WO2020253875A1 - 一种化合物的盐、其晶型以及制备方法与应用 - Google Patents

一种化合物的盐、其晶型以及制备方法与应用 Download PDF

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WO2020253875A1
WO2020253875A1 PCT/CN2020/097482 CN2020097482W WO2020253875A1 WO 2020253875 A1 WO2020253875 A1 WO 2020253875A1 CN 2020097482 W CN2020097482 W CN 2020097482W WO 2020253875 A1 WO2020253875 A1 WO 2020253875A1
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cancer
salt
fumarate
fluoro
crystal form
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PCT/CN2020/097482
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English (en)
French (fr)
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尹磊
姚郑林
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甘李药业股份有限公司
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Priority to AU2020296048A priority patent/AU2020296048A1/en
Priority to KR1020227002390A priority patent/KR20220041090A/ko
Priority to EP20827805.1A priority patent/EP3988546A4/en
Priority to JP2021576253A priority patent/JP2022538076A/ja
Priority to CN202080045649.9A priority patent/CN115708409A/zh
Priority to MX2022000051A priority patent/MX2022000051A/es
Priority to US17/596,721 priority patent/US20220168302A1/en
Priority to BR112021025944A priority patent/BR112021025944A2/pt
Publication of WO2020253875A1 publication Critical patent/WO2020253875A1/zh
Priority to IL289231A priority patent/IL289231A/en
Priority to ZA2022/00964A priority patent/ZA202200964B/en
Priority to CONC2022/0000502A priority patent/CO2022000502A2/es

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of medicine, in particular to a series of salts of CDK4/6 inhibitors, their crystal forms, preparation methods and applications.
  • the cell cycle is an important part of cell life activities. In the normal cell growth process, the realization of the cell cycle process depends on the precise and strict regulation of the cell cycle by various levels of regulatory factors.
  • the core of these regulatory factors are Cyclin Dependent Kinase (CDK) and its positive and negative regulatory factors-Cyclin and Cyclin Dependent Kinase Inhibitor (CDI) .
  • CDK-Cyclin complex formed by cyclin-dependent protein kinase and cyclin participates in cell growth, proliferation, dormancy or enters apoptosis.
  • cyclins are continuously expressed and degraded periodically, and bind to the CDK transiently activated by them.
  • CDK activity the phosphorylation of different substrates is catalyzed to realize the advancement and progress of different phases of the cell cycle. Transformation effect.
  • CDK1-CDK13 13 members of the CDK family have been discovered, namely CDK1-CDK13; among them, CDK1, CDK2, CDK3, CDK4 and CDK6 are involved in regulating cell proliferation, and CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13 are involved in regulating transcription.
  • Cyclin is divided into A-L, and different CDKs are connected to different subtypes of Cyclin.
  • Cyclin D family (Cyclin D1, D2, D3), which begins to express in the G1 phase, binds and activates CDK4 and CDK6 to form a CDK4/6-Cyclin D complex, so that the retinoblastoma protein (Rb) is included in the A series of substrates within are phosphorylated. After phosphorylation, Rb releases the proteins that bind to and are inhibited by it, mainly transcription factors such as E2F.
  • E2F activates and transcribes some genes necessary for entering the S phase (Ma Ke, Research Progress on Antitumor Effects of CDK4/6 Inhibitors, "Foreign Medicine ⁇ Antibiotics Volume", 2013, 34(5):197-202). If the balance is broken due to various factors, whether it is the signal that promotes cell proliferation is increased, or the signal that inhibits cell proliferation is weakened to a certain extent, cell proliferation will get out of control and tumors will appear. Studies have found that about 80% of human tumors have abnormalities in the Cyclin D-CDK4/6-INK4-Rb pathway (1. Malumbres M, Barbacid M., To cycle or not to cycle: a critical decision in cancer [J].
  • CDK4/6 as an anti-tumor target are: (1) Most proliferating cells rely on CDK2 or CDK4/6 for proliferation, but CDK4/6 inhibitors do not show the cytotoxicity of "pan-CDK inhibitors", such as Bone marrow suppression and intestinal reactions. (2) Preclinical experiments have shown that if the level of Cyclin D in cells is increased or p16INK4a is inactivated, it can increase the sensitivity of cells to drugs. Due to the above phenomenon of tumor cells compared with normal cells, the target of drugs is increased to a certain extent. .
  • CDks inhibitors are also used in the treatment of other diseases; such as the treatment of cardiovascular disorders, including atherosclerosis, restenosis after vascular stent implantation, and other cardiovascular disorders caused by abnormal cell proliferation; For example, it is used to treat diseases caused by fungi, protozoan parasites (such as Plasmodium falciparum) and DNA and RNA virus infections, including malaria, AIDS, etc.
  • CDKs inhibitors can also be used for autoimmune system diseases (such as psoriasis, rheumatoid arthritis, glomerulonephritis and lupus erythematosus, etc.) to inhibit the proliferation of inflammatory cells.
  • the compound is an effective CDK4/6 inhibitor, there are still problems with the application of the compound in pharmaceutical products.
  • the free base (also called free amine) of the compound has low solubility in water, Even if the optimal crystalline form A of the compound is screened out (ie Comparative Example 1 below), the solubility in water is only 75 ⁇ g/mL, and it exhibits a higher food effect in simulated intestinal fluid, that is, in simulated intestinal fluid.
  • the solubility in fasting intestinal fluid (FaSSIF) and feeding intestinal fluid (FeSSiF) is quite different, and it has a higher risk of food effect.
  • the first object of the present invention is to provide a salt of a CDK4/6 inhibitor to better replace 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole Indole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine, which overcomes the risks of solubility, food effects, Defects such as stability and stability, while having low hygroscopicity.
  • the present invention provides a salt of a compound represented by formula I:
  • the salt is selected from fumarate, maleate, adipate or succinate, namely 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopenta/ane-1 ,3'-Indole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine four types of salts: 5-fluoro -4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen-(5-(1-methylpiperidine-4- (Yl)pyridin-2-yl)pyrimidin-2-amine fumarate, maleate, adipate and succinate.
  • the present invention has passed numerous tests including but not limited to hydrochloride, phosphate, lactate, maleate, fumarate, succinate, malate, adipate , Tartrate, hippurate, citrate, glycolate, malonate, benzoate, gentisate, sebacate, 1-hydroxy-2-naphthoate, oxalic acid Salt, methanesulfonate, ethanedisulfonate, benzenesulfonate, p-toluenesulfonate, hydrobromide, etc., and a large number of crystal forms of the above salt obtained under various reaction conditions.
  • the present invention provides (5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl )-N-(5-(1-Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate.
  • the fumarate has higher solubility in water and FaSSIF than free base, and similar solubility in FaSSIF and FeSSIF, that is, lower risk of food effects. Moreover, during the solubility test, the crystal form of the fumarate dispersed in water, FaSSIF and FeSSIF is very stable and will not change, while other salts of free bases such as methanesulfonate will have crystal forms. The change. At the same time, unexpectedly, the fumarate has relatively low hygroscopicity compared to the free base, and the crystal form is stable after moisture absorption, and will not change. Generally, in the field of medicine, the base of the compound is converted into a salt. Compared with the free base, it has higher hygroscopicity.
  • each crystal form of the methanesulfonate and hydrochloride salt of the free base of the present invention has strong hygroscopicity, and the crystal form changes after moisture absorption. . And under high humidity and light conditions, the fumarate has better physical and chemical stability than free base and other salts.
  • the 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen- (herein the molar ratio) is n: 1.
  • n 0.5, 1 or 2, more preferably n is 1, such as the monofumarate represented by the following formula II:
  • the fumarate of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine includes one or more crystal forms, preferably the fumarate is in one crystal form. Form or multiple polymorphic forms are mixed, and it is particularly preferred that the fumarate is present in one crystal form.
  • the fumarate of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine contains (preferably variable content) solvent molecules, preferably the salt contains (preferably may Variable content) water molecules.
  • variable content in the “solvent molecules with variable content” in this article refers to various salts (such as fumarate, adipate, maleate, succinate, etc.), the solvent molecules
  • the quantity can vary, ideally such as 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen-(5 -(1-Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate and the molar ratio of the solvent are 1:m, where m ⁇ 0.5, preferably m is 0.5, 1 , 2, 3, 4 or 5, more preferably m is 0.5 or 1.
  • the fumarate of piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine includes one or more of the following crystal forms, and preferably the fumarate is any one of the following
  • the crystalline form of fumarate or a mixture of multiple crystalline forms of the fumarate is more preferably one of the following crystalline forms
  • the X-ray powder diffraction pattern represented by the diffraction angle of 2 ⁇ 0.2° is at least in:
  • the crystalline form of the fumarate has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ 0.2° at least:
  • the crystalline form of the fumarate has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ 0.2° at least:
  • the crystalline form of the fumarate particularly preferably has XRPD data and/or patterns selected from any one of (1) to (3) below:
  • the above (1), (2), (3) correspond to 5-fluoro-4-(7'-fluoro-2'-methyl spiro[cyclopentane-1,3'-indole]-5'- Yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate form A (hereinafter referred to as fumarate form A ), XRPD information of crystal form B (hereinafter referred to as fumarate crystal form B), and crystal form C (hereinafter referred to as fumarate crystal form C).
  • the above crystal forms can be distinguished by X-ray diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), or nuclear magnetic resonance method.
  • XRPD X-ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • nuclear magnetic resonance method X-ray diffraction
  • the above-mentioned fumarate salt A crystal form heated from room temperature to 180°C has a weight loss of 2.50%;
  • the above-mentioned fumarate A crystal form has DSC and TGA diagrams substantially as shown in FIG. 3.
  • the fumarate A crystal form of the present invention has higher crystallinity and higher melting point, and has higher solubility in water and FaSSIF compared to free base, and has similar solubility in FaSSIF and FeSSIF , That is, a lower risk of food effects; and, unexpectedly, compared to free alkali, it has a relatively low hygroscopicity, and the crystal form is stable after moisture absorption and does not change. At the same time, it has better physical and chemical stability than free alkali under high humidity and light conditions.
  • the above-mentioned fumarate B crystal form has a weight loss of 2.71% when heated from room temperature to 130°C.
  • the above-mentioned fumarate salt B crystal form has DSC and TGA diagrams substantially as shown in FIG. 6.
  • the fumarate B crystal form of the present invention has higher crystallinity and higher melting point, and has higher solubility in water and FaSSIF compared to free alkali, and has similar solubility in FaSSIF and FeSSIF , That is, a lower risk of food effects; and, unexpectedly, compared to free alkali, it has a relatively low hygroscopicity, and the crystal form is stable after moisture absorption and does not change. At the same time, it has better physical and chemical stability than free alkali under high humidity and light conditions.
  • the DSC spectrum of the above-mentioned fumarate salt form C has an endothermic peak at 240.2°C;
  • the above crystalline form of fumarate C has a weight loss of 1.95% when heated from room temperature to 130°C.
  • the above-mentioned fumarate C crystal form has DSC and TGA diagrams substantially as shown in FIG. 9.
  • the fumarate C crystal form of the present invention has higher crystallinity and higher melting point, FeSSIF has higher solubility, and, unexpectedly, has relatively low hygroscopicity compared to free alkali , And the crystal form is stable after moisture absorption, and the crystal form will not change. At the same time, it has better physical and chemical stability than free alkali under high humidity and light conditions.
  • the present invention provides a maleate of a CDK4/6 inhibitor, namely (5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane -1,3'-Indole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine maleate.
  • the maleic acid salt has higher solubility in water and FaSSIF than free base, and has similar solubility in FaSSIF and FeSSIF, that is, lower risk of food effects. Moreover, unexpectedly, compared to the free base, it has a relatively low hygroscopicity, and the crystal form is stable after moisture absorption and does not change. At the same time, it has better physical and chemical stability under high humidity and light conditions.
  • the 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen- is n:1, where n ⁇ 0.5, Preferably n is 0.5, 1 or 2, and more preferably n is 1, such as the monomaleate represented by the following formula III.
  • the maleate salt of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine includes one crystal form or multiple polymorphic forms, preferably the maleate salt is One crystalline form or multiple polymorphic forms are mixed, and it is particularly preferred that the maleate is present in one crystalline form.
  • the fumarate of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine contains (preferably variable content) solvent molecules, preferably the salt contains (preferably may Variable content) water molecules.
  • the maleic acid salt includes one of the following maleic acid salt crystal forms or multiple maleic acid salt crystal forms, and preferably the maleic acid salt is any one of the following maleic acid salt crystal forms.
  • the X-ray powder diffraction pattern of the crystal form expressed at a diffraction angle of 2 ⁇ 0.2° is at least:
  • the crystalline form of the maleate salt has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ 0.2° at least:
  • the crystalline form of the maleate salt has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ 0.2° at least:
  • the crystalline form of the maleate salt has XRPD data and/or patterns selected from any of the following (1) to (2):
  • maleate crystal form A (hereinafter referred to as maleate crystal form A)
  • crystal B XRPD information of the form (hereinafter referred to as maleate B crystal form).
  • the above-mentioned crystal forms can be distinguished by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or nuclear magnetic resonance method.
  • the DSC spectrum of the maleate salt A crystal form above has an endothermic peak at 188.3°C;
  • the above maleate salt A crystal form heated from room temperature to 130°C has a weight loss of 3.48%.
  • the maleate salt A crystal form described above has DSC and TGA diagrams substantially as shown in FIG. 12.
  • the maleate salt A crystal form of the present invention has higher crystallinity and higher melting point, and has higher solubility in water and FaSSIF compared to free base, and has similar solubility in FaSSIF and FeSSIF , That is, lower risk of food effects. Moreover, unexpectedly, compared to the free base, it has a relatively low hygroscopicity, and the crystal form is stable after moisture absorption and does not change. At the same time, it has better physical and chemical stability under high humidity and light conditions.
  • the above maleate salt B crystal form heated from room temperature to 130°C has a weight loss of 3.61%.
  • the above-mentioned maleate salt B crystal form has DSC and TGA diagrams substantially as shown in FIG. 15.
  • the maleate B crystal form of the present invention has higher crystallinity and higher melting point, and has higher solubility in water and FaSSIF compared to free base, and has similar solubility in FaSSIF and FeSSIF , That is, lower risk of food effects. Moreover, unexpectedly, compared to the free base, it has a relatively low hygroscopicity, and the crystal form is stable after moisture absorption and does not change. At the same time, it has better physical and chemical stability under high humidity and light conditions.
  • the present invention provides (5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl )-Nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine adipate:
  • the adipate is neutralized in water compared to the free base
  • FaSSIF has higher solubility, and has similar solubility in FaSSIF and FeSSIF, that is, lower food effect risk.
  • it has relatively low hygroscopicity and hygroscopicity compared to free alkali
  • the later crystal form is stable and will not change. At the same time, it has better physical and chemical stability under high humidity and light conditions.
  • the ratio of adipate ion to free base of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine adipate is n:1, where n ⁇ 0.5, Preferably n is 0.5, 1 or 2, and more preferably n is 1, such as the monoadipate represented by the following formula IV.
  • the adipate salt of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine includes one crystal form or multiple polymorphs or can be in one crystal form or multiple The two polymorphic forms are mixed, and the salt is preferably present in one crystal form.
  • the adipate salt of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine contains (preferably variable content) solvent molecules, preferably the salt contains (preferably may Variable content) water molecules.
  • the 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen-(5-(1 -Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine adipate includes the following crystal form (hereinafter may also be referred to as adipate salt A crystal form) or only the following crystal form
  • the crystalline form of the diacid salt exists, and the X-ray powder diffraction pattern represented by the diffraction angle of 2 ⁇ 0.2° of the crystalline form shows characteristic diffraction peaks at least at 4.3°, 8.5°, 15.7°, 21.7° and 28.2°.
  • the crystalline form of the adipate salt has an X-ray powder diffraction pattern represented by a 2 ⁇ 0.2° diffraction angle at least: 4.3°, 8.5°, 13.0°, 15.7°, 18.2°, 19.9°, 21.7° and 28.2°
  • the characteristic diffraction peak is shown at
  • the crystal form of the adipate salt has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ 0.2° at least: 4.3°, 8.5°, 13.0°, 15.3°, 15.7°, 18.2°, 19.4°, 19.9° °, 21.7° and 28.2° show characteristic diffraction peaks;
  • the crystalline form of the adipate salt has the XRPD data substantially as shown in Table 6; and/or, the XRPD pattern substantially as shown in FIG. 17.
  • the above crystal form can be confirmed by X-ray diffraction (XRPD), differential scanning calorimetry (DSC), or nuclear magnetic resonance.
  • the above-mentioned adipate salt A crystal form has a weight loss of 0.95% when heated from room temperature to 130°C.
  • the above-mentioned adipate salt A crystal form has DSC and TGA diagrams substantially as shown in FIG. 18.
  • the present invention provides (5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl )-Nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine succinate.
  • the succinate has higher solubility in water and FaSSIF than free base, and has similar solubility in FaSSIF and FeSSIF, that is, lower risk of food effects. Moreover, unexpectedly, compared to the free base, it has a relatively low hygroscopicity, and the crystal form is stable after moisture absorption and does not change. At the same time, it has better physical and chemical stability under high humidity and light conditions.
  • the 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen- is n:1, where n ⁇ 0.5, preferably n It is 0.5, 1 or 2, more preferably n is 1, such as a monosuccinate represented by the following formula V.
  • the succinate salt of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine includes one crystal form or multiple polymorphs or can be in one crystal form or multiple Polymorphs exist in a mixture, and preferably the salt exists in one crystal form.
  • the succinate salt of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine contains (preferably variable content) solvent molecules, preferably the salt contains (preferably variable Content) water molecules.
  • the succinate of pyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine includes the following crystal form (hereinafter may also be referred to as succinate A crystal form) or only the crystal
  • the X-ray powder diffraction pattern expressed by the diffraction angle of 2 ⁇ 0.2° of the crystal form is at least:
  • Characteristic diffraction peaks are shown at 5.4°, 13.9°, 16.0°, 21.1° and 24.3°; preferably, the crystalline form of the succinate has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ 0.2° at least:
  • the characteristic diffraction peaks are shown at 5.4°, 9.5°, 10.1°, 13.9°, 16.0°, 18.6°, 21.1° and 24.3°; more preferably, the crystalline form of the succinate is represented by 2 ⁇ 0.2° diffraction angle X
  • the ray powder diffraction pattern is at least in:
  • the succinate A crystal form has: XRPD data substantially as shown in Table 8; and/or, an XRPD pattern substantially as shown in FIG. 22.
  • the above-mentioned succinate A crystal form has DSC and TGA diagrams substantially as shown in FIG. 23.
  • the present invention also provides the crystalline form of the fumarate of the compound represented by formula I:
  • the X-ray powder diffraction pattern of the crystal form of the fumarate at a diffraction angle of 2 ⁇ 0.2° is at least:
  • the crystalline form of the fumarate has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ 0.2° at least:
  • the crystalline form of the fumarate has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ 0.2° at least:
  • the crystalline form of the fumarate has XRPD data and/or patterns selected from any of the following (1) to (3):
  • the X-ray powder diffraction pattern of the fumarate A crystal form and the fumarate A crystal form expressed at a diffraction angle of 2 ⁇ 0.2° is at least:
  • crystal form of the fumarate has:
  • the XRPD data is basically as shown in Table 1; and/or the XRPD pattern is basically as shown in Figure 2.
  • the above-mentioned fumarate salt A crystal form heated from room temperature to 180°C has a weight loss of 2.50%;
  • the above-mentioned fumarate A crystal form has DSC and TGA diagrams substantially as shown in FIG. 3.
  • the fumarate A crystal form of the present invention has higher crystallinity and higher melting point, and has higher solubility in water and FaSSIF compared to free base, and has similar solubility in FaSSIF and FeSSIF , That is, lower risk of food effects; and, unexpectedly, compared to free alkali, it has relatively low hygroscopicity, and the crystal form is stable after moisture absorption and will not change. At the same time, it has better physical and chemical stability than free alkali under high humidity and light conditions.
  • the present invention also provides a method for preparing the above-mentioned fumarate A crystal form, which comprises making 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole] -5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine reacts with fumaric acid, and the reaction solvent is an organic solvent or the organic Aqueous solution of solvent.
  • the "5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)- Nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine” may be a commercially available crude product, or it may and especially preferably be according to Example 17 of CN 106810536 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen-(5-(1-methyl) prepared by the method Piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine.
  • the organic solvent in the present invention is not particularly limited, as long as it can make 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -Yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine reacts with fumaric acid to obtain fumarate A crystal form.
  • the organic solvent is a polar organic solvent; further preferably, the organic solvent is one or more of alcohols, ketones, halogenated alkanes, ethers, and esters; more preferably, the organic solvents are C 1- One or more of C5 linear or branched alkanol, acetone, THF, ethyl acetate, dichloromethane, and chloroform.
  • the C 1 -C 5 linear or branched alkanol is preferably methanol, ethanol, propanol or isopropanol; more preferably, the organic solvent is methanol, ethanol, propanol, isopropanol, One or more of acetone, dichloromethane and chloroform.
  • the method further comprises: making 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen -(5-(1-Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine is mixed with fumaric acid, slowly drip the fumaric acid into 5-fluoro-4-(7 '-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridine-2 -Base) pyrimidin-2-amine.
  • 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl is set at a temperature of 20°C to reflux the reaction solvent.
  • -Nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine reacts with fumaric acid.
  • the method further comprises: making 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen -(5-(1-Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine and fumaric acid before reacting 5-fluoro-4-(7'-fluoro-2' -Methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidine-2 -The amine dissolves.
  • the solvent used for dissolving methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine includes a first solvent and a second solvent, wherein the first solvent is one of ketones, ethers, esters and alcohols.
  • the first solvent is one or more of C 1 -C 5 linear and branched alkanols, more preferably methanol, ethanol , One or more of propanol and isopropanol; the second solvent is dichloromethane, chloroform or a combination of the two.
  • the mixing volume ratio of the first solvent and the second solvent is not particularly limited, as long as it can make 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indyl Dole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine can be dissolved.
  • the mixing volume ratio of the first solvent and the second solvent is 1:(1-10), preferably 1:(1-3), and most preferably 1:1; in this case, a particularly ideal combination is methanol
  • ethanol propanol and isopropanol are used as the first solvent, and dichloromethane, chloroform or a combination of the two are used as the second solvent.
  • the method further comprises: adding 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)- After nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine is dissolved, the resulting solution is filtered to remove 5-fluoro-4-(7'- Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl ) Impurities in pyrimidin-2-amine to ensure the formation of fumarate A crystal form with high quality and purity.
  • the method further comprises: making 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)- Nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine will dissolve 5-fluoro-4-(7'-fluoro-2) before reacting with fumaric acid '-Methylspiro[cyclopentane-1,3'-indole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidine- The solvent used for the 2-amine is evaporated.
  • the method further comprises: making 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)- After the reaction of nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine with fumaric acid is completed, the temperature of the reaction system is cooled to 10-35°C, preferably to 20 -30°C, so that the fumarate A crystal form can be fully analyzed.
  • the method includes: adding 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]- 5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine is dissolved in a solvent, the solvent being the first solvent and the second solvent Wherein the first solvent is methanol, ethanol, propanol or isopropanol; the second solvent is dichloromethane or chloroform, and the volume ratio of the two is 1: (1-3);
  • the present invention can prepare the fumarate A crystal form repeatedly, stably and efficiently, and ensure the crystal quality.
  • Another object of the present invention is to provide a pharmaceutical composition containing a therapeutically effective amount of the above-mentioned 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3 '-Indole]-5'-yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate, maleate , At least one of succinate or adipate.
  • the pharmaceutical composition further includes pharmaceutically acceptable excipients, and the pharmaceutically acceptable excipients include one or more of a carrier, a diluent, and an excipient.
  • pharmaceutically acceptable excipients include one or more of a carrier, a diluent, and an excipient.
  • At least one pharmaceutically acceptable carrier, diluent, or excipient can be easily selected by those skilled in the art, and is determined by the desired mode of administration.
  • suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and transrectal.
  • the pharmaceutical composition of the present invention may be in any pharmaceutical form deemed suitable by those skilled in the art. Suitable pharmaceutical forms include solid, semi-solid, liquid, or lyophilized preparations, such as tablets, powders, capsules, suppositories, suspensions, liposomes and sprays.
  • kits comprising the above 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -Yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate, maleate, succinate or adipic acid
  • the kit also includes pharmaceutically acceptable excipients; more preferably, the pharmaceutically acceptable excipients include carriers and diluents , And at least one of excipients;
  • the other biologically active substances include, but are not limited to, anticancer agents, immunosuppressive agents, antiviral agents and the like.
  • the other biologically active substances include alkylating agents, anti-metabolic anti-tumor drugs, platinum complexing agents, antibiotic anti-tumor drugs, natural-source anti-tumor drugs, hormone anti-tumor drugs, VEGFR or EGFR inhibitors Drugs, antibody anti-tumor drugs, mTOR inhibitors, drugs for the treatment of brain tumors, etc.
  • the alkylating agent includes cyclophosphamide, ifosfamide, cytepa, semustine, chlorambucil, busulfan, chlorambucil, chlorambucil, nitrocaine Mustard, azamethine, carmustine, lomustine, hexamethylmelamine, dibromomannitol, temozolomide, etc.;
  • the antimetabolites antineoplastic drugs include cytarabine, fluorouracil, methotrexate, and hydroxyurea , Tegafur, meisoindigo, mercaptopurine, etc.
  • the platinum complexing agents such as cisplatin, carboplatin, oxaliplatin, etc.
  • the antibiotic antitumor drugs include actinomycin D, mitotic
  • the anti-tumor drugs of natural origin include homoharringtonine and its derivatives, and the anti-tumor drugs of natural origin, such as epirubicin, pirarubici
  • the hormone anti-tumor drugs include aminoglutamin, tamoxifen, dexamethasone, dutasteride, flutamide, Gonarelin, leuprolide acetate, letrozole, etc.;
  • the VEGFR or EGFR inhibitors include sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vanilla Detinib, pazopanib, lapatinib, canetinib, afatinib, mulitinib, dasatinib, lenatinib, etc.
  • the antibody anti-tumor drugs include trastinib, sorafenib, imatinib, gefitinib, erlotinib, vanilla Detinib, pazopanib, lapatinib, canetinib, afatinib, mulitinib, dasatinib, lenati
  • the salt of the CDK4/6 inhibitor is combined with temozolomide to obtain an ideal effect in the treatment of brain tumors.
  • the present invention also provides a salt of the compound (also known as a CDK4/6 inhibitor), the pharmaceutical composition or the kit for preparing and treating diseases that respond to the inhibition of cell cycle regulatory protein-dependent kinase Application in medicine; and a method for treating diseases in which the salt form of the CDK4/6 inhibitor or the pharmaceutical composition is responsive to the inhibition of cell cycle regulator protein-dependent kinase.
  • a salt of the compound also known as a CDK4/6 inhibitor
  • a method for treating diseases in which the salt form of the CDK4/6 inhibitor or the pharmaceutical composition is responsive to the inhibition of cell cycle regulator protein-dependent kinase.
  • the diseases include, but are not limited to, brain tumors, breast cancer, urogenital cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, head and neck cancer or bladder cancer, Leukemia, hyperplasia, gastric cancer, colon cancer, laryngeal cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, prostate cancer, small cell lung cancer, glioma cancer, colorectal cancer, kidney cancer, epithelial cancer, liver cancer, Esophageal cancer, hematopoietic cancer, lymphoma, myeloma, thyroid follicular carcinoma; tumors of mesenchymal origin; tumors of the central or peripheral nervous system; melanoma; seminoma; teratoma; osteosarcoma; Xeroderma; Keratoacanthoma; Follicular thyroid carcinoma; Kaposi's sarcoma, chronic lymphocytic
  • the tumor of mesenchymal origin is fibrosarcoma or rhabdomyosarcoma; the tumor of the central or peripheral nervous system is astrocytoma, neuroblastoma, glioma or schwannoma.
  • an effective amount of the salt of the above-mentioned CDK4/6 inhibitor is administered to the patient to treat, alleviate or prevent the above-mentioned diseases.
  • the specific form can adopt various known methods, and the present invention does not specifically limit this.
  • treatment refers to the administration of at least one of the salts of the CDK4/6 inhibitor disclosed herein or other compatible active ingredients to a subject confirmed to be in need thereof, for example, the subject Patients suffer from lung cancer.
  • the “effective amount” herein refers to the amount of the salt of the CDK4/6 inhibitor disclosed herein that is effective to "treat” (as defined above) a disease or dysfunction in a subject.
  • “combined product” not only refers to a dosage form containing all components (the so-called fixed combination product), and a combined product package containing separate components, but also refers to Separate components administered simultaneously or sequentially, as long as these components are used to prevent and/or treat the same disease.
  • Figure 1 is a 1 H-NMR chart of the crystalline form of fumarate A in CD 3 OD.
  • Figure 2 is the XRPD spectrum of the fumarate A crystal form, in which the "Position[°2theta](Copper(Cu))" on the abscissa is translated as "position (2 ⁇ )(°)( ⁇ (Cu))", It refers to the 2 ⁇ angle expressed in (°); the "Counts” of the ordinate is translated as “count”, which refers to the diffraction peak intensity (the same below).
  • Figure 3 shows the DSC and TGA diagrams of fumarate A crystal form, in which the abscissa "Temperature (°C)” translates to “temperature”; the ordinate on the left side translates “Weight (%)” to “weight (%)” ”, the “Heat Flow (W/g)” on the right ordinate means “Heat Flow (W/g)” (the same below).
  • Figure 4 shows the 1 H-NMR of the crystalline form of fumarate B in CD 3 OD.
  • Figure 5 shows the XRPD pattern of fumarate B crystal.
  • Figure 6 shows the DSC and TGA graphs of fumarate B crystal form.
  • Figure 7 shows the 1 H-NMR of the crystalline form C of fumarate in CD 3 OD.
  • Fig. 8 shows the XRPD pattern of Fumarate C crystal form.
  • Figure 9 shows the DSC and TGA graphs of the crystalline form C of fumarate.
  • Figure 10 shows the 1 H-NMR of the maleate salt form A in CD 3 Cl.
  • Figure 11 is the XRPD pattern of maleate salt A crystal form.
  • Figure 12 shows the DSC and TGA graphs of maleate salt A crystal form.
  • Figure 13 shows the 1 H-NMR of maleate salt B crystal in CD 3 Cl.
  • Figure 14 shows the XRPD pattern of maleate salt B crystal form.
  • Figure 15 is the DSC and TGA graphs of maleate salt B crystal form.
  • Figure 16 shows the 1 H-NMR of crystalline form A of adipate at CD 3 OD.
  • Figure 17 shows the XRPD pattern of the adipate salt form A.
  • Figure 18 shows the DSC and TGA graphs of crystalline form A of adipate.
  • Figure 19 is the XRPD pattern of free amine A crystal form.
  • Figure 20 shows the DSC and TGA graphs of free amine A crystal form.
  • Figure 21 shows the 1 H-NMR of succinate A crystal form in CDCl 3 .
  • Figure 22 shows the XRPD pattern of succinate A crystal form.
  • Figure 23 shows the DSC and TGA graphs of succinate A crystal form.
  • Figure 24 shows the 1 H-NMR of mesylate salt form A in CD 3 OD.
  • Figure 25 is the XRPD pattern of mesylate salt form A.
  • Figure 26 shows the DSC and TGA graphs of mesylate salt form A.
  • Figure 27 shows the XRPD pattern of the hydrochloride salt B crystal form.
  • Figure 28 shows the DSC and TGA graphs of the hydrochloride salt form B.
  • Figure 29 is a comparison diagram of XRPD of maleate B crystal form before and after DVS test.
  • Figure 30 is the XRPD comparison chart of Fumarate A crystal form before and after DVS test.
  • Figure 31 is the XRPD comparison chart of succinate A crystal form before and after DVS test.
  • Figure 32 shows the comparison of XRPD of adipate salt form A before and after the DVS test.
  • Figure 33 is the XRPD comparison chart of hydrochloride salt form A before and after the DVS test.
  • Figure 34 is a comparison diagram of XRPD of mesylate salt form A before and after DVS test.
  • the above solution was filtered through a microporous filter and transferred to the reactor, stirred, and distilled off dichloromethane and ethanol under normal pressure, and then kept the temperature of the reactor to 80 ⁇ 5 degrees Celsius, and the fumaric acid ( 1.0 eq) ethanol solution (12 volumes) was slowly dripped into the reaction kettle through a microporous filter, and kept warm and stirred overnight. Cool down to 20-30 degrees Celsius, continue stirring for at least 1 hour, centrifuge, and collect the filter cake.
  • the filter cake was placed in a vacuum drying oven and dried overnight to obtain 1.605kg 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -Yl)-nitrogen-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate, crystal form A, yield 63.6%.
  • the XPRD pattern is shown in Figure 19, and the XRPD data is shown in Table 7.
  • the DSC data shows that an endothermic peak appears when heated to 222.0 degrees Celsius
  • the TGA data shows that heating from room temperature to 150 degrees Celsius has a weight loss of 1.71% (Figure 20).
  • the purpose of this test example is to compare the solubility of various salts (also called salt forms) obtained in the present invention with the crystal forms/salt forms obtained in the comparative example.
  • the sample and the solvent were mixed in a centrifuge tube (the initial dosage is 10 mg/ml), and then the centrifuge tube was sealed and fixed on a rotating disk with a speed of 25 revolutions per minute, and the mixture was rotated and mixed at 37°C. Samples were taken after 24 hours. The turbid sample was centrifuged, and the filtered supernatant was taken to determine the HPLC concentration. If the sample is clear, test the concentration of the resulting solution.
  • the solubility of maleate crystal form B, fumarate crystal form A, fumarate crystal form C, adipate crystal form A, and succinate crystal form A in water are respectively It is 12.9, 6.3, 0.48, 6.5, and 7.5 mg/ml, which is significantly higher than the solubility of the free base crystal form A in water (0.075 mg/ml).
  • solubility of form A in FeSSIF is equivalent to the solubility of free base crystal form A in FeSSIF (10.2 mg/ml), but compared to free base crystal form A, it is more effective in fasting intestinal fluid (FaSSIF) and feeding intestinal fluid (FeSSIF). The solubility is close, suggesting a lower risk of food effects.
  • This test example compares the hygroscopicity of the various salt forms provided by the present invention with the crystal forms/salt forms prepared in the comparative example.
  • the dynamic moisture adsorption (DVS) test was performed to test the moisture adsorption capacity of the representative salts and free alkalis of the above-mentioned examples and control examples when the humidity reached 80% RH for comparison of hygroscopicity.
  • Test objects free base crystal form A, maleate crystal form B, fumarate crystal form A, adipate crystal form A, succinic acid crystal form A, mesylate crystal form A, and hydrochloric acid Salt crystal form B.
  • This test example compares the stability of the various salt forms provided by the present invention with the crystal forms/salt forms prepared in the comparative example.
  • free amine crystal form A, maleate crystal form B, fumarate crystal form A, fumarate crystal form C, adipate crystal form A, succinate crystal form A , Methanesulfonate crystal form A is placed for one week under the illumination of 4500lux, the relative initial purity of HPLC is 99.3%, 99.9%, 100%, 100%, 100%, 100%, 98.5%, so under light conditions, Malay Salt crystal form B, fumarate crystal form A, adipate crystal form A, succinate crystal form A are more stable than free amine crystal form A, but mesylate crystal form A is more stable than free amine crystal form A is more unstable.
  • maleate crystalline form B, fumarate crystalline form A, fumarate crystalline form C, adipate crystalline form A and succinate crystalline form A under the condition of 40°C/75%RH It also has high stability. After one week, the HPLC relative initial purity is 100%, and the HPLC relative initial purity of the mesylate crystal form A is 99.4%, so under 40°C/75%RH conditions, Maleate crystalline form B, fumarate crystalline form A, fumarate crystalline form C, adipate crystalline form A and succinate crystalline form A have better or equivalent stability than the free base, but The sulfonate form A is more unstable than the free amine form A.
  • the XRPD spectrum was collected on PANalytacal Empyrean and Bruker X-ray powder diffraction analyzers in reflection mode.
  • the XRPD test parameters are shown in Table 15.
  • TGA Thermogravimetric analysis
  • DSC differential scanning calorimetry
  • TGA and DSC spectra were collected on the TA Q500/5000 thermogravimetric analyzer and TA Q200/2000 differential scanning calorimeter respectively. Table 16 lists the test parameters.

Abstract

化合物5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐、马来酸盐及已二酸盐、琥珀酸盐及多个晶型，以及其制备方法与应用被公开，已证实上述盐或其晶型可以更好地替代5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺，克服其在包括溶解性、食物效应风险大及稳定性等方面的缺陷，同时具有较低的吸湿性，具有极大的应用价值。

Description

一种化合物的盐、其晶型以及制备方法与应用
本申请要求2019年6月21日提交的发明名称为“一种化合物的盐、其晶型以及制备方法与应用”的中国专利申请No.201910542355.6的优先权，将其内容完整并入本文作为参考。
技术领域
本发明涉及医药领域，具体涉及一系列CDK4/6抑制剂的盐、其晶型以及制备方法与应用。
背景技术
细胞周期是细胞生命活动的重要部分，在正常的细胞生长过程中，细胞周期进程的实现有赖于各级调控因子对细胞周期精确而严密的调控。这些调控因子的核心是细胞周期蛋白依赖性蛋白激酶(Cyclin Dependent Kinase,CDK)及其正、负性调控因子———细胞周期蛋白(Cyclin)和细胞周期蛋白依赖性蛋白激酶抑制剂(CDI)。细胞周期蛋白依赖性蛋白激酶和细胞周期蛋白形成的CDK-Cyclin复合物，参与细胞的生长、增殖、休眠或者进入凋亡。细胞周期的过程中，细胞周期蛋白周期性连续的表达和降解，并分别结合到由它们瞬时活化的CDK上，通过CDK活性，催化不同底物磷酸化，实现对细胞周期不同时相的推进和转化作用。
目前CDK家族已经发现了13个成员，分别是CDK1-CDK13；其中CDK1、CDK2、CDK3、CDK4和CDK6与调节细胞增殖有关，CDK7、CDK8、CDK9、CDK11、CDK12和CDK13参与调控转录。
Cyclin分为A-L，不同的CDK分别连接不同亚型的Cyclin。其中，Cyclin D家族(Cyclin D1，D2，D3)，在G1期开始表达，结合并激活CDK4和CDK6，形成CDK4/6-Cyclin D复合物，使包括视网膜母细胞瘤蛋白(Retinoblastomaprotein,Rb)在内的一系列底物磷酸化。Rb磷酸化后释放与其结合并被其抑制的蛋白，主要是转录因子E2F等，E2F激活并转录进入S期所必须的一些基因(马珂，CDK4/6抑制剂抗肿瘤作用研究进展，《国外医药·抗生素分册》，2013，34(5)：197-202)。如果由于各种因素使平衡被打破，无论是促进细胞增殖的信号增强，或者是抑制细胞增殖的信号减弱到某种程度，细胞增殖都会失控，进而出现肿瘤。研究发现，大约80％的人类肿瘤中存在Cyclin D–CDK4/6–INK4–Rb通路的异常(1.Malumbres M,Barbacid M.,To cycle or not to cycle:a critical decision in  cancer[J].Nature Reviews Cancer,2001,1(3):222；2.Shapiro GI.,Cyclin-dependent kinase pathways as targets for cancer treatment[J].J Clinical Oncology,2006,24(11):1770)。这条通路的改变，加速了G1期进程，使得肿瘤细胞增殖加快而获得生存优势。因此，对其的干预成为一种治疗策略，CDK4/6因此成为潜在的抗肿瘤的靶点之一。
CDK4/6作为抗肿瘤靶点的优势在于：(1)大多数增殖的细胞依赖CDK2或者CDK4/6增殖，但CDK4/6的抑制剂不表现出“泛-CDK抑制剂”的细胞毒性，如骨髓抑制和肠道反应。(2)临床前实验表明，如果细胞Cyclin D水平升高或者p16INK4a失活，能够增加细胞对药物的敏感性，由于肿瘤细胞相对于正常细胞存在上述现象，所以一定程度上增加了药物的靶向。
除了抑制肿瘤生长，也有CDks抑制剂用于其它病症的治疗；如用于治疗心血管障碍，包括动脉粥样硬化、血管支架植入后再狭窄和其它由细胞异常增殖引起的心血管障碍；再如用于治疗真菌、原生动物寄生虫(如恶性疟原虫)和DNA与RNA病毒感染引起的疾病，包括疟疾、艾滋病等。此外，还有研究发现CDKs抑制剂还可以用于自身免疫系统疾病(如牛皮癣、类风湿性关节炎、肾小球性肾炎和红斑狼疮等)，抑制炎症细胞的增殖。
中国申请CN 106810536中报道了一种有效的CDK4/6抑制剂，5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺，如式I所示：
Figure PCTCN2020097482-appb-000001
虽然该化合物是一种有效的CDK4/6抑制剂，但是该化合物在药物产品中的应用仍然存在问题，例如，1)该化合物的游离碱(也称为游离胺)在水中的溶解度较低，即使筛选出的该化合物的最优的晶型A(即下文中的对比例1)，在水中的溶解度也仅为75μg/mL，且在模拟肠液中表现出较高的食物效应，即在模拟禁食肠液(FaSSIF)和喂食肠液(FeSSiF)中的溶解度相差较大，具有较高的食物效应风险，应用于患者时有较 高的食物效应风险，而且稳定性不好，温度稍高或光照条件下(例如4500lux)以及高温高湿条件下(例如40℃/75％RH)化合物纯度降低，不利于化合物的应用以及存储，因此，迫切需要提出合适的替代物以解决该类问题。
发明内容
本发明的第一目的在于提供CDK4/6抑制剂的盐，以更好地替代5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺，克服其在包括溶解性、食物效应风险大、及稳定性等方面的缺陷，同时具有较低的吸湿性。
具体而言，本发明提供了如式I所示的化合物的盐：
Figure PCTCN2020097482-appb-000002
所述盐选自富马酸盐、马来酸盐、己二酸盐或琥珀酸盐，即5-氟-4-(7'-氟-2'-甲基螺[环戊/烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的四类盐：5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐、马来酸盐、己二酸盐和琥珀酸盐。
虽然5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺已被证实是一种有效的CDK4/6抑制剂，但随后的研究表明是该化合物在药物产品中的应用仍然存在问题，为了寻找合适的替代物，发明人对5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的大量的盐进行了研究，然而在随后的进一步研究中发现，5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的各类盐在溶解度、食物效应、吸湿性和稳定性方面差异很大，很多盐相比于游离碱具有更差的稳定性和较高的吸湿性，为了得到更好的替代物，本发明通过大量试验，在包括但不限于盐酸盐，磷酸盐，乳酸盐，马来酸盐，富马酸盐，琥珀酸盐，苹果酸盐，己二酸盐，酒石酸盐，马尿酸盐，柠檬酸盐，乙醇酸盐，丙二酸盐，苯甲酸盐，龙胆酸盐，葵二酸盐，1-羟基-2-萘甲酸盐， 草酸盐，甲磺酸盐，乙二磺酸盐，苯磺酸盐，对甲苯磺酸盐，氢溴酸盐等大量的盐、以及各种反应条件下得到的上述盐的大量的晶型进行了研究，出乎预料地发现5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐，马来酸盐，琥珀酸盐，己二酸盐这四种具体的盐，相对于5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺及其它各种盐和晶型，具有下述一种或多种优异的特性：
1)在水中和禁食肠液(FaSSIF)中具有更优异的溶解性；
2)在禁食肠液(FaSSIF)和喂食肠液(FeSSiF)中的溶解度接近，具有较低的食物效应风险；
3)具有更优异的稳定性；
4)具有与游离碱最优的晶型A相当的较低的吸湿性。
作为本申请的并列方案之一，本发明提供了(5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐。
所述富马酸盐相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险。而且，在进行溶解度测试时，分散在水中、FaSSIF和FeSSIF中的所述富马酸盐的晶型非常稳定，不会发生变化，而游离碱的其他盐如甲磺酸盐则会发生晶型的变化。同时，出乎预料地是，所述富马酸盐相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生变化，而通常在医药领域，化合物的碱转化成盐时，相对于游离碱会具有较高的吸湿性，比如本发明的所述游离碱的甲磺酸盐和盐酸盐的各晶型均具有较强的吸湿性，且吸湿后晶型发生变化。并且在高湿度和光照条件下，所述富马酸盐相对于游离碱和其他盐，具有更好的物理化学稳定性。
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐的富马酸离子与游离碱的比例(此处指摩尔比)为n:1，其中n≥0.5，优选n为0.5、1或2，更优选n为1，例如下述式II所示的单富马酸盐：
Figure PCTCN2020097482-appb-000003
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐包括一种或多种晶型，优选所述富马酸盐以一种晶型或多种多晶型混合存在，特别优选所述富马酸盐以一种晶型存在。
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐含(优选可变含量的)溶剂分子，优选所述盐中含(优选可变含量的)水分子。
本文中“含可变含量的溶剂分子”中的“可变含量”是指各种盐(如富马酸盐、己二酸盐、马来酸盐、琥珀酸盐等)中，溶剂分子的数量可以不等，理想的如5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐与溶剂的摩尔比为1:m，其中m≥0.5，优选m为0.5、1、2、3、4或5，更优选m为0.5或1。
优选地，5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐包括下述一种晶型或多种晶型，优选所述富马酸盐为下述任一种富马酸盐的晶型或多种所述富马酸盐的晶型混合物，更优选为下述一种晶型，所述晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)7.0°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
(2)4.5°、10.5°、18.3°、20.6°和23.9°处显示出特征衍射峰；或
(3)5.9°、14.4°、18.6°、23.6°和23.9°处显示出特征衍射峰；
优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)5.5°、7.0°、9.2°、10.6°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
(2)4.5°、8.9°、10.5°、17.9°、18.3°、20.6°、22.5°和23.9°处显示出特征衍射峰；或
(3)5.9°、14.4°、17.6°、18.6°、21.6°、23.6°、23.9°和28.4°处显示出特征衍射峰；
更优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)5.5°、7.0°、9.2°、10.6°、13.9°、15.7°、17.2°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
(2)4.5°、8.9°、10.5°、17.1°、17.9°、18.3°、20.6°、22.5°、23.9°和27.5°处显示出特征衍射峰；或
(3)5.9°、11.7°、14.4°、17.6°、18.6°、21.6°、23.6°、23.9°、25.0°和28.4°处显示出特征衍射峰；
所述富马酸盐的晶型尤其优选具有选自下述(1)～(3)任一项的XRPD数据和/或图谱：
(1)基本如表1所示的XRPD数据；和/或，基本如图2所示的XRPD图谱；
(2)基本如表2所示的XRPD数据；和/或，基本如图5所示的XRPD图谱；
(3)基本如表表3所示的XRPD数据；和/或，基本如图8所示的XRPD图谱。
上述(1)、(2)、(3)分别对应于5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐的A晶型(下文简称富马酸盐A晶型)、B晶型(下文简称富马酸盐B晶型)、C晶型(下文简称富马酸盐C晶型)的XRPD信息。
上述各晶型可以通过X射线衍射(XRPD)，差式扫描量热法(DSC)，热重分析(TGA)，或核磁共振法加以区分。
关于富马酸盐A晶型：
进一步地，上述富马酸盐A晶型的DSC图谱在254.6℃时出现吸热峰；
进一步地，上述富马酸盐A晶型从室温加热至180℃有2.50％的失重；
优选地，上述富马酸盐A晶型具有基本如图3所示的DSC和TGA图。
本发明所述的富马酸盐A晶型具有较高的结晶度和较高的熔点，相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险；而且，出乎预料地是，相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生变化。同时在高湿度和光照条件下，相对于游离碱，具有 更好的物理化学稳定性。
关于富马酸盐B晶型：
进一步地，上述富马酸盐B晶型的DSC图谱在254.4℃时出现吸热峰；
进一步地，上述富马酸盐B晶型从室温加热至130℃有2.71％的失重。
优选地，上述富马酸盐B晶型具有基本如图6所示的DSC和TGA图。
本发明所述的富马酸盐B晶型具有较高的结晶度和较高的熔点，相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险；而且，出乎预料地是，相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生变化。同时在高湿度和光照条件下，相对于游离碱，具有更好的物理化学稳定性。
关于富马酸盐C晶型：
进一步地，上述富马酸盐C晶型的DSC图谱在240.2℃时出现吸热峰；
进一步地，上述富马酸盐C晶型从室温加热至130℃有1.95％的失重。
优选地，上述富马酸盐C晶型具有基本如图9所示的DSC和TGA图。
本发明所述的富马酸盐C晶型具有较高的结晶度和较高的熔点，FeSSIF具有较高的溶解度，而且，出乎预料地是，相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生晶型的变化。同时在高湿度和光照条件下相对于游离碱具有更好的物理化学稳定性。
作为本申请的并列方案之二，本发明提供了一种CDK4/6抑制剂的马来酸盐，即(5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的马来酸盐。
所述马来酸盐相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险。而且，出乎预料地是，相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生变化。同时在高湿度和光照条件下具有更好的物理化学稳定性。
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的马来酸盐的马来酸离子与游离碱的比例为n:1，其中n≥0.5，优选n为0.5、1或2，更优选n为1，例如下述式III所示的单马来酸盐。
Figure PCTCN2020097482-appb-000004
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的马来酸盐包括一种晶型或多种多晶型，优选所述马来酸盐以一种晶型或多种多晶型混合存在，特别优选所述马来酸盐以一种晶型存在。
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐含(优选可变含量的)溶剂分子，优选所述盐中含(优选可变含量的)水分子。
优选地所述马来酸盐包括下述一种马来酸盐的晶型或多种马来酸盐的晶型，优选所述马来酸盐为下述任一种马来酸盐的晶型或多种所述马来酸盐的晶型混合物，特别优选为下述任一种马来酸盐的晶型；
所述晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)7.8°、9.0°、15.7°、18.4°和22.7°处显示出特征衍射峰；或
(2)5.7°、13.7°、17.9°、18.9°和23.6°处显示出特征衍射峰；
优选所述马来酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)7.3°、7.8°、9.0°、15.7°、17.9°、18.4°、20.7°和22.7°处显示出特征衍射峰；或
(2)5.7°、13.7°、17.6°、17.9°、18.9°、21.9°、23.6°和24.8°处显示出特征衍射峰；
更优选所述马来酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)7.3°、7.8°、9.0°、13.6°、15.7°、17.9°、18.4°、20.7°、22.7°和24.1°处显示出特征衍射峰；或
(2)5.7°、13.7°、14.1°、17.2°、17.6°、17.9°、18.9°、21.9°、23.6°和24.8°处显示出特征衍射峰；
尤其优选所述马来酸盐的晶型具有选自下述(1)～(2)任一项的XRPD数据和/ 或图谱：
(1)基本如表4所示的XRPD数据；和/或，基本如图11所示的XRPD图谱；
(2)基本如表5所示的XRPD数据；和/或，基本如图14所示的XRPD图谱。
上述(1)、(2)分别对应于5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的马来酸盐的A晶型(下文简称马来酸盐A晶型)、B晶型(下文简称马来酸盐B晶型)的XRPD信息。
上述各晶型可以通过X射线粉末衍射(XRPD)，差式扫描量热法(DSC)，或核磁共振法加以区分。
关于马来酸盐A晶型：
进一步地，上述马来酸盐A晶型的DSC图谱在188.3℃时出现吸热峰；
进一步地，上述马来酸盐A晶型从室温加热至130℃有3.48％的失重。
优选地，上述马来酸盐A晶型具有基本如图12所示的DSC和TGA图。
本发明所述的马来酸盐A晶型具有较高的结晶度和较高的熔点，相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险。而且，出乎预料地是，相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生变化。同时在高湿度和光照条件下具有更好的物理化学稳定性。
关于马来酸盐B晶型：
进一步地，上述马来酸盐B晶型的DSC图谱在216.6℃时出现吸热峰；
进一步地，上述马来酸盐B晶型从室温加热至130℃有3.61％的失重。
优选地，上述马来酸盐B晶型具有基本如图15所示的DSC和TGA图。
本发明所述的马来酸盐B晶型具有较高的结晶度和较高的熔点，相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险。而且，出乎预料地是，相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生变化。同时在高湿度和光照条件下具有更好的物理化学稳定性。
作为本申请的并列方案之三，本发明提供了(5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的已二酸盐：所述已二酸盐相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险。而且，出乎预料地是，相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生变化。同时在高湿度和光照条件下具有更好 的物理化学稳定性。
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的己二酸盐的己二酸离子与游离碱的比例为n:1，其中n≥0.5，优选n为0.5、1或2，更优选n为1，例如下述式IV所示的单己二酸盐。
Figure PCTCN2020097482-appb-000005
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的己二酸盐包括一种晶型或多种多晶型或能够以一种晶型或多种多晶型混合存在，优选所述盐以一种晶型存在。
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的己二酸盐含(优选可变含量的)溶剂分子，优选所述盐中含(优选可变含量的)水分子。
优选地，所述5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的己二酸盐包括下述晶型(下文也可称为己二酸盐A晶型)或仅以下述已二酸盐的晶型存在，所述晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：4.3°、8.5°、15.7°、21.7°和28.2°处显示出特征衍射峰。
优选所述己二酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：4.3°、8.5°、13.0°、15.7°、18.2°、19.9°、21.7°和28.2°处显示出特征衍射峰；
更优选所述己二酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：4.3°、8.5°、13.0°、15.3°、15.7°、18.2°、19.4°、19.9°、21.7°和28.2°处显示出特征衍射峰；
尤其优选所述己二酸盐的晶型具有：具有基本如表6所示的XRPD数据；和/或，基 本如图17所示的XRPD图谱。
上述晶型可以通过X射线衍射(XRPD)，差式扫描量热法(DSC)，或核磁共振法加以确认。
进一步地，上述已二酸盐A晶型的DSC图谱在171.8℃时出现吸热峰；
进一步地，上述已二酸盐A晶型从室温加热至130℃有0.95％的失重。
优选地，上述已二酸盐A晶型具有基本如图18所示的DSC和TGA图。
作为本申请的并列方案之四，本发明提供了(5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的琥珀酸盐。
所述琥珀酸盐相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险。而且，出乎预料地是，相比于游离碱具有相当的低吸湿性，且吸湿后晶型稳定，不会发生变化。同时在高湿度和光照条件下具有更好的物理化学稳定性。
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的琥珀酸盐的琥珀酸离子与游离碱的比例为n:1，其中n≥0.5，优选n为0.5、1或2，更优选n为1，例如下述式V所示的单琥珀酸盐。
Figure PCTCN2020097482-appb-000006
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的琥珀酸盐包括一种晶型或多种多晶型或能够以一种晶型或多种多晶型混合存在，优选所述盐以一种晶型存在。
在一个实施方案中，本发明的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的琥珀酸盐含(优选可变含量的)溶剂分子，优选所述盐中含(优选可变含量的)水分子。
优选地，5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡 啶-2-基)嘧啶-2-胺的琥珀酸盐包括下述晶型(下文也可称为琥珀酸盐A晶型)或仅以下述琥珀酸盐的晶型存在，所述晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
5.4°、13.9°、16.0°、21.1°和24.3°处显示出特征衍射峰；优选所述琥珀酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
5.4°、9.5°、10.1°、13.9°、16.0°、18.6°、21.1°和24.3°处显示出特征衍射峰；更优选所述琥珀酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
5.4°、9.5°、10.1°、13.4°、13.9°、16.0°、17.7°、18.6°、21.1°和24.3°处显示出特征衍射峰；或
尤其优选所述琥珀酸盐A晶型具有：基本如表8所示的XRPD数据；和/或，基本如图22所示的XRPD图谱。
关于琥珀酸盐A晶型：
进一步地，上述琥珀酸盐A晶型的DSC图谱在192.3℃和235.9℃时出现吸热峰；
进一步地，上述琥珀酸盐A晶型从室温加热至130℃有2.43％的失重。
优选地，上述琥珀酸盐A晶型具有基本如图23所示的DSC和TGA图。
作为尤其优选的技术方案，本发明同时提供了如式I所示化合物的富马酸盐的晶型：
Figure PCTCN2020097482-appb-000007
所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)7.0°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
(2)4.5°、10.5°、18.3°、20.6°和23.9°处显示出特征衍射峰；或
(3)5.9°、14.4°、18.6°、23.6°和23.9°处显示出特征衍射峰；
优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)5.5°、7.0°、9.2°、10.6°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰； 或
(2)4.5°、8.9°、10.5°、17.9°、18.3°、20.6°、22.5°和23.9°处显示出特征衍射峰；或
(3)5.9°、14.4°、17.6°、18.6°、21.6°、23.6°、23.9°和28.4°处显示出特征衍射峰；
更优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
(1)5.5°、7.0°、9.2°、10.6°、13.9°、15.7°、17.2°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
(2)4.5°、8.9°、10.5°、17.1°、17.9°、18.3°、20.6°、22.5°、23.9°和27.5°处显示出特征衍射峰；或
(3)5.9°、11.7°、14.4°、17.6°、18.6°、21.6°、23.6°、23.9°、25.0°和28.4°处显示出特征衍射峰；
优选所述富马酸盐的晶型具有选自下述(1)～(3)任一项的XRPD数据和/或图谱：
(1)基本如表1所示的XRPD数据；和/或，基本如图2所示的XRPD图谱；
(2)基本如表2所示的XRPD数据；和/或，基本如图5所示的XRPD图谱；
(3)基本如表3所示的XRPD数据；和/或，基本如图8所示的XRPD图谱。
特别是，所述富马酸盐A晶型，所述富马酸盐A晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
7.0°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
5.5°、7.0°、9.2°、10.6°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
5.5°、7.0°、9.2°、10.6°、13.9°、15.7°、17.2°、18.4°、21.8°和24.1°处显示出特征衍射峰；
尤其优选所述富马酸盐的晶型具有：
基本如表1所示的XRPD数据；和/或，基本如图2所示的XRPD图谱。
进一步地，上述富马酸盐A晶型的DSC图谱在254.6℃时出现吸热峰；
进一步地，上述富马酸盐A晶型从室温加热至180℃有2.50％的失重；
优选地，上述富马酸盐A晶型具有基本如图3所示的DSC和TGA图。
本发明所述的富马酸盐A晶型具有较高的结晶度和较高的熔点，相比于游离碱在水中和FaSSIF中具有较高的溶解度，而且在FaSSIF和FeSSIF中具有相近的溶解度，即，较低的食物效应风险；而且，出乎预料地是，相比于游离碱具有相当的低吸湿性， 且吸湿后晶型稳定，不会发生变化。同时在高湿度和光照条件下，相对于游离碱，具有更好的物理化学稳定性。
本发明还提供了上述富马酸盐A晶型的制备方法，包括使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应，反应溶剂为有机溶剂或所述有机溶剂的水溶液。
本发明所述的制备方法，作为原料的“5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺”，可以是市售粗品，也可以并尤其优选为按照CN 106810536的实施例17的方法制备的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺。本发明中所述有机溶剂不受特别限制，只要能够实现使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应得到富马酸盐A晶型即可。优选地，所述有机溶剂为极性有机溶剂；进一步优选，所述有机溶剂为醇、酮、卤代烷烃、醚和酯中的一种或多种；更优选地所述有机溶剂为C 1-C 5直链或支链链烷醇、丙酮、THF、乙酸乙酯、二氯甲烷、和氯仿中的一种或多种。其中，所述C 1-C 5直链或支链链烷醇优选为甲醇、乙醇、丙醇或异丙醇；更优选地，所述有机溶剂为甲醇、乙醇、丙醇、异丙醇、丙酮、二氯甲烷和氯仿中的一种或多种。
优选地，所述方法还包括：在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸混合时，将富马酸缓慢地滴入5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺中。
优选地，在20℃至使反应溶剂回流的温度使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应。
优选地，所述方法还包括：在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应前，先将5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺溶解。
优选地，将5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺溶解所使用的溶剂包括第一溶剂和第二溶剂，其中所述第一溶剂为酮、醚、酯和醇中的一种或多种，优选为一种或多种醇、进一步优选所述第一溶剂为C 1-C 5直链和支链链烷醇中的一种或多种，更优选为甲醇、乙醇、丙醇和异丙醇中的一种或多 种；所述第二溶剂为二氯甲烷、氯仿或二者的组合。
所述第一溶剂和第二溶剂地混合体积比不受特别限制，只要能使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺溶解即可。
优选地，所述第一溶剂和第二溶剂地混合体积比为1：(1-10)、优选为1：(1-3)，最优选为1；1，此时尤为理想的组合为甲醇、乙醇、丙醇和异丙醇中一种或多种作为第一溶剂，二氯甲烷、氯仿或二者的组合作为第二溶剂。
进一步优选地，所述方法还包括：在将5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺溶解后，对得到的溶液进行过滤，以除去5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺中的杂质，以确保以高质量、高纯度地形成富马酸盐A晶型。
进一步优选地，所述方法还包括：在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应前，将溶解5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺所用的溶剂蒸出。
进一步优选地，所述方法还包括：在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应完成后，将反应体系降温至10-35℃，优选降温至20-30℃，以使富马酸盐A晶型充分析出。
作为本发明的其中一种具体的优选方式，所述方法包括：将5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺在溶剂中溶解，所述溶剂为第一溶剂和第二溶剂的混合物，其中所述第一溶剂为甲醇、乙醇、丙醇或异丙醇；所述第二溶剂为二氯甲烷或氯仿，二者的体积比为1：(1-3)；
将溶解5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺所用的溶剂蒸出，以确保能较稳定地形成富马酸盐A晶型。
将富马酸缓慢地滴入上述溶剂蒸出后的5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺中，使二者在溶剂中反应，所述的溶剂为甲醇、乙醇、丙醇或异丙醇。反应温度为20℃至使所述溶剂回流的温度。
在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应完成后，将反应体系降温至20-30℃，以使富马酸盐A晶型充分析出。
采用上述制备方法，本发明可重复、稳定、高效地制得所述富马酸盐A晶型，确保晶体质量。
本发明的另一目的在于提供一种药物组合物，该药物组合物含有治疗有效量的上述5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐，马来酸盐，琥珀酸盐或己二酸盐中的至少一种。
优选地，所述药物组合物中还包括药学上可以接受的辅料，所述药物上可接受的辅料包括载体、稀释剂、和赋形剂中的一种或多种。
“至少一种药物上可接受的载体、稀释剂、或赋形剂”可轻易地由此技术中一般具有技能的技术人员选定，且由所需给药方式决定。适宜的给药方式的说明性实施例包括经口、经鼻、非经肠、局部、经皮、及经直肠。
本发明的药物组合物可为熟悉此项技术者认为适合的任何药物形式。适宜的药物形式包括固体、半固体、液体、或冻干的制剂，如片剂、粉末剂、胶囊剂、栓剂、混悬剂、脂质体及喷雾剂。
本发明的另一目的在于提供试剂盒，该试剂盒包括上述5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺的富马酸盐，马来酸盐，琥珀酸盐或己二酸盐中的至少一种、和一种或多种其他具有生物活性的物质；优选所述试剂盒中还包括药学上可以接受的辅料；更优选所述药学上可以接受的辅料包括载体、稀释剂、和赋形剂中的至少一种；
优选地，所述其它具有生物活性的物质包括但不限于抗癌剂、免疫抑制剂、抗病毒剂等。
优选地，所述其它具有生物活性的物质包括烷化剂、抗代谢类抗肿瘤药、铂络合剂、抗生素类抗肿瘤药、天然来源抗肿瘤药、激素类抗肿瘤药、VEGFR或EGFR抑制剂、抗体抗肿瘤药、mTOR抑制剂、治疗脑瘤类用药等。
优选地，所述烷化剂包括环磷酰胺、异环磷酰胺、塞替派、司莫司汀、盐酸氮芥、白消安、苯丁酸氮芥、苯丙氨酸氮芥、硝卡芥、氮甲、卡莫司汀、洛莫司汀、六甲蜜胺、二溴甘露醇、替莫唑胺等；所述抗代谢类抗肿瘤药包括阿糖胞苷、氟尿嘧啶、甲氨喋呤、羟基脲、替加氟、甲异靛、巯嘌呤等；所述铂络合剂(如顺铂、卡铂、奥沙利铂等)；所述抗生素类抗肿瘤药包括放线菌素D、丝裂霉素、阿霉素、平阳霉素、表柔比星、吡柔比星、柔红霉素、博来霉素等；所述天然来源抗肿瘤药包括高三尖杉酯碱及其衍生物、 长春新碱及其衍生物、羟喜树碱及其衍生物、依托泊苷及其衍生物、长春地辛及其衍生物、长春碱及其衍生物、重酒石酸长春瑞宾、紫杉醇及其衍生物、秋水仙碱及其衍生物、榄香烯及其衍生物等；所述激素类抗肿瘤药包括氨鲁米特、他莫昔芬、地塞米松、度他雄胺、氟他胺、戈那瑞林、醋酸亮丙瑞林、来曲唑等；所述VEGFR或EGFR抑制剂包括舒尼替尼、索拉非尼、伊马替尼、吉非替尼、埃罗替尼、凡德替尼、帕唑帕尼、拉帕替尼、卡奈替尼、阿法替尼、木利替尼、达沙替尼、来那替尼等；所述抗体抗肿瘤药包括曲妥单抗、帕妥珠单抗、利妥昔单抗、帕尼单抗、贝伐单抗、伊匹单抗、奥法木单抗、雷莫卢单抗等；所述mTOR抑制剂包括依维莫司、西罗莫司、佐他莫司等；所述治疗脑瘤类用药包括替莫唑胺等。
进一步优选地，将所述CDK4/6抑制剂的盐与替莫唑胺联用，以获得在脑瘤治疗方面理想的效果。
本发明同时提供了所述化合物(也可称为CDK4/6抑制剂)的盐、所述药物组合物或所述试剂盒在制备治疗对细胞周期调节蛋白依赖性激酶的抑制具有反应的疾病的药物中的应用；以及使用所述CDK4/6抑制剂的盐型或所述药物组合物对细胞周期调节蛋白依赖性激酶的抑制具有反应的疾病的治疗方法。
优选地，所述疾病包括但不限于脑瘤、乳腺癌、泌尿生殖癌、肺癌、胃肠癌、表皮样癌、黑色素瘤、卵巢癌、胰腺癌、神经母细胞瘤、头颈癌或膀胱癌、白血病、增生、胃癌、结肠癌、喉癌、淋巴系统癌、生殖泌尿道癌、骨癌、前列腺癌、小细胞型肺癌、神经胶质瘤癌、结肠直肠癌、肾癌、上皮癌、肝癌、食道癌、造血系统癌、淋巴瘤、骨髓瘤、甲状腺滤泡状癌；间质来源的肿瘤；中枢或周围神经系统的肿瘤；黑色素瘤；精原细胞瘤；畸胎瘤；骨肉瘤；着色性干皮病；角化棘皮瘤；甲状腺滤泡状癌；卡波西氏(Kaposi's)肉瘤、慢性淋巴细胞白血病、外套细胞淋巴瘤、大B细胞淋巴瘤。
优选所述间质来源的肿瘤为纤维肉瘤或横纹肌肉瘤；所述中枢或周围神经系统的肿瘤为星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤。
应用时，将有效量的上述CDK4/6抑制剂的盐施予患者，以治疗、缓解或预防上述疾病，具体的形式可采用已知的多种手段，本发明对此不作特别限定。
此处“治疗”或者“缓解”指的是施用本文公开的CDK4/6抑制剂的盐的至少一种或其他可配伍使用的活性成分给确认需要其的受试者，例如，所述受试者患有肺癌。
此处“有效量”指的是本文公开的CDK4/6抑制剂的盐的以下量，所述量可在受试者中 有效“治疗”(如上所定义)疾病或机能紊乱。
在本发明中，“联合产品”(或称为“试剂盒”)不仅是指含有所有组分的剂型(所谓的固定联合产品)，和含有相互分离的组分的联合产品包装，而且还指同时或顺序施用的分离组分，只要这些组分用于预防和/或治疗同一疾病即可。
附图说明
图1为富马酸盐A晶型在CD 3OD中的 1H-NMR图。
图2为富马酸盐A晶型的XRPD图谱，其中，横坐标的“Position[°2theta](Copper(Cu))”翻译为“位置(2θ)(°)(铜(Cu))”,是指以(°)表示的2θ角；纵坐标的“Counts”翻译为“计数”，是指衍射峰强度(下同)。
图3为富马酸盐A晶型的DSC和TGA图，其中，横坐标“Temperature(℃)”翻译为“温度”；左侧纵坐标的“Weight(％)”翻译为“重量(％)”，右侧纵坐标“Heat Flow(W/g)”是指“热流量(W/g)”(下同)。
图4为富马酸盐B晶型在CD 3OD中的 1H-NMR。
图5为富马酸盐B晶型的XRPD图谱。
图6为富马酸盐B晶型的DSC和TGA图。
图7为富马酸盐C晶型在CD 3OD中的 1H-NMR。
图8为富马酸盐C晶型的XRPD图谱。
图9为富马酸盐C晶型的DSC和TGA图。
图10为马来酸盐A晶型在CD 3Cl中的 1H-NMR。
图11为马来酸盐A晶型的XRPD图谱。
图12为马来酸盐A晶型的DSC和TGA图。
图13为马来酸盐B晶型在CD 3Cl中的 1H-NMR。
图14为马来酸盐B晶型的XRPD图谱。
图15为马来酸盐B晶型的DSC和TGA图。
图16为己二酸盐A晶型在CD 3OD的 1H-NMR。
图17为己二酸盐A晶型的XRPD图谱。
图18为己二酸盐A晶型的DSC和TGA图。
图19为游离胺A晶型的XRPD图谱。
图20为游离胺A晶型的DSC和TGA图。
图21为琥珀酸盐A晶型在CDCl 3中的 1H-NMR。
图22为琥珀酸盐A晶型的XRPD图谱。
图23为琥珀酸盐A晶型的DSC和TGA图。
图24为甲磺酸盐A晶型在CD 3OD中的 1H-NMR。
图25为甲磺酸盐A晶型的XRPD图谱。
图26为甲磺酸盐A晶型的DSC和TGA图。
图27为盐酸盐B晶型的XRPD图谱。
图28为盐酸盐B晶型的DSC和TGA图。
图29为马来酸盐B晶型在DVS测试前后的XRPD对比图。
图30为富马酸盐A晶型在DVS测试前后的XRPD对比图。
图31为琥珀酸盐A晶型在DVS测试前后的XRPD对比图。
图32为己二酸盐A晶型在DVS测试前后的XRPD对比图。
图33为盐酸盐A晶型在DVS测试前后的XRPD对比图。
图34为甲磺酸盐A晶型在DVS测试前后的XRPD对比图。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域技术人员在没有作出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
实施例1
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺富马酸盐的制备(A晶型)的制备
Figure PCTCN2020097482-appb-000008
氮气保护下，室温，向反应釜中加入二氯甲烷(22.0体积)和乙醇(22.0体积)，边搅拌边加入5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(2.070kg)，升温至30-40摄氏度，搅拌直至全部溶解，降温至室温，将溶液转移至溶剂桶中备用。在氮气保护下，将上述溶液通过微孔过滤器过滤，并转移至反应釜中，搅拌，常压蒸出二氯甲烷和乙醇，然后保持反应釜温度至80±5摄氏度，将富马酸(1.0eq)的乙醇溶液(12体积)通过微孔过滤器缓慢滴入反应釜中，保温搅拌过夜。降温至20-30摄氏度，继续搅拌至少1个小时，离心，收集滤饼。将滤饼置于真空干燥箱中，干燥过夜，得到1.605kg 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺富马酸盐的A晶型，收率63.6％。
1H-NMR表明该晶型为单富马酸盐(图1)；XPRD图如图2所示，XRPD数据如表1所示；DSC数据显示，加热至254.6摄氏度时出现吸热峰，TGA数据显示，从室温加热至180摄氏度有2.50％的失重(图3)。
表1富马酸盐A晶型的X衍射数据
Figure PCTCN2020097482-appb-000009
Figure PCTCN2020097482-appb-000010
实施例2
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺富马酸盐的制备(B晶型)的制备
Figure PCTCN2020097482-appb-000011
称取349.7毫克5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺至20毫升玻璃瓶中，加入5毫升THF，然后将含有83.4毫 克富马酸的THF(3.75毫升)溶液滴入玻璃瓶中，室温搅拌4天，离心分离固体，50摄氏度干燥1.5h，得到5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺富马酸盐B晶型。
1H-NMR表明该晶型为单富马酸盐(图4)；XPRD图如图5所示，XRPD数据如表2所示；DSC数据显示，在254.4摄氏度时出现吸热峰，TGA数据显示，从室温加热至130摄氏度有2.71％的失重(图6)。
表2富马酸盐B晶型的X衍射数据
Figure PCTCN2020097482-appb-000012
实施例3
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺富马酸盐的制备(C晶型)的制备
Figure PCTCN2020097482-appb-000013
称取349.7毫克5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺至20毫升玻璃瓶中，加入5毫升异丙醇/水(19:1)，然后将含有83.4毫克富马酸的异丙醇/水(19:1；3.75毫升)溶液滴入玻璃瓶中，室温搅拌4天，离心分离固体，50摄氏度干燥1.5h，得到富马酸盐C晶型。
1H-NMR表明该晶型为单富马酸盐(图7)；XPRD图如图8所示，XRPD数据如表3所示；DSC数据显示，在240.2摄氏度时开始出现吸热峰，TGA数据显示，从室温加热至130摄氏度有1.95％的失重(图9)。
表3富马酸盐C晶型X衍射数据
Figure PCTCN2020097482-appb-000014
实施例4
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基) 嘧啶-2-胺马来酸盐的制备(A晶型)的制备
Figure PCTCN2020097482-appb-000015
称取3.5毫克5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺和8.4毫克马来酸至5毫升玻璃瓶中，加入1毫升THF，室温搅拌4天，离心分离，50摄氏度干燥5小时，得到4.0毫克马来酸盐A晶型，收率92.5％。
1H-NMR表明该晶型为单马来酸盐(图10)；XPRD图如图11所示，XRPD数据如表4所示；DSC数据显示，加热至188.3摄氏度时出现吸热峰，TGA数据显示，从室温加热至130摄氏度有3.48％的失重(图12)。
表4马来酸盐A晶型X衍射数据
Figure PCTCN2020097482-appb-000016
实施例5
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基) 嘧啶-2-胺马来酸盐的制备(B晶型)的制备
Figure PCTCN2020097482-appb-000017
称取353.5毫克5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺至20毫升玻璃瓶中，加入5毫升IPA/H 2O(19:1,v/v)，将含有83.7毫克马来酸的IPA/H 2O(19:1,v/v；3.75毫升)溶液滴入玻璃瓶中，室温搅拌4天，离心分离，50摄氏度干燥5小时，得到405.1毫克马来酸盐B晶型，收率92.7％。
1H-NMR表明该晶型为单马来酸盐(图13)；XPRD图如图14所示，XRPD数据如表5所示；DSC数据显示，加热至216.6摄氏度时出现吸热峰，TGA数据显示，从室温加热至130摄氏度有3.61％的失重(图15)。
表5马来酸盐B晶型X衍射数据
Figure PCTCN2020097482-appb-000018
Figure PCTCN2020097482-appb-000019
实施例6
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺己二酸盐(A晶型)的制备
Figure PCTCN2020097482-appb-000020
称取350.6毫克5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺至20毫升玻璃瓶中，加入5毫升THF，将含有105.4毫克己二酸的四氢呋喃溶液(3.75毫升)滴入玻璃瓶中，室温搅拌4天，离心分离固体，50摄氏度干燥5小时，得到362.4毫克己二酸盐A晶型，收率79.5％。
1H-NMR表明该晶型为单己二酸盐(图16)；XPRD图如图17所示，XRPD数据如表6所示；DSC数据显示，加热至171.8摄氏度时出现吸热峰，TGA数据显示，从室温加热至130摄氏度有0.95％的失重(图18)。
表6己二酸盐A晶型X衍射数据
Figure PCTCN2020097482-appb-000021
Figure PCTCN2020097482-appb-000022
对比例1
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(A晶型)的制备
Figure PCTCN2020097482-appb-000023
将按照CN 106810536的实施例17的方法制备的5-氟-4-(7'-氟-2'-甲基螺[环戊烷
-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺300g和3升四氢呋喃加入到10升的反应釜中，将反应釜加热至70度直到固体完全溶解，并回流反应1小时，然后缓慢降温冷却，析出固体，过滤，滤饼用正己烷洗涤，红外灯烘干得到260g浅黄色固体,即游离胺A晶型，收率86.66％。
XPRD图如图19所示，XRPD数据如表7所示；DSC数据显示，加热至222.0摄氏度时出现吸热峰，TGA数据显示，从室温加热至150摄氏度有1.71％的失重(图20)。
表7游离胺A晶型X衍射数据
Figure PCTCN2020097482-appb-000024
Figure PCTCN2020097482-appb-000025
实施例7
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺琥珀酸盐(A晶型)的制备
Figure PCTCN2020097482-appb-000026
将351.6毫克5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4- 基)吡啶-2-基)嘧啶-2-胺和5毫升丙酮加入到反应瓶中，磁力搅拌，然后将含有85.1毫克琥珀酸的3.75毫升丙酮溶液滴加入反应瓶中，室温搅拌四天，离心分离固体，50摄氏度干燥5小时，得到377.7毫克固体，即琥珀酸盐A晶型，收率86.5％。
1H-NMR表明该晶型为单琥珀酸盐(图21)；XPRD图如图22所示，XRPD数据如表8所示；DSC数据显示，在192.3℃和235.9℃摄氏度时出现吸热峰，TGA数据显示，从室温加热至130摄氏度有2.4％的失重(图23)。
表8琥珀酸盐A晶型X衍射数据
Figure PCTCN2020097482-appb-000027
Figure PCTCN2020097482-appb-000028
对比例2
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺甲磺酸盐(A晶型)的制备
将61.1毫克甲磺酸和305.3毫克5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺加入到反应瓶中，加入10毫升乙酸乙酯，室温搅拌3天，离心分离固体，50摄氏度干燥3小时，得到370.2毫克固体，即甲磺酸盐A晶型，产率101.0％。
1H-NMR表明该晶型为单甲磺酸盐(图24)；XPRD图如图25所示，XRPD数据如表9所示；DSC数据显示，加热至102.9摄氏度时出现宽吸热峰，TGA数据显示，从室温加热至150摄氏度有11.07％的失重(图26)。
表9甲磺酸盐A晶型X衍射数据
Figure PCTCN2020097482-appb-000029
对比例3
5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺盐酸盐(B晶型)的制备
称取352.2毫克5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺至20毫升玻璃瓶中，并加入5毫升THF。称取60微升盐酸并用3.75毫升THF稀释，然后将得到的酸溶液逐步加入游离碱悬浊液中，于室温搅拌4天。离心分离固体，50℃干燥5小时，收集361.4毫克固体，即得到盐酸盐B晶型(产率：83.3％)。
XPRD图如图27所示；DSC数据显示，在281.9℃(起点温度)熔化前有三个吸热峰，TGA数据显示，在200℃前存在5.5％失重(图28)。
试验例1
本试验例的目的在于对比本发明得到的各类盐(也可以称为盐型)与对比例所制得的晶型/盐型的溶解度。
实验方法：溶解度测试在水、模拟禁食肠液(FaSSIF)以及模拟喂食肠液(FeSSIF)三种溶媒中进行，用以评估本发明的盐的溶解度。
试验中，分别将样品与溶媒在离心管中混合(起始投料量为10毫克/毫升)，再将离心管密封固定在转速为25转/分钟的旋转盘上，在37℃条件下旋转混合24小时后取样。对浑浊样品离心分离，取过滤后的上清液测定HPLC浓度。若样品溶清，则测试所得溶液浓度。
实验对象：游离碱晶型A、马来酸盐晶型B、富马酸盐晶型A、富马酸盐晶型C、己二酸盐晶型A、和琥珀酸晶型A。
实验结果：见表10-12，不同盐型和晶型在水中、FaSSIF和FeSSIF中的溶解度。
表10不同盐型和晶型在水中的溶解度
样品名称 溶解度(毫克/毫升)
游离碱晶型A 0.075
马来酸盐晶型B 12.9
富马酸盐晶型A 6.3
富马酸盐晶型C 0.48
己二酸盐晶型A 6.5
琥珀酸盐晶型A 7.5
如表10所示，马来酸盐晶型B，富马酸盐晶型A，富马酸盐晶型C、己二酸盐晶型A、和琥珀酸盐晶型A在水中的溶解度分别为12.9、6.3、0.48、6.5、和7.5毫克/毫升，显著高于游离碱晶型A在水中的溶解度(0.075毫克/毫升)。
表11不同盐型和晶型在FaSSIF中的溶解度
样品名称 溶解度(毫克/毫升)
游离碱晶型A 0.19
马来酸盐晶型B 7.1
富马酸盐晶型A 7.6
富马酸盐晶型C 5.9
己二酸盐晶型A 6.8
琥珀酸盐晶型A 6.4
表12不同盐型和晶型在FeSSIF中的溶解度
样品名称 溶解度(毫克/毫升)
游离碱晶型A 10.2
马来酸盐晶型B 7.8
富马酸盐晶型A 8.0
富马酸盐晶型C 13.6
己二酸盐晶型A 11.6
琥珀酸盐晶型A 10.7
如表11所示，马来酸盐晶型B，富马酸盐晶型A，富马酸盐晶型C，己二酸盐晶型A、和琥珀酸盐晶型A在FaSSIF中的溶解度分别显著高于游离碱晶型A在FaSSIF中的溶解度(0.19毫克/毫升)。
如表12所示，马来酸盐晶型B，富马酸盐晶型A，富马酸盐晶型C，己二酸盐晶型A、琥珀酸盐晶型A和甲磺酸盐晶型A在FeSSIF中的溶解度与游离碱晶型A在FeSSIF中的溶解度(10.2毫克/毫升)相当，但相对于游离碱晶型A，在禁食肠液(FaSSIF)和喂食肠液(FeSSIF)中的溶解度接近，提示具有较低的食物效应风险。
试验例2
本试验例对比了本发明所提供的各种盐型与对比例所制得的晶型/盐型的吸湿性。
25℃条件下，通过动态水分吸附(DVS)试验，测试上述实施例和对照例的代表性盐及游离碱在湿度达到80％RH时的水分吸附量，以进行吸湿性比对。
试验对象：游离碱晶型A、马来酸盐晶型B、富马酸盐晶型A、己二酸盐晶型A、琥珀酸晶型A、甲磺酸盐晶型A、和盐酸盐晶型B。
实验结果：测试结果如表13所示。其中，>15％为非常吸湿，2～15％为吸湿，0.2～2％为略有吸湿性，<0.2％为几乎无吸湿性
表13不同盐型和晶型的吸湿性
样品名称 吸湿性(％) 晶型是否变化
游离碱晶型A 0.10 无变化
马来酸盐晶型B 2.00 无变化
富马酸盐晶型A 0.35 无变化
己二酸盐晶型A 0.22 无变化
琥珀酸盐晶型A 0.33 无变化
甲磺酸盐晶型A 12.02 有变化
盐酸盐晶型B 9.12 有变化
结果显示(见图29-34)：马来酸盐晶型B、富马酸盐晶型A、琥珀酸盐晶型A和己二酸盐晶型A在25℃/80％RH条件下水分吸附量为0.10～2.00％，仅具有轻微吸湿性，几乎与游离碱的吸湿性相当，且DVS测试前后样品晶型未发生改变，在相应测试条件下均表现出较好的物理稳定性；而盐酸盐晶型B和甲磺酸盐晶型A在25℃/80％RH条件下水分吸附量分别为9.12％和12.02％，具有较高的吸湿性，且DVS测试后样品转变为无定形。
试验例3
本试验例对比了本发明所提供的各种盐型与对比例所制得的晶型/盐型的稳定性。
实验方法：分别称取适量样品在光照4500lux、25℃/60％RH和40℃/75％RH条 件下敞口放置,以进行1周固态稳定性试验评估。一周后对测试样品HPLC纯度测试以检测纯度变化。每种测试条件均设置三组平行试验。
实验对象：游离碱晶型A、马来酸盐晶型B、富马酸盐晶型A、富马酸盐晶型C、己二酸盐晶型A、琥珀酸晶型A、和甲磺酸盐晶型A。
实验结果：测试结果如表14所示。
表14不同盐型和晶型的稳定性
Figure PCTCN2020097482-appb-000030
Figure PCTCN2020097482-appb-000031
如表14所示，游离胺晶型A，马来酸盐晶型B，富马酸盐晶型A，富马酸盐晶型C，己二酸盐晶型A，琥珀酸盐晶型A，甲磺酸盐晶型A在光照4500lux条件下放置一周，HPLC相对起始纯度分别为99.3％，99.9％，100％，100％，100％，100％，98.5％，因此在光照条件下马来酸盐晶型B，富马酸盐晶型A，己二酸盐晶型A，琥珀酸盐晶型A比游离胺晶型A更加稳定，但是甲磺酸盐晶型A比游离胺晶型A更加不稳定。同时，马来酸盐晶型B，富马酸盐晶型A，富马酸盐晶型C，己二酸盐晶型A和琥珀酸盐晶型A，在40℃/75％RH条件下也具有较高的稳定性，放置一周，HPLC相对起始纯度均为100％，而甲磺酸盐晶型A的HPLC相对起始纯度为99.4％，因此在40℃/75％RH条件下，马来酸盐晶型B，富马酸盐晶型A，富马酸盐晶型C，己二酸盐晶型A和琥珀酸盐晶型A比游离碱稳定性更好或相当，但是甲磺酸盐晶型A要比游离胺晶型A更加不稳定。
本发明所涉及的仪器信息和方法
(1)X射线粉末衍射(XRPD)
XRPD图谱在PANalytacal Empyrean和Bruker X射线粉末衍射分析仪上通过反射模式采集，XRPD测试参数如表15所示。
表15 XRPD测试参数
Figure PCTCN2020097482-appb-000032
(2)热重分析(TGA)和差示扫描量热(DSC)
TGA和DSC图谱分别在TA Q500/5000热重分析仪和TA Q200/2000差示扫描量热仪上采集，表16列出了测试参数。
表16 DSC和TGA测试参数
Figure PCTCN2020097482-appb-000033
(3)高效液相色谱(HPLC)
高效液相色谱在Agilent 1100 HPLC上采集。具体仪器和测试参数见表17。
表17 HPLC纯度测试参数
Figure PCTCN2020097482-appb-000034
(4)液态核磁(Solution NMR)
液态核磁谱图在Bruker 400M核磁共振仪上采集。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (22)

  1. 如式I所示的化合物的盐：
    Figure PCTCN2020097482-appb-100001
    所述盐选自富马酸盐、马来酸盐、己二酸盐或琥珀酸盐。
  2. 根据权利要求1所述的盐，其特征在于：所述盐中富马酸离子、马来酸离子、己二酸离子或琥珀酸离子与游离碱的摩尔比各自独立地为n:1，其中n≥0.5，优选n为0.5、1或2，更优选n为1；
    和/或，所述盐包括一种或多种晶型，优选所述盐以一种晶型或多种晶型混合存在，特别优选所述盐以一种晶型存在；
    和/或，所述盐中含溶剂分子，优选所述盐中含可变含量的溶剂分子，进一步优选所述盐中含水分子，优选可变含量的水分子。
  3. 根据权利要求1或2所述的盐，其特征在于：所述富马酸盐包括下述一种富马酸盐的晶型或多种富马酸盐的晶型，优选所述富马酸盐为下述任一种富马酸盐的晶型或多种所述富马酸盐的晶型混合物，特别优选为下述任一种富马酸盐的晶型；
    所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)7.0°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
    (2)4.5°、10.5°、18.3°、20.6°和23.9°处显示出特征衍射峰；或
    (3)5.9°、14.4°、18.6°、23.6°和23.9°处显示出特征衍射峰；
    优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)5.5°、7.0°、9.2°、10.6°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
    (2)4.5°、8.9°、10.5°、17.9°、18.3°、20.6°、22.5°和23.9°处显示出特征衍射峰；或
    (3)5.9°、14.4°、17.6°、18.6°、21.6°、23.6°、23.9°和28.4°处显示出特征衍射峰；
    更优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)5.5°、7.0°、9.2°、10.6°、13.9°、15.7°、17.2°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
    (2)4.5°、8.9°、10.5°、17.1°、17.9°、18.3°、20.6°、22.5°、23.9°和27.5°处显示出特征衍射峰；或
    (3)5.9°、11.7°、14.4°、17.6°、18.6°、21.6°、23.6°、23.9°、25.0°和28.4°处显示出特征衍射峰；
    尤其优选所述富马酸盐的晶型具有选自下述(1)～(3)任一项的XRPD数据和/或图谱：
    (1)基本如表1所示的XRPD数据；和/或，基本如图2所示的XRPD图谱；
    (2)基本如表2所示的XRPD数据；和/或，基本如图5所示的XRPD图谱；
    (3)基本如表3所示的XRPD数据；和/或，基本如图8所示的XRPD图谱。
  4. 根据权利要求1或2所述的盐，其特征在于：所述马来酸盐包括下述一种马来酸盐的晶型或多种马来酸盐的晶型，优选所述马来酸盐为下述任一种马来酸盐的晶型或多种所述马来酸盐的晶型混合物，特别优选为下述任一种马来酸盐的晶型；
    所述马来酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)7.8°、9.0°、15.7°、18.4°和22.7°处显示出特征衍射峰；或
    (2)5.7°、13.7°、17.9°、18.9°和23.6°处显示出特征衍射峰；
    优选所述马来酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)7.3°、7.8°、9.0°、15.7°、17.9°、18.4°、20.7°和22.7°处显示出特征衍射峰；或
    (2)5.7°、13.7°、17.6°、17.9°、18.9°、21.9°、23.6°和24.8°处显示出特征衍射峰；
    更优选所述马来酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)7.3°、7.8°、9.0°、13.6°、15.7°、17.9°、18.4°、20.7°、22.7°和24.1°处显示出特征衍射峰；或
    (2)5.7°、13.7°、14.1°、17.2°、17.6°、17.9°、18.9°、21.9°、23.6°和24.8°处显示出特征衍射峰；
    尤其优选所述马来酸盐的晶型具有选自下述(1)～(2)任一项的XRPD数据和/或图谱：
    (1)基本如表4所示的XRPD数据；和/或，基本如图11所示的XRPD图谱；
    (2)基本如表5所示的XRPD数据；和/或，基本如图14所示的XRPD图谱。
  5. 根据权利要求1或2所述的盐，其特征在于：所述己二酸盐包括下述己二酸盐的晶型或仅以下述已二酸盐的晶型存在，所述己二酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：4.3°、8.5°、15.7°、21.7°和28.2°处显示出特征衍射峰；
    优选所述己二酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：4.3°、8.5°、13.0°、15.7°、18.2°、19.9°、21.7°和28.2°处显示出特征衍射峰；
    更优选所述己二酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：4.3°、8.5°、13.0°、15.3°、15.7°、18.2°、19.4°、19.9°、21.7°和28.2°处显示出特征衍射峰；
    尤其优选所述己二酸盐的晶型具有基本如表6所示的XRPD数据；和/或，基本如图17所示的XRPD图谱。
  6. 根据权利要求1或2所述的盐，其特征在于：所述琥珀酸盐包括下述琥珀酸盐的晶型或仅以下述琥珀酸盐的晶型存在，所述琥珀酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    5.4°、13.9°、16.0°、21.1°和24.3°处显示出特征衍射峰；
    优选所述琥珀酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    5.4°、9.5°、10.1°、13.9°、16.0°、18.6°、21.1°和24.3°处显示出特征衍射峰；
    更优选所述琥珀酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    5.4°、9.5°、10.1°、13.4°、13.9°、16.0°、17.7°、18.6°、21.1°和24.3°处显示出特征衍射峰；
    尤其优选所述琥珀酸盐的晶型具有基本如表8所示的XRPD数据；和/或，基本如图22所示的XRPD图谱。
  7. 如式I所示化合物的富马酸盐的晶型：
    Figure PCTCN2020097482-appb-100002
    其特征在于：所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)7.0°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
    (2)4.5°、10.5°、18.3°、20.6°和23.9°处显示出特征衍射峰；或
    (3)5.9°、14.4°、18.6°、23.6°和28.4°处显示出特征衍射峰；
    优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)5.5°、7.0°、9.2°、10.6°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
    (2)4.5°、8.9°、10.5°、17.9°、18.3°、20.6°、22.5°和23.9°处显示出特征衍射峰；或
    (3)5.9°、14.4°、17.6°、18.6°、21.6°、23.6°、23.9°和28.4°处显示出特征衍射峰；
    更优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    (1)5.5°、7.0°、9.2°、10.6°、13.9°、15.7°、17.2°、18.4°、21.8°和24.1°处显示出特征衍射峰；或
    (2)4.5°、8.9°、10.5°、17.1°、17.9°、18.3°、20.6°、22.5°、23.9°和27.5°处显示出特征衍射峰；或
    (3)5.9°、11.7°、14.4°、17.6°、18.6°、21.6°、23.6°、23.9°、25.0°和28.4°处显示出特征衍射峰；
    尤其优选所述富马酸盐的晶型具有选自下述(1)～(3)任一项的XRPD数据和/或图谱：
    (1)基本如表1所示的XRPD数据；和/或，基本如图2所示的XRPD图谱；
    (2)基本如表2所示的XRPD数据；和/或，基本如图5所示的XRPD图谱；
    (3)基本如表3所示的XRPD数据；和/或，基本如图8所示的XRPD图谱。
  8. 根据权利要求7所述的富马酸盐的晶型，其特征在于：所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    7.0°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；
    优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    5.5°、7.0°、9.2°、10.6°、13.9°、18.4°、21.8°和24.1°处显示出特征衍射峰；
    更优选所述富马酸盐的晶型以2θ±0.2°衍射角表示的X射线粉末衍射图谱至少在：
    5.5°、7.0°、9.2°、10.6°、13.9°、15.7°、17.2°、18.4°、21.8°和24.1°处显示出特征衍射峰；
    尤其优选所述富马酸盐的晶型具有基本如表1所示的XRPD数据；和/或，基本如图2所示的XRPD图谱。
  9. 权利要求8所述的富马酸盐的晶型的制备方法，其特征在于：包括使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应，反应溶剂为有机溶剂或所述有机溶剂的水溶液；
    优选所述有机溶剂为极性有机溶剂；
    进一步优选，所述有机溶剂为醇、酮、卤代烷烃、醚和酯中的一种或多种；
    更优选所述有机溶剂选自C 1-C 5直链或支链链烷醇、丙酮、THF、乙酸乙酯、二氯甲烷、和氯仿中的一种或多种；尤其优选地，所述有机溶剂为甲醇、乙醇、丙醇、异丙醇、丙酮、二氯甲烷和氯仿中的一种或多种，更优选，所述有机溶剂为甲醇、乙醇、二氯甲烷和氯仿中的一种或多种，最优选，所述有机溶剂为乙醇、二氯甲烷，或二者的组合。
  10. 根据权利要求9所述的方法，其特征在于：所述方法还包括，在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸混合时，将富马酸缓慢地滴入5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺中；和/或
    在20℃至使反应溶剂回流的温度，使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应；和/或
    所述方法还包括：在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应前，先将5-氟-4-(7'-氟-2'-甲基螺[环戊烷 -1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺溶解。
  11. 根据权利要求10所述的方法，其特征在于：将5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺溶解所使用的溶剂包括第一溶剂和第二溶剂，其中所述第一溶剂为酮、醚、酯和醇中的一种或多种，优选为一种或多种醇，更优选所述第一溶剂为C 1-C 5直链和支链链烷醇中的一种或多种，尤其优选为甲醇、乙醇、丙醇和异丙醇中的一种或多种；所述第二溶剂为二氯甲烷、氯仿或二者的组合；
    优选地，所述第一溶剂和第二溶剂的混合体积比为1：(0.1-10)，优选为1：(1-3)，最优选为1：1。
  12. 根据权利要求9-11中任一项所述的方法，其特征在于：所述方法还包括，在将5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺溶解后，对得到的溶液进行过滤；和/或
    所述方法还包括：在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应前，将溶解5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺所用的溶剂蒸出；和/或
    所述方法还包括：在使5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺与富马酸反应完成后，将反应体系降温至10-35℃，优选降温至20-30℃。
  13. 药物组合物，其特征在于，含有治疗有效量的权利要求1-6任一项所述的盐或权利要求7-8任一项所述的富马酸盐的晶型；优选地，所述药物组合物中还包括药学上可以接受的辅料；更优选所述药学上可以接受的辅料包括载体、稀释剂、和赋形剂中的至少一种。
  14. 根据权利要求13所述的药物组合物，其特征在于，所述药物组合物进一步包含一种或多种其他具有生物活性的物质；
    优选所述其他具有生物活性的物质选自抗癌剂、免疫抑制剂和抗病毒剂中的一种或多种；
    更优选所述其它具有生物活性的物质选自烷化剂、抗代谢类抗肿瘤药、铂络合剂、抗生素类抗肿瘤药、天然来源抗肿瘤药、激素类抗肿瘤药、VEGFR或EGFR抑制剂、抗体抗肿瘤药、mTOR抑制剂、治疗脑瘤类用药中的一种或多种；
    尤其优选：
    所述烷化剂选自环磷酰胺、异环磷酰胺、塞替派、司莫司汀、盐酸氮芥、白消安、苯丁酸氮芥、苯丙氨酸氮芥、硝卡芥、氮甲、卡莫司汀、洛莫司汀、六甲蜜胺、二溴甘露醇、和替莫唑胺中的一种或多种；
    所述抗代谢类抗肿瘤药选自阿糖胞苷、氟尿嘧啶、甲氨喋呤、羟基脲、替加氟、和甲异靛、巯嘌呤中的一种或多种；
    所述铂络合剂选自顺铂、卡铂、和奥沙利铂中的一种或多种；
    所述抗生素类抗肿瘤药选自放线菌素D、丝裂霉素、阿霉素、平阳霉素、表柔比星、吡柔比星、柔红霉素、和博来霉素中的一种或多种；
    所述天然来源抗肿瘤药选自高三尖杉酯碱及其衍生物、长春新碱及其衍生物、羟喜树碱及其衍生物、依托泊苷及其衍生物、长春地辛及其衍生物、长春碱及其衍生物、重酒石酸长春瑞宾、紫杉醇及其衍生物、秋水仙碱及其衍生物、和榄香烯及其衍生物中的一种或多种；
    所述激素类抗肿瘤药选自氨鲁米特、他莫昔芬、地塞米松、度他雄胺、氟他胺、戈那瑞林、醋酸亮丙瑞林、和来曲唑中的一种或多种；
    所述VEGFR或EGFR抑制剂选自舒尼替尼、索拉非尼、伊马替尼、吉非替尼、埃罗替尼、凡德替尼、帕唑帕尼、拉帕替尼、卡奈替尼、阿法替尼、木利替尼、达沙替尼、和来那替尼中的一种或多种；
    所述抗体抗肿瘤药选自曲妥单抗、帕妥珠单抗、利妥昔单抗、帕尼单抗、贝伐单抗、伊匹单抗、奥法木单抗、和雷莫卢单抗；所述mTOR抑制剂包括依维莫司、西罗莫司、和佐他莫司中的一种或多种；
    所述治疗脑瘤类用药包括替莫唑胺。
  15. 试剂盒，其特征在于，包括权利要求1-6任一项所述的盐或权利要求7-8任一项所述的富马酸盐的晶型、和一种或多种其他具有生物活性的物质；优选所述试剂盒中还包括药学上可以接受的辅料；更优选所述药学上可以接受的辅料包括载体、稀释剂、和赋形剂中的至少一种；
    优选所述其他具有生物活性的物质选自抗癌剂、免疫抑制剂和抗病毒剂中的一种或多种；
    更优选所述其它具有生物活性的物质选自烷化剂、抗代谢类抗肿瘤药、铂络合剂、 抗生素类抗肿瘤药、天然来源抗肿瘤药、激素类抗肿瘤药、VEGFR或EGFR抑制剂、抗体抗肿瘤药、mTOR抑制剂、治疗脑瘤类用药中的一种或多种；
    尤其优选：
    所述烷化剂选自环磷酰胺、异环磷酰胺、塞替派、司莫司汀、盐酸氮芥、白消安、苯丁酸氮芥、苯丙氨酸氮芥、硝卡芥、氮甲、卡莫司汀、洛莫司汀、六甲蜜胺、二溴甘露醇、和替莫唑胺中的一种或多种；
    所述抗代谢类抗肿瘤药选自阿糖胞苷、氟尿嘧啶、甲氨喋呤、羟基脲、替加氟、和甲异靛、巯嘌呤中的一种或多种；
    所述铂络合剂选自顺铂、卡铂、和奥沙利铂中的一种或多种；
    所述抗生素类抗肿瘤药选自放线菌素D、丝裂霉素、阿霉素、平阳霉素、表柔比星、吡柔比星、柔红霉素、和博来霉素中的一种或多种；
    所述天然来源抗肿瘤药选自高三尖杉酯碱及其衍生物、长春新碱及其衍生物、羟喜树碱及其衍生物、依托泊苷及其衍生物、长春地辛及其衍生物、长春碱及其衍生物、重酒石酸长春瑞宾、紫杉醇及其衍生物、秋水仙碱及其衍生物、和榄香烯及其衍生物中的一种或多种；
    所述激素类抗肿瘤药选自氨鲁米特、他莫昔芬、地塞米松、度他雄胺、氟他胺、戈那瑞林、醋酸亮丙瑞林、和来曲唑中的一种或多种；
    所述VEGFR或EGFR抑制剂选自舒尼替尼、索拉非尼、伊马替尼、吉非替尼、埃罗替尼、凡德替尼、帕唑帕尼、拉帕替尼、卡奈替尼、阿法替尼、木利替尼、达沙替尼、和来那替尼中的一种或多种；
    所述抗体抗肿瘤药选自曲妥单抗、帕妥珠单抗、利妥昔单抗、帕尼单抗、贝伐单抗、伊匹单抗、奥法木单抗、和雷莫卢单抗；所述mTOR抑制剂包括依维莫司、西罗莫司、和佐他莫司中的一种或多种；
    所述治疗脑瘤类用药包括替莫唑胺。
  16. 根据权利要求15所述的试剂盒，其特征在于，所述其他具有生物活性的物质为替莫唑胺。
  17. 权利要求1-6任一项所述的盐、权利要求7-8任一项所述的富马酸盐的晶型、权利要求13-14任一项所述的药物组合物、或权利要求15-16任一项所述的试剂盒在制备治疗对细胞周期调节蛋白依赖性激酶的抑制具有反应的疾病的药物中的应用。
  18. 根据权利要求17所述的应用，其特征在于：所述的疾病选自脑瘤、乳腺癌、泌尿生殖癌、肺癌、胃肠癌、表皮样癌、黑色素瘤、卵巢癌、胰腺癌、神经母细胞瘤、头颈癌或膀胱癌；白血病、增生、胃癌、结肠癌、喉癌、淋巴系统癌、生殖泌尿道癌、骨癌、前列腺癌、小细胞型肺癌、神经胶质瘤癌、结肠直肠癌、肾癌、上皮癌、肝癌、食道癌、造血系统癌、淋巴瘤、骨髓瘤、甲状腺滤泡状癌；间质来源的肿瘤；中枢或周围神经系统的肿瘤；精原细胞瘤；畸胎瘤；骨肉瘤；着色性干皮病；角化棘皮瘤；甲状腺滤泡状癌；卡波西氏(Kaposi's)肉瘤、慢性淋巴细胞白血病、外套细胞淋巴瘤、或大B细胞淋巴瘤；
    优选所述间质来源的肿瘤为纤维肉瘤或横纹肌肉瘤；所述中枢或周围神经系统的肿瘤为星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤。
  19. 权利要求1-6任一项所述的盐、权利要求7-8任一项所述的富马酸盐的晶型、权利要求13-14任一项所述的药物组合物、或权利要求15-16任一项所述的试剂盒，其用于治疗对细胞周期调节蛋白依赖性激酶的抑制具有反应的疾病。
  20. 权利要求19所述用途的盐、富马酸盐的晶型、药物组合物或试剂盒，其中所述的疾病选自脑瘤、乳腺癌、泌尿生殖癌、肺癌、胃肠癌、表皮样癌、黑色素瘤、卵巢癌、胰腺癌、神经母细胞瘤、头颈癌或膀胱癌；白血病、增生、胃癌、结肠癌、喉癌、淋巴系统癌、生殖泌尿道癌、骨癌、前列腺癌、小细胞型肺癌、神经胶质瘤癌、结肠直肠癌、肾癌、上皮癌、肝癌、食道癌、造血系统癌、淋巴瘤、骨髓瘤、甲状腺滤泡状癌；间质来源的肿瘤；中枢或周围神经系统的肿瘤；精原细胞瘤；畸胎瘤；骨肉瘤；着色性干皮病；角化棘皮瘤；甲状腺滤泡状癌；卡波西氏(Kaposi's)肉瘤、慢性淋巴细胞白血病、外套细胞淋巴瘤或大B细胞淋巴瘤；
    优选所述间质来源的肿瘤为纤维肉瘤或横纹肌肉瘤；所述中枢或周围神经系统的肿瘤为星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤。
  21. 一种治疗对细胞周期调节蛋白依赖性激酶的抑制具有反应的疾病的方法，其包括对患有所述疾病的个体施用治疗有效量的权利要求1-6任一项所述的盐、权利要求7-8任一项所述的富马酸盐的晶型、权利要求13-14任一项所述的药物组合物、或施用权利要求15-16任一项所述的试剂盒。
  22. 权利要求21所述的方法，其中所述的疾病包括脑瘤、乳腺癌、泌尿生殖癌、肺癌、胃肠癌、表皮样癌、黑色素瘤、卵巢癌、胰腺癌、神经母细胞瘤、头颈癌或膀胱 癌；白血病、增生、胃癌、结肠癌、喉癌、淋巴系统癌、生殖泌尿道癌、骨癌、前列腺癌、小细胞型肺癌、神经胶质瘤癌、结肠直肠癌、肾癌、上皮癌、肝癌、食道癌、造血系统癌、淋巴瘤、骨髓瘤、甲状腺滤泡状癌；间质来源的肿瘤；中枢或周围神经系统的肿瘤；精原细胞瘤；畸胎瘤；骨肉瘤；着色性干皮病；角化棘皮瘤；甲状腺滤泡状癌；卡波西氏(Kaposi's)肉瘤、慢性淋巴细胞白血病、外套细胞淋巴瘤、大B细胞淋巴瘤；
    优选所述间质来源的肿瘤为纤维肉瘤或横纹肌肉瘤；所述中枢或周围神经系统的肿瘤为星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022042738A1 (zh) * 2020-08-31 2022-03-03 甘李药业股份有限公司 一种含cdk4/6抑制剂的药物组合物
WO2022242563A1 (zh) * 2021-05-17 2022-11-24 甘李药业股份有限公司 一种cdk4/6抑制剂的医药用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106810536A (zh) 2015-11-30 2017-06-09 甘李药业股份有限公司 一种蛋白激酶抑制剂及其制备方法和医药用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106810536A (zh) 2015-11-30 2017-06-09 甘李药业股份有限公司 一种蛋白激酶抑制剂及其制备方法和医药用途

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BRONNER, S.M. ET AL.: "Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 29, no. 16, 26 June 2019 (2019-06-26), XP085759050, ISSN: 0960-894X, DOI: 20200904170814PX *
MA KE: "Research progress in antitumor effect of a CDK4/6 inhibitor", WORLD NOTES ON ANTIBIOTICS, vol. 34, no. 5, 2013, pages 197 - 202
MALUMBRES MBARBACID M.: "To cycle or not to cycle: a critical decision in cancer [J", NATURE REVIEWS CANCER, vol. 1, no. 3, 2001, pages 222, XP008150580, DOI: 10.1038/35106065
SHAPIRO GI.: "Cyclin-dependent kinase pathways as targets for cancer treatment [J", J CLINICAL ONCOLOGY, vol. 24, no. 11, 2006, pages 1770, XP009148872, DOI: 10.1200/JCO.2005.03.7689
YIN, L. ET AL.: "A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 144, 6 December 2017 (2017-12-06), XP055766971, ISSN: 0223-5234, DOI: 20200904170248PX *
YIN, L. ET AL.: "A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 144, 6 December 2017 (2017-12-06), XP055766971, ISSN: 0223-5234, DOI: 20200904174508X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022042738A1 (zh) * 2020-08-31 2022-03-03 甘李药业股份有限公司 一种含cdk4/6抑制剂的药物组合物
WO2022242563A1 (zh) * 2021-05-17 2022-11-24 甘李药业股份有限公司 一种cdk4/6抑制剂的医药用途

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