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WO2024067085A1 - 一种细胞周期蛋白依赖性激酶(cdk4/6)抑制剂的枸橼酸盐、其晶型、制备方法和用途 - Google Patents

一种细胞周期蛋白依赖性激酶(cdk4/6)抑制剂的枸橼酸盐、其晶型、制备方法和用途 Download PDF

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WO2024067085A1
WO2024067085A1 PCT/CN2023/118429 CN2023118429W WO2024067085A1 WO 2024067085 A1 WO2024067085 A1 WO 2024067085A1 CN 2023118429 W CN2023118429 W CN 2023118429W WO 2024067085 A1 WO2024067085 A1 WO 2024067085A1
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formula
compound
crystalline form
citrate
compound represented
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PCT/CN2023/118429
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English (en)
French (fr)
Inventor
王可心
彭昱晖
朱乔有
黄文姝
刘九知
靳美霞
余江天
朱霜
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锦州奥鸿药业有限责任公司
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Publication of WO2024067085A1 publication Critical patent/WO2024067085A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a citrate of a protein kinase inhibitor, its crystal form A, crystal form B, crystal form C and crystal form D, and a preparation method and use thereof.
  • Hyperproliferative diseases such as cancer and inflammation have attracted the attention of the research community to provide them with effective treatments, and efforts have been made in this regard to identify and target specific mechanisms that play a role in proliferative diseases.
  • CDKs cyclin-dependent kinases
  • CDKs are serine/threonine protein kinases that are the driving force of the cell cycle and cell proliferation. CDKs regulate the initiation, progression, and completion of the mammalian cell cycle and are critical for cell growth. Most known CDKs, including CDK1 to CDK9, are directly or indirectly involved in the cell cycle progression process. CDKs that are directly involved in cell cycle progression, such as CDK1-4 and CDK6, can be divided into G1, S, or G2M phase enzymes. Abnormal proliferation is a characteristic of cancer cells, and abnormal CDK function occurs frequently in many solid tumors.
  • CDKs and their associated proteins play a critical role in coordinating and driving the cell cycle in proliferating cells. Therefore, targeting multiple CDKs or specific CDKs to treat dysplastic diseases, such as cancer, has great potential.
  • CDK inhibitors can also be used to treat other diseases such as viral infections, autoimmune diseases, and neurodegenerative diseases.
  • CDK-targeted therapies can also be used in combination with other therapeutic drugs to treat the above diseases.
  • CDK4/6 inhibitors have been reported in the literature, such as WO2010020675 and WO2012064805, many of them have short half-lives or are toxic.
  • CDK4/6 inhibitor anti-tumor drugs approved by the FDA for marketing namely Pfizer's palbociclib, Novartis' ribociclib and Eli Lilly's abemaciclib, which are used to treat postmenopausal women with HR+, HER2- advanced or metastatic breast cancer.
  • CDK4/6 inhibitors for the treatment of hyperproliferative diseases will become more and more urgent, and they have advantages in at least one aspect of efficacy, stability, selectivity, safety, pharmacodynamic characteristics and pharmacokinetic characteristics.
  • the present invention provides a citrate salt of the compound represented by formula (I).
  • the molar ratio of the compound of formula (I) to citric acid is about 1:1-1:3.
  • the present invention provides a crystalline form A of a citrate salt of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2 ⁇ angles: 17.9 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.2 ⁇ 0.2°, 19.5 ⁇ 0.2° and 20.5 ⁇ 0.2°.
  • the present invention provides a crystalline form B of a citrate salt of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.3 ⁇ 0.2°, 11.2 ⁇ 0.2°, 14.1 ⁇ 0.2°, 16.7 ⁇ 0.2° and 18.4 ⁇ 0.2°.
  • the present invention provides a crystalline form C of a citrate salt of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2 ⁇ angles: 10.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.2 ⁇ 0.2° and 20.8 ⁇ 0.2°.
  • the present invention provides a crystalline form D of a citrate salt of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2 ⁇ angles: 14.0 ⁇ 0.2°, 16.8 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.8 ⁇ 0.2° and 24.6 ⁇ 0.2°.
  • the present invention provides a method for preparing the crystalline form A, crystalline form B and crystalline form C of the citrate salt of the compound represented by formula (I).
  • the present invention provides a pharmaceutical composition comprising one or more selected from the following: (i) a citrate salt of a compound represented by formula (I) of the present invention; (ii) a crystalline form A of a citrate salt of a compound represented by formula (I) of the present invention; (iii) a crystalline form B of a citrate salt of a compound represented by formula (I) of the present invention; (iv) a crystalline form C of a citrate salt of a compound represented by formula (I) of the present invention; (v) a crystalline form D of a citrate salt of a compound represented by formula (I) of the present invention.
  • the present invention provides the use of the citrate salt, crystalline form A, crystalline form B, crystalline form C, crystalline form D of the compound represented by formula (I) of the present invention and the composition of the present invention in the preparation of a drug for treating, ameliorating or preventing a disease responsive to the inhibition of cyclin-dependent kinase 4/6.
  • the present invention provides the use of the citrate salt, crystalline form A, crystalline form B, crystalline form C, crystalline form D of the compound represented by formula (I) of the present invention and the composition of the present invention in the preparation of a drug for treating, improving or preventing abnormal cell proliferation.
  • the present invention provides the citrate salt, crystalline form A, crystalline form B, crystalline form C, crystalline form D of the compound represented by formula (I) of the present invention and the composition of the present invention, which are optionally combined with a second therapeutic agent for the preparation of a drug for treating, ameliorating or preventing a disease responsive to the inhibition of cyclin-dependent kinase 4/6.
  • the present invention provides the citrate salt, crystalline form A, crystalline form B, crystalline form C, crystalline form D of the compound represented by formula (I) of the present invention and the composition of the present invention, which are optionally combined with a second therapeutic agent for use in the preparation of a medicament for treating, improving or preventing abnormal cell proliferation.
  • FIG1 is an X-ray powder diffraction (XRPD) pattern of the citrate salt form A of the compound represented by formula (I).
  • FIG2 is a DSC spectrum of the citrate crystal form A of the compound represented by formula (I).
  • FIG3 is a TGA spectrum of the citrate crystal form A of the compound represented by formula (I).
  • FIG4 is an NMR spectrum of the citrate crystal form A of the compound represented by formula (I), wherein the test solvent is DMSO-d 6 .
  • FIG5 is an NMR spectrum of the citrate crystal form A of the compound represented by formula (I), wherein the test solvent is D 2 O.
  • FIG6 is an X-ray powder diffraction (XRPD) pattern of the citrate salt form B of the compound represented by formula (I).
  • FIG7 is a DSC spectrum of the citrate crystal form B of the compound represented by formula (I).
  • FIG8 is a TGA spectrum of the citrate crystal form B of the compound represented by formula (I).
  • FIG. 9 is an NMR spectrum of the citrate crystal form B of the compound represented by formula (I), wherein the test solvent is DMSO-d 6 .
  • FIG10 is an X-ray powder diffraction (XRPD) pattern of the citrate salt form C of the compound represented by formula (I).
  • FIG11 is a DSC spectrum of the citrate crystal form C of the compound represented by formula (I).
  • FIG12 is a TGA spectrum of the citrate crystal form C of the compound represented by formula (I).
  • FIG. 13 is an NMR spectrum of the citrate crystal form C of the compound represented by formula (I), wherein the test solvent is DMSO-d 6 .
  • FIG14 is an NMR spectrum of the citrate crystal form C of the compound represented by formula (I), wherein the test solvent is D 2 O.
  • FIG15 is an X-ray powder diffraction (XRPD) spectrum of the citrate salt form D of the compound represented by formula (I).
  • FIG16 is a DSC spectrum of the citrate crystal form D of the compound represented by formula (I).
  • FIG17 is a TGA spectrum of the citrate crystal form D of the compound represented by formula (I).
  • FIG18 is a single crystal image of the citrate crystal form D of the compound represented by formula (I).
  • FIG19 is an X-ray powder diffraction (XRPD) pattern of the citrate salt form E of the compound represented by formula (I).
  • FIG20 is an X-ray powder diffraction (XRPD) pattern of the citrate salt form F of the compound represented by formula (I).
  • FIG21 is an X-ray powder diffraction (XRPD) pattern of the citrate salt form G of the compound represented by formula (I).
  • FIG22 is an X-ray powder diffraction (XRPD) pattern of the citrate salt form G of the compound represented by formula (I) after being placed at room temperature for 1 day.
  • XRPD X-ray powder diffraction
  • FIG. 23 is a DVS curve of the citrate crystal form A of the compound represented by formula (I).
  • FIG24 is an XRPD spectrum of the citrate crystal form A of the compound represented by formula (I) before and after DVS testing.
  • FIG. 25 is a DVS curve diagram of the citrate crystal form B of the compound represented by formula (I).
  • FIG26 is an XRPD spectrum of the citrate crystal form B of the compound represented by formula (I) before and after DVS testing.
  • FIG. 27 is a DVS curve of the citrate crystal form C of the compound represented by formula (I).
  • FIG28 is an XRPD spectrum of the citrate crystal form C of the compound represented by formula (I) before and after DVS testing.
  • FIG. 29 is a DVS curve of the citrate crystal form D of the compound represented by formula (I).
  • FIG30 is an XRPD spectrum of the citrate crystal form D of the compound represented by formula (I) before and after DVS testing.
  • FIG31 is a stability test XRPD spectrum of the citrate crystal form A of the compound represented by formula (I).
  • FIG32 is a stability test XRPD spectrum of the citrate crystal form B of the compound represented by formula (I).
  • FIG33 is a stability test XRPD spectrum of the citrate crystal form C of the compound represented by formula (I).
  • FIG34 is a stability test XRPD spectrum of the citrate crystal form D of the compound represented by formula (I).
  • “1:1-1:5" encompasses 1:1, 1:2, 1:3, 1:4, 1:5 and any sub-range consisting of any two values therein, such as 1:1-1:4, 1:1-1:3, 1:1-1:2, 1:2-1:4, 1:2-1:3, etc.
  • the terms "about” and “approximately” when used in conjunction with a numerical variable generally refer to the value of that variable and all values of that variable are within experimental error (e.g., within a 95% confidence interval for the mean) or within ⁇ 10% of the specified value, or a wider range.
  • the term "selected from" means that one or more elements in the group listed thereafter are independently selected and may include combinations of two or more elements.
  • the terms “one or more” or “at least one” refer to one, two, three, four, five, six, seven, eight, nine or more.
  • the terms “combination thereof” and “mixture thereof” refer to a multi-component mixture of the elements, such as a two-component mixture, a three-component mixture, a four-component mixture and the maximum possible multi-component mixture.
  • the terms "optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence of said event or circumstance and the non-occurrence of said event or circumstance.
  • pharmaceutically acceptable means that it can, within the scope of normal medical judgment, come into contact with the patient's tissue without undue toxicity, irritation, allergic response, etc., has a reasonable benefit-risk ratio and can be effectively used for the intended purpose.
  • crystalline form or “crystal” refers to any solid material that exhibits a three-dimensional ordering, as opposed to amorphous material, which produces a characteristic X-ray powder diffraction pattern with well-defined cells.
  • amorphous refers to any solid material that has no order in three dimensions.
  • hydrate refers to a salt of a compound provided herein that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • mixture refers to a substance formed by a mixture of two or more substances.
  • a “mixture” is connected or combined in the form of non-covalent bonds, has a molecular formula and composition ratio (molar ratio or mass ratio) of a specific value or a specific range of values, and has stable physical and chemical properties and biological characteristics.
  • citrate and “citrate salt” are used interchangeably to refer to the salt form of the free base compound with citric acid.
  • the term “citrate salt of the compound of formula (I)” refers to the salt formed by the free base of the compound of formula (I) and citric acid.
  • the term “monocitrate salt of the compound of formula (I)” means that in the citrate salt, the molar ratio of the compound of formula (I) to citric acid is about 1:1.
  • the term “dicitrate salt of the compound of formula (I)” means that in the citrate salt, the molar ratio of the compound of formula (I) to citric acid is about 1:2.
  • crystalline form of the citrate salt of the compound of formula (I) refers to the citrate salt of the compound of formula (I) in crystalline form.
  • the crystal form may be a crystal form of a solvate, or the crystal form may not contain solvent molecules.
  • the solvent may be methanol or water. When the solvent is water, it may also be referred to as a corresponding hydrate.
  • composition refers to an active ingredient, which is optionally combined with one or more pharmaceutically acceptable chemical components (such as, but not limited to, carriers and/or excipients).
  • the active ingredient can be, for example, a citrate salt of the compound represented by formula (I), a crystalline form thereof, or a combination thereof.
  • active ingredient refers to a chemical entity that is effective in treating or preventing a target disease or condition.
  • pharmaceutically acceptable carrier refers to those carriers that have no significant irritation to an organism and do not impair the biological activity and performance of the active compound, including but not limited to any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier acceptable for use in humans or animals (e.g., livestock).
  • Non-limiting examples of the carrier include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, and the like.
  • Remington The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • administering refers to methods that can deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc.
  • an "effective amount” of an active substance in the composition can be It is the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • non-covalent bond form refers to weak intermolecular interactions other than covalent bonds, including but not limited to hydrogen bonds, van der Waals forces, salt bonds, hydrophobic forces, aromatic ring stacking, ⁇ - ⁇ stacking, halogen bonds, etc.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters derived therefrom.
  • An XRPD pattern is usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
  • the diffraction pattern obtained from a crystalline compound is often characteristic for a specific crystal form, where the relative intensity of the bands (especially at low angles) may vary due to the effect of the preferred orientation caused by differences in crystallization conditions, particle size and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic for the crystal form being targeted, and when judging whether it is the same as a known crystal form, more attention should be paid to the relative position of the peaks rather than their relative intensity. In addition, for any given crystal form, there may be slight errors in the position of the peaks, which is also well known in the field of crystallography.
  • the position of the peak can move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining the structure of each crystal form. If the crystal form of the present invention is described as being substantially as shown in a specified figure, the term "substantially” is also intended to cover such differences in the position of the diffraction peaks.
  • d the crystal plane distance
  • ⁇ the wavelength of the incident X-ray
  • ⁇ the diffraction angle.
  • the peak position of its XRPD spectrum is similar on the whole, and the relative intensity error may be large. It should also be pointed out that in the identification of a mixture, due to factors such as a decrease in content, some diffraction lines may be missing. At this time, there is no need to rely on all the bands observed in a high-purity sample, and even one band may be characteristic for a given crystal.
  • 2 ⁇ refers to the peak position expressed in degrees based on the experimental setup of an X-ray diffraction experiment, and is typically the unit of the abscissa in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle ⁇ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2 ⁇ . It should be understood that the specific 2 ⁇ values of a specific crystalline form mentioned herein are intended to represent the 2 ⁇ values (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • thermogravimetric analysis (TGA) spectrum refers to a curve recorded by a thermogravimetric analyzer.
  • DSC differential scanning calorimetry
  • nuclear magnetic resonance (1H-NMR) spectrum refers to signal peaks recorded by a nuclear magnetic resonance instrument.
  • the present invention provides a protein kinase inhibitor, namely, the citrate of the compound represented by formula (I).
  • the molar ratio of the compound of formula (I) to citric acid is about 1:1-1:3. In a preferred embodiment, in the citrate of the compound of formula (I), the molar ratio of the compound to citric acid is about 1:1-1:2. In a more preferred embodiment, in the citrate of the compound of formula (I), the molar ratio of the compound to citric acid is about 1:2. For example, about 1:1, about 1:2, about 1:3.
  • the molar ratio of the compound to citric acid is about 1:2, and it has the chemical structure shown below:
  • the molar ratio of the compound to citric acid is about 1:1, and it has the chemical structure shown below:
  • the suitable molar ratio of the compound to citric acid is conducive to making the citrate have excellent properties. Too high a molar ratio of the compound to citric acid is not conducive to obtaining a citrate with excellent properties, for example, too high a molar ratio of the compound to citric acid reduces the stability and solubility of the citrate. Too low a molar ratio of the compound to citric acid is not conducive to obtaining a citrate with excellent properties, for example, too low a molar ratio of the compound to citric acid reduces the stability and solubility of the citrate.
  • the present invention provides a crystalline form A of a citrate salt of the compound represented by formula (I).
  • the compound The molar ratio of the product to citric acid is about 1:2.
  • the crystalline form A of the citrate salt of the compound represented by formula (I) of the present invention does not contain crystal water.
  • the X-ray powder diffraction pattern of the crystalline form A of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 17.9 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.2 ⁇ 0.2°, 19.5 ⁇ 0.2° and 20.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 9.8 ⁇ 0.2°, 11.6 ⁇ 0.2°, 15.0 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.2 ⁇ 0.2°, 19.5 ⁇ 0.2° and 20.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 3.8 ⁇ 0.2°, 9.8 ⁇ 0.2°, 11.2 ⁇ 0.2°, 11.6 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.6 ⁇ 0.2°, 12.8 ⁇ 0.2°, 15.0 ⁇ 0.2°, 16.8 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.2 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.9 ⁇ 0.2°, 24.7 ⁇ 0.2° and 25.2 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form A is shown in FIG1 .
  • the XRPD spectrum analysis data of the crystalline form A is shown in Table 1.
  • the differential scanning calorimetry (DSC) curve of the crystalline form A of the citrate salt of the compound represented by formula (I) of the present invention has an endothermic peak at 190.1 ⁇ 3°C.
  • the DSC spectrum of the crystal form A of the citrate salt of the compound represented by formula (I) of the present invention is shown in FIG2 .
  • thermogravimetric analysis curve (TGA) of the crystal form A of the citrate salt of the compound represented by formula (I) of the present invention has a weight loss of 1.2% at 120.52 ⁇ 3°C.
  • the thermogravimetric analysis (TGA) curve of the crystalline form A of the citrate salt shows a weight loss of 38.4% at 140-300 ⁇ 3°C.
  • the TGA spectrum of the crystal form A of the citrate salt of the compound represented by formula (I) of the present invention is shown in FIG3 .
  • the present invention provides a crystalline form B of a citrate salt of the compound represented by formula (I).
  • the molar ratio of the compound to citric acid is about 1:2.
  • the crystal form B of the citrate salt of the compound represented by formula (I) of the present invention is a crystal form of a hydrate of the citrate salt.
  • the molar ratio of the citrate salt of the compound represented by formula (I) to crystal water is about 1:2.
  • the X-ray powder diffraction pattern of the crystalline form B of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 8.3 ⁇ 0.2°, 11.2 ⁇ 0.2°, 14.1 ⁇ 0.2°, 16.7 ⁇ 0.2° and 18.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 5.3 ⁇ 0.2°, 7.0 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.2 ⁇ 0.2°, 11.8 ⁇ 0.2°, 14.1 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.7 ⁇ 0.2°, 18.4 ⁇ 0.2°, 22.5 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.4 ⁇ 0.2° and 25.0 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal B of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 5.3 ⁇ 0.2°, 7.0 ⁇ 0.2°, 8.3 ⁇ 0.2°, 10.2 ⁇ 0.2°, 11.2 ⁇ 0.2°, 11.8 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.3 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.0 ⁇ 0.2°, 23.0 ⁇ 0.2°, 24.0 ⁇ 0.2°, 25.0 ⁇ 0.2°, 26.0 ⁇ 0.2°, 27.0 ⁇ 0.2°, 28.0 ⁇ 0.2°, 29.1 ⁇ 0.2°, 30.0 ⁇ 0.2°, 31.0 ⁇ 0.2°, 33.0 ⁇ 0.2°, 34.0 ⁇ 0.2°, 36.0 ⁇ 0.2°, 37.0 ⁇ 0.2°, 38.0 ⁇ 0.2°, 39.0 ⁇ 0.
  • the XRPD pattern of Form B is shown in FIG6 .
  • the XRPD spectrum analysis data of the crystalline form B is shown in Table 2.
  • the differential scanning calorimetry (DSC) curve of the crystalline form B of the citrate salt of the compound represented by formula (I) of the present invention has an endothermic peak at 81.0 ⁇ 3°C, 133.2 ⁇ 3°C, 150.6 ⁇ 3°C and 177.9 ⁇ 3°C, respectively.
  • the DSC spectrum of the crystal form B of the citrate salt of the compound represented by formula (I) of the present invention is shown in FIG7 .
  • thermogravimetric analysis curve (TGA) of the crystal form B of the citrate salt of the compound represented by formula (I) of the present invention loses 2.2% of its weight at 90 ⁇ 3°C. In one embodiment, the thermogravimetric analysis curve (TGA) of the crystal form B of the citrate salt of the compound represented by formula (I) of the present invention loses 1.8% of its weight at 90-140 ⁇ 3°C. In one embodiment, the thermogravimetric analysis curve (TGA) of the crystal form B of the citrate salt of the compound represented by formula (I) of the present invention loses 36.9% of its weight at 140-300 ⁇ 3°C.
  • the TGA spectrum of the crystal form B of the citrate salt of the compound represented by formula (I) of the present invention is shown in FIG8 .
  • the present invention provides a crystalline form C of a citrate salt of the compound represented by formula (I).
  • the molar ratio of the compound to citric acid is about 1:1.
  • the crystalline form C of the citrate salt of the compound represented by formula (I) of the present invention does not contain crystal water.
  • the X-ray powder diffraction pattern of the crystalline form C of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 10.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.2 ⁇ 0.2° and 20.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form C of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 6.7 ⁇ 0.2°, 10.0 ⁇ 0.2°, 11.9 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.2 ⁇ 0.2° and 20.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form C of the citrate salt of the compound represented by formula (I) of the present invention has characteristic diffraction peaks at the following 2 ⁇ angles: 6.7 ⁇ 0.2°, 10.0 ⁇ 0.2°, 10.6 ⁇ 0.2°, 11.2 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.6 ⁇ 0.2°, 13.0 ⁇ 0.2°, 13.4 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.8 ⁇ 0.2°, 17.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.4 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.8 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.7 ⁇ 0.2°, 25.4 ⁇ 0.2° and 26.2 ⁇ 0.2°.
  • the XRPD pattern of Form C is shown in FIG10 .
  • the XRPD spectrum analysis data of the crystalline form C is shown in Table 3.
  • the differential scanning calorimetry (DSC) curve of the crystalline form C of the citrate salt of the compound represented by formula (I) of the present invention has an endothermic peak at 194.3 ⁇ 3°C.
  • the DSC spectrum of the crystal form C of the citrate salt of the compound represented by formula (I) of the present invention is shown in FIG. 11 .
  • thermogravimetric analysis curve (TGA) of the crystal form C of the citrate salt of the compound represented by formula (I) of the present invention has a weight loss of 0.1% at 120 ⁇ 3°C. In one embodiment, the thermogravimetric analysis curve (TGA) of the crystal form C of the citrate salt of the compound represented by formula (I) of the present invention has a weight loss of 25.8% at 120-300 ⁇ 3°C.
  • the TGA spectrum of the crystal form C of the citrate salt of the compound represented by formula (I) of the present invention is shown in FIG12 .
  • the present invention provides a crystalline form D of a citrate salt of the compound represented by formula (I).
  • the molar ratio of the compound to citric acid is about 1:1.
  • the crystalline form D of the citrate salt of the compound represented by formula (I) of the present invention is a methanol solvate of the citrate salt of the compound represented by formula (I).
  • the molar ratio of the citrate salt of the compound represented by formula (I) to methanol is about 1:1.
  • the X-ray powder diffraction pattern of the crystalline form D of the citrate salt of the compound represented by formula (I) of the invention has characteristic diffraction peaks at the following 2 ⁇ angles: 14.0 ⁇ 0.2°, 16.8 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.8 ⁇ 0.2° and 24.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form D of the citrate salt of the compound represented by formula (I) of the invention has characteristic diffraction peaks at the following 2 ⁇ angles: 6.0 ⁇ 0.2°, 7.1 ⁇ 0.2°, 14.0 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.8 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 19.8 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.6 ⁇ 0.2° and 28.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form D of the citrate salt of the compound represented by formula (I) of the invention has characteristic diffraction peaks at the following 2 ⁇ angles: 6.0 ⁇ 0.2°, 7.1 ⁇ 0.2°, 9.2 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.1 ⁇ 0.2°, 14.0 ⁇ 0.2°, 15.4 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.8 ⁇ 0.2°, 17.4 ⁇ 0.
  • the XRPD pattern of Form D is shown in FIG. 15 .
  • the XRPD spectrum analysis data of the crystal form D is shown in Table 4.
  • the differential scanning calorimetry curve of the crystalline form D of the citrate salt of the compound represented by formula (I) of the present invention has an endothermic peak at 148.4 ⁇ 3°C, 160.8°C and 184.1°C, respectively.
  • the DSC spectrum of the crystalline form D of the citrate salt of the compound represented by formula (I) of the present invention is as follows: As shown in Figure 16.
  • thermogravimetric analysis curve (TGA) of the crystal form D of the citrate salt of the compound represented by formula (I) of the present invention has a weight loss of 0.6% at 110 ⁇ 3°C. In one embodiment, the thermogravimetric analysis curve (TGA) of the crystal form D of the citrate salt of the compound represented by formula (I) of the present invention has a weight loss of 1.7% at 110-150 ⁇ 3°C. In one embodiment, the thermogravimetric analysis curve (TGA) of the crystal form D of the citrate salt of the compound represented by formula (I) of the present invention has a weight loss of 27.7% at 150-300 ⁇ 3°C.
  • the TGA spectrum of the crystal form D of the citrate salt of the compound represented by formula (I) of the present invention is shown in FIG. 17 .
  • the present invention provides a method for preparing a crystalline form A of a citrate salt of a compound represented by formula (I), comprising the following steps:
  • the citrate salt of the compound represented by formula (I) is the dicitrate salt of the compound represented by formula (I).
  • the solvent of the solution of citric acid is an alcohol solvent. In a specific embodiment, the solvent of the solution of citric acid is an ether solvent. In a specific embodiment, the solvent of the solution of citric acid is a nitrile solvent. In a specific embodiment, the solvent of the solution of citric acid is a ketone solvent.
  • the solvent of the solution of the compound of formula (I) is an alcohol solvent. In a specific embodiment, the solvent of the solution of the compound of formula (I) is an ether solvent. In a specific embodiment, the solvent of the solution of the compound of formula (I) is a nitrile solvent. In a specific embodiment, the solvent of the solution of the compound of formula (I) is a ketone solvent.
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol and combinations thereof. In a more preferred embodiment, the alcohol solvent is selected from methanol, ethanol, isopropanol and combinations thereof. For example, methanol, ethanol or n-propanol.
  • the ether solvent is selected from diethyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether and combinations thereof. In a more preferred embodiment, the ether solvent is selected from ethylene glycol methyl ether, ethylene glycol dimethyl ether and combinations thereof.
  • the nitrile solvent is selected from acetonitrile, propionitrile, butyronitrile and combinations thereof. In a more preferred embodiment, the nitrile solvent is acetonitrile.
  • the ketone solvent is selected from acetone, butanone, 4-methyl-2-pentanone and combinations thereof. In a more preferred embodiment, the ketone solvent is selected from acetone, 4-methyl-2-pentanone and combinations thereof.
  • a suitable alcohol solvent is conducive to obtaining Form A of the present invention.
  • the solution of the compound of formula (I) is heated. In a preferred embodiment, Heat the solution of the compound of formula (I) and control the internal temperature of the solution to 50-55°C.
  • the obtained solution is further stirred and solid precipitation is observed.
  • the mixed solution of the compound of formula (I) and citric acid is cooled to an internal temperature of 10° C.
  • the mixed solution of the compound of formula (I) and citric acid is controlled to have an internal temperature of 10 ⁇ 2° C. and the solution is stirred, and crystal precipitation can be observed.
  • the molar ratio of the compound of formula (I) added to the citric acid is about 1:3-1:5. In a preferred embodiment, the molar ratio of the compound of formula (I) added to the citric acid is about 1:3-1:4. For example, about 1:3, about 1:3.5, about 1:4, about 1:5.
  • the appropriate molar ratio of the compound of formula (I) to citric acid is conducive to obtaining the crystalline form A of the present invention.
  • the present invention provides a method for preparing a crystalline form B of a citrate salt of a compound represented by formula (I), comprising the following steps:
  • the citrate salt of the compound represented by formula (I) is the dicitrate salt of the compound represented by formula (I).
  • the solvent of the solution is selected from alcohol solvents, water and combinations thereof.
  • the solvent of the citric acid solution is an alcohol solvent.
  • the solvent of the solution of the compound of formula (I) is an alcohol solvent and water.
  • the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol and combinations thereof. In a preferred embodiment, the alcohol solvent is selected from methanol, ethanol and combinations thereof. For example, methanol, ethanol or n-propanol.
  • a suitable alcohol solvent is conducive to obtaining Form B of the present invention.
  • the mass ratio of the alcohol solvent to water is about 10:1-3:1. In a more preferred embodiment, in step (2), the mass ratio of the alcohol solvent to water is about 6:1-4:1. For example, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1.
  • a suitable molar ratio of the compound of formula (I) to citric acid is conducive to obtaining Form B of the present invention.
  • the solution of the compound of formula (I) is heated.
  • the solution of the compound of formula (I) is heated and the internal temperature of the solution is controlled to be 50-55°C.
  • the obtained solution is further stirred and solid precipitation is observed.
  • the mixed solution of the compound of formula (I) and citric acid is cooled to an internal temperature of 10°C.
  • the mixed solution of the compound of formula (I) and citric acid is controlled to have an internal temperature of 10 ⁇ 2°C, and The solution was stirred and precipitation of crystals was observed.
  • the molar ratio of the compound of formula (I) added to the citric acid is about 1:3-1:5. In a preferred embodiment, the molar ratio of the compound of formula (I) added to the citric acid is about 1:3-1:4. For example, about 1:3, about 1:4, about 1:5.
  • a suitable molar ratio of the compound of formula (I) to citric acid is conducive to obtaining Form B of the present invention.
  • the present invention provides a method for preparing a crystalline form C of a citrate salt of a compound represented by formula (I), comprising the following steps:
  • Form C was obtained by centrifugation.
  • the citrate salt of the compound represented by formula (I) is the dicitrate salt of the compound represented by formula (I).
  • the solvent X is selected from dimethylformamide, ethylene glycol methyl ether and combinations thereof.
  • the solvent Y is selected from acetonitrile, ethyl acetate, methanol, ethanol, isopropanol and combinations thereof.
  • a suitable alcohol solvent is conducive to obtaining the crystalline form C of the present invention.
  • the volume ratio of solvent X to solvent Y is about 5:1-10:1, such as about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1.
  • the solution is stirred for about 1-3 days, such as 1 day, 2 days or 3 days.
  • the preparation method of Form C is used to prepare Form D, and the solvent is an alcohol solvent.
  • the solvent is methanol.
  • the present invention provides a pharmaceutical composition comprising one or more selected from the following: (i) a citrate salt of a compound represented by formula (I) of the present invention; (ii) a crystalline form A of a citrate salt of a compound represented by formula (I) of the present invention; (iii) a crystalline form B of a citrate salt of a compound represented by formula (I) of the present invention; (iv) a crystalline form C of a citrate salt of a compound represented by formula (I) of the present invention; and (v) a crystalline form D of a citrate salt of a compound represented by formula (I) of the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a citrate salt of a compound represented by formula (I), and one or more pharmaceutically acceptable carriers.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form A of the citrate salt of the compound represented by formula (I), and one or more pharmaceutically acceptable carriers.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form B of the citrate salt of the compound represented by formula (I), and one or more pharmaceutically acceptable carriers.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Form C of the citrate salt of the compound represented by formula (I), and one or more pharmaceutically acceptable carriers.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystal form D of the citrate salt of the compound represented by formula (I), and one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered and which is suitable, within the scope of sound medical judgment, for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Administration of the salt of the compound of the present invention or its crystalline form in pure form or in the form of a suitable pharmaceutical composition can be carried out by any acceptable mode of administration of medicaments that provide similar uses.
  • the pharmaceutical composition of the present invention can be prepared by combining the salt of the compound of the present invention or its crystalline form with a suitable pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods and the like.
  • a daily dosage of 0.001 to 100 mg/kg body weight in particular, from about 0.03 to 2.5 mg/kg body weight.
  • the daily dosage for larger mammals, such as humans can be from about 0.5 mg to about 2000 mg, or more particularly, from 0.5 mg to 1000 mg, administered in a convenient form, for example, in divided doses up to four times a day or in a sustained release form.
  • Suitable unit dosage forms for oral administration contain about 1 to 50 mg of active ingredient.
  • Typical routes of administration of the compounds of the present invention or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be prepared by mixing the active compound with a pharmaceutically acceptable carrier, excipient and/or medium well known in the art.
  • the pharmaceutical composition of the present invention can be manufactured in a conventional manner by mixing, granulating, coating, dissolving or freeze-drying processes. These carriers, excipients and media enable the compound of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the pharmaceutical composition comprises a compound of the present invention in combination with at least one pharmaceutically acceptable carrier or diluent, and can be prepared in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
  • the unit dosage form for oral administration includes, for example, from about 0.1 mg to about 500 mg of active substance.
  • the pharmaceutical composition is a solution of the active ingredient, comprising a suspension or dispersion, such as an isotonic aqueous solution.
  • a suspension or dispersion such as an isotonic aqueous solution.
  • the dispersion or suspension can be supplemented before use.
  • the pharmaceutical composition can be sterilized and/or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for regulating osmotic pressure and/or buffers.
  • Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides, such as sorbic acid or benzoic acid.
  • the solution or suspension can also contain a viscosity increasing agent, including, but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinyl pyrrolidone, gelatin, or a solubilizing agent, such as Tween 80 (polyoxyethylene (20) sorbitan monooleate).
  • a viscosity increasing agent including, but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinyl pyrrolidone, gelatin, or a solubilizing agent, such as Tween 80 (polyoxyethylene (20) sorbitan monooleate).
  • the suspension in oil may contain as the oily component a vegetable oil, a synthetic or semi-synthetic oil, commonly used for injection purposes.
  • oils include liquid fatty acid esters containing as the acid component a long-chain fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms.
  • Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid or the corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassenoic acid and linoleic acid, and, if desired, may contain an antioxidant, such as vitamin E, 3-carotene or 3,5-di-tert-butylhydroxytoluene.
  • the alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di- or trivalent alcohols. Suitable
  • the alcohol component includes, but is not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof, ethylene glycol and glycerol.
  • Suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, M2375 (polyoxyethylene glycerol), M1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis of almond oil and containing glycerides and polyethylene glycol esters), LABRASOL TM (saturated polyglycolized glycerides prepared by alcoholysis of TCM and containing glycerides and polyethylene glycol esters; both available from GaKefosse, France), and/or 812 (saturated fatty acid triglycerides with a chain length of C8 to C12 from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil
  • the solid oral composition can be prepared by conventional mixing, filling or tableting methods.
  • the active compound is mixed with a solid excipient, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules to obtain a tablet or a core of a dragee.
  • Suitable carriers include, but are not limited to, fillers such as sugars, cellulose preparations and/or calcium phosphates, binders, and/or, if desired, disintegrants. Additional excipients include flow conditioners and lubricants.
  • Tablet cores may be provided with a suitable, optionally enteric coating, either with a coating solution dissolved in a suitable organic solvent or solvent mixture, or, for an enteric coating. Dyes or pigments may be added to the tablet or tablet coating.
  • the pharmaceutical composition for oral administration can also include hard capsules, including gelatin or containing gelatin and plasticizer, such as the soft sealed capsules of glycerol or sorbitol.
  • the hard capsule can contain the form of the particles of active ingredient, for example with filler such as corn starch, adhesive and/or glidant such as talcum powder or magnesium stearate, and optional stabilizer mix.
  • active ingredient can be dissolved or suspended in suitable liquid excipient such as fatty oil, in the fatty acid ester of paraffin oil or liquid polyethylene glycol or ethylene glycol or propylene glycol, to which stabilizer and detergent, for example the fatty acid ester type of polyoxyethylene sorbitol, also can be added.
  • compositions suitable for rectal administration contain a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions suitable for parenteral administration may contain the active ingredient in water-soluble form, such as a water-soluble salt or an aqueous injection suspension containing a substance that increases viscosity, such as sodium carboxymethylcellulose, an aqueous solution of sorbitol and/or dextran, if desired, and a stabilizer.
  • the active ingredient optionally with an excipient, may also be in a freeze-dried form, and a solution may be prepared by adding a suitable solvent before parenteral administration.
  • the solution used, for example, for parenteral administration may also be used as an infusion solution.
  • the preparation of the injection preparation is usually under sterile conditions, filled into, for example, an ampoule or a vial, and sealed in a container.
  • the compounds of the present invention can be used as the sole active ingredient, or can be administered together with other drugs useful in immunomodulatory therapy or anti-tumor diseases.
  • the compounds of the present invention can be used together with pharmaceutical compositions effective for the above-mentioned various diseases, for example, the compounds of the present invention can be used together with aromatase inhibitors (e.g., letrozole, anastrozole, exemestane); or also with selective estrogen receptor modulators (e.g., fulvestrant, tamoxifen); or also with gonadal hormone-releasing hormone agonists (e.g., goserelin, leuprorelin, triptorelin, buserelin); or also with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, Cisplatin, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituximab,
  • the present invention provides the use of the citrate of the compound represented by formula (I) of the present invention, or the crystalline form A of the citrate of the compound represented by formula (I) of the present invention, or the crystalline form B of the citrate of the compound represented by formula (I) of the present invention, or the crystalline form C of the citrate of the compound represented by formula (I) of the present invention, or the crystalline form D of the citrate of the compound represented by formula (I) of the present invention, or the pharmaceutical composition of the present invention in the preparation of a drug for treating, improving or preventing abnormal cell proliferation.
  • the present invention provides a method for treating, ameliorating or preventing abnormal cell proliferation, comprising administering to an individual in need thereof a therapeutically effective amount of a citrate of a compound of formula (I) of the present invention, or a crystalline form A of a citrate of a compound of formula (I) of the present invention, or a crystalline form B of a citrate of a compound of formula (I) of the present invention, or a crystalline form C of a citrate of a compound of formula (I) of the present invention, or a crystalline form D of a citrate of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention.
  • the present invention provides a citrate salt of a compound of formula (I) of the present invention, or a crystalline form A of a compound of formula (I) of the present invention, or a crystalline form B of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form C of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form D of a citrate salt of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention, for use in treating, improving or preventing abnormal cell proliferation.
  • the present invention provides the use of the citrate of the compound of formula (I) of the present invention, or the crystalline form A of the citrate of the compound of formula (I) of the present invention, or the crystalline form B of the citrate of the compound of formula (I) of the present invention, or the crystalline form C of the citrate of the compound of formula (I) of the present invention, or the crystalline form D of the citrate of the compound of formula (I) of the present invention, or the pharmaceutical composition of the present invention in the preparation of a drug for treating, ameliorating or preventing a disease responsive to the inhibition of cyclin-dependent kinase 4/6.
  • the present invention provides a method for treating, ameliorating or preventing a condition responsive to inhibition of cyclin-dependent kinase 4/6, comprising administering to an individual in need thereof a therapeutically effective amount of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form A of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form B of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form C of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form D of a citrate salt of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention.
  • the present invention provides a citrate salt of a compound of formula (I) of the present invention, or a crystalline form A of a citrate salt of a compound represented by formula (I) of the present invention, or a crystalline form B of a citrate salt of a compound represented by formula (I) of the present invention, or a crystalline form C of a citrate salt of a compound represented by formula (I) of the present invention, or a crystalline form D of a citrate salt of a compound represented by formula (I) of the present invention, or a pharmaceutical composition of the present invention, for use in treating, ameliorating or preventing a disease responsive to inhibition of cyclin-dependent kinase 4/6.
  • the cell proliferative disease is selected from: a cancerous proliferative disease (e.g., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovarian, prostate, colorectal, epidermal, esophageal, testicular, gynecological, or thyroid cancer); a noncancerous proliferative disease (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidney disease; pain; preventing blastocyst implantation; treating diseases associated with angiogenesis or angiogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, arteriosclerosis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes,
  • the cell proliferative disease is hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • a 4/6 gene mutation causes the above-mentioned diseases, such as melanoma, lung cancer, colon cancer, etc.
  • citrate salt of the compound represented by formula (I), its crystal forms A-D or the composition described in the present invention can be used alone or in combination with other therapeutic agents.
  • the use of adjuvant drugs can enhance the therapeutic effect of the citrate salt or its crystalline form of the compound of the present invention (for example, the therapeutic benefit of the adjuvant drug alone is minimal, but when used in combination with another drug, the therapeutic benefit of the individual can be enhanced), or, for example, the citrate salt or its crystalline form of the compound of the present invention can be used in combination with another therapeutic agent with the same therapeutic effect to enhance the therapeutic benefit of the individual.
  • the citrate salt or its crystalline form of the compound of the present invention when treating gout, when the citrate salt or its crystalline form of the compound of the present invention is used, the combined use of another drug for treating gout may enhance the clinical benefit.
  • the combined therapy includes, but is not limited to, physical therapy, psychotherapy, radiotherapy, compression therapy of the diseased area, rest and dietary improvement, etc. Regardless of the disease, discomfort or symptom, the two therapies should have an additive effect or a synergistic effect to benefit the individual's treatment.
  • the route of administration of the pharmaceutical composition of the compound of the present invention may be the same as that of the other drugs, or the route of administration may be different due to different physical and chemical properties.
  • oral administration of the citrate salt of the compound of the present invention or its crystal form can produce and maintain good blood drug levels, while another therapeutic agent may require intravenous administration. Therefore, the citrate salt of the compound of the present invention or its crystal form and another therapeutic agent can be administered simultaneously, sequentially or separately.
  • the citrate of the compound represented by formula (I) or its crystal form is expected to be effective when used in combination with one or more of the following drugs: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotic, antiproliferative, antiviral agents, aurora kinase inhibitors, other apoptosis promoters (e.g., Bcl-xL, Bcl-w and Bfl-1) inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, BiTE (bispecific T cell engager) antibodies, antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homologous genes (ErbB2 ) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone acetylase (HDAC) inhibitors, hormone therapy, immunotherapies, inhibitors of
  • the present invention provides a citrate of a compound of formula (I) of the present invention, or a crystalline form A of a citrate of a compound of formula (I) of the present invention, or a crystalline form B of a citrate of a compound of formula (I) of the present invention, or a crystalline form C of a citrate of a compound of formula (I) of the present invention, or a crystalline form D of a citrate of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention, optionally in combination with a second therapeutic agent, for use in the preparation of a medicament for treating, ameliorating or preventing a condition responsive to inhibition of cyclin-dependent kinase 4/6.
  • the present invention provides a method for treating, ameliorating or preventing a condition responsive to inhibition of cyclin-dependent kinase 4/6, comprising administering to an individual in need thereof a therapeutically effective amount of a citrate of a compound of formula (I) of the present invention, or a crystalline form A of a citrate of a compound of formula (I) of the present invention, or a crystalline form B of a citrate of a compound of formula (I) of the present invention, or a crystalline form C of a citrate of a compound of formula (I) of the present invention, or a crystalline form D of a citrate of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention, and optionally a second therapeutic agent.
  • the present invention provides a citrate salt of a compound of formula (I) of the present invention, or a crystalline form A of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form B of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form C of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form D of a citrate salt of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention, which is optionally combined with a second therapeutic agent for treating, ameliorating or preventing a condition responsive to inhibition of cyclin-dependent kinase 4/6.
  • the present invention provides a citrate salt of a compound of formula (I) of the present invention, or a crystalline form A of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form B of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form C of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form D of a citrate salt of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention, optionally in combination with a second therapeutic agent, for use in the preparation of a medicament for treating, ameliorating or preventing abnormal cell proliferation.
  • the present invention provides a method for preparing a drug for treating, improving or preventing abnormal cell proliferation, comprising administering to an individual in need thereof a therapeutically effective amount of a citrate of a compound of formula (I) of the present invention, or a crystalline form A of a citrate of a compound of formula (I) of the present invention, or a crystalline form B of a citrate of a compound of formula (I) of the present invention, or a crystalline form C of a citrate of a compound of formula (I) of the present invention, or a crystalline form D of a citrate of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention, and optionally a second therapeutic agent.
  • the present invention provides a citrate salt of a compound of formula (I) of the present invention, or a crystalline form A of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form B of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form C of a citrate salt of a compound of formula (I) of the present invention, or a crystalline form D of a citrate salt of a compound of formula (I) of the present invention, or a pharmaceutical composition of the present invention, which is optionally combined with a second therapeutic agent for treating, ameliorating or preventing abnormal cell proliferation.
  • the citrate salt of the compound represented by formula (I) of the present invention has the beneficial effects of high stability and good solubility.
  • the crystalline forms A, B, C and D of the citrate salt of the compound represented by formula (I) of the present invention also have excellent hygroscopicity, hygroscopicity and humidity stability.
  • the crystalline form of the present invention will not change, showing excellent hygroscopicity, hygroscopicity and humidity stability.
  • the crystalline forms A, B and C of the citrate salt of the compound represented by formula (I) of the present invention have significantly improved hygroscopicity, hygroscopicity, and humidity stability.
  • the crystalline forms A, B and C of the present invention will not change, showing significantly improved hygroscopicity, hygroscopicity, and humidity stability.
  • the crystal forms A, B, C and D of the citrate of the compound shown in the formula (I) of the present invention also have excellent stability, such as high temperature stability and light stability.
  • the crystal form of the present invention will not change, showing excellent high temperature stability and light stability.
  • the crystal forms A, B and C of the citrate of the compound shown in the formula (I) of the present invention have significantly improved stability, such as high temperature stability and light stability.
  • the crystal forms A, B and C of the citrate of the compound shown in the formula (I) of the present invention will not change, showing significantly improved high temperature stability and light stability.
  • the citrate crystalline forms A, B, C and D of the compound represented by formula (I) of the present invention have excellent solubility, for example, in biological media such as FaSSIF, FeSSIF and FaSSGF, they exhibit excellent solubility.
  • citrate salt of the compound represented by formula (I) of the present invention and its crystal form A, crystal form B, crystal form C and crystal form D have broad prospects for drug development.
  • Agilent 1290 Infinity-6546 LC/Q-TOF was used to detect the mass spectra of the compound, its salts and crystalline forms, and its ion source was ESI(+).
  • the nuclear magnetic resonance spectra of the compound, its salt and crystal form are detected by using a BRUKER Av NEO 400M nuclear magnetic resonance spectrometer, wherein D 2 O or DMSO-d 6 is used as the solvent.
  • the XRPD patterns of each crystal form were collected using a Panalytical EMPYREAN (Malvern Panalytical, UK) powder diffractometer.
  • the instrument used Cu palladium irradiation and Absolute scan for continuous projection scanning at room temperature. The scanning 2 ⁇ range was 3 to 45°, the step size was 0.013°, and the scanning time for a single sample was 5 minutes.
  • the tube voltage and current were 45 kV and 40 mA, respectively, and the sample pan was a zero background sample pan.
  • TA Discovery 250 (TA, US) was used to collect the DSC spectrum of the crystal form.
  • the sample was heated to the final temperature at a rate of 10°C/min.
  • the nitrogen purge rate at the sample was 60 mL/min, and the nitrogen purge rate at the balance was 40 mL/min.
  • TA Discovery 550 (TA, US) was used to collect TGA spectra of the crystal form. The sample was heated to the final temperature at a rate of 10°C/min. The nitrogen purge rate at the sample was 60 mL/min, and the nitrogen purge rate at the balance was 40 mL/min.
  • DVS Intrinsic SMS, UK was used to perform dynamic moisture adsorption and desorption analysis of the crystal form to evaluate the hygroscopicity of the crystal form.
  • the test used a gradient mode, with a humidity change of 50%-95%-50%, a humidity change of 15% for each gradient, and the gradient end point was determined by the dm/dt method, with dm/dt less than 0.002% and maintained for 10 minutes as the gradient end point, or the longest maintenance time for each gradient was 60 minutes. After the test was completed, the sample was analyzed by XRPD to confirm whether the solid form had changed.
  • the compound represented by formula (I) it is prepared according to the method of CN109153686A.
  • Citric acid purchased from General-Reagent.
  • Methanol purchased from General-Reagent.
  • Acetonitrile purchased from General-Reagent.
  • Ethylene glycol dimethyl ether purchased from General-Reagent.
  • Ethylene glycol methyl ether purchased from General-Reagent.
  • Acetone purchased from Guangzhou Chemical Reagent Factory.
  • FaSSIF purchased from Biorelevant, batch number: FASBUF-1121-A.
  • FaSSGF purchased from Biorelevant, batch number: FASBUF-1121-A.
  • FeFFIF purchased from Biorelevant, batch number: FASBUF-0122-A.
  • Biorelevant powder purchased from Biorelevant, batch number: FFF-0521-A.
  • the above solvent can be methanol or tetrahydrofuran.
  • step (3) Add the citric acid methanol solution of step (1) to the solution of step (2) (i.e., the molar ratio of the compound of formula (I) to citric acid in the solution is 1:4), control the internal temperature of the solution to 50-55° C., and stir the solution for 15 minutes. During the stirring process, solid precipitation can be observed.
  • step (3) Cool the mixed solution obtained in step (3) for 3 h until its internal temperature reaches 10°C.
  • step (4) Stir the mixture of step (4) at an internal temperature of 10 ⁇ 2°C for 1 h, and crystal precipitation can be observed.
  • step (6) Filter the mixture obtained in step (5), and dry the filtrate under reduced pressure at 50°C to obtain 27g of the citrate crystal form A of the compound represented by formula (I) of the present application, with a yield of 93.4%.
  • the obtained crystal form A is a light yellow powder, odorless, and slightly hygroscopic. Crystal form A is easily soluble in water, 0.1mol/L hydrochloric acid solution, and acetic acid; slightly soluble in methanol; and almost insoluble in ethanol.
  • the melting point of crystal form A is 176.5°C-180.5°C.
  • the pKa is 3.47, 4.86, and 8.18.
  • the TGA test results of Form A show that there is a 1.2% weight loss during the heating of Form A to 120°C, and a 38.4% weight loss at 140-300°C.
  • the DSC test results of Form A show that there is an endothermic peak at 190°C.
  • the NMR test results of Form A in DMSO-d 6 do not show an obvious solvent peak. Among them, the peak corresponding to citric acid at 2.53-2.73ppm partially overlaps with the solvent peak of DMSO.
  • step (3) adding the citric acid methanol solution of step (1) to the solution of step (2) (i.e., the compound of formula (I) and citric acid in the solution); The solution was stirred for 15 min and solid precipitation was observed during the stirring process.
  • step (3) Cool the mixed solution obtained in step (3) for 3 h until its internal temperature reaches 10°C.
  • step (4) Stir the mixture of step (4) at an internal temperature of 10 ⁇ 2°C for 1 h, and crystal precipitation can be observed.
  • step (6) Filter the mixture obtained in step (5), and dry the filtrate under reduced pressure at 50° C. to obtain 27 g of the citrate crystal form B of the compound represented by formula (I) of the present application, with a yield of 76.1%.
  • the TGA test results of Form B show that there is a 2.2% weight loss during the heating of Form B to 90° C., a 1.8% weight loss from 90° C. to 140° C., and a 36.9% weight loss from 140° C. to 300° C. It can be seen that when Form B is heated to 140° C., Form B loses a total weight of 4%, which is equivalent to the theoretical water content (3.7%) of the dihydrate.
  • the DSC test results of Form B show that Form B has endothermic peaks at about 81, 133, 151 and 178° C.
  • Form B contains crystal water and is a hydrate of the dicitrate salt of the compound represented by formula (I), and in Form B, the molar ratio of the citrate salt of the compound represented by formula (I) to crystal water is about 1:2.
  • step (1) adding dimethylformamide or ethylene glycol methyl ether or trifluoroethanol into the container of step (1);
  • step (3) adding acetonitrile, ethyl acetate, methanol, ethanol or isopropanol to the solution of step (2);
  • step (3) stirring the mixture obtained in step (3) at room temperature for 1-2 days;
  • the solvent in step (3) can be ethanol, isopropanol or acetonitrile.
  • the solvent in step (3) can be ethanol.
  • the solvent added in step (2) is ethylene glycol monomethyl ether, the solvent in step (2) can be ethyl acetate.
  • the TGA test results of Form C show that there is a 0.1% weight loss during the heating of Form C to 120° C., and a 25.8% weight loss at 120-300° C.
  • the DSC test results of Form C show that at about 194° C., Form C has an endothermic peak corresponding to melting and decomposition.
  • the NMR test results of Form C in DMSO-d 6 show that the integral result at 2.54-2.75 ppm is different from the compound represented by formula (I).
  • FIG. 12 the TGA test results of Form C show that there is a 0.1% weight loss during the heating of Form C to 120° C., and a 25.8% weight loss at 120-300° C.
  • the DSC test results of Form C show that at about 194° C., Form C has an endothermic peak corresponding to melting and decomposition.
  • the NMR test results of Form C in DMSO-d 6 show that the integral result at 2.54-2.75 ppm is different from the compound represented by formula (I).
  • the preparation method of the citrate salt form D of the compound represented by formula (I) is similar to the preparation method of the form C, except that the solvent added in step (2) is dimethylformamide, and the solvent added in step (3) is methanol.
  • Form D is a methanol-citrate solvate of the compound represented by formula (I).
  • the added acid is methanesulfonic acid
  • the methanesulfonate of the compound represented by formula (I) is obtained.
  • the added acid is maleic acid
  • the maleate of the compound represented by formula (I) is obtained.
  • the fumarate of the compound represented by formula (I) is obtained.
  • L-tartrate of the compound represented by formula (I) is obtained.
  • the added acid is succinic acid
  • the succinate of the compound represented by formula (I) is obtained.
  • the crystal form B of the present invention is heated to 81° C. on an in-situ hot plate to obtain the crystal form E of the compound represented by formula (I).
  • the crystal form B of the present invention is placed in a methanol solvent, wherein the methanol solvent contains 5% water, the solution is heated to 50° C., and suspended at this temperature for 21 hours, and then the suspension is centrifuged to obtain the crystal form F of the compound represented by formula (I).
  • the preparation method of Form G is similar to that of Example 2, except that the solvent used is tetrahydrofuran, and the molar ratio of the compound represented by formula (I) to citric acid is 1:1.
  • the hydrochloride, hydrobromide, methanesulfonate, L-tartrate, succinate and citrate of the compound represented by formula (I) have excellent solubility.
  • the citrate of the compound represented by formula (I) used includes the monocitrate of the compound represented by formula (I) (the molar ratio of the compound represented by formula (I) to citric acid is 1:1) and the dicitrate of the compound represented by formula (I) (the molar ratio of the compound represented by formula (I) to citric acid is 1:2).
  • the compound of formula (I) is placed in a humid environment, wherein the initial humidity of the environment is 50%, and the humidity of the environment is increased by 15% to 95%, wherein the maintenance time of each humidity gradient is 60 minutes. After the environmental humidity is maintained at 95% for 60 minutes, the weight gain of each salt form is tested respectively to determine the hygroscopicity of the corresponding salt form.
  • the citrate salt of the compound represented by formula (I) has more excellent comprehensive properties, and its solubility and hygroscopicity are better than other salt forms.
  • the dicitrate of the compound shown in formula (I) (the molar ratio of the compound of formula (I) to citric acid is 1:2) has relatively more excellent comprehensive properties.
  • the above test results confirm that in the citrate of the compound shown in (I), the appropriate molar ratio of the compound of formula (I) to citric acid is conducive to the salt having more excellent solubility and hygroscopicity.
  • DVS Intrinsic SMS, UK was used to perform dynamic moisture adsorption and desorption analysis of the crystal form to evaluate the hygroscopicity of the crystal form.
  • the test used a gradient mode, with a humidity change of 50%-95%-50%, and a humidity change of 15% for each gradient.
  • the gradient end point was determined by the dm/dt method, with dm/dt less than 0.002% and maintained for 10 minutes as the gradient end point, or the longest maintenance time for each gradient was 60 minutes.
  • the sample was analyzed by XRPD to confirm the solid form. Whether the state has changed.
  • Form A gained 0.64% weight at 95% RH, and gained 0.25% weight at 80% RH during the adsorption process.
  • Form B gained 0.69% weight at 95% RH and gained 0.24% weight at 80% RH during the adsorption process.
  • Form C gained 3.45% weight at 95% RH, and gained 0.42% weight at 80% RH during the adsorption process.
  • Form D gained 4.45% weight at 95% RH, while only gained 0.85% weight at 80% RH during the adsorption process.
  • the stability of the crystalline form of the compound represented by formula (I) was studied under high temperature (60°C), high humidity (25°C/92.5% RH), light (25°C/4500Lux), and accelerated (40°C/75% RH) conditions, and samples were taken for XRPD characterization at 7 days and 15 days, respectively.
  • the crystal form G was placed at room temperature for 1 day, and the XRPD spectrum showed (see Figure 22) that after being placed at room temperature for one day, the crystal form G underwent a crystal form transformation.
  • the citrate crystal form A of the compound represented by formula (I) was added to water or three biological media (FaSSIF, FeSSIF and FaSSGF) to determine its solubility in the above solvents.
  • FaSSIF can be used to simulate the intestinal fluid in the small intestine of humans in a hungry state before a meal
  • FeSSIF can be used to simulate the intestinal fluid in the small intestine of humans in a full state after a meal
  • FaSSGF can be used to simulate the empty stomach of humans in a hungry state.
  • Form A was suspended in four media and dissolved within 0.5 hours, and the solution was still clear after 24 hours of suspension; the solubility of the citrate salt of the compound represented by formula (I) in the four media was FaSSGF>FeSSIF>FaSSIF>water.
  • the pH of the supernatant of Form A decreased to varying degrees after the FaSSIF and FeSSIF solubility tests, and increased after the FaSSGF solubility test.
  • Form E will transform into Form B.
  • Form B (2) placing Form B in a methanol solvent, wherein the methanol solvent contains 5% water, heating the solution to 50° C., and suspending at this temperature for 21 hours to obtain Form F;
  • Form E or Form F can be converted into Form B at room temperature, which proves that Form B has better stability than Form E or Form F.

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Abstract

本发明涉及一种式(I)化合物的枸橼酸盐。本发明还涉及一种式(I)化合物的枸橼酸盐的晶型A、晶型B、晶型C以及晶型D。本发明还涉及一种药物组合物，其包含本发明的(I)化合物的枸橼酸盐、其晶型A、晶型B、晶型C以及晶型D中的至少一种。本发明还涉及本发明的枸橼酸盐、其晶型A、晶型B、晶型C、晶型D以及本发明的药物组合物在制备用于治疗、预防或改善细胞增殖异常的药物中的用途。本发明还涉及本发明的枸橼酸盐、其晶型A、晶型B、晶型C、晶型D以及本发明的药物组合物，任选地与第二治疗剂组合，在制备用于治疗、预防或改善细胞增殖异常的药物中的用途。

Description

一种细胞周期蛋白依赖性激酶(CDK4/6)抑制剂的枸橼酸盐、其晶型、制备方法和用途
本申请要求2022年9月28日提交的，题为“一种蛋白激酶抑制剂的枸橼酸盐、其晶型、制备方法和用途”的第202211195360.2号中国专利申请的优先权，其内容整体援引加入本文。
技术领域
本发明属于药物化学领域，具体涉及一种蛋白激酶抑制剂的枸橼酸盐、其晶型A、晶型B、晶型C和晶型D，及其制备方法和用途。
背景技术
过度增殖性疾病如癌症和炎症吸引着学术界为其提供有效治疗手段，并在这方面已做出努力，识别并靶向了在增殖性疾病中发挥作用的特定机制。
肿瘤的发展与细胞周期蛋白依赖性激酶(cyclin-dependent kinase，CDK)及其调控蛋白的基因变异和调控异常密切相关，表明CDK抑制剂可能是有效的抗癌疗法。
CDK是丝氨酸/苏氨酸蛋白激酶，其是细胞周期和细胞增殖的原动力。CDK调节哺乳动物细胞周期的启动、进展和完成，并且对细胞生长很关键。大部分已知的CDK，包括CDK1至CDK9，都直接或间接参与细胞周期进展过程。直接参与细胞周期进展的CDK，如CDK1-4和CDK6，可分为G1、S或G2M期酶。异常增殖是癌症细胞的特征，CDK功能异常在许多实体瘤中高频发生。
CDK及其相关蛋白在增殖细胞中协调和驱动细胞周期的作用十分关键。因此，靶向多个CDKs或特定CDKs治疗增生异常疾病，如癌症的疗法具有极大潜力。CDK抑制剂也可被用于治疗如病毒感染，自身免疫性疾病和神经退行性疾病等其他疾病。CDK靶向疗法也可与其他治疗药物联合使用用于上述疾病的治疗。
因此，具有CDK抑制活性的化合物对癌症的预防和治疗具有重要意义。虽然CDK4/6抑制剂在文献中已有报道，如WO2010020675和WO2012064805，许多半衰期较短或者有毒性，目前全球已有三款CDK4/6抑制剂类抗肿瘤药物获得FDA上市批准，分别是辉瑞的palbociclib、诺华的ribociclib和礼来公司的abemaciclib，其用于HR+、HER2-的晚期或转移性乳腺癌绝经后女性患者的治疗。
目前对于治疗过度增殖性疾病的新型CDK4/6抑制剂的需求将越来越迫切，其在疗效、稳定性、选择性、安全性、药效学特征和药代动力学特征至少有一方面具有优势。另外，鉴于上述对CDK4/6抑制剂的稳定性、安全性等方面的考虑，也迫切需要寻求可用于长效治疗的盐型及其晶型形式。
发明内容
在一方面，本发明提供一种式(I)所示化合物的枸橼酸盐。
在一个实施方案中，所述式(I)所示化合物与枸橼酸的摩尔比为约1∶1-1∶3。
在另一方面，本发明提供式(I)所示化合物的枸橼酸盐的晶型A，其中所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：17.9±0.2°、18.4±0.2°、19.2±0.2°、19.5±0.2°和20.5±0.2°。
在另一方面，本发明提供式(I)所示化合物的枸橼酸盐的晶型B，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.3±0.2°、11.2±0.2°、14.1±0.2°、16.7±0.2°和18.4±0.2°。
在另一方面，本发明提供式(I)所示化合物的枸橼酸盐的晶型C，其中所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.0±0.2°、15.6±0.2°、19.4±0.2°、20.2±0.2°和20.8±0.2°。
在另一方面，本发明提供式(I)所示化合物的枸橼酸盐的晶型D，其中所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.0±0.2°、16.8±0.2°、18.6±0.2°、19.8±0.2°和24.6±0.2°。
在一方面，本发明提供制备式(I)所示化合物的枸橼酸盐的晶型A、晶型B以及晶型C的方法。
在一方面，本发明提供一种药物组合物，其包含选自以下的一种或多种：(i)本发明的式(I)所示化合物的枸橼酸盐；(ii)本发明的式(I)所示化合物的枸橼酸盐的晶型A；(iii)本发明的式(I)所示化合物的枸橼酸盐的晶型B；(iv)本发明的式(I)所示的化合物的枸橼酸盐的晶型C；(v)本发明的式(I)所示的化合物枸橼酸盐的晶型D。
在一方面，本发明提供本发明的式(I)所示化合物的枸橼酸盐、晶型A、晶型B、晶型C、晶型D以及本发明的组合物在制备用于治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症的药物中的用途。
在另一方面，本发明提供本发明的式(I)所示化合物的枸橼酸盐、晶型A、晶型B、晶型C、晶型D以及本发明的组合物在制备用于治疗、改善或预防细胞增殖异常的药物中的用途。
在又一方面，本发明提供本发明的式(I)所示化合物的枸橼酸盐、晶型A、晶型B、晶型C、晶型D以及本发明的组合物，其任选地与第二治疗剂组合，在制备用于治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症的药物中的用途。
在还一方面，本发明提供本发明的式(I)所示化合物的枸橼酸盐、晶型A、晶型B、晶型C、晶型D以及本发明的组合物，其任选地与第二治疗剂组合，在制备用于治疗、改善或预防细胞增殖异常的药物中的用途。
附图说明
图1为式(I)所示化合物的枸橼酸盐晶型A的X射线粉末衍射(XRPD)图谱。
图2为式(I)所示化合物的枸橼酸盐晶型A的DSC谱图。
图3为式(I)所示化合物的枸橼酸盐晶型A的TGA谱图。
图4为式(I)所示化合物的枸橼酸盐晶型A的NMR谱图，其中测试溶剂为DMSO-d6。
图5为式(I)所示化合物的枸橼酸盐晶型A的NMR谱图，其中测试溶剂为D2O。
图6为式(I)所示化合物的枸橼酸盐晶型B的X射线粉末衍射(XRPD)图谱。
图7为式(I)所示化合物的枸橼酸盐晶型B的DSC谱图。
图8为式(I)所示化合物的枸橼酸盐晶型B的TGA谱图。
图9为式(I)所示化合物的枸橼酸盐晶型B的NMR谱图，其中测试溶剂为DMSO-d6。
图10为式(I)所示化合物的枸橼酸盐晶型C的X射线粉末衍射(XRPD)图谱。
图11为式(I)所示化合物的枸橼酸盐晶型C的DSC谱图。
图12为式(I)所示化合物的枸橼酸盐晶型C的TGA谱图。
图13为式(I)所示化合物的枸橼酸盐晶型C的NMR谱图，其中测试溶剂为DMSO-d6。
图14为式(I)所示化合物的枸橼酸盐晶型C的NMR谱图，其中测试溶剂为D2O。
图15为式(I)所示化合物的枸橼酸盐晶型D的X射线粉末衍射(XRPD)图谱。
图16为式(I)所示化合物的枸橼酸盐晶型D的DSC谱图。
图17为式(I)所示化合物的枸橼酸盐晶型D的TGA谱图。
图18为式(I)所示化合物的枸橼酸盐晶型D的单晶图。
图19为式(I)所示化合物的枸橼酸盐晶型E的X射线粉末衍射(XRPD)图谱。
图20为式(I)所示化合物的枸橼酸盐晶型F的X射线粉末衍射(XRPD)图谱。
图21为式(I)所示化合物的枸橼酸盐晶型G的X射线粉末衍射(XRPD)图谱。
图22为式(I)所示化合物的枸橼酸盐晶型G于室温下放置1天后的X射线粉末衍射(XRPD)图谱。
图23为式(I)所示化合物的枸橼酸盐晶型A的DVS曲线图。
图24为式(I)所示化合物的枸橼酸盐晶型A在DVS测试前后的XRPD谱图。
图25为式(I)所示化合物的枸橼酸盐晶型B的DVS曲线图。
图26为式(I)所示化合物的枸橼酸盐晶型B在DVS测试前后的XRPD谱图。
图27为式(I)所示化合物的枸橼酸盐晶型C的DVS曲线图。
图28为式(I)所示化合物的枸橼酸盐晶型C在DVS测试前后的XRPD谱图。
图29为式(I)所示化合物的枸橼酸盐晶型D的DVS曲线图。
图30为式(I)所示化合物的枸橼酸盐晶型D在DVS测试前后的XRPD谱图。
图31为式(I)所示化合物的枸橼酸盐晶型A的稳定性测试XRPD谱图。
图32为式(I)所示化合物的枸橼酸盐晶型B的稳定性测试XRPD谱图。
图33为式(I)所示化合物的枸橼酸盐晶型C的稳定性测试XRPD谱图。
图34为式(I)所示化合物的枸橼酸盐晶型D的稳定性测试XRPD谱图。
具体实施方式
以下将对本发明进一步详细说明。这样的描述为说明目的，而非限制本发明。本领域技术人员可由本说明书公开的内容容易地了解本发明的其它优点与功效。本发明也可以通过其它不同的具体实施例加以施行或应用。本领域技术人员在不背离本发明的精神前提下，进行各种修饰与变更。
一般定义和术语
如果没有另行指出，在此所提及的所有出版物、专利申请、专利和其它参考文献通过援引以其全部并入本文。
除非另有定义，本文使用的所有技术和科学术语具有与本发明所属领域技术人员通常理解的相同的含义。若存在矛盾，则以本文提供的定义为准。
除非另有说明，所有的百分比、份数、比例等都是按重量计的。
当给出数量、浓度或其它值或参数作为范围、优选范围或优选的上限值和下限值或者具体的值时，应将其理解为特定公开了从任意上限范围或优选值与任意下限范围或优选值的成对数值所形成的所有范围，而无论范围是否单独地被公开。除非另有说明，当本文引用数值范围时，所述的范围是指包括其端点、以及所有该范围内的整数和分数。本发明的范围并不限制于当定义范围时所引用的特定数值。例如“1-20”涵盖1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20以及由其中任何两个值组成的任何亚范围，例如2-6、3-5、2-10、3-15、4-20、5-19等。例如“1∶1-1∶5”涵盖1∶1、1∶2、1∶3、1∶4、1∶5以及由其中任何两个值组成的任何亚范围，例如1∶1-1∶4、1∶1-1∶3、1∶1-1∶2、1∶2-1∶4、1∶2-1∶3等。
文中所使用的术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。
文中所使用的术语“选自...”是指在后面所列的组中的一个或多个元素，独立地加以选择，并且可以包括两个或更多个元素的组合。
本文所使用的术语“一种或多种”或“至少一种”指一种、两种、三种、四种、五种、六种、七种、八种、九种或更多种。
除非另有说明，术语“其组合”及“其混合物”，表示所述各元素的多组分混合物，例如两种、三种、四种以及直到最大可能的多组分混合物。
此外，本发明的部件或组分之前未标明个数的，表示对于部件或组分的出现(或存在)数是没有限制的。因此，应当解读为包括一个或至少一个，并且部件或组分的单数词形式也包括复数，除非该数值明显地表示单数。
文中所使用的本文所使用的术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
文中所使用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由...组成”的含义。表述“由...组成”排除未指明的任何元素、步骤或成分。表述“基本上由...组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤 或成分。应当理解，表述“包含”涵盖表述“基本上由...组成”和“由...组成”。
文中所使用的术语“药学上可接受的”是指在正常的医学判断范围内与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比且能有效用于目的用途。
文中所使用的术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定型物质相反，其产生有边界清楚的蜂的特征性X射线粉末衍射图谱。
文中所使用的术语“无定形”是指三维上无排序的任意固体物质。
文中所使用的术语“水合物”是指本文提供的化合物的盐，其进一步包括通过非共价键分子间作用力结合的化学计量或非化学计量的量的水。
文中所使用的术语“混合物”指由两种或更多种物质混合而成的物质。在本发明中，“混合物”以非共价键形式连接或结合，具有特定数值或特定数值范围的分子式、组成比(摩尔比或质量比)，具有稳定的物理化学性质及生物学特性。
在本文中，术语“枸橼酸盐”与“柠檬酸盐”可以互换使用，均指游离碱化合物与柠檬酸形成的盐型。
在本文中，术语“式(I)所示化合物的枸橼酸盐”是指式(I)所示化合物的游离碱与枸橼酸形成的盐。术语“式(I)所示化合物的一枸橼酸盐”是指在所述枸橼酸盐中，式(I)化合物与枸橼酸的摩尔比为约1∶1。术语“式(I)所示化合物的二枸橼酸盐”是指在所述枸橼酸盐中，式(I)化合物与枸橼酸的摩尔比为约1∶2。术语“式(I)所示化合物的枸橼酸盐的晶型”是指晶体形式的式(I)化合物的枸橼酸盐。根据晶型中是否包含溶剂分子，其可以是溶剂合物的晶型，或者晶型中也可以不包含溶剂分子。其中所述溶剂可以为甲醇或水。在溶剂为水的情况下，也可以称为相应的水合物。
文中所使用的术语“药物组合物”指活性成分，其任选地与一种或多种药学上可接受的化学成分(例如，但不限于载体和/或赋形剂)组合。所述活性成分例如可以为式(I)所示化合物的枸橼酸盐、其晶型或其组合。
文中所使用的术语“活性成分”是指一种化学实体，其可以有效地治疗或预防目标疾病或病症。
文中所使用的术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体，包括但不限于可接受用于人或动物(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。所述载体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、植物油和聚乙二醇等。关于载体的其他信息，可以参考Remington：The Science and Practice of Pharmacy，21st Ed.，Lippincott，Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
文中所使用的术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服、肠胃外(包括静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。
针对药物或药理学活性剂而言，术语“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。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”可以 是与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。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。
文中所使用的术语“非共价键形式”指共价键以外的分子间弱相互作用，包括但不限于氢键、范德华力、盐键、疏水作用力、芳环堆积作用、π-π堆积、卤键等。
本文中所使用的术语“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。
在X-射线粉末衍射(XRPD或XRD)光谱中，由结晶化合物得到的衍射谱图对于特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径和其他测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶型并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的晶型而言，峰的位置可能存在轻微误差，这在晶体学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动或仪器的标定等，峰的位置可以移动，2θ值的测定误差有时约为±0.2°。因此，在确定每种晶型结构时，应该将此误差考虑在内。如果本发明的晶型被描述为基本上如指定附图所示，则术语“基本上”也意图涵盖衍射峰位中的这样的差异性。
在XRPD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ表入射X射线的波长，θ为衍射角。对于同种化合物的同种晶型，其XRPD谱的峰位置在整体上具有相似性，相对强度误差可能较大。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的晶体是特征性的。
本文中所使用的术语“2θ”是指基于X射线衍射实验的实验设置的以度数表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果当入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶体形式的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。
本文中所使用的术语“热重分析(TGA)图谱”是指由热重分析仪记录到的曲线。
本文中所使用的术语“差示扫描量热(DSC)图谱”是指由差示扫描量热仪记录到的曲线。
本文中所使用的术语“核磁共振(1H-NMR)图谱”是指由核磁共振仪记录到的信号峰。
式(I)化合物的盐
本发明提供一种蛋白激酶抑制剂，也即式(I)所示化合物的枸橼酸盐。
在一个实施方案中，式(I)所示化合物与枸橼酸的摩尔比为约1∶1-1∶3。在一个优选的实施方案中，在式(I)所示化合物的枸橼酸盐中，所述化合物与枸橼酸的摩尔比为约1∶1-1∶2。在一个更优选的实施方案中，在式(I)所示化合物的枸橼酸盐中，所述化合物与枸橼酸的摩尔比为约1∶2。例如约1∶1、约1∶2、约1∶3。
在一个优选的实施方案中，在式(I)所示化合物的枸橼酸盐中，所述化合物与枸橼酸的摩尔比为约1∶2，其具有如下所示的化学结构：
在另一个优选的实施方案中，在式(I)所示化合物的枸橼酸盐中，所述化合物与枸橼酸的摩尔比为约1∶1，其具有如下所示的化学结构：
在本发明的式(I)所示化合物的枸橼酸盐中，所述化合物与枸橼酸的合适的摩尔比有利于使枸橼酸盐具有优异的性质。过高的化合物与枸橼酸的摩尔比不利于获得性质优异的枸橼酸盐，例如，过高的化合物与枸橼酸的摩尔比使得枸橼酸盐的稳定性及溶解度降低。过低的化合物与枸橼酸的摩尔比不利于获得性质优异的枸橼酸盐，例如，过低的化合物与枸橼酸的摩尔比使得枸橼酸盐的稳定性及溶解度降低。
式(I)化合物的枸橼酸盐的晶型
晶型A
在一方面，本发明提供式(I)所示化合物的枸橼酸盐的晶型A。
在一个实施方案中，在本发明的式(I)所示化合物的枸橼酸盐的晶型A中，所述化合 物与枸橼酸的摩尔比为约1∶2。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型A不含有结晶水。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：17.9±0.2°、18.4±0.2°、19.2±0.2°、19.5±0.2°和20.5±0.2°。
在一个优选的实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.8±0.2°、11.6±0.2°、15.0±0.2°、17.2±0.2°、17.6±0.2°、17.9±0.2°、18.4±0.2°、19.2±0.2°、19.5±0.2°和20.5±0.2°。
在一个更优选的实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.8±0.2°、9.8±0.2°、11.2±0.2°、11.6±0.2°、11.8±0.2°、12.6±0.2°、12.8±0.2°、15.0±0.2°、16.8±0.2°、17.2±0.2°、17.6±0.2°、17.9±0.2°、18.4±0.2°、19.2±0.2°、19.5±0.2°、20.5±0.2°、21.1±0.2°、21.9±0.2°、24.7±0.2°和25.2±0.2°。
在一个特别优选的实施方案中，所述晶型A的XRPD图谱如图1所示。
在一个具体的实施方案中，所述晶型A的XRPD图谱解析数据如表1所示。
表1晶型A的XRPD图谱解析数据
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型A的示差扫描量热曲线(DSC)在190.1±3℃处有一个吸热峰。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型A的DSC图谱如图2所示。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型A的热重分析曲线(TGA)在120.52±3℃时失重达1.2％。在一个实施方案中本发明的式(I)所示化合物的枸 橼酸盐的晶型A的热重分析曲线(TGA)在140-300±3℃时失重达38.4％。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型A的TGA图谱如图3所示。
晶型B
在一方面，本发明提供式(I)所示化合物的枸橼酸盐的晶型B。
在一个实施方案中，在本发明的式(I)所示的化合物的枸橼酸盐的晶型B中，所述化合物与枸橼酸的摩尔比为约1∶2。
在另一个实施方案中，在本发明的式(I)所示化合物的枸橼酸盐的晶型B中，所述晶型B为枸橼酸盐的水合物的晶型。
在一个具体的实施方案中，在本发明的式(I)所示化合物的枸橼酸盐的晶型B中，式(I)所示化合物的枸橼酸盐与结晶水的摩尔比为约1∶2。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.3±0.2°、11.2±0.2°、14.1±0.2°、16.7±0.2°和18.4±0.2°。
在一个优选的实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.3±0.2°、7.0±0.2°、8.3±0.2°、11.2±0.2°、11.8±0.2°、14.1±0.2°、14.8±0.2°、16.0±0.2°、16.7±0.2°、18.4±0.2°、22.5±0.2°、22.8±0.2°、23.9±0.2°、24.4±0.2°和25.0±0.2°。
在一个更优选的实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶体B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.3±0.2°、7.0±0.2°、8.3±0.2°、10.2±0.2°、11.2±0.2°、11.8±0.2°、13.2±0.2°、14.1±0.2°、14.8±0.2°、16.0±0.2°、16.7±0.2°、18.4±0.2°、19.7±0.2°、20.1±0.2°、21.0±0.2°、21.3±0.2°、22.5±0.2°、22.8±0.2°、23.0±0.2°、23.9±0.2°、24.4±0.2°和25.0±0.2°。
在一个实施方案中，所述晶型B的XRPD图谱如图6所示。
在一个具体的实施方案中，所述晶型B的XRPD图谱解析数据如表2所示。
表2晶型B的XRPD图谱解析数据

在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型B的示差扫描量热曲线(DSC)在81.0±3℃、133.2±3℃、150.6±3℃和177.9±3℃处分别有一个吸热峰。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型B的DSC图谱如图7所示。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型B的热重分析曲线(TGA)在90±3℃时失重达2.2％。在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型B的热重分析曲线(TGA)在90-140±3℃失重达1.8％。在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型B的热重分析曲线(TGA)在140-300±3℃失重达36.9％。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型B的TGA图谱如图8所示。
晶型C
在另一方面，本发明提供式(I)所示化合物的枸橼酸盐的晶型C。
在一个实施方案中，在本发明的式(I)所示化合物的枸橼酸盐的晶型C中，所述化合物与枸橼酸的摩尔比为约1∶1。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C不含有结晶水。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.0±0.2°、15.6±0.2°、19.4±0.2°、20.2±0.2°和20.8±0.2°。
在一个优选的实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.7±0.2°、10.0±0.2°、11.9±0.2°、15.0±0.2°、15.6±0.2°、16.8±0.2°、19.4±0.2°、19.9±0.2°、20.2±0.2°和20.8±0.2°。
在一个更优选的实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.7±0.2°、10.0±0.2°、10.6±0.2°、11.2±0.2°、11.9±0.2°、12.6±0.2°、13.0±0.2°、13.4±0.2°、14.6±0.2°、15.0±0.2°、15.6±0.2°、16.0±0.2°、16.8±0.2°、17.5±0.2°、17.8±0.2°、18.0±0.2°、19.4±0.2°、19.9±0.2°、20.2±0.2°、20.8±0.2°、23.0±0.2°、23.7±0.2°、25.4±0.2°和26.2±0.2°。
在一个实施方案中，所述晶型C的XRPD图谱如图10所示。
在一个具体的实施方案中，所述晶型C的XRPD图谱解析数据如表3所示。
表3晶型C的XRPD图谱解析数据

在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C的示差扫描量热曲线(DSC)在194.3±3℃处有一个吸热峰。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C的DSC图谱如图11所示。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C的热重分析曲线(TGA)在120±3℃时失重达0.1％。在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C的热重分析曲线(TGA)在120-300±3℃时失重达25.8％。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型C的TGA图谱如图12所示。
晶型D
在另一方面，本发明提供式(I)所示化合物的枸橼酸盐的晶型D。
在一个实施方案中，在本发明的式(I)所示的化合物的枸橼酸盐的晶型D中，所述化合物与枸橼酸的摩尔比为约1∶1。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型D为式(I)化合物的枸橼酸盐的甲醇溶剂合物。
在一个实施方案中，在本发明的式(I)所示的化合物的枸橼酸盐的晶型D中，式(I)化合物的枸橼酸盐与甲醇的摩尔比为约1∶1。
在另一个实施方案中，发明的式(I)所示化合物的枸橼酸盐的晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.0±0.2°、16.8±0.2°、18.6±0.2°、19.8±0.2°和24.6±0.2°。
在一个优选的实施方案中，发明的式(I)所示化合物的枸橼酸盐的晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.0±0.2°、7.1±0.2°、14.0±0.2°、15.4±0.2°、 16.8±0.2°、18.2±0.2°、18.6±0.2°、19.6±0.2°、19.8±0.2°、23.3±0.2°、24.6±0.2°和28.1±0.2°。
在一个更优选的实施方案中，发明的式(I)所示化合物的枸橼酸盐的晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.0±0.2°、7.1±0.2°、9.2±0.2°、11.3±0.2°、12.1±0.2°、14.0±0.2°、15.4±0.2°、15.7±0.2°、16.8±0.2°、17.4±0.2°、18.2±0.2°、18.6±0.2°、19.0±0.2°、19.6±0.2°、19.8±0.2°、21.0±0.2°、21.2±0.2°、22.4±0.2°、22.7±0.2°、23.3±0.2°、23.5±0.2°、23.7±0.2°、24.6±0.2°、28.1±0.2°和28.8±0.2°。
在一个实施方案中，所述晶型D的XRPD图谱如图15所示。
在一个具体的实施方案中，所述晶型D的XRPD图谱解析数据如表4所示。
表4晶型D的XRPD图谱解析数据
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型D的示差扫描量热曲线在148.4±3℃、160.8℃和184.1℃处分别有一个吸热峰。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型D的DSC图谱如 图16所示。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型D的热重分析曲线(TGA)在110±3℃时失重达0.6％。在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型D的热重分析曲线(TGA)在110-150±3℃时失重达1.7％。在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型D的热重分析曲线(TGA)在150-300±3℃时失重达27.7％。
在一个实施方案中，本发明的式(I)所示化合物的枸橼酸盐的晶型D的TGA图谱如图17所示。
制备方法
晶型A的制备方法
在另一方面，本发明提供一种制备式(I)所示化合物的枸橼酸盐的晶型A方法，其包括以下步骤：
提供枸橼酸的溶液；
提供式(I)化合物的溶液；
向式(I)化合物的溶液中加入枸橼酸的溶液；
搅拌获得的溶液并冷却；
过滤冷却的溶液并干燥滤出物，获得式(I)化合物的晶型A。
在一个具体地实施方案中，所述式(I)所示化合物的枸橼酸盐为式(I)所示化合物的二枸橼酸盐。
在一个具体的实施方案中，所述枸橼酸的溶液溶剂为醇类溶剂。在一个具体的实施方案中，所述枸橼酸的溶液溶剂为醚类溶剂。在一个具体的实施方案中，所述枸橼酸的溶液溶剂为腈类溶剂。在一个具体的实施方案中，所述枸橼酸的溶液溶剂为酮类溶剂。
在一个具体的实施方案中，所述式(I)化合物的溶液的溶剂为醇类溶剂。在一个具体的实施方案中，所述式(I)化合物的溶液的溶剂为醚类溶剂。在一个具体的实施方案中，所述式(I)化合物的溶液的溶剂为腈类溶剂。在一个具体的实施方案中，所述式(I)化合物的溶液的溶剂为酮类溶剂。
在一个优选的实施方案中，所述醇类溶剂选自甲醇、乙醇、异丙醇、正丙醇、正丁醇及其组合。在一个更优选的实施方案中，所述醇类溶剂选自甲醇、乙醇、异丙醇及其组合。例如甲醇、乙醇或正丙醇。
在一个优选的实施方案中，所述醚类溶剂选自乙醚、乙二醇甲醚、乙二醇二甲醚及其组合。在一个更优选的实施方案中，所述醚类溶剂选自乙二醇甲醚、乙二醇二甲醚及其组合。
在一个优选的实施方案中，所述腈类溶剂选自乙腈、丙腈、丁腈及其组合。在一个更优选的实施方案中，所述腈类溶剂为乙腈。
在一个优选的实施方案中，所述酮类溶剂选自丙酮、丁酮、4-甲基-2-戊酮及其组合。在一个更优选的实施方案中，所述酮类溶剂选自丙酮、4-甲基-2-戊酮及其组合。
在本发明的制备晶型A的方法中，合适的醇类溶剂有利于获得本发明的晶型A。
在一个具体的实施方案中，加热式(I)化合物的溶液。在一个优选的实施方案中，加 热式(I)化合物的溶液，并控制溶液的内温为50-55℃。
在一个具体的实施方案中，加热并控制式(I)化合物的溶液内温为50-55℃后，进一步搅拌获得的溶液，可观察到固体析出。
在一个具体的实施方案中，冷却式(I)化合物与枸橼酸的混合溶液至内温为10℃。在一个进一步的实施方案中，控制式(I)化合物与枸橼酸的混合溶液内温为10±2℃，并搅拌所述溶液，可观察到晶体析出。
在一个实施方案中，在枸橼酸的溶液中，加入的式(I)化合物与枸橼酸的摩尔比为约1∶3-1∶5。在一个优选的实施方案中，加入的式(I)化合物与枸橼酸的摩尔比为约1∶3-1∶4。例如约1∶3、约1∶3.5、约1∶4、约1∶5。在本发明的制备晶型A的方法中，合适的式(I)化合物与枸橼酸的摩尔比有利于获得本发明的晶型A。
晶型B的制备方法
在另一方面，本发明提供一种制备式(I)所示化合物的枸橼酸盐的晶型B方法，其包括以下步骤：
提供枸橼酸的溶液；
提供式(I)化合物的溶液；
向式(I)化合物的溶液中加入枸橼酸的溶液；
搅拌获得的溶液并冷却；
过滤冷却的溶液并干燥滤出物，获得式(I)化合物的晶型B。
在一个具体地实施方案中，所述式(I)所示化合物的枸橼酸盐为式(I)所示化合物的二枸橼酸盐。
在一个实施方案中，所述溶液的溶剂选自醇类溶剂、水及其组合。
在一个具体的实施方案中，所述枸橼酸的溶液的溶剂为醇类溶剂。
在一个具体的实施方案中，所述式(I)化合物的溶液的溶剂为醇类溶剂和水。
在一个实施方案中，所述醇类溶剂选自甲醇、乙醇、异丙醇、正丙醇及其组合。在一个优选的实施方案中，所述醇类溶剂选自甲醇、乙醇及其组合。例如甲醇、乙醇或正丙醇。
在本发明的制备晶型B的方法中，合适的醇类溶剂有利于获得本发明的晶型B。
在一个优选的实施方案中，在式(I)化合物的溶液中，所述醇类溶剂与水的质量比为约10∶1-3∶1。在一个更优选的实施方案中，在步骤(2)中，所述醇类溶剂与水的质量比为约6∶1-4∶1。例如约10∶1、约9∶1、约8∶1、约7∶1、约6∶1、约5∶1、约4∶1、约3∶1。在本发明的制备晶型B的方法中，合适的式(I)化合物与枸橼酸的摩尔比有利于获得本发明的晶型B。
在一个具体的实施方案中，加热式(I)化合物的溶液。在一个优选的实施方案中，加热式(I)化合物的溶液，并控制溶液的内温为50-55℃。
在一个具体的实施方案中，加热并控制式(I)化合物的溶液内温为50-55℃后，进一步搅拌获得的溶液，可观察到固体析出。
在一个具体的实施方案中，冷却式(I)化合物与枸橼酸的混合溶液至内温为10℃。在一个进一步的实施方案中，控制式(I)化合物与枸橼酸的混合溶液内温为10±2℃，并 搅拌所述溶液，可观察到晶体析出。
在一个实施方案中，在枸橼酸的溶液，加入的式(I)化合物与枸橼酸的摩尔比为约1∶3-1∶5。在一个优选的实施方案中，加入的式(I)化合物与枸橼酸的摩尔比为约1∶3-1∶4。例如约1∶3、约1∶4、约1∶5。在本发明的制备晶型B的方法中，合适的式(I)化合物与枸橼酸的摩尔比有利于获得本发明的晶型B。
晶型C的制备方法
在另一方面，本发明提供一种制备式(I)所示化合物的枸橼酸盐的晶型C方法，其包括以下步骤：
向溶剂X中加入式(I)所示化合物的枸橼酸盐，以获得溶液；
上述溶液中加入溶剂Y，并于室温下搅拌；
离心分离获得晶型C。
在一个具体的实施方案中，所述式(I)所示化合物的枸橼酸盐为式(I)所示化合物的二枸橼酸盐。
在一个实施方案中，所述溶剂X选自二甲基甲酰胺、乙二醇甲醚及其组合。
在一个实施方案中，所述溶剂Y选自乙腈、乙酸乙酯、甲醇、乙醇、异丙醇及其组合。
在本发明的制备晶型C的方法中，合适的醇类溶剂有利于获得本发明的晶型C。
在一个优选的实施方案中，所述溶剂X与溶剂Y的体积比为约5∶1-10∶1。例如约5∶1、约6∶1、约7∶1、约8∶1、约9∶1、约10∶1。
在一个优选的实施方案中，溶液搅拌的时间为约1-3天。例如1天、2天或3天。
晶型D的制备方法
在一个实施方案中，使用晶型C的制备方法制备晶型D，所述溶剂为醇类溶剂。在一个更优先的实施方案中，所述溶剂为甲醇。
药物组合物和给药
在一方面，本发明提供一种药物组合物，其包含选自以下的一种或多种：(i)本发明式(I)所示化合物的枸橼酸盐；(ii)本发明式(I)所示化合物的枸橼酸盐的晶型A；(iii)本发明式(I)所示化合物的枸橼酸盐的晶型B；(iv)本发明式(I)所示的化合物的枸橼酸盐的晶型C；(v)本发明式(I)所示的化合物的枸橼酸盐的晶型D。
在一方面，本发明提供一种药物组合物，其包含式(I)所示化合物的枸橼酸盐，以及一种或多种药学上可接受的载体。
在另一方面，本发明提供一种药物组合物，其包含式(I)所示化合物的枸橼酸盐的晶型A，以及一种或多种药学上可接受的载体。
在又一方面，本发明提供一种药物组合物，其包含式(I)所示化合物的枸橼酸盐的晶型B，以及一种或多种药学上可接受的载体。
在还一方面本发明提供一种药物组合物，其包含式(I)所示化合物的枸橼酸盐的晶型C，以及一种或多种药学上可接受的载体。
在另一方面，本发明提供一种药物组合物，其包含式(I)所示化合物的枸橼酸盐的晶型D，以及一种或多种药学上可接受的载体。
本文中所使用的术语“药学上可接受的载体”是指与活性成分一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
以纯的形式或以适宜的药物组合物形式给药本发明化合物的盐或其晶型可通过提供类似用途的药剂的任何可接受给药模式来进行。本发明的药物组合物可通过将本发明的化合物的盐或其晶型与适宜的药学上可接受的载体组合而制备。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法等等。
一般地，每日剂量为0.001至100mg/kg体重时可达到满意的结果，具体来说，从约0.03至2.5mg/kg体重。较大型哺乳动物的日剂量，如人类，可从约0.5mg至约2000mg，或更具体来说，从0.5mg至1000mg，以方便的形式给药，例如，以分剂量最多每日四次或以缓释形式。合适的口服给药的单位剂量形式包含约1至50mg活性成分。
给药本发明的化合物或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、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。
在优选的实施方案中，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物可接受的载体、赋形剂和/或介质混合，来配制该药物组合物。可以常规方式通过混合、制粒、包衣、溶解或冷冻干燥流程来制造本发明的药物组合物。这些载体、赋形剂和介质能使本发明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。例如，药物组合物包含一个本发明所述化合物与至少一个药学可接受载体或稀释剂组合，可以以常规方式通过与药学可接受载体或稀释剂混合制成。用于口服的单位剂量形式包含，例如，从约0.1mg至约500mg活性物质。
在一个实施例中，药物组合物为活性成分的溶液，包含混悬剂或分散物，如等张水溶液。在仅包含活性成分或与如甘露醇的载体混合的冻干组合物的情况下，分散体或悬浮液可在使用前进行补充。药物组合物可以被灭菌和/或含有佐剂，如防腐剂、稳定剂、湿润剂或乳化剂、溶解促进剂、调节渗透压的盐和/或缓冲剂。合适的防腐剂包括但不仅限于抗氧化剂如抗坏血酸，杀微生物剂，如山梨酸或苯甲酸。溶液或悬浮液还可以包含增粘剂，包括但不仅限于羧甲基纤维素钠、羧甲基纤维素、葡聚糖、聚乙烯吡咯烷酮、明胶，或增溶剂，例如吐温80(聚氧乙烯(20)失水山梨醇单油酸酯)。
悬浮液在油中可能包含作为油性成分的植物油，合成或半合成的油，常用于注射目的。实施例包括含有作为酸组分的具有8至22个碳原子，或在一些实施方案中，从12至22个碳原子的长链脂肪酸的液体脂肪酸酯。合适的液体脂肪酸酯包括但不限于月桂酸、十三烷酸、肉豆蔻酸、十五烷酸、棕榈酸、十七烷酸、硬脂酸、花生酸、山萮酸或相应的不饱和酸，例如油酸、反油酸、芥酸、巴西烯酸和亚油酸，如果需要，可以含有抗氧化剂，例如维生素E、3-胡萝卜素或3，5-二-叔丁基羟基甲苯。这些脂肪酸酯的醇组分可以具有六个碳原子，并且可以是单价或多价的，例如单-，二-或三价的醇。合适的 醇组分包括但不限于甲醇、乙醇、丙醇、丁醇或戊醇或者其异构体、乙二醇和甘油。
其它合适的脂肪酸酯包括但不限于油酸乙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、M2375(聚氧乙烯甘油)、M1944 CS(通过醇解杏仁油的不饱和聚乙二醇化甘油酯和含有甘油酯和聚乙二醇酯)、LABRASOLTM(通过醇解TCM制备的饱和聚乙二醇化甘油酯和包含甘油酯和聚乙二醇酯；均可从法国GaKefosse公司获得)、和/或812(德国Hüls AG公司的链长为C8至C12的饱和脂肪酸甘油三酯)，以及植物油如棉子油、杏仁油、橄榄油、蓖麻油、芝麻油、豆油或花生油。
在一个实施方案中，可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其他合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。
合适的载体包括但不限于填充剂，例如糖，纤维素制剂和/或磷酸钙，粘合剂，和/或，如果需要的话，崩解剂。另外的赋形剂包括流动调节剂和润滑剂。
可以为片剂芯提供合适的，可选肠溶的包衣，或者溶于合适有机溶剂或溶剂混合物的涂层溶液，或者，对于肠溶衣。染料或颜料可以加入片剂或片剂包衣中。
用于口服给药的药物组合物还可以包括硬胶囊，包括明胶或含有明胶和增塑剂，如甘油或山梨醇的软密封胶囊。硬胶囊剂可含有活性成分的颗粒的形式，例如与填充剂如玉米淀粉，粘合剂和/或助流剂如滑石粉或硬脂酸镁，和任选的稳定剂混合。在软胶囊中，活性成分可以溶解或悬浮于合适的液体赋形剂如脂肪油，石蜡油或液体聚乙二醇或者乙二醇或丙二醇的脂肪酸酯中，向其中稳定剂和洗涤剂，例如聚氧乙烯山梨糖醇的脂肪酸酯型，也可加入。
适用于直肠给药的药物组合物，例如栓剂，其包含活性成分和栓剂基质的组合。合适的栓剂基质是，例如，天然或合成的甘油三酯、石蜡烃、聚乙二醇或高级链烷醇。
适于胃肠外给药的药物组合物可包含水溶性形式的活性成分，例如水溶性盐或包含增加粘度的物质的含水注射悬浮液，例如羧甲基纤维素钠，山梨糖醇的水溶液和/或葡聚糖，如果需要，和稳定剂。将活性成分，任选地与赋形剂，也可以是在一个冷冻干燥的形式，并且可在非肠道给药前通过加入合适的溶剂制成的溶液。使用的解决方案，例如，用于胃肠外给药，也可以用作输注溶液。注射制剂的制备通常在无菌条件下，填充进，例如，安瓿或小瓶，和密封的容器中。
本发明所述化合物可以作为唯一的活性成分，或与其它在免疫调节疗法有用的或抗肿瘤性疾病有用的药物一起给药。例如，本发明所述化合物与对上述各种疾病有效的药学组合物一起使用，例如，可以使用本发明所述化合物与芳香化酶抑制剂(例如来曲唑、阿那曲唑、依西美坦)；或者也与选择性雌激素受体调节剂(例如氟维司群、他莫昔芬)；或者也与性腺激素释放激素激动剂(例如戈舍瑞林、亮丙瑞林、曲普瑞林、布舍瑞林)；或者也与环磷酰胺、5-氟尿嘧啶、氟达拉滨、吉西他滨、顺铂、卡铂、长春新碱、长春碱、依托泊苷、伊立替康、紫杉醇、多西他赛、利妥昔单抗、多柔比星、吉非替尼或伊马替尼；或者也与环孢菌素、雷帕霉素、子囊霉素或它们的免疫抑制类似物，例如环孢菌素A、环孢菌素G、FK-506、西罗莫司和依维莫司，糖皮质激素，如：泼尼松、环磷酰胺、硫唑嘌呤、甲氨蝶呤、金盐、柳氮磺吡啶、抗疟药、布喹那、来氟米特、咪唑立 宾、麦考酚酸、麦考酚酸、酚酸酯和15-脱氧精胍菌素，免疫抑制单克隆抗体，例如单克隆抗体白细胞受体，例如MHC、CD2、CD3、CD4、CD7、CD25、CD28、I CD40、CD45、CD58、CD80、CD86、CD152、CD137、CD154、ICOS、LFA-1、VLA-4或它们的配体或其它免疫调节化合物，例如CTLA41g。
制药用途
在一方面，本发明提供本发明式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物在制备用于治疗、改善或预防细胞增殖异常的药物中的用途。
在一个实施方案中，本发明提供一种治疗、改善或预防细胞增殖异常的方法，其包括向有需要的个体给药治疗有效量的本发明式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物。
在另一个实施方案中，本发明提供本发明式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物，其用于治疗、改善或预防细胞增殖异常。
在另一方面，本发明提供本发明式(I)所示化合物的枸橼酸盐或本发明式(I)化合物的枸橼酸盐的晶型A或本发明式(I)化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物在制备用于治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症的药物中的用途。
在一个实施方案中，本发明提供一种治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症的方法，其包括向有需要的个体给药治疗有效量的本发明式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物。
在另一个实施方案中，本发明提供本发明式(I)化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物，其用于治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症。
在一个实施方案中，所述细胞增殖性疾病选自：癌性增殖性疾病(例如脑、肺、鳞状细胞、膀胱、胃、胰腺、乳腺、头、颈、肾、卵巢、前列腺、结肠直肠、表皮、食道、睾丸、妇科或甲状腺癌)；非癌性增殖性疾病(例如良性皮肤增生(如银屑病)、再狭窄和良性前列腺肥大(BPH))；胰腺炎；肾脏疾病；疼痛；防止胚泡着床；治疗与血管发生或血管生成相关疾病(例如肿瘤血管生成、急性和慢性炎症性疾病如类风湿性关节炎、动 脉粥样硬化、炎性肠病、皮肤病如银屑病、湿疹和硬皮病、糖尿病、糖尿病性视网膜病变、早产儿视网膜病变、老年性黄斑变性、血管瘤、神经胶质瘤、黑色素瘤、卡波济氏肉瘤和卵巢癌、乳腺癌、肺癌、胰腺癌、前列腺癌、结肠癌和表皮样癌)；哮喘；中性粒细胞趋化性(例如，心肌梗死和中风的再灌注损伤和炎症性关节炎)；感染性休克；T细胞介导的疾病，其中免疫抑制很有价值(如预防器官移植排斥、移植物抗宿主病、红斑狼疮、多发性硬化和类风湿关节炎)；动脉粥样硬化；抑制对生长因子混合物反应的角质细胞；肺慢性阻塞性疾病(COPD)和其他疾病。
在一个优选的实施方案中，所述细胞增殖性疾病并为激素受体(HR)、人表皮生长因子受体2(HER2)阴性的晚期或转移性乳腺癌。
在一个实施方案中，4/6基因突变造成上述疾病，例如黑色素瘤、肺癌、结肠癌等。
联合用药
本发明所述的式(I)所示的化合物的枸橼酸盐、其晶型A-D或组合物可以单独使用，或与其他治疗剂联合使用。
例如，使用辅佐药物可增强本发明中的化合物的枸橼酸盐或其晶型的治疗效果(例如，单独使用辅佐药物的治疗性获益极小，但与另一种药物合用时，可增强个体的治疗性获益)，或者，例如，本发明化合物的枸橼酸盐或其晶型与另一个同样具有疗效的治疗剂合用可增强个体的治疗获益。例如，治疗痛风时，使用本发明的化合物的枸橼酸盐或其晶型时，合并使用另一种治疗痛风的药物，有可能会增强临床获益。或者，例如，如果使用本发明化合物的枸橼酸盐或其晶型的不良反应是恶心，那么可合用抗恶心的药物。或者，还可以联合的疗法包括，但不仅限于物理疗法、心理疗法、放射疗法、疾病区域的压迫疗法、休息和膳食改善等。无论何种疾病、不适或症状，两种疗法使个体的治疗受益应具有加成效应或协同效应。
在本发明化合物的枸橼酸盐或其晶型与其他治疗剂合用情况下，本发明化合物的药物组合物给药途径可与其他药物相同，或由于物理和化学性质不同，给药途径可以不相同。例如，本发明化合物的枸橼酸盐或其晶型口服给药可产生并维持良好血药水平，而另一种治疗剂可能需要静脉给药。因此本发明化合物的枸橼酸盐或其晶型与另一治疗剂可同时、先后或分别给药。
式(I)所示的化合物的枸橼酸盐或其晶型与如下一种或多种药物合用预期有效：烷化剂、血管生成抑制剂、抗体、抗代谢物、抗有丝分裂、抗增生、抗病毒剂、aurora激酶抑制剂、其他细胞凋亡的启动子(例如，Bcl-xL、Bcl-w和Bfl-1)抑制剂、死亡受体途径活化剂、Bcr-Abl激酶抑制剂、BiTE(双特异性T细胞衔接器)的抗体、抗体药物偶联物、生物反应调节剂、细胞周期蛋白依赖性激酶抑制剂、细胞周期抑制剂、环氧合酶-2抑制剂、DVDs、白血病病毒癌基因同源基因(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白乙酰化酶(HDAC)抑制剂、激素疗法、免疫制剂、细胞凋亡蛋白抑制剂的抑制剂(IAPs)、嵌入抗生素、激酶抑制剂、驱动蛋白抑制剂、JAK2抑制剂、针对哺乳动物的雷帕霉素抑制剂、微RNA、丝裂原活化的细胞外信号调节的激酶抑制剂、多价结合蛋白、非类固醇类抗炎药(NSAIDs)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂、铂类化疗药物、polo样激酶(Plk)抑制剂、磷酸肌醇3激酶(PI3K)抑制 剂、蛋白酶体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、类视黄醇/deltoid植物生物碱、小干扰RNA(siRNAs)、拓扑异构酶抑制剂、泛素连接酶抑制剂和类似物。
在一个实施方案中，本发明提供本发明的式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物，其任选地与第二治疗剂组合，在制备用于治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症的药物中的用途。
在一个实施方案，本发明提供一种治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症的方法，其包括向有需要的个体给药治疗有效量的本发明式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物，以及任选的第二治疗剂。
在一个实施方案，本发明提供本发明的式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物，其任选地与第二治疗剂组合，用于治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症。
在一个实施方案中，本发明提供本发明的式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物，其任选地与第二治疗剂组合，在制备用于治疗、改善或预防细胞增殖异常的药物中的用途。
在一个实施方案中，本发明提供一种制备用于治疗、改善或预防细胞增殖异常的方法，其包括向有需要的个体给药治疗有效量的本发明式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物，以及任选的第二治疗剂。
在一个实施方案中，本发明提供本发明的式(I)所示化合物的枸橼酸盐或本发明式(I)所示化合物的枸橼酸盐的晶型A或本发明式(I)所示化合物的枸橼酸盐的晶型B或本发明式(I)所示化合物的枸橼酸盐的晶型C或本发明式(I)所示化合物的枸橼酸盐的晶型D或本发明的药物组合物，其任选地与第二治疗剂组合，用于治疗、改善或预防细胞增殖异常。
有益效果
相比其他盐型，本发明的式(I)所示的化合物的枸橼酸盐具有稳定性高、溶解性好的有益效果。
另外，相比其他晶型或无定型，本发明的式(I)所示的化合物的枸橼酸盐的晶型A、晶型B、晶型C以及晶型D也具有优异的吸湿性、引湿性、以及湿度稳定性，例如在湿度循环以及高湿的条件下，本发明的晶型不会发生转变，显示出优异的吸湿性、引湿 性、以及湿度稳定性。进一步地，相比其他晶型或无定型，本发明的式(I)所示的化合物的枸橼酸盐的晶型A、晶型B和晶型C具有明显改善的吸湿性、引湿性、以及湿度稳定性，例如在湿度循环以及高湿的条件下，本发明的晶型A、晶型B和晶型C不会发生转变，显示出明显改善的吸湿性、引湿性、以及湿度稳定性。
此外，相比其他晶型或无定型，本发明的式(I)所示的化合物的枸橼酸盐的晶型A、晶型B、晶型C以及晶型D也具有优异的稳定性，例如高温稳定性和光照稳定性。例如在高温和/或光照的条件下，本发明的晶型不会发生转变，显示出优异的高温稳定性和光照稳定性。进一步地，相比其他晶型或无定型，本发明的式(I)所示的化合物的枸橼酸盐的晶型A、晶型B和晶型C具有明显改善的稳定性，例如高温稳定性和光照稳定性。例如在高温和/或光照的条件下，本发明的晶型A、晶型B和晶型C不会发生转变，显示出明显改善的高温稳定性和光照稳定性。
再有，相比其他晶型或无定型，本发明的式(I)所示的化合物的枸橼酸盐的晶型A、晶型B、晶型C以及晶型D具有优异的溶解性，例如，在诸如FaSSIF、FeSSIF和FaSSGF等的生物介质中，表现出优异的溶解性。
基于此，本发明的式(I)所示的化合物的枸橼酸盐及其晶型A、晶型B、晶型C以及晶型D成药前景广阔。
实施例
下面结合具体实施例对本发明的方案做进一步详细的描述。
需要说明的是，以下实施例仅仅是为清楚地说明本发明的技术方案所作的举例，而并非对本发明的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无需也无法对所有的实施方式予以穷举，而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。除非另外指明，本文所用的仪器设备和试剂材料都是可以商购的。
高分辨质谱(HRMS)：
采用Agilent 1290 Infinity-6546 LC/Q-TOF检测化合物及其盐和晶型的质谱，其离子源为ESI(+)。
核磁共振波谱(NMR)：
采用BRUKER Av NEO 400M型核磁共振仪检测化合物及其盐和晶型的核磁共振波谱，其中溶剂采用D2O或DMSO-d6。
X射线粉末衍射(XRPD)：
采用Panalytical EMPYREAN(Malvern Panalytical，UK)粉末衍射仪采集各晶型的XRPD图谱，该仪器采用Cu钯照射，在室温下使用Absolute scan进行连续投射扫描，扫描2θ范围为3至45°，步长为0.013°，单个样品扫描时长为5min。测试样品时光管电压和电流分别为45kV和40mA，样品盘为零背景样品盘。
示差扫描量热(DSC)：
采用TA Discovery 250(TA，US)采集晶型的DSC图谱，样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。
热重分析(TGA)：
采用TA Discovery 550(TA，US)采集晶型的TGA图谱，样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。
动态水分吸脱附分析(DVS)
采用DVS Intrinsic(SMS，UK)进行晶型的动态水分吸脱附分析，以评估晶型的引湿性。测试采用梯度模式，湿度变化为50％-95％-50％，每个梯度的湿度变化量为15％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点，或每个梯度最长的维持时间为60min。测试完成后，对样品进行XRPD分析确认固体形态是否发生变化。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
材料
式(I)所示的化合物：其根据CN109153686A的方法制备。
枸橼酸：购自General-Reagent。
甲醇：购自General-Reagent。
二甲基甲酰胺：购自General-Reagent。
4-甲基-2-戊酮：购自General-Reagent。
乙腈：购自General-Reagent。
乙二醇二甲醚：购自General-Reagent。
乙二醇甲醚：购自General-Reagent。
丙酮：购自广州化学试剂厂。
FaSSIF：购自Biorelevant公司，批号：FASBUF-1121-A。
FaSSGF：购自Biorelevant公司，批号：FASBUF-1121-A。
FeFFIF：购自Biorelevant公司，批号：FASBUF-0122-A。
生物介质粉末：购自Biorelevant公司，批号：FFF-0521-A。
制备实施例
实施例1式(I)所示化合物的枸橼酸盐的制备
将27.5mg的式(I)所示化合物加入至2.0mL的溶剂中，随后将枸橼酸加入至上述溶液中。获得的溶液于室温下混悬2天，随后将悬浮液离心分离，以获得本发明的枸橼酸盐。
上述溶剂可以为甲醇或四氢呋喃。
当式(I)所示化合物与枸橼酸的投料摩尔比为约1∶3时，获得式(I)所示化合物的二枸橼酸盐，其中式(I)所示化合物与枸橼酸的摩尔比为1∶2。
当式(I)所示化合物与枸橼酸的投料摩尔比为约1∶1时，获得式(I)所示化合物的一枸橼酸盐，其中式(I)所示化合物与枸橼酸的摩尔比为1∶1。
其中式(I)所示化合物的二枸橼酸盐的表征数据如下：
1H NMR(400MHz，DMSO-d6)δppm 10.580(brs，1H)，9.681(s，1H)，9.681(s，1H)，8.042(brs，1H)，7.426(brd，1H)，8.140(brd，1H)，3.715(brd，2H)，3.149(m，1H)，3.149(m，2H)，3.043(brs，3H)，2.933(brs，3H)，2.933(brs，2H)，2.834(brs，2H)，2.648(m，3H)，2.648 (m，2H)，2.648(m，2H)，2.648(m，2H)，2.211(brs，3H)，1.906(brd，2H)，1.906(brd，2H)，1.674(m，2H)，1.586(m，2H).
式(I)所示化合物的一枸橼酸盐的表征数据如下：
1H NMR(400MHz，DMSO-d6)δ9.53(s，1H)，9.16(s，1H)，8.11(d，1H)，8.01(d，1H)，7.40(dd，1H)，3.70(br d，2H)，3.03(s，3H)，2.92(s，3H)，2.67(m，10H)，2.19(br d，2H)，1.88(br d，6H)，1.66(br d，2H)，1.56(m，2H).
实施例2式(I)所示化合物的枸橼酸盐晶型A的制备
(1)将23.8g的无水枸橼酸溶于100g的甲醇中，获得的溶液备用。
(2)向1000ml的反应瓶中加入300g甲醇、17g式(I)所示的化合物；搅拌并加热获得的溶液，控制溶液的内温为50-55℃。
(3)向步骤(2)的溶液中加入步骤(1)的枸橼酸甲醇溶液(即，溶液中式(I)化合物与枸橼酸的摩尔比为1∶4)，控制溶液内温为50-55℃，并搅拌溶液15min。搅拌的过程中，可观察到固体析出。
(4)冷却步骤(3)获得的混合液3h至其内温为10℃。
(5)在内温为10±2℃的条件下，搅拌步骤(4)的混合液1h，可观察到晶体析出。
(6)过滤步骤(5)获得的混合物，滤出物于50℃下减压干燥，即可获得27g本申请的式(I)所示化合物的枸橼酸盐晶型A，产率为93.4％。获得的晶型A为浅黄色粉末、无臭、略有引湿性。晶型A在水、0.1mol/L盐酸溶液、乙酸中易溶；在甲醇中微溶；在乙醇中几乎不溶。晶型A的熔点为176.5℃-180.5℃。pKa为3.47、4.86和8.18。1H NMR(400MHz，DMSO-d6)δppm 9.57(s，1H)，9.17(s，1H)，8.12(d，1H)，8.02(d，1H)，7.41(dd，1H)，3.72(m，2H)，3.17(m，2H)，3.04(s，4H)，2.93(s，3H)，2.80(br s，2H)，2.62(m，15H)，2.19(m，2H)，1.90(m，6H)，1.61(m，4H).
1H NMR(400MHz，D2O)δ9.00(s，1H)，7.80(dd，1H)，7.52(d，1H)，7.39(d，1H)，3.61(m，2H)，3.16(m，3H)，2.94(s，3H)，2.83(s，3H)，2.79(m，4H)，2.66(m，6H)，2.09(br d，2H)，1.84(m，6H)，1.63(m，4H).
参见图3，晶型A的TGA测试结果显示，加热晶型A至120℃的过程中有1.2％的失重，在140-300℃有38.4％的失重。参见图2，晶型A的DSC测试结果显示，在190℃时具有吸热峰。另外，参见图4，晶型A在DMSO-d6中的NMR测试结果未显示明显的溶剂峰。其中，2.53-2.73ppm处的对应枸橼酸的峰与DMSO的溶剂峰部分重叠。而晶型A在D2O中的NMR测试结果显示(参见图5)，2.80、2.76、2.68、2.64ppm处的峰表示为枸橼酸的特征峰，并且根据其积分可以判断，在晶型A中，式(I)所示化合物：枸橼酸＝1∶2。综合上述所有晶型的测试结果可知，晶型A为式(I)所示化合物的二枸橼酸盐，并且晶型A不含有结晶水。
实施例3式(I)所示化合物的枸橼酸盐晶型B的制备
(1)将23.8g的无水枸橼酸溶于100g的甲醇中，获得的溶液备用。
(2)向1000ml的反应瓶中加入300g甲醇、80g纯化水、17g式(I)所示的化合物；搅拌并加热获得的溶液，控制溶液的内温为50-55℃。
(3)向步骤(2)的溶液中加入步骤(1)的枸橼酸甲醇溶液(即，溶液中式(I)化合物与枸 橼酸的摩尔比为1∶4)，控制溶液内温为50-55℃，并搅拌溶液15min。搅拌的过程中，可观察到固体析出。
(4)冷却步骤(3)获得的混合液3h至其内温为10℃。
(5)在内温为10±2℃的条件下，搅拌步骤(4)的混合液1h，可观察到晶体析出。
(6)过滤步骤(5)获得的混合物，滤出物于50℃下减压干燥，即可获得27g本申请的式(I)所示化合物的枸橼酸盐晶型B，产率为76.1％。
1H NMR(400MHz，D2O)δ9.04(s，1H)，7.86(br d，1H)，7.56(s，1H)，7.40(d，1H)，3.64(br d，2H)，3.05(s，3H)，2.94(s，3H)，2.79(s，3H)，2.75(m，3H)，2.65(m，6H)，2.08(br d，2H)，1.84(m，6H)，1.62(m，4H).
参见图8，晶型B的TGA测试结果显示，加热晶型B至90℃的过程中有2.2％的失重，从90℃加热至140℃有1.8％的失重，而从140℃加热至300℃有36.9％的失重。由此可见，将晶型B加热至140℃时，晶型B共失重4％，这与二水合物的理论水含量(3.7％)相当。另外，参见图7，晶型B的DSC测试结果显示，晶型B在约81、133、151和178℃处具有吸热峰。综合上述测试结果以及晶型B在D2O中的NMR数据可知，晶型B包含结晶水，为式(I)所示化合物的二枸橼酸盐的水合物，并且在晶型B中，式(I)所示化合物的枸橼酸盐与结晶水的摩尔比为约1∶2。
实施例5式(I)所示化合物的枸橼酸盐晶型C的制备
(1)将99.9mg的(I)所示化合物的二枸橼酸盐加入到玻璃瓶中；
(2)向步骤(1)的容器中加入二甲基甲酰胺或乙二醇甲醚或三氟乙醇；
(3)向步骤(2)的溶液中加入乙腈或乙酸乙酯或甲醇或乙醇或异丙醇；
(4)室温下搅拌步骤(3)获得的混合物1-2天；
(5)离心分离步骤(4)获得的混合物，以获得式(I)所示化合物的晶型C。
其中，步骤(2)加入的溶剂为二甲基甲酰胺时，步骤(3)的溶剂可以为乙醇或异丙醇或乙腈。步骤(2)加入的溶剂为三氟乙醇时，步骤(3)的溶剂可以为乙醇。步骤(2)加入的溶剂为乙二醇甲醚时，步骤(2)的溶剂可以为乙酸乙酯。
1H NMR(400MHz，DMSO-d6)δ9.53(s，1H)，9.16(s，1H)，8.11(d，1H)，8.01(d，1H)，7.40(dd，1H)，3.70(br d，2H)，3.03(s，3H)，2.92(s，3H)，2.67(m，10H)，2.19(br d，2H)，1.88(br d，6H)，1.66(br d，2H)，1.56(m，2H).
1H NMR(400MHz，D2O)δ8.94(s，1H)，7.62(br s，1H)，7.58(br s，1H)，7.53(m，1H)，3.53(m，2H)，3.10(s，3H)，2.75(m，5H)，2.62(m，5H)，1.99(br d，2H)，1.84(br s，4H)，1.73(br s，2H)，1.61(br s，2H)，1.53(br d，2H).
参见图12，晶型C的TGA测试结果显示，加热晶型C至120℃的过程中有0.1％的失重，在120-300℃有25.8％的失重。另外，参见图11，晶型C的DSC测试结果显示，在约194℃，晶型C具有对应熔融伴随分解的吸热峰。此外，参见图13，晶型C在DMSO-d6中的NMR测试结果显示，2.54-2.75ppm处的积分结果与式(I)所示化合物不同。另外，参见图14，晶型C在D2O中的NMR测试结果显示，2.74、2.70、2.64、2.60ppm处的特征峰对应枸橼酸，其积分结果表明，在晶型C中，式(I)所示化合物：枸橼酸＝1∶1。综合上述测试结果可知，晶型C为式(I)所示化合物的一枸橼酸盐，并且晶型C不含有结晶水。
实施例6式(I)所示化合物的枸橼酸盐晶型D的制备
式(I)所示化合物的枸橼酸盐晶型D的制备方法与晶型C的制备方法相似，其区别在于，步骤(2)加入的溶剂为二甲基甲酰胺，并且步骤(3)加入的溶剂为甲醇。
1H NMR(400MHz，DMSO-d6)δ9.56(s，1H)，9.16(s，1H)，8.12(d，1H)，8.02(d，1H)，7.41(dd，1H)，4.09(br s，1H)，3.71(br d，2H)，2.61(m，13H)，2.19(br d，2H)，1.90(m，6H)，1.67(br d，2H)，1.57(m，2H).
参见图18，晶型D的单晶图显示，晶型D为式(I)所示化合物的一枸橼酸甲醇溶剂合物。
另外，根据图18的单晶图可知，在晶型D中，式(I)所示化合物的枸橼酸盐与甲醇的比例为1∶1。
对比例式(I)所示化合物其他盐型的制备
将27.5mg的式(I)所示化合物加入至2.0mL的溶剂中，随后将酸加入至上述溶液中。获得的溶液于室温下混悬2天，随后将悬浮液离心分离，以获得本发明的盐。
对比例1式(I)所示化合物的盐酸盐
所述加入的酸为盐酸时，获得式(I)所示化合物的盐酸盐。
对比例2式(I)所示化合物的硫酸盐。
所述加入的酸为硫酸时，获得式(I)所示化合物的硫酸盐。
对比例3式(I)所示化合物的氢溴酸盐
所述加入的酸为氢溴酸时，获得式(I)所示化合物的氢溴酸盐。
对比例4式(I)所示化合物的甲磺酸盐
所述加入的酸为甲磺酸时，获得式(I)所示化合物的甲磺酸盐。
对比例5式(I)所示化合物的对甲苯磺酸盐
所述加入的酸为对甲苯磺酸时，获得式(I)所示化合物的对甲苯磺酸盐。
对比例6式(I)所示化合物的马来酸盐
所述加入的酸为马来酸时，获得式(I)所示化合物的马来酸盐。
对比例7式(I)所示化合物的富马酸盐
所述加入的酸为富马酸时，获得式(I)所示化合物的富马酸盐。
对比例8式(I)所示化合物的草酸盐
所述加入的酸为草酸时，获得式(I)所示化合物的草酸盐。
对比例9式(I)所示化合物的L-酒石酸盐
所述加入的酸为L-酒石酸时，获得式(I)所示化合物的L-酒石酸盐。
对比例10式(I)所示化合物的琥珀酸盐
所述加入的酸为琥珀酸时，获得式(I)所示化合物的琥珀酸盐。
对比例式(I)所示化合物其他晶型的制备
对比例a式(I)所示化合物的晶型E
将本发明的晶型B原位热台加热至81℃，即可获得式(I)所示化合物的晶型E。
晶型E的XRPD谱图如图19所示。
晶型E的XRPD谱图数据如下表所示：
表5晶型E的XRPD图谱解析数据
对比例b式(I)所示化合物的晶型F
将本发明的晶型B置甲醇溶剂中，其中所述甲醇溶剂中含有5％的水，加热所述溶液至50℃，并在此温度下悬浮21小时，随后将悬浮液离心分离，可获得式(I)所示化合物的晶型F。
晶型F的XRPD谱图如图20所示。
晶型F的XRPD谱图数据如下表所示：
表6晶型F的XRPD图谱解析数据

对比例c式(I)所示化合物的晶型G
晶型G的制备方法与实施例2相似，其区别在于，使用的溶剂为四氢呋喃，且式(I)所示化合物与枸橼酸的投料摩尔比为1∶1。
晶型G的XRPD谱图如图21所示。
晶型G的XRPD谱图数据如下表所示：
表7晶型G的XRPD图谱解析数据
测试实施例
试验例1式(I)所示的化合物的盐的溶解度测试实验
称取约4-20mg的式(I)化合物的盐，将所述盐加入至EP管中，室温下逐次加入一定量溶剂，搅拌溶液并观察固体是否完全溶解，若加到10.0mL溶剂后仍未溶清，则停 止实验。根据固体完全溶解时所用的溶剂体积估算化合物在该溶剂中的溶解度。实验结果如下表所示。
表8式(I)化合物的盐的溶解度测试结果
根据上述溶解度测试结果可知，相比其他盐型，式(I)所示化合物的盐酸盐、氢溴酸盐、甲磺酸盐、L-酒石酸盐、琥珀酸盐以及枸橼酸盐具有优异的溶解性。在本试验例中，使用的式(I)所示化合物的枸橼酸盐包括式(I)所示化合物的一枸橼酸盐(式(I)化合物与枸橼酸的摩尔比为1∶1)以及式(I)所示化合物的二枸橼酸盐(式(I)化合物与枸橼酸的摩尔比为1∶2)。
试验例2式(I)所示的化合物的盐的吸湿性
将式(I)所示的化合物放置在潮湿环境中，其中所述环境的初始湿度为50％，并且所述环境以15％的变化量升高湿度至95％，其中每个湿度梯度的维持时间为60min。环境湿度在95％的条件下维持60min后，分别测试各个盐型的增重情况，以确定相应盐型的吸湿性。
表9式(I)化合物的盐的吸湿性测试结果

根据上述吸湿性测试结果可知，相比其他盐型，式(I)所示化合物的对甲苯磺酸盐、马来酸盐、富马酸盐、草酸盐以及枸橼酸盐的增重较低，证实这些盐型具有改善的吸湿性，在潮湿的环境下具有更加优异的稳定性。
另外根据试验例1-2的结果可知，相比其他盐型，式(I)所示化合物的枸橼酸盐具有更加优异的综合性质，其溶解性以及吸湿性优于其他盐型。
试验例3式(I)所示的化合物的枸橼酸盐的溶解度及吸湿性研究
根据试验例1的测试方法，分别测试式(I)所示的化合物的一枸橼酸盐和二枸橼酸盐的溶解度，得到如下表10所示的测试结果。
根据试验例2的测试方法，分别测试式(I)所示的化合物的一枸橼酸盐和二枸橼酸盐的溶解度，得到如下表11所示的测试结果。
表10式(I)化合物的枸橼酸盐的溶解度测试结果
表11式(I)化合物的枸橼酸盐的吸湿性测试结果
根据表10以及表11的测试结果可知，式(I)所示的化合物的二枸橼酸盐(式(I)化合物与枸橼酸的摩尔比为1∶2)具有相对更加优异的综合性质。上述测试结果证实，在(I)所示的化合物的枸橼酸盐中，合适的式(I)化合物与枸橼酸的摩尔比为有利于所述盐型具有更加优异的溶解度和吸湿性。
试验例4式(I)所示的化合物的晶型的引湿性研究
采用DVS Intrinsic(SMS，UK)进行晶型的动态水分吸脱附分析，以评估晶型的引湿性。测试采用梯度模式，湿度变化为50％-95％-50％，每个梯度的湿度变化量为15％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点，或每个梯度最长的维持时间为60min。测试完成后，对样品进行XRPD分析确认固体形 态是否发生变化。
晶型A
如图23所示，以50％RH条件下的质量为参考，晶型A在95％RH下增重0.64％，在吸附过程中，80％RH下增重0.25％。
如图24所示，测试后晶型A的XRPD谱图无明显变化。
上述结果表明，经历湿度变化循环后，晶型A的增重较低，并且晶型A未发生晶型变化，证实其具有优异的湿度稳定性。
晶型B
如图25所示，以50％RH条件下的质量为参考，晶型B在95％RH时增重0.69％，在吸附过程中80％RH时增重0.24％。
如图26所示，测试后晶型B的XRPD谱图无明显变化。
上述结果表明，经历湿度变化循环后，晶型B的增重较低，并且晶型B未发生晶型变化，证实其具有优异的湿度稳定性。
晶型C
如图27所示，以50％RH条件下的质量为参考，晶型C在95％RH下增重3.45％，在吸附过程中，80％RH下增重0.42％。
如图28所示，测试后晶型C的XRPD谱图无明显变化。
上述结果表明，经历湿度变化循环后，晶型C的增重较低，并且晶型C未发生晶型变化，证实其具有优异的湿度稳定性。
晶型D
如图29所示，以50％RH条件下的质量为参考，晶型D在95％RH时增重4.45％，而在吸附过程中80％RH时仅增重0.85％。
如图30所示，测试后晶型D的XRPD谱图并未发生明显的变化。
上述结果表明，经历湿度变化循环后，晶型D的增重较低，并且晶型D并未发生晶型的明显变化，证实其具有较好的湿度稳定性。
试验例5式(I)所示的化合物的晶型的稳定性研究
对式(I)所示的化合物的晶型进行高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)条件下的稳定性研究，分别于7天和15天取样进行XRPD表征。
对晶型A进行上述稳定性研究，试验结果如图31所示。XRPD结果显示，晶型A在高温、高湿、光照、加速条件下15天均稳定，没有发生晶型转变。
上述试验结果证实，式(I)所示的化合物的晶型A具有优异的稳定性。
对晶型B进行上述稳定性研究，试验结果如图32所示。XRPD结果显示，晶型B在高温、高湿、光照、加速条件下保持7天和15天后，没有发生晶型转变。
上述试验结果证实，式(I)所示的化合物的晶型B具有优异的稳定性。
对晶型C进行上述稳定性研究，试验结果如图33所示。XRPD结果显示，晶型C在高温、高湿、光照、加速条件下保持8天和15天后，没有发生晶型转变。
上述试验结果证实，式(I)所示的化合物的晶型C具有优异的稳定性。
对晶型D进行上述稳定性研究，试验结果如图34所示。XRPD结果显示，晶型D在高湿、高温、光照、加速条件下状态下保持8、15天后，未发生明显的晶型转变。
上述试验结果证实，式(I)所示的化合物的晶型D具有优异的稳定性。
将晶型G于室温下放置1天，XRPD谱图显示(参见图22)，于室温下放置一天后，晶型G发生晶型转变。
上述结果表明，相比式(I)所示化合物的其他晶体形式，晶型A、B、C和D具有改善的稳定性。特别地，相比式(I)所示化合物的其他晶体形式，晶型A、B和C具有明显改善的稳定性。
试验例6式(I)所示的化合物的盐型及晶型的生物介质和水溶解度测试
将式(I)所示的化合物的枸橼酸盐晶型A加入到水或3种生物介质(FaSSIF、FeSSIF和FaSSGF)中，以测定其在上述溶剂中的溶解度。其中，FaSSIF可用于模拟人类餐前饥饿状态下的小肠内的肠液；FeSSIF可用于模拟人类餐后饱食状态下小肠内的肠液；FaSSGF可用于模拟人类饥饿状态下空胃时的胃。
结果显示，晶型A在四种介质中悬浮，0.5h内均溶解，悬浮24h后溶液仍澄清；式(I)所示的化合物的枸橼酸盐在四种介质中的溶解度从大到小依次为FaSSGF＞FeSSIF＞FaSSIF＞水。晶型A在FaSSIF和FeSSIF溶解度测试后上清液的pH均有不同程度降低，在FaSSGF溶解度测试后上清液pH升高。
上述结果证实，式(I)所示的化合物的晶型A在FaSSIF和水中具有优异的溶解度。由此可见，本发明的式(I)所示的化合物的晶型A具有优异的溶解度。
表12生物介质和水中的动态溶解度测试
试验例7式(I)所示的化合物的晶型转化
根据上述对比例的制备可知：
(1)将式(I)所示的化合物的晶型B原位加热至81℃时，可获得式(I)所示的化合物的晶型E；
而停止加热并降至室温后，晶型E又将转化为晶型B；
(2)将晶型B置甲醇溶剂中，其中所述甲醇溶剂中含有5％的水，加热所述溶液至50℃，并在此温度下悬浮21小时，可获得晶型F；
将上述悬浮液常温常湿放置后，晶型F又将转化为晶型B；
由此可见，晶型E或F在常温条件下即可转化为晶型B，即证实相比晶型E或F，晶型B具有更加优异的稳定性。
以上所述仅为本发明的具体实施例，并非因此限制本发明的专利范围，凡是利用本发明作的等效变换，或直接或间接运用在其它相关的技术领域，均同理包括在本发明的专利保护范围之中。

Claims (21)

  1. 一种式(I)所示化合物的枸橼酸盐
  2. 权利要求1所述的式(I)所示化合物的枸橼酸盐，其中
    式(I)所示化合物与枸橼酸的摩尔比为约1∶1-1∶3，优选为约1∶1-1∶2，更优选为约1∶2。
  3. 式(I)所示化合物的枸橼酸盐的晶型A，其中
    所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：17.9±0.2°、18.4±0.2°、19.2±0.2°、19.5±0.2°和20.5±0.2°；
    优选地，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.8±0.2°、11.6±0.2°、15.0±0.2°、17.2±0.2°、17.6±0.2°、17.9±0.2°、18.4±0.2°、19.2±0.2°、19.5±0.2°和20.5±0.2°；
    更优选地，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.8±0.2°、9.8±0.2°、11.2±0.2°、11.6±0.2°、11.8±0.2°、12.6±0.2°、12.8±0.2°、15.0±0.2°、16.8±0.2°、17.2±0.2°、17.6±0.2°、17.9±0.2°、18.4±0.2°、19.2±0.2°、19.5±0.2°、20.5±0.2°、21.1±0.2°、21.9±0.2°、24.7±0.2°和25.2±0.2°；
    特别优选地，所述晶型A的X射线粉末衍射图谱如图1所示。
  4. 式(I)所示化合物的枸橼酸盐的晶型A，其中
    晶型A的示差扫描量热分析曲线在190.1±3℃处有一个吸热峰；优选地，晶型A的示差扫描量热分析曲线如图2所示；和/或
    晶型A的热重分析曲线在120±3℃时失重达1.2％，在140-300±3℃时失重达38.4％；优选地，晶型A的热重分析曲线如图3所示。
  5. 式(I)所示化合物的枸橼酸盐的晶型B，其中
    所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.3±0.2°、11.2±0.2°、14.1±0.2°、16.7±0.2°和18.4±0.2°；
    优选地，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.3±0.2°、7.0±0.2°、8.3±0.2°、11.2±0.2°、11.8±0.2°、14.1±0.2°、14.8±0.2°、16.0±0.2°、16.7±0.2°、18.4±0.2°、22.5±0.2°、22.8±0.2°、23.9±0.2°、24.4±0.2°和25.0±0.2°；
    更优选地，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.3±0.2°、7.0±0.2°、8.3±0.2°、10.2±0.2°、11.2±0.2°、11.8±0.2°、13.2±0.2°、14.1±0.2°、14.8±0.2°、16.0±0.2°、16.7±0.2°、18.4±0.2°、19.7±0.2°、20.1±0.2°、21.0±0.2°、21.3±0.2°、22.5±0.2°、22.8±0.2°、23.0±0.2°、23.9±0.2°、24.4±0.2°和25.0±0.2°；
    特别优选地，所述晶型B的X射线粉末衍射图谱如图6所示。
  6. 式(I)所示化合物的枸橼酸盐的晶型B，其中
    晶型B的示差扫描量热分析曲线在81.0±3℃、133.2±3℃、150.6±3℃和177.9±3℃处分别有一个吸热峰；优选地，晶型B的示差扫描量热分析曲线如图7所示；和/或
    晶型B的热重分析曲线在90±3℃时失重达2.2％，在90-140±3℃失重达1.8％，在140-300±3℃失重达36.9％；优选地，晶型B的热重分析曲线如图8所示。
  7. 式(I)所示化合物的枸橼酸盐的晶型C，其中
    所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.0±0.2°、15.6±0.2°、19.4±0.2°、20.2±0.2°和20.8±0.2°；
    优选地，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.7±0.2°、10.0±0.2°、11.9±0.2°、15.0±0.2°、15.6±0.2°、16.8±0.2°、19.4±0.2°、19.9±0.2°、20.2±0.2°和20.8±0.2°；
    更优选地，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.7±0.2°、10.0±0.2°、10.6±0.2°、11.2±0.2°、11.9±0.2°、12.6±0.2°、13.0±0.2°、13.4±0.2°、14.6±0.2°、15.0±0.2°、15.6±0.2°、16.0±0.2°、16.8±0.2°、17.5±0.2°、17.8±0.2°、18.0±0.2°、19.4±0.2°、19.9±0.2°、20.2±0.2°、20.8±0.2°、23.0±0.2°、23.7±0.2°、25.4±0.2°和26.2±0.2°；
    特别优选地，所述晶型C的X射线粉末衍射图谱如图10所示。
  8. 式(I)所示化合物的枸橼酸盐的晶型C，其中
    晶型C的示差扫描量热曲线在194.3±3℃处有一个吸热峰；优选地，晶型C的示差扫描量热曲线如图11所示；和/或
    晶型C的热重分析曲线在120±3℃时失重达0.1％，在120-300±3℃时失重达25.8％；优选地，晶型C的热重分析曲线如图12所示。
  9. 式(I)所示化合物的枸橼酸盐的晶型D，其中
    所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.0±0.2°、16.8±0.2°、18.6±0.2°、19.8±0.2°和24.6±0.2°；
    优选地，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.0±0.2°、7.1±0.2°、14.0±0.2°、15.4±0.2°、16.8±0.2°、18.2±0.2°、18.6±0.2°、19.6±0.2°、19.8±0.2°、23.3±0.2°、24.6±0.2°和28.1±0.2°；
    更优选地，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.0±0.2°、7.1±0.2°、9.2±0.2°、11.3±0.2°、12.1±0.2°、14.0±0.2°、15.4±0.2°、15.7±0.2°、16.8±0.2°、17.4±0.2°、18.2±0.2°、18.6±0.2°、19.0±0.2°、19.6±0.2°、19.8±0.2°、21.0±0.2°、21.2±0.2°、22.4±0.2°、22.7±0.2°、23.3±0.2°、23.5±0.2°、23.7±0.2°、24.6±0.2°、28.1±0.2°和28.8±0.2°；
    特别优选地，所述晶型D的X射线粉末衍射图谱如图15所示。
  10. 式(I)所示化合物的枸橼酸盐的晶型D，其中
    晶型D的示差扫描量热曲线在148.4±3℃、160.8℃和184.1℃处分别有一个吸热峰；优选地，晶型D的示差扫描量热曲线如图16所示；和/或
    晶型D的热重分析曲线在110±3℃时失重达0.6％，在110-150±3℃时失重达1.7％，在150-300±3℃时失重达27.7％；优选地，晶型D的热重分析曲线如图17所示。
  11. 制备式(I)所示化合物的枸橼酸盐的晶型A的方法，其包括以下步骤：
    提供枸橼酸的溶液；
    提供式(I)化合物的溶液；
    向式(I)化合物的溶液中加入枸橼酸的溶液；
    搅拌获得的溶液并冷却；
    过滤冷却的溶液并干燥滤出物，获得式(I)化合物的晶型A；
    其中所述溶液的溶剂选自醇类溶剂、醚类溶剂、腈类溶剂、酮类溶剂及其组合；
    优选地，
    醇类溶剂选自甲醇、乙醇、异丙醇、正丙醇、正丁醇及其组合，更优选选自甲醇、乙醇、异丙醇及其组合；
    醚类溶剂选自乙醚、乙二醇甲醚、乙二醇二甲醚及其组合，更优选选自乙二醇甲醚、乙二醇二甲醚及其组合；
    腈类溶剂选自乙腈、丙腈及其组合，更优选为乙腈；
    酮类溶剂选自丙酮、丁酮、4-甲基-2-戊酮及其组合，更优选选自丙酮、4-甲基-2-戊酮及其组合。
  12. 权利要求11所述的方法，其中
    加入的式(I)化合物与枸橼酸的摩尔比为约1∶3-1∶5，优选为约1∶3-1∶4。
  13. 制备式(I)所示化合物的枸橼酸盐的晶型B的方法，其包括以下步骤：
    提供枸橼酸的溶液；
    提供式(I)化合物的溶液；
    向式(I)化合物的溶液中加入枸橼酸的溶液；
    搅拌获得的溶液并冷却；
    过滤冷却的溶液并干燥滤出物，获得式(I)化合物的晶型B；
    其中所述溶液的溶剂选自醇类溶剂、水及其组合；
    优选地，
    所述醇类溶剂选自甲醇、乙醇、异丙醇、正丙醇及其组合，优选选自甲醇、乙醇及其组合。
  14. 权利要求13所述的方法，其中
    加入的式(I)化合物与枸橼酸的摩尔比为约1∶3-1∶5，优选为约1∶3-1∶4。
  15. 权利要求13所述的方法，其中
    所述醇类溶剂与水的质量比为约10∶1-3∶1，优选为约6∶1-4∶1。
  16. 制备式(I)所示化合物的枸橼酸盐的晶型C的方法，其包括以下步骤：
    向溶剂X中加入式(I)所示化合物的枸橼酸盐，以获得溶液；
    上述溶液中加入溶剂Y，并于室温下搅拌；
    离心分离获得晶型C；
    其中
    所述溶剂X选自二甲基甲酰胺、乙二醇甲醚、三氟乙醇及其组合；
    所述溶剂Y选自乙腈、乙酸乙酯、甲醇、乙醇、异丙醇及其组合。
  17. 一种药物组合物，其包含选自以下的一种或多种：
    (i)权利要求1-2所述的式(I)所示化合物的枸橼酸盐；
    (ii)权利要求3-4所述的式(I)所示化合物的枸橼酸盐的晶型A；
    (iii)权利要求5-6所述的式(I)所示化合物的枸橼酸盐的晶型B；
    (iv)权利要求7-8所述的式(I)所示化合物的枸橼酸盐的晶型C；
    (v)权利要求9-10所述的式(I)所示化合物枸橼酸盐的晶型D。
  18. 权利要求1-2所述的式(I)所示化合物的枸橼酸盐或权利要求3-4所述的式(I)所示化合物的枸橼酸盐的晶型A或权利要求5-6所述的式(I)所示化合物的枸橼酸盐的晶型B或权利要求7-8所述的式(I)所示化合物的枸橼酸盐的晶型C或权利要求9-10所述的式(I)所示化合物的枸橼酸盐的晶型D或权利要求17所述的药物组合物在制备用于治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症的药物中的用途。
  19. 权利要求1-2所述的式(I)所示化合物的枸橼酸盐或权利要求3-4所述的式(I)所示化合物的枸橼酸盐的晶型A或权利要求5-6所述的式(I)所示化合物的枸橼酸盐的晶型B或权利要求7-8所述的式(I)所示化合物的枸橼酸盐的晶型C或权利要求9-10所述的式(I)所示化合物的枸橼酸盐的晶型D或权利要求17所述的药物组合物在制备用于治疗、改善或预防细胞增殖异常的药物中的用途。
  20. 权利要求1-2所述的式(I)所示化合物的枸橼酸盐或权利要求3-4所述的式(I)所示化合物的枸橼酸盐的晶型A或权利要求5-6所述的式(I)所示化合物的枸橼酸盐的晶型B或权利要求7-8所述的式(I)所示化合物的枸橼酸盐的晶型C或权利要求9-10所述的式(I)所示化合物的枸橼酸盐的晶型D或权利要求17所述的药物组合物，任选地与第二治疗剂组合，在制备用于治疗、改善或预防对抑制细胞周期蛋白依赖性激酶4/6有响应的病症的药物中的用途。
  21. 权利要求1-2所述的式(I)所示化合物的枸橼酸盐或权利要求3-4所述的式(I)所示化合物的枸橼酸盐的晶型A或权利要求5-6所述的式(I)所示化合物的枸橼酸盐的晶型B或权利要求7-8所述的式(I)所示化合物的枸橼酸盐的晶型C或权利要求9-10所述的式(I)所示化合物的枸橼酸盐的晶型D或权利要求17所述的药物组合物，任选地与第二治疗剂组合，在制备用于治疗、改善或预防细胞增殖异常的药物中的用途。
PCT/CN2023/118429 2022-09-28 2023-09-13 一种细胞周期蛋白依赖性激酶(cdk4/6)抑制剂的枸橼酸盐、其晶型、制备方法和用途 WO2024067085A1 (zh)

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CN106795179A (zh) * 2014-05-28 2017-05-31 上海复尚慧创医药研究有限公司 一类激酶抑制剂
CN109153686A (zh) * 2016-05-07 2019-01-04 上海复尚慧创医药研究有限公司 一类蛋白激酶抑制剂

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106795179A (zh) * 2014-05-28 2017-05-31 上海复尚慧创医药研究有限公司 一类激酶抑制剂
CN109153686A (zh) * 2016-05-07 2019-01-04 上海复尚慧创医药研究有限公司 一类蛋白激酶抑制剂

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