图谱具有如图3所示的XRPD图谱所代表的特征。
在一些实施方案中，所述晶型A的差示扫描量热曲线(DSC)图谱具有如图4所示的DSC图谱所代表的特征。
在一些实施方案中，所述晶型A的DSC图谱在149.61℃±3℃处有吸热峰。在一些实施方案中，所述晶型A的DSC图谱在101.14℃±3℃处有吸热峰。在一些实施方案中，所述晶型A的DSC图谱在80.15℃±3℃处有吸热峰。在一些实施方案中，所述晶型A的DSC图谱在62.98℃±3℃处有吸热峰。在一些实施方案中，所述晶型A的DSC图谱在149.61℃±3℃、和/或101.14℃±3℃、和/或80.15℃±3℃、和/或62.98℃±3℃处有吸热峰。
本申请中描述失重、水分含量时的％均是指wt％。
在一些实施方案中，所述晶型A的热重分析曲线(TGA)图谱具有如图5所示的TGA图谱所代表的特征。
在一些实施方案中，所述晶型A的热重分析曲线在119.1±3℃处失重达2.37±0.2％。
在一些实施方案中，所述晶型A的热重分析曲线在119.1±3℃处失重达2.37±0.2％，和/或在258.7±3℃处失重达16.78±0.2％，和/或在494.1±3℃处失重达38.60±0.2％。
在一些实施方案中，所述晶型A是在选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型A是在选自甲醇、乙醇、或异丙醇中制备得到的。在一些实施方案中，所述晶型A是在甲醇中制备得到的。
本申请还提供式(I)化合物的盐酸盐的晶型A的制备方法，包括如下步骤：
(1)将式(I)化合物与溶剂A混合；
(2)向步骤(1)的混合物中加入盐酸；
(3)过滤，干燥。
其中，所述溶剂A选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈的一种或一种以上的混合溶剂，优选自甲醇、乙醇或异丙醇，更优选为甲醇。
在一些实施方案中，所述晶型A的水分含量为5.0％～9.0％，优选为5.5％～8.5％，更优选为5.8％～8.1％。在一些实施方案中，所述晶型A的水分含量为4.7％。在一些实施方案中，所述晶型A的水分含量为5.8％。在一些实施方案中，所述晶型A的水分含量为6.6％。在一些实施方案中，所述晶型A的水分含量为8.1％。
本申请提供式(I)化合物的盐酸盐的晶型B，其特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝8.7°±0.2°、9.5°±0.2°、10.5°±0.2°、14.5°±0.2°、17.4°±0.2°的衍射峰。
在一些实施方案中，所述晶型B的特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.8°±0.2°、8.7°±0.2°、9.5°±0.2°、10.5°±0.2°、14.5°±0.2°、17.4°±0.2°、21.0°±0.2°、22.2°±0.2°的衍射峰。
在一些实施方案中，所述晶型B的特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.8°±0.2°、8.7°±0.2°、9.5°±0.2°、10.5°±0.2°、14.5°±0.2°、17.4°±0.2°、18.8°±0.2°、20.1°±0.2°、21.0°±0.2°、22.2°±0.2°、24.6°±0.2°的衍射峰。
在一些实施方案中，所述晶型B的X-射线粉末衍射(XRPD)图谱中，特征衍射峰的位置及相对强度如表3所示：
表3：晶型B的X-射线粉末衍射图谱的特征峰位置及相对强度
编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％)
1 6.8 7.8 7 18.8 10.4
2 8.7 100.0 8 20.1 10.6
3 9.5 14.9 9 21.0 13.9
4 10.5 48.3 10 22.2 13.3
5 14.5 16.6 11 24.6 12.7
6 17.4 35.9 12    
。
在一些实施方案中，所述晶型B的X-射线粉末衍射(XRPD)图谱具有如图6所示的XRPD图谱所代表的特征。
在一些实施方案中，所述晶型B的水分含量为2.0％～5.5％，优选为3.0％～5.0％，更优选为3.6％～4.6％。在一些实施方案中，所述晶型B的水分含量为3.6％。在一些实施方案中，所述晶型B的水分含量为4.6％。
在一些实施方案中，所述晶型B是晶型A于60±2℃环境下制备得到的。
本申请还提供式(I)化合物的盐酸盐的晶型B的制备方法，包括将晶型A于60±2℃环境下静置30天。
本申请提供式(I)化合物的盐酸盐的晶型C，其特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.8°±0.2°、9.5°±0.2°、12.9°±0.2°、20.5°±0.2°、24.6°±0.2°的衍射峰。
在一些实施方案中，所述晶型C的特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.8°±0.2°、9.5°±0.2°、12.9°±0.2°、14.8°±0.2°、17.5°±0.2°、20.5°±0.2°、23.3°±0.2°、24.6°±0.2°的衍射峰。
在一些实施方案中，所述晶型C的特征在于，在X-射线粉末衍射(XRPD)图谱中具有2θ＝6.8°±0.2°、9.5°±0.2°、11.9°±0.2°、12.9°±0.2°、14.8°±0.2°、15.8°±0.2°、17.5°±0.2°、20.5°±0.2°、23.3°±0.2°、24.6°±0.2°、28.7°±0.2°的衍射峰。
在一些实施方案中，所述晶型C的X-射线粉末衍射(XRPD)图谱中，特征衍射峰的位置及相对强度如表4所示：
表4：晶型C的X-射线粉末衍射图谱的特征峰位置及相对强度
编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％)
1 6.8 69.1 9 20.5 46.3
2 9.5 100.0 10 21.7 12.8
3 11.9 14.6 11 23.3 19.9
4 12.9 20.2 12 23.9 9.9
5 14.8 16.7 13 24.6 50.5
6 15.8 15.7 14 26.0 10.2
7 16.5 10.5 15 28.2 12.6
8 17.5 17.2 16 28.7 24.0
。
在一些实施方案中，所述晶型C的X-射线粉末衍射(XRPD)图谱具有如图7所示的XRPD图谱所代表的特征。
在一些实施方案中，所述晶型C的水分含量为9.0％～14.0％，优选为9.5％～13.5％，更优选为10.0％～13.0％。在一些实施方案中，所述晶型C的水分含量为11.9％。在一些实施方案中，所述晶型C的水分含量为12.2％。在一些实施方案中，所述晶型C的水分含量为13.0％。
在一些实施方案中，所述晶型C是晶型A于室温、相对湿度92.5±5％的环境下制备得到的。
本申请还提供式(I)化合物的盐酸盐的晶型C的制备方法，包括将晶型A于室温、相对湿度92.5±5％的环境下静置30天。
另一方面，本申请提供式(I)化合物的硫酸盐：
Figure PCTCN2021072651-appb-000004
在一些实施方案中，上述式(I)化合物的硫酸盐如式II所示
Figure PCTCN2021072651-appb-000005
其中，x选自0.5～1。
在一些实施方案中，上述x选自0.5或1。
在一些实施方案中，上述x选自1。
在一些实施方案中，所述式(I)化合物的硫酸盐中的硫酸含量是15～20wt％，优选16～19wt％、17～19wt％；或者所述式(I)化合物的硫酸盐中的硫酸含量选自16.1wt％、16.2wt％、16.3wt％、16.4wt％、16.5wt％、16.6wt％、16.7wt％、16.8wt％、16.9wt％、17.0wt％、17.1wt％、17.2wt％、17.3wt％、17.4wt％、17.5wt％、17.6wt％、17.7wt％、17.8wt％、17.9wt％、18.0wt％、18.1wt％、18.2wt％、18.3wt％、18.4wt％、18.5wt％、18.6wt％、18.7wt％、18.8wt％、18.9wt％、19.0wt％或者由任选上述值形成的范围。
本申请还提供了式II所示化合物的晶型D，其中x为1，所述晶型D的特征在于，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝13.5°±0.2°、14.7°±0.2°、18.6°±0.2°、21.2°±0.2°、23.0°±0.2°、24.1°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型D在X-射线粉末衍射(XRPD)图谱中具有2θ＝7.1°±0.2°、8.9°±0.2°、9.8°±0.2°、13.2°±0.2°、13.5°±0.2°、14.7°±0.2°、18.6°±0.2°、21.2°±0.2°、23.0°±0.2°、24.1°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型D在X-射线粉末衍射(XRPD)图谱中具有2θ＝7.1°±0.2°、8.9°±0.2°、9.8°±0.2°、13.2°±0.2°、13.5°±0.2°、14.7°±0.2°、16.3°±0.2°、18.6°±0.2°、19.7°±0.2°、21.2°±0.2°、21.9°±0.2°、23.0°±0.2°、24.1°±0.2°、26.2°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型D的X-射线粉末衍射(XRPD)图谱中，特征衍射峰的位置及相对强度如表5所示：
表5：晶型D的X-射线粉末衍射图谱的特征峰位置及相对强度
编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％)
1 7.1 7.8 14 20.9 10.1
2 8.9 8.7 15 21.2 29.8
3 9.8 28.1 16 21.9 22.5
4 13.2 29.4 17 22.4 13.0
5 13.5 30.4 18 23.0 100.0
6 13.8 12.3 19 24.1 46.2
7 14.7 90.8 20 26.2 31.9
8 16.3 19.7 21 27.5 17.2
9 17.3 12.9 22 27.8 17.1
10 18.0 14.6 23 28.6 10.2
11 18.6 42.9 24 29.7 12.7
12 19.7 25.8 25 33.1 16.1
13 20.1 20.9      
。
在一些实施方案中，所述晶型D的X-射线粉末衍射(XRPD)图谱具有如图8所示的XRPD图谱所代表的特征。
在一些实施方案中，所述晶型D的差示扫描量热曲线(DSC)图谱具有如图9所示的DSC图谱所代表的特征。
在一些实施方案中，所述晶型D的DSC图谱在262.82℃±3℃处有放热峰。在一些实施方案中，所述 晶型D的DSC图谱在272.31℃±3℃处有放热峰。在一些实施方案中，所述晶型D的DSC图谱在272.31℃±3℃、和/或262.82℃±3℃处有放热峰。
在一些实施方案中，所述晶型D的热重分析曲线(TGA)图谱具有如图10所示的TGA图谱所代表的特征。
在一些实施方案中，所述晶型D的热重分析曲线在425.0±3℃处失重达40.74±0.2％。
在一些实施方案中，所述晶型D是在选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型D是在选自甲醇、乙醇或异丙醇的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型D是在甲醇中制备得到的。
本申请还提供式(I)化合物的硫酸盐的晶型D的制备方法，包括式(I)化合物与硫酸接触。
在一些实施方案中，上述晶型D的制备方法，包括如下步骤：
(1)将式(I)化合物与溶剂D混合；
(2)向步骤(1)的混合物中加入硫酸的溶剂D溶液；
(3)过滤，干燥。
其中，所述溶剂D选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯的一种或一种以上的混合溶剂，优选自甲醇、乙醇或异丙醇，更优选为甲醇。
又一方面，本申请提供式(I)化合物的磷酸盐：
Figure PCTCN2021072651-appb-000006
在一些实施方案中，上述式(I)化合物的磷酸盐如式III所示
Figure PCTCN2021072651-appb-000007
其中，x选自0.5～1。
在一些实施方案中，上述x选自0.5或1。
在一些实施方案中，上述x选自1。
在一些实施方案中，所述式(I)化合物的磷酸盐中的磷酸含量是10～20wt％，优选12～19wt％；或者所述式(I)化合物的磷酸盐中的磷酸含量选自12.1wt％、12.2wt％、12.3wt％、12.4wt％、12.5wt％、12.6wt％、12.7wt％、12.8wt％、12.9wt％、13.0wt％、13.1wt％、13.2wt％、13.3wt％、13.4wt％、13.5wt％、13.6wt％、13.7wt％、13.8wt％、13.9wt％、14.0wt％、14.1wt％、14.2wt％、14.3wt％、14.4wt％、14.5wt％、14.6wt％、14.7wt％、14.8wt％、14.9wt％、15.0wt％、15.1wt％、15.2wt％、15.3wt％、15.4wt％、15.5wt％、15.6wt％、15.7wt％、15.8wt％、15.9wt％、16.0wt％、16.1wt％、16.2wt％、16.3wt％、16.4wt％、16.5wt％、16.6wt％、16.7wt％、16.8wt％、16.9wt％、17.0wt％、17.1wt％、17.2wt％、17.3wt％、17.4wt％、17.5wt％、17.6wt％、17.7wt％、17.8wt％、17.9wt％、18.0wt％、18.1wt％、18.2wt％、18.3wt％、18.4wt％、18.5wt％、18.6wt％、18.7wt％、18.8wt％、18.9wt％、19.0wt％或者由任选上述值形成的范围。
本申请还提供了式(III)化合物的晶型E，所述晶型E的特征在于，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝10.1°±0.2°、10.5°±0.2°、19.0°±0.2°、21.0°±0.2°、22.7°±0.2°、24.0°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型E的特征在于，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝9.0°±0.2°、10.1°±0.2°、10.5°±0.2°、17.9°±0.2°、19.0°±0.2°、21.0°±0.2°、21.7°±0.2°、22.7°±0.2°、24.0°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型E的特征在于，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝5.2°±0.2°、9.0°±0.2°、10.1°±0.2°、10.5°±0.2°、15.5°±0.2°、17.9°±0.2°、19.0°±0.2°、20.2°±0.2°、21.0°±0.2°、21.7°±0.2°、22.2°±0.2°、22.7°±0.2°、23.4°±0.2°、24.0°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型E的X-射线粉末衍射(XRPD)图谱中，特征衍射峰的位置及相对强度如表6所示：
表6：晶型E的X-射线粉末衍射图谱的特征峰位置及相对强度
编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％)
1 5.2 4.2 15 21.7 31.8
2 9.0 12.3 16 22.2 24.3
3 10.1 32.7 17 22.7 40.6
4 10.5 30.9 18 23.4 29.7
5 13.6 10.2 19 24.0 32.1
6 14.3 14.3 20 25.8 10.7
7 15.5 25.0 21 26.1 12.2
8 15.7 20.5 22 27.4 11.7
9 17.0 18.6 23 28.9 13.8
10 17.3 16.4 24 29.2 15.7
11 18.0 30.1 25 29.4 14.2
12 19.0 37.6 26 29.6 16.0
13 20.2 22.9 27 33.3 13.3
14 21.0 100.0      
。
在一些实施方案中，所述晶型E的X-射线粉末衍射(XRPD)图谱具有如图11所示的XRPD图谱所代表的特征。
在一些实施方案中，所述晶型E的差示扫描量热曲线(DSC)图谱具有如图12所示的DSC图谱所代表的特征。
在一些实施方案中，所述晶型E的DSC图谱在171.37℃±3℃处有吸热峰。在一些实施方案中，所述晶型E的DSC图谱在159.07℃±3℃处有吸热峰。在一些实施方案中，所述晶型E的DSC图谱在141.12℃±3℃处有吸热峰。在一些实施方案中，所述晶型E的DSC图谱在116.46℃±3℃处有吸热峰。在一些实施方案中，所述晶型E的DSC图谱在171.37℃±3℃、和/或159.07℃±3℃、和/或141.12℃±3℃、和/或116.46℃±3℃处有吸热峰。
在一些实施方案中，所述晶型E的热重分析曲线(TGA)图谱具有如图13所示的TGA图谱所代表的特征。
在一些实施方案中，所述晶型E的热重分析曲线在157.5±3℃处失重达2.24±0.2％。
在一些实施方案中，所述晶型E的热重分析曲线在157.5±3℃处失重达2.24±0.2％，和/或在270.8±3℃处失重达7.85±0.2％，和/或在493.8±3℃处失重达27.85±0.2％。
在一些实施方案中，所述晶型E是在选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型E是在选自乙酸乙酯、乙腈的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型E是在乙腈中制备得到的。
本申请还提供式(I)化合物的磷酸盐的晶型E的制备方法，包括式(I)化合物与磷酸接触。
在一些实施方案中，上述晶型E的制备方法，包括如下步骤：
(1)将式(I)化合物与溶剂E混合；
(2)向步骤(1)的混合物中加入磷酸；
(3)过滤，干燥。
其中，所述溶剂E选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈的一种或一种以上的混合溶剂，优选自乙酸乙酯、乙腈，更优选为乙腈。
又一方面，本申请提供式(I)化合物的甲磺酸盐：
Figure PCTCN2021072651-appb-000008
在一些实施方案中，上述式(I)化合物的甲磺酸盐如式IV所示
Figure PCTCN2021072651-appb-000009
其中，x选自0.5～1。
在一些实施方案中，上述x选自0.5或1。
在一些实施方案中，上述x选自1。
在一些实施方案中，所述式(I)化合物的甲磺酸盐中的甲磺酸含量是10～20wt％，优选12～19wt％；或者所述式(I)化合物的甲磺酸盐中的甲磺酸含量选自12.1wt％、12.2wt％、12.3wt％、12.4wt％、12.5wt％、12.6wt％、12.7wt％、12.8wt％、12.9wt％、13.0wt％、13.1wt％、13.2wt％、13.3wt％、13.4wt％、13.5wt％、13.6wt％、13.7wt％、13.8wt％、13.9wt％、14.0wt％、14.1wt％、14.2wt％、14.3wt％、14.4wt％、14.5wt％、14.6wt％、14.7wt％、14.8wt％、14.9wt％、15.0wt％、15.1wt％、15.2wt％、15.3wt％、15.4wt％、15.5wt％、15.6wt％、15.7wt％、15.8wt％、15.9wt％、16.0wt％、16.1wt％、16.2wt％、16.3wt％、16.4wt％、16.5wt％、16.6wt％、16.7wt％、16.8wt％、16.9wt％、17.0wt％、17.1wt％、17.2wt％、17.3wt％、17.4wt％、17.5wt％、17.6wt％、17.7wt％、17.8wt％、17.9wt％、18.0wt％、18.1wt％、18.2wt％、18.3wt％、18.4wt％、18.5wt％、18.6wt％、18.7wt％、18.8wt％、18.9wt％、19.0wt％或者由任选上述值形成的范围。
本申请还提供了式(IV)化合物的晶型F，所述晶型F的特征在于，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝8.8°±0.2°、10.1°±0.2°、17.7°±0.2°、18.0°±0.2°、24.1°±0.2°、24.8°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型F的特征在于，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝8.8°±0.2°、10.1°±0.2°、16.4°±0.2°、17.7°±0.2°、18.0°±0.2°、21.7°±0.2°、22.1°±0.2°、24.1°±0.2°、24.8°±0.2°、26.6°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型F的特征在于，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝8.8°±0.2°、10.1°±0.2°、13.1°±0.2°、14.3°±0.2°、16.4°±0.2°、17.7°±0.2°、18.0°±0.2°、20.2°±0.2°、21.7°±0.2°、22.1°±0.2°、24.1°±0.2°、24.8°±0.2°、26.0°±0.2°、26.6°±0.2°的特征衍射峰。
在一些实施方案中，所述晶型F的X-射线粉末衍射(XRPD)图谱中，特征衍射峰的位置及相对强度如表7所示：
表7：晶型F的X-射线粉末衍射图谱的特征峰位置及相对强度
编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％)
1 8.8 42.5 9 21.7 24.0
2 10.1 59.0 10 22.1 11.3
3 13.1 6.4 11 24.1 31.4
4 14.3 7.6 12 24.8 46.6
5 16.4 9.5 13 26.0 8.6
6 17.7 100.0 14 26.6 17.8
7 18.0 39.0 15 30.6 18.5
8 20.2 9.5      
。
在一些实施方案中，所述晶型F的X-射线粉末衍射(XRPD)图谱具有如图14所示的XRPD图谱所代表的特征。
在一些实施方案中，所述晶型F的差示扫描量热曲线(DSC)图谱具有如图15所示的DSC图谱所代表的特征。
在一些实施方案中，所述晶型F的DSC图谱在282.74℃±3℃处有放热峰。在一些实施方案中，所述晶型F的DSC图谱在221.41℃±3℃处有吸热峰。在一些实施方案中，所述晶型F的DSC图谱在167.36℃±3℃处有吸热峰。在一些实施方案中，所述晶型F的DSC图谱在167.36℃±3℃处有吸热峰、和/或在221.41℃±3℃处有吸热峰、和/或在282.74℃±3℃处有放热峰。
在一些实施方案中，所述晶型F的热重分析曲线(TGA)图谱具有如图16所示的TGA图谱所代表的特征。
在一些实施方案中，所述晶型F的热重分析曲线在170.2±3℃处失重达2.80±0.2％。
在一些实施方案中，所述晶型F的热重分析曲线在170.2±3℃处失重达2.80±0.2％，和/或在261.4±3℃处失重达5.28±0.2％，和/或在311.4±3℃处失重达9.21±0.2％，和/或在396.3±3℃处失重达25.22±0.2％，和/或在554.9±3℃处失重达13.88±0.2％。
在一些实施方案中，所述晶型F是在选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型F是在选自乙酸乙酯、乙腈的一种或一种以上的混合溶剂中制备得到的。在一些实施方案中，所述晶型F是在乙腈中制备得到的。
本申请还提供晶型F的制备方法，包括式(I)化合物与甲磺酸接触。
在一些实施方案中，上述晶型F的制备方法，包括如下步骤：
(1)将式(I)化合物与溶剂F混合；
(2)向步骤(1)的混合物中加入甲磺酸；
(3)过滤，干燥。
其中，所述溶剂F选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈的一种或一种以上的混合溶剂，优选自乙酸乙酯、乙腈，更优选为乙腈。
又一方面，本申请提供包含上述晶型的结晶组合物，其中，所述晶型占结晶组合物重量的50％以上，较好为80％以上，更好是90％以上，最好是95％以上。
又一方面，本申请提供一种药物组合物，其包含上述晶型或其结晶组合物。所述药物组合物还可以任选地包含药学上可接受的载体、赋形剂和/或介质。此外，本申请的药物组合物可进一步包括一种或多种其他治疗剂。
在一些实施方案中，上述药物组合物，其包含晶型I或其结晶组合物、晶型A或其结晶组合物、晶型B或其结晶组合物、晶型C或其结晶组合物、晶型D或其结晶组合物、晶型E或其结晶组合物、或晶型F或其结晶组合物。在一些实施方案中，上述药物组合物，其包含晶型I、晶型A、晶型B、晶型C、晶型D、晶型E、或晶型F。在一些实施方案中，上述药物组合物，其包含0.0001到500mg的晶型I、晶型A、晶型B、晶型C、晶型D、晶型E、或晶型F，优选0.001到250mg的晶型I、晶型A、晶型B、晶型C、晶型D、晶型E、或晶型F，更优选0.005到100mg的晶型I、晶型A、晶型B、晶型C、晶型D、晶型E、或晶型F，最优选0.005到50mg的晶型I、晶型A、晶型B、晶型C、晶型D、晶型E、或晶型F。本申请还提供了一种治疗哺乳动物由BET蛋白介导的疾病的方法，包括对需要该治疗的哺乳动物(优选人类)给予治疗有效量的上述晶型、或盐型、或其结晶组合物或者药物组合物。
本申请还提供了上述晶型、或盐型、或其结晶组合物或者药物组合物在制备治疗由BET蛋白介导的疾病的药物中的用途。
本申请还提供了用于治疗由BET蛋白介导的疾病的上述晶型、或盐型、或其结晶组合物或者药物组合物。
本申请还提供了上述晶型、或盐型、或其结晶组合物或者药物组合物治疗由BET蛋白介导的疾病的用 途。
在本申请的一些实施方案中，所述由BET蛋白介导的疾病选自癌症。优选地，所述癌症选自实体瘤或血液肿瘤。更优选地，所述实体瘤选自乳腺癌或前列腺癌。更优选地，所述血液肿瘤选自急性髓细胞性白血病、多发性骨髓瘤或弥漫性大B细胞淋巴瘤。
技术效果
本申请的晶型具有良好的稳定性，在高湿、高温或光照等稳定性试验下表现出良好的结果；在体内或体外试验中表现出良好的药理活性；当作为原料在制剂中使用时，所得产品具有良好的溶解、溶出或药代动力学性质，说明本申请的晶型其良好的药学性质和较高的成药前景。本申请的晶型为化合物的固体形式作出了贡献。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
需要说明的是，在粉末X-射线衍射光谱中，峰的位置或峰的相对强度可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的晶型，峰的位置可能存在误差，2θ值的测定误差可以为±0.2°。因此，在确定每种晶型时，应该将此误差考虑在内，在误差内也属于本申请的范围。
需要说明的是，对于同种晶型，DSC的吸热峰出现位置可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的晶型，吸热峰的位置可能存在误差，误差可以为±5℃，可以为±3℃。因此，在确定每种晶型时，应该将此误差考虑在内，在误差内也属于本申请的范围。
在药物领域术语“水合物”指药物分子与结晶水发生水合反应而形成共晶固体物质状态。一个本申请化合物分子可以与一个水分子相结合，比如一水合物；一个本申请化合物分子也可以与多于一个的水分子相结合，比如二水合物、三水合物或四水合物；一个本申请化合物分子还可以与少于一个的水分子相结合，比如半水合物。本申请所述的水合物保留有非水合形式的所述化合物的生物有效性。
所述词语“包括(comprise)”或“包含(comprise)”及其英文变体例如“comprises”或“comprising”或等同物应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。“药学上可接受的辅料”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述辅料的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请所述晶型或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本申请所述的水分含量是按照水分测定法(中国药典2015年版四部通则0832第一法1)测定的。
术语“粒度分布X 90”表示粉体样品中体积累积分布数达到90％时所对应的粒径。
本申请所述的粒度分布X 90是按照光散射法(中国药典2020版四部通则0982粒度和粒度分布测定第三法)测定的。
本申请所述晶型的治疗有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
本申请所述晶型的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受晶型的每日剂量，接着在若干天或更多天的期间，患者不接受晶型的每日剂量。
本申请的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。
在本文中，除非另有说明，各参数值(包括2θ值、反应条件)均被视为由术语“约”修饰，以反映各值存在的测量等误差，例如相对于给定值，存在±5％的误差。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
附图说明
图1：晶型I的XRPD图谱；
图2：晶型I的DSC图谱；
图3：晶型A的XRPD图谱；
图4：晶型A的DSC图谱；
图5：晶型A的TGA图谱；
图6：晶型B的XRPD图谱；
图7：晶型C的XRPD图谱；
图8：晶型D的XRPD图谱；
图9：晶型D的DSC图谱；
图10：晶型D的TGA图谱；
图11：晶型E的XRPD图谱；
图12：晶型E的DSC图谱；
图13：晶型E的TGA图谱；
图14：晶型F的XRPD图谱；
图15：晶型F的DSC图谱；
图16：晶型F的TGA图谱。
具体实施方式
为了更好的理解本申请的内容，下面结合具体实施例来做进一步的说明但具体的实施方式并不是对本申请的内容所做的限制。本申请所使用的所有溶剂是市售的，无需进一步纯化即可使用。本申请采用下述缩略词：DCM代表二氯甲烷；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；MeOH代表甲醇；ACN代表乙腈；EtOAc代表乙酸乙酯；PE代表石油醚；CDCl 3代表氘代氯仿；(Boc) 2O代表二碳酸二叔丁酯；Boc代表叔丁氧羰基；DMAP代表4-二甲氨基吡啶；N 2代表氮气；MS代表质谱；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；XantPhos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；Xphos代表2-二环己基磷-2’,4’,6’-三异丙基联苯。本申请的“室温”是指常温，一般在10-30℃。
XRPD、DSC、TGA的具体方法(包括设备型号以及各参数)
本申请粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号：Bruker D8 Advance X射线衍射仪
详细的XRPD参数如下：
靶型：Cu
光管电压：40kV，光管电流：40mA
扫描角度范围：3.00-60.00Deg
步长：0.02°
扫描间隔：0.1s
本申请差示扫描量热(Differential Scanning Calorimeter,DSC)方法
仪器型号：METTLER TOLEDO DSC1型差热分析仪
温度范围：50-320℃
升温速率：10K/min
本申请热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号：NETZSCH TG 209F3型热重分析仪
温度范围：30-700℃
升温速率：10K/min
实施例1：式(Ⅰ)化合物
Figure PCTCN2021072651-appb-000010
步骤A：5-氟吡啶甲酸乙酯
Figure PCTCN2021072651-appb-000011
0℃下，向5-氟吡啶甲酸(5.00g)的乙醇(42mL)溶液中依次缓慢滴加DMF(0.1mL)和氯化亚砜(5.6mL)，加完继续搅拌15分钟，随后慢慢加热至回流反应4小时。冷却，减压浓缩，余物倒入冰水中，饱和碳酸氢钠溶液调pH到8-9，乙酸乙酯萃取3次。合并萃取液，依次用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩除去溶剂得到产物(5.50g)。
步骤B：5-(2,4-二氟苯氧基)吡啶甲酸乙酯
Figure PCTCN2021072651-appb-000012
室温下，向5-氟吡啶甲酸乙酯(5.40g)的DMF(60mL)溶液中依次加入2,4-二氟苯酚(4.15g)和碳酸钾(8.82g)，加完加热至100℃反应过夜。冷却，加水(400mL)稀释，乙酸乙酯萃取3次。合并萃取液，依次用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩除去溶剂得到产物(8.40g)。
1H NMR(400MHz,CDCl 3)δ8.48(d,J＝2.8Hz,1H),8.10(d,J＝8.8Hz,1H),7.15-7.24(m,2H),6.92-7.04m,2H),4.46(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H)。
步骤C：5-(2,4-二氟苯氧基)-2-(乙氧基羰基)吡啶1-氧化物
Figure PCTCN2021072651-appb-000013
室温下，向5-(2,4-二氟苯氧基)吡啶甲酸乙酯(1.00g)的二氯甲烷(30mL)溶液中加入85％间氯过氧苯甲酸(1.45g)，加完室温反应过夜。反应完毕，加入饱和碳酸氢钠溶液(40mL)，搅拌15分钟，二氯甲烷萃取3次。合并萃取液，依次用饱和硫代硫酸钠溶液、水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩除去溶剂得到产物(1.00g)。
1H NMR(400MHz,CDCl 3)δ7.95(d,J＝2.4Hz,1H),7.63(d,J＝8.8Hz,1H),7.19(td,J＝8.8Hz,5.6Hz,1H),6.93-7.04(m,2H),6.86(dd,J＝8.8Hz,2.4Hz,1H),4.44(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H)。
步骤D：6-溴-5-(2,4-二氟苯氧基)吡啶甲酸乙酯
Figure PCTCN2021072651-appb-000014
0℃下，向5-(2,4-二氟苯氧基)-2-(乙氧基羰基)吡啶1-氧化物(1.00g)的DMF(15mL)溶液中依次加入四甲基溴化铵(1.37g)和甲磺酸酐(1.24g)。加完慢慢升温至室温反应3小时。反应完毕，倒入含冰水的碳酸氢钠溶液(40mL)，搅拌5分钟，乙酸乙酯萃取3次。合并萃取液，依次用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩。余物经硅胶柱层析(EtOAc/PE＝1/5～1/1)纯化得到产物(0.80g)。
1H NMR(400MHz,CDCl 3)δ7.99(d,J＝8.0Hz,1H),7.20(td,J＝8.8Hz,5.6Hz,1H),6.94-7.05(m,3H),4.46(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H)。
步骤E：6-溴-5-(2,4-二氟苯氧基)吡啶甲酸
Figure PCTCN2021072651-appb-000015
0℃下，向6-溴-5-(2,4-二氟苯氧基)吡啶甲酸乙酯(0.60g)的四氢呋喃(10mL)溶液中加入30％氢氧化钾溶液(1.50mL)。加完升温至室温反应2小时。反应完毕，减压浓缩，加水，稀盐酸调pH至4-5，搅拌5分钟，过滤收集固体得到产物(0.50g)。
步骤F：[6-溴-5-(2,4-二氟苯氧基)吡啶-2-基]氨基甲酸叔丁酯
Figure PCTCN2021072651-appb-000016
室温下，向6-溴-5-(2,4-二氟苯氧基)吡啶甲酸(0.45g)的无水叔丁醇(10mL)溶液中依次加入叠氮磷酸二苯酯(0.75g)、三乙胺(0.80mL)和二碳酸二叔丁酯(1.19g)。加完升温至90℃反应4小时。反应完毕，减压浓缩，倒入含冰水的饱和碳酸氢钠溶液(20mL)，乙酸乙酯萃取3次。合并萃取液，依次用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩。余物经硅胶柱层析(EtOAc/PE＝1/10～1/3)纯化得到产物(0.31g)。
1H NMR(400MHz,CDCl 3)δ7.84(d,J＝8.8Hz,1H),7.21(s,1H),7.15(d,J＝8.8Hz,1H),6.92-6.99(m,2H),6.81-6.87(m,1H),1.51(s,9H)。
步骤G：6-溴-5-(2,4-二氟苯氧基)吡啶-2-胺
Figure PCTCN2021072651-appb-000017
0℃下，向[6-溴-5-(2,4-二氟苯氧基)吡啶-2-基]氨基甲酸叔丁酯(0.31g)的二氧六环(10mL)溶液中滴加浓盐酸(5mL)，加完升至室温反应24小时。反应完毕，减压浓缩，倒入含冰水的饱和碳酸氢钠溶液(20mL)，乙酸乙酯萃取3次。合并萃取液，依次用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到产物(0.22g)。
1H NMR(400MHz,CDCl 3)δ7.09(d,J＝8.4Hz,1H),6.91-6.97(m,1H),6.75-6.86(m,2H),6.42(d,J＝8.4Hz,1H),4.52(brs,2H)。
步骤H：2-溴-3-(2,4-二氟苯氧基)-6-碘吡啶
Figure PCTCN2021072651-appb-000018
室温下，向6-溴-5-(2,4-二氟苯氧基)吡啶-2-胺(0.32g)的二碘甲烷(4mL)溶液中依次加入碘(0.27g)和碘化亚铜(0.20g)，加热至80℃，滴加亚硝酸异戊酯(0.34g)，加完继续反应2小时。反应完毕，冷却，倒入含冰水的碳酸氢钠溶液(20mL)，二氯甲烷萃取3次。合并萃取液，依次用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩，余物经硅胶柱层析(DCM/PE＝1/10～1/3)纯化得到产物(0.20g)。
1H NMR(400MHz,CDCl 3)δ7.55(d,J＝8.4Hz,1H),7.11(td,J＝8.8Hz,5.6Hz,1H),6.97-7.02(m,1H),6.89-6.94(m,1H),6.67(dd,J＝8.4Hz,0.8Hz,1H)。
步骤I：((6-溴-5-(2,4-二氟苯氧基)吡啶-2-基)亚氨基)二甲基-λ 6-磺酰亚胺
Figure PCTCN2021072651-appb-000019
N 2保护下，向无水二氧六环(4mL)中依次加入2-溴-3-(2,4-二氟苯氧基)-6-碘吡啶(0.09g)、二甲基亚磺酰亚胺(25mg)、碳酸铯(0.14g)、Xantphos(10mg)和Pd 2(dba) 3(8mg)，随后加热至100℃搅拌3小时。将反应混合物冷却至室温，加入水，乙酸乙酯萃取。萃取液用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩。残余物用制备薄层板(EtOAc/PE＝1/1)分离得到产物。
1H NMR(400MHz,CDCl 3)δ7.10(d,J＝8.4Hz,1H),6.92-6.97(m,1H),6.87(td,J＝8.8Hz,5.6Hz,1H),6.77-6.82(m,1H),6.69(d,J＝8.4Hz,1H),3.37(s,6H)。
步骤J：4-溴-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-1-甲酸叔丁酯
Figure PCTCN2021072651-appb-000020
向4-溴-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(1.73g)的乙腈(20mL)溶液中依次加入(Boc) 2O(2.47g)和DMAP(1.44g)并在室温下搅拌过夜。将反应液浓缩，残留物经过硅胶柱层析(乙酸乙酯/石油醚＝1/20)纯化后得到产物(2.10g)。
1H NMR(400MHz,CDCl 3)δ7.55(d,J＝3.6Hz,1H),7.21(s,1H),6.35(d,J＝3.6Hz,1H),3.55(s,3H),1.62(s,9H)。
步骤K：6-甲基-7-氧代-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-6,7-二氢-1H-吡咯并[2,3-c]吡啶-1-甲酸叔丁酯
Figure PCTCN2021072651-appb-000021
N 2保护下，向1,4-二氧六环(20mL)和水(2mL)的混合溶剂中依次加入4-溴-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-1-甲酸叔丁酯(0.53g)、联硼酸频哪醇酯(0.66g)、Xphos(31mg)、乙酸钾(0.28g)和Pd 2(dba) 3(30mg)，加热至80℃搅拌过夜，冷却至室温，将反应液分散到乙酸乙酯中，并用饱和NaHCO 3水溶液洗，水洗，经无水硫酸钠干燥后，蒸除溶剂，残余物用硅胶柱层析(EtOAc/PE＝1/3～1/1)纯化得到产品。
1H NMR(400MHz,CDCl 3)δ7.60(s,1H),7.55(d,J＝3.6Hz,1H),6.79(d,J＝3.6Hz,1H),3.62(s,3H),1.65(s,9H),1.341.65(s,12H)。
步骤L：4-{3-(2,4-二氟苯氧基)-6-{[二甲基(氧代)-λ 6-亚硫基]氨基}-吡啶-2-基}-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-1-甲酸叔丁酯
Figure PCTCN2021072651-appb-000022
氮气保护下，向80％的二氧六环水溶液(3mL)中依次加入((6-溴-5-(2,4-二氟苯氧基)吡啶-2-基)亚氨基)二甲基-λ 6-磺酰亚胺(59mg)、6-甲基-7-氧代-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-6,7-二氢-1H-吡咯并[2,3-c]吡啶-1-甲酸叔丁酯(65mg)、氟化铯(83mg)和PdCl 2(AtaPhos)(9mg)，随后加热至85℃搅拌过夜。冷却至室温，加入水，乙酸乙酯萃取，萃取液用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩。残余物用制备薄层板(MeOH/DCM＝1/20)分离得到产物(58mg)。
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.58-7.59(m,1H),7.23(d,J＝8.4Hz,1H),7.15-7.17(m,1H),6.85-6.92(m,1H),6.65-6.75(m,3H),3.63(s,3H),3.33(s,6H),1.65(s,9H)。
步骤M：4-{3-(2,4-二氟苯氧基)-6-{[二甲基(氧代)-λ 6-亚硫基]氨基}-吡啶-2-基}-6-甲基-1,6-二氢-7H-吡咯并[23-c]吡啶-7-酮
Figure PCTCN2021072651-appb-000023
室温下，向4-{3-(2,4-二氟苯氧基)-6-{[二甲基(氧代)-λ 6-亚硫基]氨基}-吡啶-2-基}-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-1-甲酸叔丁酯(50mg)中加入4moL/L的氯化氢二氧六环溶液(1mL)，加完升至室温反应2小时。反应完毕，减压浓缩，倒入含冰水的碳酸氢钠溶液(5mL)，乙酸乙酯萃取3次。合并萃取液，依次用水和饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到产物(35mg)。
1H NMR(400MHz,CDCl 3)δ12.01(brs,1H),9.56(brs,1H),7.72(s,1H),7.24(d,J＝8.8Hz,1H),7.14(t,J＝2.4Hz,1H),6.85-6.91(m,1H),6.64-6.76(m,3H),3.66(s,3H),3.35(s,6H)。
实施例2：晶型I的制备方法
方法一：
取1g式(I)化合物，加入10ml DMSO，升温至80℃，搅拌至溶解。取30ml纯化水，冰浴搅拌，滴加上述式(I)化合物的DMSO溶液，搅拌10min，过滤析出的固体，滤饼于60℃减压干燥2h，得产物，测试XRPD，即为晶型I。
方法二：
取1g式(I)化合物，加入5ml DMSO，升温至100℃，搅拌至溶清，自然降温析晶，过滤，滤饼于60℃减压干燥，得产物，测试XRPD，即为晶型I。
方法三：
取1g式(I)化合物，加入10ml DMSO，升温至80℃，搅拌至溶解。取30ml无水甲醇，冰浴搅拌，滴加上述式(I)化合物的DMSO溶液，搅拌10min，过滤析出的固体，滤饼于60℃减压干燥3.5h，得产物，测试XRPD，即为晶型I，其XRPD图谱如图1所示。
方法四：
取1.0g式(I)化合物，加入400ml DCM、100ml甲醇，室温搅拌至溶清，30-35℃减压浓缩，35℃减压干燥，得产物，测试XRPD，即为晶型I，其DSC图谱如图2所示。
方法五：
取10g式(I)化合物盐酸盐，加入200ml纯化水，室温搅拌4h，过滤，收集滤饼，于50℃下减压干燥3.5h，得产物，测试XRPD，即为晶型I。
方法六：
取0.5g式(I)化合物盐酸盐，加入10ml 20％的乙腈/水溶液，室温搅拌3h，过滤，收集滤饼，于50℃下减压干燥4h，得产物，测试XRPD，即为晶型I。
方法七：
取1g式(I)化合物盐酸盐，加入15ml甲醇，升温至60℃，搅拌至溶清，加入30ml水，降至室温析晶0.5h，过滤，滤饼于60℃检验干燥3h，得产物，测试XRPD，即为晶型I。
方法五至方法七中使用的式(I)化合物盐酸盐为晶型A。
实施例3：盐酸盐晶型的制备方法
晶型A制备方法：取100g式(I)化合物，加入1300ml无水甲醇，加入160ml 6mol/L的盐酸，搅拌至溶解，加入10g活性炭，脱色10min，过滤，收集滤液。浓缩至料液重量约380g，将料液升温至溶清，自然降温析晶，0℃析晶，过滤，滤饼50℃减压干燥4h以上，得产物，测试XRPD，即为晶型A，水分含量5.8％，其XRPD图谱如图3所示，其DSC图谱如图4所示，其TGA图谱如图5所示。所得产物的盐酸含量是7.7％。
晶型B制备方法：将晶型A于60±2℃环境下静置30天，得产物，测试XRPD，即为晶型B，水分含量4.6％。其XRPD图谱如图6所示。
晶型C制备方法：将晶型A于室温、相对湿度92.5±5％的环境下静置30天，得产物，测试XRPD，即为晶型C，水分含量11.9％。其XRPD图谱如图7所示。
实施例4：硫酸盐晶型的制备方法
取12g式(I)化合物，加入100ml甲醇，分散均匀，加入2.2ml 3mol/L的硫酸/甲醇溶液，室温搅拌3h，过滤，收集滤饼，于50℃减压干燥4h以上，得产物，测试XRPD，即为晶型D，其XRPD图谱如图8所示，其DSC图谱如图9所示，其TGA图谱如图10所示。所得产物的硫酸含量是18.3％。
实施例5：磷酸盐晶型的制备方法
方法一：
取0.4g式(I)化合物，加入4ml乙腈，室温下加入0.22g 85％磷酸，加热至70℃搅拌0.5h，自然降温至室温，过滤，滤饼50℃减压干燥4h，得产物，测试XRPD，即为晶型E。
方法二：
取3.5g式(I)化合物，加入35ml乙腈，升温至70℃，加入4.5g 85％磷酸，保温搅拌2h，降至室温，过滤。收集滤饼，于60℃减压干燥6h，得得产物，测试XRPD，即为晶型E，其XRPD图谱如图11所示，其DSC图谱如图12所示，其TGA图谱如图13所示。
实施例6：甲磺酸盐晶型的制备方法
取3.5g式(I)化合物，加入17.5g乙腈，升温至70℃，加入1.89g甲磺酸，保温搅拌0.5h，缓慢降温至室温，冰浴搅拌2h，过滤，收集滤饼，于60℃减压干燥6.5h，得产物，测试XRPD，即为晶型F，其XRPD图谱如图14所示，其DSC图谱如图15所示，其TGA图谱如图16所示。所得产物的甲磺酸含量17.9％。
实验例1：影响因素稳定性研究
为评估本申请晶型的固体稳定性，分别对晶型I、晶型A、晶型D、晶型E和晶型F进行了影响因素(高温、高湿及光照)稳定性的考察。将上述晶型分别在高温(60℃±2℃，敞口(称量瓶))、高湿(室温，92.5％RH±5％，敞口(称量瓶)及带包装)下放置5天、10天、30天，按照ICH光照条件(5500Lux，0.9w/m 2，闭口(称量瓶)及带包装)放置5天、10天。带包装的样品内包材为药用低密度聚乙烯袋，外包材为聚酯/铝/聚乙烯药用复合袋。对放置后的样品进行性状、纯度(HPLC)、晶型(XRD)、水分表征，以检测晶型及纯度的变化；结果如表8～12显示(“ #”表示ICH条件)。
表8：晶型I的影响因素稳定性研究结果
Figure PCTCN2021072651-appb-000024
表9：晶型A的影响因素稳定性研究结果
Figure PCTCN2021072651-appb-000025
表10：晶型D的影响因素稳定性研究结果
Figure PCTCN2021072651-appb-000026
表11：晶型E的影响因素稳定性研究结果
Figure PCTCN2021072651-appb-000027
表12：晶型F的影响因素稳定性研究结果
Figure PCTCN2021072651-appb-000028
实验结论：本申请晶型稳定性好，易于成药。
实验例2：晶型I的稳定性研究
1.影响因素稳定性研究
为评估本申请晶型I的固体稳定性，对其进行了影响因素(高温、高湿及光照)稳定性的考察。将晶型I分别在高温(40℃，敞口(称量瓶))、高温(60℃，敞口(称量瓶))、高湿(室温，75％RH，敞口(称量瓶))、高湿(室温，92.5％RH，敞口(称量瓶)及带包装)下放置5天、10天、30天，按照ICH光照条件(5500Lux，0.9w/m2，敞口(称量瓶)及带包装)放置5天、10天。带包装的样品内包材为双层药用低密度聚乙烯袋，外包材为聚酯/铝/聚乙烯药品包装用复合袋。对放置后的样品进行性状、有关物质(HPLC)、晶型(XRD)、水分和含量测定，以考察高温、高湿及光照条件对本品的影响。结果如表13显示(“#”表示ICH条件)。
表13：晶型I的影响因素稳定性研究结果
Figure PCTCN2021072651-appb-000029
2.加速稳定性和长期稳定性研究
对本申请晶型I进行了加速和长期稳定性的考察，分别在加速(40±2℃，75％RH±5％，带包装)条件下放置1、2、3、6月，长期(25±2℃，65％RH±5％，带包装)条件下放置3、6、9、12、18、24、36月。带包装的样品内包材为双层药用低密度聚乙烯袋，外包材为聚酯/铝/聚乙烯药品包装用复合袋。对放置后的样品进行性状、有关物质(HPLC)、晶型(XRD)、水分和含量测定，以考察本品的稳定性情况。
表14：晶型I的加速稳定性和长期稳定性研究结果
Figure PCTCN2021072651-appb-000030
Figure PCTCN2021072651-appb-000031
实验结论：本申请的晶型I稳定性好，易于成药。
实验例3：生物活性试验
1.体外酶学活性测定BRD4(BD2)
本申请中，式(I)化合物对BRD4(BD2)酶结合反应的抑制IC 50值采用匀相时间分辨荧光(HTRF)的方法进行。将式(I)化合物从1mM开始用100％DMSO进行5倍的梯度稀释(共7个浓度)，每个浓度取2μL的式(I)化合物加入到18μL的反应缓冲液(20mM HEPES pH 7.5，150mM NaCl，5mM DTT，0.005％Tween 20和100μg/mL BSA)中进行稀释，混匀后每个浓度取2μL的式(I)化合物加入到48μL的上述反应缓冲液中进行再次稀释混匀(式(I)化合物DMSO终浓度为0.1％)。取2.5μL加入到384孔板(OptiPlate-384，购买于PerkinElmer)中，然后加入5μL的GST-BRD4(BD2，349-460aa)(终浓度为2nM)，离心混匀，再加入2.5μL的Biotin-AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV肽(终浓度为200nM)启动反应(总反应体积为10μL)。将384孔板放于孵育箱中23℃反应1小时，然后加入5μL的Eu3+cryptate-labled anti-GST antibody(购买于Cisbio)，5μL的Streptavidin-XL-665(购买于Cisbio)停止反应。在孵育箱中再次孵育1小时后，在Envision(购买于PerkinElmer)上读取荧光值(320nm激发，检测665nm与620nm的发射光，二者比值为酶的结合信号)。分别在7个浓度下测定式(I)化合物与BRD4(BD2)蛋白的结合强度，数据使用GraphPad Prism软件计算得到式(I)化合物的IC 50值。
2.体外酶学活性测定BRD4(BD1)
本申请中，式(I)化合物对BRD4(BD1)酶结合反应的抑制IC 50值采用匀相时间分辨荧光(HTRF)的方法进行。将式(I)化合物从0.2mM开始用100％DMSO进行5倍的梯度稀释(共7个浓度)，每个浓度取2μL的式(I)化合物加入到48μL的反应缓冲液(20mM HEPES pH 7.5，150mM NaCl，5mM DTT，0.005％Tween 20和100μg/ml BSA)中进行稀释混匀。取2.5μL加入到384孔板(OptiPlate-384，购买于PerkinElmer)中，然后加入5μL的GST-BRD4(BD1，44-168aa)(终浓度为1nM)，离心混匀，再加入2.5μL的Biotin-AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV)短肽(终浓度为100nM)启动反应(总反应体积为10μL)。将384孔板放于孵育箱中23℃反应1小时，然后加入5μL的Eu3+cryptate-labled anti-GST antibody(购买于Cisbio)，5μL的Streptavidin-XL-665(购买于Cisbio)停止反应。在孵育箱中再次孵育1小时后，在Envision(购买于PerkinElmer)上读取荧光值(320nm激发，检测665nm与620nm的发射光，二者比值为酶的结合信号)。分别在7个浓度下测定式(I)化合物与BRD4(BD1)蛋白的结合强度，数据使用GraphPad Prism软件计算得到式(I)化合物的IC 50值。
上述测试结果如表15所示。
表15：体外酶学活性结果
Figure PCTCN2021072651-appb-000032
3.MV4-11细胞增殖活性测定
人急性淋巴细胞白血病细胞系细胞MV4-11使用PRIM1640培养基加10％的胎牛血清(FBS，购买于Biological Industries，BI)和1％青霉素/链霉素双抗(P/S，购买于Life Techonology)进行培养，培养条件为37℃、5％CO 2。进行式(I)化合物检测的前一天，将MV4-11细胞以8000个细胞/195μL/孔的浓度铺于96孔板(购买于Corning)中。24小时后将式(I)化合物从10mM开始用100％DMSO进行4倍的梯度稀释(共9个浓度)，然后每个浓度取2μL的式(I)化合物加入到48μL的PRIM1640培养基中进行稀释。稀释后的式(I)化合物每个浓度取5μL加入铺好的细胞悬液中，将式(I)化合物与细胞在细胞培养箱中共孵育72小时(3天)后加入35μL的Cell-Titer Blue(购买于Promega)试剂再次孵育4小时。之后在Flexstation III上读取荧光值(560nm激发、590nm检测)，数据使用GraphPad Prism软件计算得到式(I)化合物对细胞增殖的抑制的IC 50值。
4.Kasumi-1细胞增殖活性测定
人急性成髓细胞白血病细胞系Kasumi-1细胞使用PRIM1640培养基加20％的胎牛血清(FBS，购买于Biological Industries，BI)和1％青霉素/链霉素双抗(P/S，购买于Life Techonology)进行培养，培养条件为37℃、5％CO 2。进行式(I)化合物检测的前一天，将Kasumi-1细胞以5000个细胞/195μL/孔的浓度铺 于96孔板(购买于Corning)中。24小时后将式(I)化合物从10mM开始用100％DMSO进行4倍的梯度稀释(共9个浓度)，然后每个浓度取2μL的式(I)化合物加入到48μL的PRIM1640培养基中进行稀释。稀释后的式(I)化合物每个浓度取5μL加入铺好的细胞悬液中，将式(I)化合物与细胞在细胞培养箱中共孵育72小时(3天)后加入35μL的Cell-Titer Blue(购买于Promega)试剂再次孵育4小时。之后在Flexstation III上读取荧光值(560nm激发、590nm检测)，数据使用GraphPad Prism软件计算得到式(I)化合物对细胞增殖的抑制的IC 50值。上述测试结果如表16所示。
表16：体外细胞学活性结果
Figure PCTCN2021072651-appb-000033
5.动物药代动力学研究
动物药代实验使用3只健康成年雄性大鼠，来源于北京维通利华实验动物技术有限公司。式(I)化合物混悬于2％无水乙醇、5％吐温80、20％聚乙二醇400、73％(水中5％的羟丙基甲基纤维素)(V/V/V/V)中，浓度为1mg/mL，给药体积为5mL/kg，单次灌胃给药，剂量为5mg/kg。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、6、8和24小时采血。动物通过异氟烷浅麻醉，用玻璃采血管于眼眶静脉丛采血约0.4mL全血，放于肝素抗凝管中，样品于4℃、4200rpm离心5分钟，血浆转移至离心管中，并放于-80℃保存直到分析。血浆样品分析使用乙腈蛋白质沉淀法萃取大鼠血浆中的待测化合物和内标(华法林或普萘洛尔)，萃取液通过LC/MS/MS分析。测到的个体动物的血浆浓度-时间数据用WinNonlin(版本5.2.1；Pharsight公司)软件的非房室模型进行分析，得到如下表17所示的药代动力学参数：最大(峰值)血浆药物浓度C max；达峰时间T max；半衰期T 1/2和外推到无限长时间的血药浓度-时间曲线下面积AUC 0-inf。
表17：药代动力学参数的研究结果
参数 单位 式(I)化合物
t 1/2 hr 5.25
T max hr 2.67
C max ng/mL 372
AUC 0-inf hr·ng/mL 3466
可见，式(I)化合物具有良好的活性和良好的药代动力学性质。
实验例4：粒度分布测试
晶型I经气流粉碎后，参考2020版中国药典四部通则0982粒度和粒度分布测定第三法(光散射法)进行粒度分布测试，具体如下：称取样品10mg，置于激光散射粒度分布仪进行测试(触发条件：10s、1％；分散压力：2.0bar)，测试结果如表18所示。
表18：粒度分布测试结果
Figure PCTCN2021072651-appb-000034

Claims (17)

  1. 式(I)化合物或其药学上可接受的盐的晶型：
    Figure PCTCN2021072651-appb-100001
    其中，所述晶型选自：
    式(I)化合物的晶型I，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.4°±0.2°、14.5°±0.2°、17.4°±0.2°、18.5°±0.2°、20.4°±0.2°、24.7°±0.2°；
    式(I)化合物的盐酸盐的晶型A，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.8°±0.2°、8.4°±0.2°、9.4°±0.2°、10.2°±0.2°、16.8°±0.2°；
    式(I)化合物的盐酸盐的晶型B，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.7°±0.2°、9.5°±0.2°、10.5°±0.2°、14.5°±0.2°、17.4°±0.2°；
    式(I)化合物的盐酸盐的晶型C，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.8°±0.2°、9.5°±0.2°、12.9°±0.2°、20.5°±0.2°、24.6°±0.2°；
    式(I)化合物的硫酸盐的晶型D，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.5°±0.2°、14.7°±0.2°、18.6°±0.2°、21.2°±0.2°、23.0°±0.2°、24.1°±0.2°；
    式(I)化合物的磷酸盐的晶型E，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.1°±0.2°、10.5°±0.2°、19.0°±0.2°、21.0°±0.2°、22.7°±0.2°、24.0°±0.2°；或者
    式(I)化合物的甲磺酸盐的晶型F，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.8°±0.2°、10.1°±0.2°、17.7°±0.2°、18.0°±0.2°、24.1°±0.2°、24.8°±0.2°。
  2. 如权利要求1所述的式(I)化合物或其药学上可接受的盐的晶型，其中，所述晶型为式(I)化合物的晶型I，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.6°±0.2°、9.3°±0.2°、12.4°±0.2°、14.5°±0.2°、16.6°±0.2°、17.4°±0.2°、18.5°±0.2°、20.0°±0.2°、20.4°±0.2°、24.7°±0.2°；
    典型地，在下列2θ角处具有特征衍射峰：6.6°±0.2°、9.3°±0.2°、12.4°±0.2°、14.5°±0.2°、16.6°±0.2°、17.4°±0.2°、18.5°±0.2°、20.0°±0.2°、20.4°±0.2°、21.5°±0.2°、22.5°±0.2°、23.6°±0.2°、24.7°±0.2°、25.2°±0.2°；
    更典型的具有如下的XRPD图谱解析数据：
    编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％) 1 6.6 20.0 12 21.5 20.9 2 9.3 16.2 13 21.8 8.1 3 12.4 63.4 14 22.5 21.8 4 14.5 100.0 15 23.3 8.0 5 14.7 27.5 16 23.7 26.4 6 15.2 10.2 17 24.7 36.7 7 16.6 21.1 18 25.2 26.9 8 17.4 32.4 19 26.9 11.1 9 18.5 99.2 20 29.3 15.5 10 20.0 25.3 21 29.7 14.8 11 20.4 45.0 22 30.3 12.5
    最典型的所述晶型I的XRPD图谱具有如图1所示的XRPD图谱所代表的特征。
  3. 如权利要求1所述的式(I)化合物或其药学上可接受的盐的晶型，其中，所述晶型为式(I)化合物的盐酸盐的晶型；优选地，所述晶型为水合物；更优选地，所述水合物选自半水合物、一水合物、二水合物、 三水合物和四水合物；进一步优选地，所述水合物选自一水合物、二水合物和四水合物；最优选地，所述水合物选自一水合物和四水合物。
  4. 如权利要求3所述的式(I)化合物或其药学上可接受的盐的晶型，其中，所述晶型为式(I)化合物的盐酸盐的晶型A，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.8°±0.2°、8.4°±0.2°、9.4°±0.2°、10.2°±0.2°、14.4°±0.2°、16.8°±0.2°、20.5°±0.2°、24.7°±0.2°；
    典型地，在下列2θ角处具有特征衍射峰：6.8°±0.2°、8.4°±0.2°、9.4°±0.2°、10.2°±0.2°、14.4°±0.2°、16.8°±0.2°、19.2°±0.2°、20.5°±0.2°、21.7°±0.2°、23.3°±0.2°、24.7°±0.2°；
    更典型的具有如下的XRPD图谱解析数据：
    编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％) 1 6.8 45.2 7 19.2 4.8 2 8.4 100.0 8 20.5 10.6 3 9.4 13.6 9 21.7 4.2 4 10.2 21.5 10 23.3 3.5 5 14.4 5.4 11 24.7 7.0 6 16.8 33.5 12    
    最典型的所述晶型的XRPD图谱具有如图3所示的XRPD图谱所代表的特征。
  5. 如权利要求3所述的式(I)化合物或其药学上可接受的盐的晶型，其中，所述晶型为式(I)化合物的盐酸盐的晶型B，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.8°±0.2°、8.7°±0.2°、9.5°±0.2°、10.5°±0.2°、14.5°±0.2°、17.4°±0.2°、21.0°±0.2°、22.2°±0.2°；
    典型地，在下列2θ角处具有特征衍射峰：6.8°±0.2°、8.7°±0.2°、9.5°±0.2°、10.5°±0.2°、14.5°±0.2°、17.4°±0.2°、18.8°±0.2°、20.1°±0.2°、21.0°±0.2°、22.2°±0.2°、24.6°±0.2°；
    更典型的具有如下的XRPD图谱解析数据：
    编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％) 1 6.8 7.8 7 18.8 10.4 2 8.7 100.0 8 20.1 10.6 3 9.5 14.9 9 21.0 13.9 4 10.5 48.3 10 22.2 13.3 5 14.5 16.6 11 24.6 12.7 6 17.4 35.9 12    
    最典型的所述晶型的XRPD图谱具有如图6所示的XRPD图谱所代表的特征。
  6. 如权利要求3所述的式(I)化合物或其药学上可接受的盐的晶型，其中，所述晶型为式(I)化合物的盐酸盐的晶型C，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.8°±0.2°、9.5°±0.2°、12.9°±0.2°、14.8°±0.2°、17.5°±0.2°、20.5°±0.2°、23.3°±0.2°、24.6°±0.2°；
    典型地，在下列2θ角处具有特征衍射峰：6.8°±0.2°、9.5°±0.2°、11.9°±0.2°、12.9°±0.2°、14.8°±0.2°、15.8°±0.2°、17.5°±0.2°、20.5°±0.2°、23.3°±0.2°、24.6°±0.2°、28.7°±0.2°；
    更典型的具有如下的XRPD图谱解析数据：
    编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％) 1 6.8 69.1 9 20.5 46.3 2 9.5 100.0 10 21.7 12.8 3 11.9 14.6 11 23.3 19.9 4 12.9 20.2 12 23.9 9.9 5 14.8 16.7 13 24.6 50.5 6 15.8 15.7 14 26.0 10.2 7 16.5 10.5 15 28.2 12.6 8 17.5 17.2 16 28.7 24.0
    最典型的所述晶型的XRPD图谱具有如图7所示的XRPD图谱所代表的特征。
  7. 如权利要求1所述的式(I)化合物或其药学上可接受的盐的晶型，其中，所述晶型为式(I)化合物的 硫酸盐的晶型D，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.1°±0.2°、8.9°±0.2°、9.8°±0.2°、13.2°±0.2°、13.5°±0.2°、14.7°±0.2°、18.6°±0.2°、21.2°±0.2°、23.0°±0.2°、24.1°±0.2°；
    典型地，在下列2θ角处具有特征衍射峰：7.1°±0.2°、8.9°±0.2°、9.8°±0.2°、13.2°±0.2°、13.5°±0.2°、14.7°±0.2°、16.3°±0.2°、18.6°±0.2°、19.7°±0.2°、21.2°±0.2°、21.9°±0.2°、23.0°±0.2°、24.1°±0.2°、26.2°±0.2°；
    更典型的具有如下的XRPD图谱解析数据：
    编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％) 1 7.1 7.8 14 20.9 10.1 2 8.9 8.7 15 21.2 29.8 3 9.8 28.1 16 21.9 22.5 4 13.2 29.4 17 22.4 13.0 5 13.5 30.4 18 23.0 100.0 6 13.8 12.3 19 24.1 46.2 7 14.7 90.8 20 26.2 31.9 8 16.3 19.7 21 27.5 17.2 9 17.3 12.9 22 27.8 17.1 10 18.0 14.6 23 28.6 10.2 11 18.6 42.9 24 29.7 12.7 12 19.7 25.8 25 33.1 16.1 13 20.1 20.9      
    最典型的所述晶型的XRPD图谱具有如图8所示的XRPD图谱所代表的特征。
  8. 如权利要求1所述的式(I)化合物或其药学上可接受的盐的晶型，其中，所述晶型为式(I)化合物的磷酸盐的晶型E，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.0°±0.2°、10.1°±0.2°、10.5°±0.2°、17.9°±0.2°、19.0°±0.2°、21.0°±0.2°、21.7°±0.2°、22.7°±0.2°、24.0°±0.2°；
    典型地，在下列2θ角处具有特征衍射峰：5.2°±0.2°、9.0°±0.2°、10.1°±0.2°、10.5°±0.2°、15.5°±0.2°、17.9°±0.2°、19.0°±0.2°、20.2°±0.2°、21.0°±0.2°、21.7°±0.2°、22.2°±0.2°、22.7°±0.2°、23.4°±0.2°、24.0°±0.2°；
    更典型的具有如下的XRPD图谱解析数据：
    编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％) 1 5.2 4.2 15 21.7 31.8 2 9.0 12.3 16 22.2 24.3 3 10.1 32.7 17 22.7 40.6 4 10.5 30.9 18 23.4 29.7 5 13.6 10.2 19 24.0 32.1 6 14.3 14.3 20 25.8 10.7 7 15.5 25.0 21 26.1 12.2 8 15.7 20.5 22 27.4 11.7 9 17.0 18.6 23 28.9 13.8 10 17.3 16.4 24 29.2 15.7 11 18.0 30.1 25 29.4 14.2 12 19.0 37.6 26 29.6 16.0 13 20.2 22.9 27 33.3 13.3 14 21.0 100.0      
    最典型的所述晶型的XRPD图谱具有如图11所示的XRPD图谱所代表的特征。
  9. 如权利要求1所述的式(I)化合物或其药学上可接受的盐的晶型，其中，所述晶型为式(I)化合物的甲磺酸盐的晶型F，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.8°±0.2°、10.1°±0.2°、16.4°±0.2°、17.7°±0.2°、18.0°±0.2°、21.7°±0.2°、22.1°±0.2°、24.1°±0.2°、24.8°±0.2°、26.6°±0.2°；
    典型地，在下列2θ角处具有特征衍射峰：8.8°±0.2°、10.1°±0.2°、13.1°±0.2°、14.3°±0.2°、16.4°±0.2°、17.7°±0.2°、18.0°±0.2°、20.2°±0.2°、21.7°±0.2°、22.1°±0.2°、24.1°±0.2°、24.8°±0.2°、26.0°±0.2°、26.6°±0.2°；
    更典型的具有如下的XRPD图谱解析数据：
    编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％) 1 8.8 42.5 9 21.7 24.0 2 10.1 59.0 10 22.1 11.3 3 13.1 6.4 11 24.1 31.4 4 14.3 7.6 12 24.8 46.6 5 16.4 9.5 13 26.0 8.6 6 17.7 100.0 14 26.6 17.8 7 18.0 39.0 15 30.6 18.5 8 20.2 9.5      
    最典型的所述晶型的XRPD图谱具有如图14所示的XRPD图谱所代表的特征。
  10. 式(I)化合物的药学上可接受的盐：
    Figure PCTCN2021072651-appb-100002
    其中，所述药学上可接受的盐选自式(I)化合物的盐酸盐、式(I)化合物的硫酸盐、式(I)化合物的磷酸盐或式(I)化合物的甲磺酸盐；
    优选地，所述盐酸盐为所述式(I)化合物与盐酸按1:1的摩尔比形成的盐；
    优选地，所述硫酸盐如式II所示，其中，x选自0.5～1，优选为1，
    Figure PCTCN2021072651-appb-100003
    优选地，所述磷酸盐如式III所示，其中，x选自0.5～1，优选为1，
    Figure PCTCN2021072651-appb-100004
    优选地，所述甲磺酸盐如式IV所示，其中，x选自0.5～1，优选为1，
    Figure PCTCN2021072651-appb-100005
  11. 含有权利要求1-9中任一项所述的晶型的结晶组合物，其中，所述晶型占结晶组合物重量的50％以上，较好为80％以上，更好是90％以上，最好是95％以上。
  12. 一种药物组合物，所述药物组合物中包含选自如下组的治疗有效量的活性成分：权利要求1-9中任一项所述的晶型、权利要求10所述的药学上可接受的盐以及权利要求11所述的结晶组合物。
  13. 权利要求1-9中任一项所述的晶型、或权利要求10所述的药学上可接受的盐、权利要求11所述的结晶组合物、或权利要求12所述的药物组合物在制备治疗由BET蛋白介导的疾病的药物中的用途。
  14. 如权利要求13所述的用途，其特征在于，所述由BET蛋白介导的疾病选自癌症；优选地，所述癌症选自实体瘤或血液肿瘤；更优选地，所述实体瘤选自乳腺癌或前列腺癌；更优选地，所述血液肿瘤选自急性髓细胞性白血病、多发性骨髓瘤或弥漫性大B细胞淋巴瘤。
  15. 一种权利要求1所述的式(I)化合物的晶型I的制备方法，包括如下步骤：
    (1)将式(I)化合物与溶剂I混合；并任选地将步骤(1)的混合物与溶剂II混合；
    (2)过滤，干燥；
    其中，所述溶剂I和溶剂II各自优选选自水、乙腈、甲醇、乙醇、异丙醇、乙酸乙酯、丙酮、二甲基亚砜、二氯甲烷中的一种或一种以上的混合溶剂，优选自水、乙腈、甲醇、二甲基亚砜、二氯甲烷中的一种或一种以上的混合溶剂，更优选自水或二甲基亚砜，进一步优选二氯甲烷和甲醇的混合溶剂。
  16. 一种权利要求1所述的式(I)化合物的晶型I的制备方法，包括如下步骤：
    (1)将式(I)化合物的盐酸盐与溶剂III混合；并任选地将步骤(1)的混合物与溶剂IV混合；
    (2)过滤，干燥；
    其中，所述溶剂III和溶剂IV各自独立地优选选自水、乙腈、甲醇、乙醇、异丙醇、乙酸乙酯或丙酮，优选自水、乙腈、甲醇、乙醇或异丙醇，更优选自水、乙腈或甲醇；
    所述式(I)化合物的盐酸盐选自晶型A、晶型B、或晶型C，优选选自晶型A。
  17. 一种权利要求1所述的式(I)化合物的药学上可接受的盐的晶型的制备方法，包括如下步骤：
    (1)将式(I)化合物与溶剂A混合；
    (2)向步骤(1)的混合物中加入盐酸、硫酸、磷酸或甲磺酸；
    (3)过滤，干燥；
    其中，所述溶剂A优选选自甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、乙腈的一种或一种以上的混合溶剂，优选自甲醇、乙醇、异丙醇、乙酸乙酯、乙腈，更优选选自甲醇、乙腈；
    优选地，所述晶型为晶型A、晶型D、晶型E或晶型F。
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