WO2022022476A1 - 己酮糖激酶抑制剂的盐、晶型及其用途 - Google Patents

己酮糖激酶抑制剂的盐、晶型及其用途 Download PDF

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WO2022022476A1
WO2022022476A1 PCT/CN2021/108515 CN2021108515W WO2022022476A1 WO 2022022476 A1 WO2022022476 A1 WO 2022022476A1 CN 2021108515 W CN2021108515 W CN 2021108515W WO 2022022476 A1 WO2022022476 A1 WO 2022022476A1
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crystal form
formula
compound
ray powder
characteristic peaks
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French (fr)
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翁振涛
王峰
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山东轩竹医药科技有限公司
轩竹生物科技有限公司
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Priority to EP21849912.7A priority Critical patent/EP4190776A4/en
Publication of WO2022022476A1 publication Critical patent/WO2022022476A1/zh
Priority to US18/160,140 priority patent/US20230271947A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a crystal form and a pharmaceutically acceptable salt of a hexokinase inhibitor, a preparation method thereof, a pharmaceutical composition, and a medicament for treating and/or preventing KHK-mediated diseases and related diseases in the preparation thereof applications in .
  • NAFLD/NASH is the hepatic manifestation of metabolic syndrome. Changes in diet and lifestyle have led to the prevalence of obesity and metabolic syndrome in Western countries and many Asian countries, resulting in a significant increase in the incidence of NAFLD, which has become one of the public health concerns of great concern.
  • NAFLD Nonalcoholic steatohepatitis
  • HCC hepatocellular carcinoma
  • NAFLD not only affects the patient's hepatobiliary system, but is also closely related to insulin resistance, dyslipidemia, atherosclerosis, fat embolism, and hematological diseases (Friedman SL et al., Nat Med, 2018, 24:908-22). Because all components of metabolic syndrome are related to liver fat content, patients with metabolic syndrome should be assessed for NAFLD risk. Patients with type 2 diabetes are associated with insulin resistance, obesity, dyslipidemia, abnormal liver enzymes, and the prevalence of NAFLD is higher in those at risk of type 2 diabetes.
  • fructose in the diet of modern people is due to the increasing amount of added sugars (usually sucrose and high fructose corn syrup) in beverages and processed foods.
  • High fructose intake has been shown to cause many adverse metabolic effects, and it has a role in the development of obesity and metabolic syndrome, such as weight gain, hyperlipidemia, hypertension and insulin resistance ((a) Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ.Fructose,weight gain,and the insulin resistance syn-drome.(b)Bray GA.Soft drink consumption and obesity:it is all about fructose.Current opinion in lipidology.2010; 21(1):51–7.(c)The American journal of clinical nutrition.2002;76(5):911–22.and cardiovascular disease.The American journal of clinical nutrition.2007;86(4):899– 906.).
  • Fructose promotes the occurrence and development of NAFLD, and aggravates the development and exacerbation of NAFLD (Shi Hongbin et al., Research on the Association between Fructose and Nonalcoholic Fatty Liver, Medical Recapitulate 2017 23(9), 1685-1689). Meanwhile, high fructose intake increases the risk of NASH and advanced liver fibrosis (2016 European Society of Liver Diseases, European Society of Diabetes and European Society of Obesity Clinical Practice Guidelines: Nonalcoholic Fatty Liver Disease). Unlike glucose, fructose metabolism is not regulated by negative feedback. Fructose is preferentially metabolized relative to other carbohydrates, and its metabolism produces various responses and signaling metabolites that promote metabolic disease progression.
  • Reducing sugar/HFCS (high fructose corn syrup) intake and/or blocking uric acid production may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease (Thomas Jensen et al, Fructose and Sugar: A Major Mediator of Nonalcoholic Fatty Liver Disease, J Hepatol. 2018 May;68(5):1063–1075.).
  • human genetic mutagenesis causes rudimentary fructoglucosuria, a rare and harmless abnormality characterized by the presence of fructose in the urine after ingestion of fructose-containing foods.
  • the high prevalence of T2D, obesity and NAFLD/NASH and related metabolic diseases such as cardiovascular disease and stroke have led to an increased need for both preventive care and therapeutic interventions.
  • Hexokinase also known as fructokinase
  • the KHK enzyme in the liver phosphorylates fructose C1 with the assistance of ATP (adenosine triphosphate) to generate fructose-1-phosphate (F1P), which enters the normal metabolic pathway; at the same time, uric acid is generated downstream of ATP.
  • ATP adenosine triphosphate
  • F1P fructose-1-phosphate
  • hKHK Two alternative mRNA spliceosome-expressed human hexokinase encodes two distinct regioisomerases, KHK-A and KHK-C.
  • KHK-C has a lower Km value, higher Kcat, and a 405-fold higher catalytic efficiency, indicating that KHK-C has significantly higher affinity and capacity for fructose phosphorylation than KHK-A.
  • KHK-A is widely expressed and KHK-C is distributed in the liver, kidney, and intestine, KHK-C is the main metabolic site of fructose in the body.
  • glucose is converted to fructose through the polyol pathway through the intermediate sorbitol, resulting in endogenous fructose (Mingule A et al., Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome, Nat Commun. 2013; 4:2434.), and the activity of this pathway increases with hyperglycemia.
  • knockout KHK mice are protected from glucose-induced weight gain, insulin resistance, and steatosis, suggesting that endogenously produced fructose contributes to insulin resistance and steatosis in hyperglycemic conditions (Lanaspa, MA et al. Human, Nature Comm. 4, 2434, 2013).
  • Fructose is the only common carbohydrate that produces uric acid during its metabolism, and fructose also stimulates the synthesis of uric acid from amino acid precursors. Thus, inhibition of KHK is speculated to be beneficial for many diseases in which alterations in either or both of endogenous or ingested fructose are involved.
  • Hepatic fructokinase deficiency is the basis of fructoseuria.
  • deficiency of aldolase B (the next enzyme in the pathway of fructose via KHK metabolism) leads to the accumulation of F1P in fructose uptake and may lead to a lethal depletion of cellular ATP (inherited fructose insufficiency). tolerance).
  • aldolase B the next enzyme in the pathway of fructose via KHK metabolism
  • the enzyme responsible for breaking down F1P immediately downstream of the KHK step is aldolase (ALDOB), the deletion of which leads to hereditary fructose intolerance (HFI).
  • Glucose in the body is converted into endogenous fructose through the polyol pathway and metabolized in the body, which is also a challenge to this treatment method.
  • the presence of fructose in most foods presents dietary challenges.
  • many sufferers face emotional and social isolation due to their unusual diet, while requiring strict adherence to dietary restrictions (HFI-INFO Discussion Board, http; //hfiinfo.proboards.com. December 14, 2015 access).
  • infusions containing fructose, sorbitol, or invert sugar can be life-threatening. This disorder has a high unmet clinical need.
  • crystal forms plays an important role in the process of drug development. Different crystal forms of the same drug have significant differences in solubility, stability, bioavailability, etc. In order to meet the requirements of production, transportation, etc., we have studied the crystal form of the compound of formula (1), in order to find a crystal form with good properties.
  • the present invention relates to a hexokinase inhibitor represented by formula (1) 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylazepine) Cyclobutan-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetic acid
  • the present invention also relates to the preparation method of crystal form A, crystal form B, crystal form C, crystal form D, pharmaceutically acceptable salt and crystal form thereof, including crystal form A, crystal form B, crystal form C, crystal form D, Pharmaceutical compositions of pharmaceutically acceptable salts and crystalline forms thereof, as well as crystalline forms A, crystalline forms B, crystalline forms C, crystalline forms D, pharmaceutically acceptable salts and crystalline forms of these compounds are prepared for the prevention and/or treatment of KHK Medication of diseases and related diseases.
  • the present invention provides a crystal form A of the compound of formula (1), which uses Cu-K ⁇ radiation and X-ray powder diffraction represented by 2 ⁇ angle at 8.0 ⁇ 0.2°, 9.4 ⁇ 0.2°, 10.5 ⁇ 0.2°, 12.7 There are characteristic peaks at ⁇ 0.2°, 19.5 ⁇ 0.2°, and 21.2 ⁇ 0.2°:
  • the crystalline form A of the compound of formula (1) on the basis of comprising the characteristic peaks described above, is further 10.2 ⁇ 0.2 by X-ray powder diffraction using Cu-K ⁇ radiation at 2 ⁇ angles. There are characteristic peaks at °, 13.6 ⁇ 0.2°, 14.2 ⁇ 0.2°, 15.8 ⁇ 0.2°, 17.2 ⁇ 0.2°, 25.3 ⁇ 0.2°.
  • the crystalline form A of the compound of formula (1) on the basis of comprising the characteristic peaks described above, is also at 6.9 ⁇ 0.2 by X-ray powder diffraction using Cu-K ⁇ radiation at 2 ⁇ angles. There are characteristic peaks at °, 15.1 ⁇ 0.2°, 16.6 ⁇ 0.2°, 18.9 ⁇ 0.2°, 22.0 ⁇ 0.2°, 23.1 ⁇ 0.2°.
  • the crystalline Form A of the compound of formula (1) has an X-ray substantially as shown in FIG. Powder diffractogram.
  • the crystalline form A of the compound of formula (1) has an endothermic peak in the range of about 167°C to 173°C in its differential scanning calorimetry analysis; in some embodiments, the The crystal form A of the compound of formula (1) has an endothermic peak in the range of 170°C ⁇ 2°C in its differential scanning calorimetry analysis; in some embodiments, the crystal form A of the compound of formula (1), Its differential scanning calorimetry analysis diagram is basically shown in Figure 2.
  • the crystalline form A of the compound of formula (1) as determined by thermogravimetric analysis, has no weight loss below 200°C; in some embodiments, the crystalline form of the compound of formula (1) has no weight loss.
  • Form A which has a thermogravimetric analysis diagram substantially as shown in FIG. 3 .
  • the present invention provides a crystal form B of the compound of formula (1), using Cu-K ⁇ radiation, X-ray powder diffraction represented by 2 ⁇ angle, at 6.4 ⁇ 0.2°, 10.0 ⁇ 0.2°, 12.7 ⁇ 0.2°, 15.5 There are characteristic peaks at ⁇ 0.2°, 17.6 ⁇ 0.2°, and 22.0 ⁇ 0.2°.
  • the crystalline form B of the compound of formula (1) on the basis of including the above characteristic peaks, is also at 8.3 ⁇ 0.2 by X-ray powder diffraction using Cu-K ⁇ radiation at 2 ⁇ angles. There are characteristic peaks at °, 16.5 ⁇ 0.2°, 17.7 ⁇ 0.2°, and 20.6 ⁇ 0.2°.
  • the crystalline Form B of the compound of formula (1) has an X-ray substantially as shown in FIG. Powder diffractogram.
  • the crystalline form B of the compound of formula (1) has an endothermic peak in the range of about 167°C to 173°C in its differential scanning calorimetry analysis; in some embodiments, the said The crystal form B of the compound of formula (1) has an endothermic peak in the range of 169°C ⁇ 2°C in its differential scanning calorimetry analysis; in some embodiments, the crystal form B of the compound of formula (1), Its differential scanning calorimetry analysis diagram is basically shown in Figure 5.
  • the crystalline form B of the compound of formula (1) as determined by thermogravimetric analysis, has no weight loss below 200°C; in some embodiments, the crystalline form of the compound of formula (1) has no weight loss.
  • Form B which has a thermogravimetric analysis profile substantially as shown in FIG. 6 .
  • the present invention provides a crystal form C of a compound of formula (1), using Cu-K ⁇ radiation, X-ray powder diffraction represented by 2 ⁇ angle, at 8.5 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.7 ⁇ 0.2°, 18.5 There are characteristic peaks at ⁇ 0.2°:
  • the crystalline form C of the compound of formula (1) on the basis of comprising the above characteristic peaks, is also at 13.0 ⁇ 0.2 by X-ray powder diffraction using Cu-K ⁇ radiation at 2 ⁇ angles. There are characteristic peaks at °, 13.4 ⁇ 0.2°, 13.8 ⁇ 0.2°, and 16.8 ⁇ 0.2°.
  • the crystalline form C of the compound of formula (1) on the basis of comprising the characteristic peaks described above, is further 19.2 ⁇ 0.2 by X-ray powder diffraction using Cu-K ⁇ radiation at 2 ⁇ angles. There are characteristic peaks at °, 20.7 ⁇ 0.2°, 21.1 ⁇ 0.2°, and 22.1 ⁇ 0.2°.
  • the crystalline form C of the compound of formula (1) has an X-ray substantially as shown in FIG. Powder diffractogram.
  • the crystalline form C of the compound of formula (1) has an endothermic peak in the range of about 170°C to 175°C in a differential scanning calorimetry analysis; in some embodiments, the The crystal form C of the compound of formula (1) has an endothermic peak in the range of 172°C ⁇ 2°C in its differential scanning calorimetry analysis; in some embodiments, the crystal form C of the compound of formula (1), Its differential scanning calorimetry analysis diagram is basically shown in Figure 8.
  • the crystalline form C of the compound of formula (1) as determined by thermogravimetric analysis, has no weight loss below 200°C; in some embodiments, the crystalline form of the compound of formula (1) has no weight loss.
  • Form C which has a thermogravimetric analysis diagram substantially as shown in FIG. 9 .
  • the present invention provides a crystal form D of a compound of formula (1), using Cu-K ⁇ radiation, X-ray powder diffraction represented by 2 ⁇ angle, at 6.4 ⁇ 0.2°, 10.0 ⁇ 0.2°, 12.7 ⁇ 0.2°, 17.7 There are characteristic peaks at ⁇ 0.2°, 18.6 ⁇ 0.2°, and 25.5 ⁇ 0.2°.
  • the crystalline form D of the compound of formula (1) on the basis of comprising the above characteristic peaks, is also 14.9 ⁇ 0.2 in X-ray powder diffraction using Cu-K ⁇ radiation in 2 ⁇ angles. There are characteristic peaks at °, 15.6 ⁇ 0.2°, and 20.6 ⁇ 0.2°.
  • the crystalline form D of the compound of formula (1) on the basis of comprising the above characteristic peaks, is at 8.3 ⁇ 0.2 by X-ray powder diffraction using Cu-K ⁇ radiation at 2 ⁇ angles. There are characteristic peaks at °, 16.5 ⁇ 0.2°, 19.1 ⁇ 0.2°, and 20.2 ⁇ 0.2°.
  • the crystalline form D of the compound of formula (1) has an X-ray powder as shown in FIG. Diffraction pattern.
  • the crystalline form D of the compound of formula (1) has an endothermic peak in the range of about 165°C to 170°C in its differential scanning calorimetry; in some embodiments, the The crystal form D of the compound of formula (1) has an endothermic peak in the range of 167°C ⁇ 2°C in its differential scanning calorimetry analysis; in some embodiments, the crystal form D of the compound of formula (1), Its differential scanning calorimetry analysis diagram is basically shown in Figure 11.
  • the crystalline form D of the compound of formula (1) as determined by thermogravimetric analysis, has no weight loss below 200°C; in some embodiments, the crystalline form of the compound of formula (1) has no weight loss.
  • Form D which has a thermogravimetric analysis profile substantially as shown in FIG. 12 .
  • the present invention also provides a pharmaceutically acceptable salt of the compound of formula (1), the pharmaceutically acceptable salt is selected from the base addition salts formed by the compound of formula (1) with an inorganic base or an organic base.
  • the base addition salt is selected from potassium, sodium, lithium, magnesium or calcium salts.
  • the inorganic base is selected from potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, potassium hydroxide, sodium hydroxide, hydrogen Lithium oxide, magnesium hydroxide or calcium hydroxide.
  • the organic base is selected from sodium methoxide, potassium ethoxide, potassium acetate, potassium tert-butoxide, or sodium tert-butoxide.
  • the crystalline Form I of the potassium salt which uses Cu-K ⁇ radiation, X-ray powder diffraction in 2 ⁇ angles, at 4.8 ⁇ 0.2°, 5.9 ⁇ 0.2°, 7.1 ⁇ 0.2°, There are characteristic peaks at 8.3 ⁇ 0.2°, 11.8 ⁇ 0.2°, and 15.5 ⁇ 0.2°.
  • the potassium salt crystal form I of the compound of formula (1) on the basis of comprising the above characteristic peaks, also has a 14.6 There are characteristic peaks at ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, and 21.5 ⁇ 0.2°.
  • the potassium salt crystal form I of the compound of formula (1) on the basis of comprising the above characteristic peaks, is further 13.0 by X-ray powder diffraction using Cu-K ⁇ radiation at 2 ⁇ angle. There are characteristic peaks at ⁇ 0.2°, 14.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, and 25.0 ⁇ 0.2°.
  • the potassium salt Form I of the compound of formula (1) has an X-ray substantially as shown in FIG. - X-ray powder diffraction pattern.
  • the potassium salt crystal form I of the compound of formula (1) has an endothermic peak in the range of about 174°C to 180°C in a differential scanning calorimetry analysis; in some embodiments, the The crystalline form I of the potassium salt of the compound of formula (1) has an endothermic peak in the range of 176°C ⁇ 2°C in its differential scanning calorimetry analysis; in some embodiments, the compound of formula (1)
  • the crystalline form I of the potassium salt of , and its differential scanning calorimetry analysis diagram is basically shown in Figure 14.
  • the potassium salt crystal form I of the compound of formula (1) as determined by thermogravimetric analysis, has weight loss below 100°C; in some embodiments, the compound of formula (1) The potassium salt of Form I, which has a thermogravimetric analysis pattern substantially as shown in Figure 15.
  • the crystalline form II of the potassium salt which uses Cu-K ⁇ radiation, X-ray powder diffraction in 2 ⁇ angles, at 4.7 ⁇ 0.2°, 6.5 ⁇ 0.2°, 7.9 ⁇ 0.2°, There are characteristic peaks at 10.3 ⁇ 0.2°, 11.0 ⁇ 0.2°, and 12.1 ⁇ 0.2°.
  • the potassium salt crystal form II of the compound of formula (1) on the basis of comprising the above characteristic peaks, also has a 5.1 There are characteristic peaks at ⁇ 0.2°, 13.0 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.4 ⁇ 0.2°, and 24.1 ⁇ 0.2°.
  • the potassium salt crystal form II of the compound of formula (1) on the basis of comprising the above characteristic peaks, also has a 8.3 There are characteristic peaks at ⁇ 0.2°, 17.6 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.1 ⁇ 0.2°, 24.5 ⁇ 0.2°.
  • the potassium salt form II of the compound of formula (1) has an X-ray substantially as shown in FIG. - X-ray powder diffraction pattern.
  • the potassium salt crystal form II of the compound of formula (1) has an endothermic peak in the range of about 155°C to 165°C in a differential scanning calorimetry analysis; in some embodiments, the The potassium salt crystal form II of the compound of the formula (1) has an endothermic peak in the range of 160°C ⁇ 2°C in its differential scanning calorimetry analysis; in some embodiments, the compound of the formula (1) has an endothermic peak.
  • the potassium salt crystal form II, the differential scanning calorimetry analysis diagram is basically as shown in FIG. 17 .
  • the potassium salt crystal form II of the compound of formula (1) as determined by thermogravimetric analysis, has weight loss below 200°C.
  • the compound of formula (1) has Potassium salt Form II, which has a thermogravimetric analysis pattern substantially as shown in Figure 17-1.
  • the crystalline form of the magnesium salt which uses Cu-K ⁇ radiation, X-ray powder diffraction in 2 theta angles, at 18.8 ⁇ 0.2°, 23.8 ⁇ 0.2°, 26.3 ⁇ 0.2°, 29.5 ⁇ There is a characteristic peak at 0.2°.
  • the crystalline form of the magnesium salt of the compound of formula (1) on the basis of comprising the characteristic peaks described above, is at 23.0 ⁇ There are characteristic peaks at 0.2°, 25.9 ⁇ 0.2°, 31.5 ⁇ 0.2°, 32.0 ⁇ 0.2°, 38.1 ⁇ 0.2°, and 39.0 ⁇ 0.2°.
  • the crystalline form of the magnesium salt of the compound of formula (1) has an X-ray substantially as shown in FIG. X-ray powder diffraction pattern.
  • the magnesium salt crystal form of the compound of formula (1) has an endothermic peak in a differential scanning calorimetry analysis pattern in the range of about 165°C to 180°C; in some embodiments, the The magnesium salt crystal form of the compound of formula (1) has an endothermic peak in the range of 170°C ⁇ 2°C in its differential scanning calorimetry analysis; in some embodiments, the magnesium salt of the compound of formula (1)
  • the crystal form, the differential scanning calorimetry analysis diagram is basically shown in Figure 19.
  • Form I of the calcium salt which uses Cu-K ⁇ radiation, X-ray powder diffraction in 2 theta angles at 15.8 ⁇ 0.2°, 16.1 ⁇ 0.2°, 26.3 ⁇ 0.2°, 28.0 There are characteristic peaks at ⁇ 0.2°, 30.2 ⁇ 0.2°, and 31.2 ⁇ 0.2°.
  • the calcium salt Form I of the compound of formula (1) has an X-ray substantially as shown in FIG. - X-ray powder diffraction pattern.
  • Form II of the calcium salt which uses Cu-K ⁇ radiation, X-ray powder diffraction in 2 ⁇ angles at 3.9 ⁇ 0.2°, 6.0 ⁇ 0.2°, 8.1 ⁇ 0.2°, 11.1 There are characteristic peaks at ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.4 ⁇ 0.2°, and 19.0 ⁇ 0.2°.
  • the calcium salt form II of the compound of formula (1) has an X-ray substantially as shown in FIG. - X-ray powder diffraction pattern.
  • the calcium salt crystal form II of the compound of formula (1) has a differential scanning calorimetry profile substantially as shown in FIG. 22 .
  • the calcium salt crystal form II of the compound of formula (1) as determined by thermogravimetric analysis, has weight loss below 250°C; in some embodiments, the compound of formula (1)
  • the calcium salt of Form II has a thermogravimetric analysis pattern substantially as shown in Figure 23.
  • Form I of the sodium salt which uses Cu-K ⁇ radiation, X-ray powder diffraction in 2 theta angles, at 3.9 ⁇ 0.2°, 4.5 ⁇ 0.2°, 7.8 ⁇ 0.2°, 9.1 There are characteristic peaks at ⁇ 0.2°, 11.8 ⁇ 0.2°, and 12.7 ⁇ 0.2°.
  • the sodium salt crystalline form I of the compound of formula (1) on the basis of comprising the above-mentioned characteristic peaks, also has a 8.5 There are characteristic peaks at ⁇ 0.2°, 10.5 ⁇ 0.2°, 14.2 ⁇ 0.2°, 16.8 ⁇ 0.2°, and 17.9 ⁇ 0.2°.
  • the sodium salt crystal form I of the compound of formula (1) on the basis of comprising the above-mentioned characteristic peaks, also has a 18.6 There are characteristic peaks at ⁇ 0.2°, 20.4 ⁇ 0.2°, 30.5 ⁇ 0.2°, and 34.7 ⁇ 0.2°.
  • the sodium salt form I of the compound of formula (1) has an X-ray substantially as shown in FIG. - X-ray powder diffraction pattern.
  • the sodium salt crystal form I of the compound of formula (1) has a differential scanning calorimetry profile substantially as shown in FIG. 25 .
  • the sodium salt crystal form I of the compound of formula (1) as determined by thermogravimetric analysis, has weight loss below 200°C;
  • the sodium salt form I of the compound of formula (1) has a thermogravimetric analysis pattern substantially as shown in FIG. 26 .
  • the present invention also provides a method for preparing the crystal form A of the compound of formula (1).
  • the compound of formula (1) is mixed with organic solvent 1 (as solvent), heated to the first temperature, cooled to below 35° C., filtered and dried to obtain the crystal form A of the compound of formula (1).
  • organic solvent 1 as solvent
  • the method for preparing the crystal form A of the compound of formula (1) further comprises adding another solvent dropwise after cooling to below 35°C, filtering and drying to obtain the crystal form A of the compound.
  • the another solvent is an ether solvent selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane.
  • the first temperature is selected from 40°C-95°C, eg 50°C-70°C, eg 50°C-80°C, eg 50°C-90°C, eg 60°C-70°C, eg 60°C °C-80°C, such as 60°C-90°C, such as 70°C-80°C, such as 70°C-90°C, such as 65°C-95°C, such as 65°C-90°C, such as 65°C-75°C, such as 85°C -95°C, in some embodiments, the first temperature refers to the temperature at which the solution is heated to clear.
  • the organic solvent one is an ester solvent.
  • the ester solvent is a fatty ester solvent.
  • the fatty ester solvent is selected from methyl formate, ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, propionic acid
  • methyl ester ethyl propionate, propyl propionate, isopropyl propionate, butyl acetate, and isobutyl acetate.
  • the fatty ester solvent is selected from one or both of ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, and isobutyl acetate Any combination of the above solvents.
  • the "arbitrary combination of two or more solvents” refers to a solvent formed by mixing the above organic solvents in a certain proportion. Including but not limited to the following specific examples: ethyl acetate/methyl formate, ethyl acetate/ethyl formate, ethyl acetate/propyl formate, ethyl acetate/methyl acetate, ethyl acetate/propyl acetate, ethyl acetate Ester/isopropyl acetate, ethyl acetate/isobutyl acetate, ethyl formate/methyl acetate, ethyl formate/propyl acetate, ethyl formate/isopropyl acetate, methyl acetate/propyl acetate, acetic acid Methyl/isopropyl acetate, etc.
  • the weight ratio of the compound of formula (1) to the organic solvent 1 is 1:6-1:12, such as 1:7-1:12, such as 1:8-1:12 , eg 1:9-1:12, eg 1:10-1:12, eg 1:11-1:12, eg 1:7-1:11, eg 1:8-1:11, eg 1:9 -1:11, eg 1:10-1:11, eg 1:7-1:10, eg 1:8-1:10, eg 1:8-1:9, eg 1:8, 1:9, 1:10, 1:11, 1:12, etc.
  • the "below 35°C" is 5°C-35°C, eg, 10°C-35°C, eg, 10°C-30°C, eg, 10°C-25°C.
  • the preparation method of Form A of the compound of formula (1) can be expressed as:
  • the compound of formula (1) is mixed with an ester solvent, heated to a feed liquid temperature of 60°C-90°C, cooled to 10°C-35°C, filtered and dried to obtain the crystal form A of the compound.
  • the preparation method of Form A of the compound of formula (1) can be expressed as:
  • the compound of formula (1) is mixed with an ester solvent, heated to a feed liquid temperature of 60°C-90°C, cooled to 10°C-35°C, added with isopropyl ether, stirred, filtered, and dried to obtain the crystal form A of the compound .
  • the present invention also provides a method for preparing the crystal form B of the compound of formula (1).
  • the compound of formula (1) is mixed with organic solvent II (as solvent), stirred, heated to the second temperature, cooled to 10°C-30°C, filtered and dried to obtain the crystal form B of the compound of formula (1).
  • organic solvent II as solvent
  • the organic solvent two is an alcohol solvent.
  • the alcohol-based solvent is selected from one or any combination of two or more solvents selected from aliphatic alcohol-based solvents, alicyclic alcohol-based solvents, and aromatic alcohol-based solvents.
  • the fatty alcohol solvent is selected from the group consisting of ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, Propylene glycol or glycerol.
  • the fatty alcohol solvent is selected from ethanol, n-propanol, isopropanol, isobutanol, and n-amyl alcohol.
  • the alicyclic alcohol solvent is selected from cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol or cyclohexanol.
  • the aromatic alcohol solvent is selected from benzyl alcohol, phenethyl alcohol, or phenylpropanol.
  • the "arbitrary combination of two or more solvents” refers to a solvent formed by mixing the above two organic solvents in a certain proportion. Including but not limited to the following specific examples: ethanol/propanol, ethanol/isopropanol, ethanol/n-butanol, ethanol/isobutanol, ethanol/tert-butanol, ethanol/n-pentanol, ethanol/cyclopentanol, ethanol /benzyl alcohol, ethanol/tert-butanol, etc.
  • the weight ratio of the compound of formula (1) to the organic solvent II is 1:7-1:13, such as 1:8-1:13, such as 1:9-1:13 , eg 1:10-1:13, eg 1:11-1:13, eg 1:12-1:13, eg 1:7-1:12, eg 1:8-1:12, eg 1:9 -1:12, eg 1:10-1:12, eg 1:11-1:12, eg 1:7-1:11, eg 1:8-1:11, eg 1:9-1:11, eg 1:10-1:11, eg 1:7-1:10, eg 1:8-1:10, eg 1:8-1:9, eg 1:8, 1:9, 1:10, 1 :11, 1:12, etc.
  • the second temperature is selected from 40°C-80°C, eg 50°C-60°C, eg 50°C-70°C, eg 50°C-80°C, eg 60°C-70°C, eg 60°C °C-80 °C, such as 70 °C-80 °C, such as 55 °C-65 °C, such as 60 °C-65 °C, in some embodiments, the second temperature refers to the temperature when the solution is heated to a clear solution.
  • the cooling refers to cooling by stirring in an air bath, natural cooling, and the like.
  • the temperature of the air bath is 20°C-30°C, eg 25°C-30°C, eg 26°C-30°C, eg 27°C-30°C, eg 28°C-30°C, eg 29 °C-30°C.
  • the present invention also provides a method for preparing the crystal form C of the compound of formula (1).
  • the compound of formula (1) is mixed with organic solvent three (as solvent), heated to the third temperature, cooled for 10h-25h, filtered, dried, and transferred to a 100°C-140°C oven for 1-5h to obtain the formula (1) Form C of the compound.
  • organic solvent three as solvent
  • the organic solvent three refers to methanol.
  • the weight ratio of the compound of formula (1) to the organic solvent three is 1:2-1:8, such as 1:3-1:8, such as 1:4-1:8 , eg 1:5-1:8, eg 1:6-1:8, eg 1:7-1:8, eg 1:2-1:7, eg 1:3-1:7, eg 1:4 -1:7, eg 1:5-1:7, eg 1:6-1:7, eg 1:2-1:6, eg 1:3-1:6, eg 1:4-1:6, e.g. 1:5-1:6, e.g. 1:2-1:5, e.g. 1:3-1:5, e.g. 1:4-1:5, e.g. 1:2-1:4, e.g. 1:3- 1:4, such as 1:2-1:3, such as 1:4, 1:5, 1:6, 1:7, etc.
  • the third temperature is selected from 40°C-80°C, eg 50°C-60°C, eg 50°C-70°C, eg 50°C-80°C, eg 60°C-70°C, eg 60°C °C-80°C, such as 70°C-80°C, such as 50°C-65°C, such as 55°C-60°C, such as 60°C-65°C, in some embodiments, the third temperature refers to heating to the solution temperature at which it dissolves.
  • the preparation method of Form C can be expressed as:
  • the compound of formula (1) is mixed with methanol, heated to 50°C-65°C, cooled for 15h-20h, filtered, dried, and transferred to an oven at 120°C-130°C for 1-3h to obtain the crystal form of the compound of formula (1) C.
  • the present invention also provides a method for preparing the crystal form D of the compound of formula (1).
  • the organic solvent four is an organic solvent that is at least slightly soluble in water, such as an organic solvent that is miscible with water.
  • the organic solvent Te is an alcoholic solvent.
  • the alcohol-based solvent is selected from one or any combination of two or more solvents selected from aliphatic alcohol-based solvents, alicyclic alcohol-based solvents, and aromatic alcohol-based solvents.
  • the fatty alcohol solvent is selected from the group consisting of ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, Propylene glycol or glycerol.
  • the fatty alcohol solvent is selected from ethanol, n-propanol, isopropanol, isobutanol, and n-amyl alcohol.
  • the alicyclic alcohol solvent is selected from cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol or cyclohexanol.
  • the aromatic alcohol solvent is selected from benzyl alcohol, phenethyl alcohol, or phenylpropanol.
  • the volume ratio of organic solvent four to water is selected from 1:6-6:1, such as 1:5-5:1, such as 1:4-4:1, such as 1:3-3:1 , eg 1:2-2:1, eg 4:5-5:4, eg 1:2, eg 1:1, eg 3:2, eg 3:4, eg 3:5, eg 4:3, eg 4:5 eg 2:3 eg 5:3 eg 5:4 eg 5:6 eg 5:7 eg 5:8 eg 5:9 eg 6:5 eg 6:7 eg 6:10 eg 6:11 eg 7:4 eg 7:5 eg 7:6 eg 7:8 eg 7:9 eg 7:10 eg 7:11 eg 7:12 eg 7:13 eg 8:5 eg 8:7 eg 8:9 eg 8:11 eg 8:13
  • the weight ratio of compound of formula (1) to organic solvent four is 1:7-1:13, such as 1:8-1:13, such as 1:9-1:13, such as 1:10- 1:13, e.g. 1:11-1:13, e.g. 1:12-1:13, e.g. 1:8-1:12, e.g. 1:9-1:12, e.g. 1:10-1:12, e.g.
  • 1:11-1:12 eg 1:8-1:11, eg 1:9-1:11, eg 1:10-1:11, eg 1:8-1:10, eg 1:9-1 :10, eg 1:8-1:9, eg 1:5, eg 1:6, eg 1:7, eg 1:8, eg 1:9, eg 1:10, eg 1:11, eg 1: 12, eg 1:13, eg 1:14, eg 1:15.
  • the organic solvent five is an ether solvent selected from the group consisting of diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane.
  • the filtration described in the method for preparing Form A, Form B, Form C or Form D may be performed by a method of suction filtration.
  • the process of preparing Form A, Form B, Form C or Form D further comprises the step of stirring.
  • the agitation is mechanical or manual. In some embodiments, the agitation is mechanical agitation.
  • the drying described in the above-mentioned method for preparing crystal form A, crystal form B, crystal form C or crystal form D can be performed by drying under reduced pressure, oven drying, natural air drying or ventilation drying, and the drying temperature Not more than 60°C, eg 30°C-55°C, eg 35°C-50°C.
  • the step of adding seed crystals of the crystal form A, crystal form B, crystal form C or crystal form D respectively during the cooling process is also included, so as to facilitate the formation and precipitation of each crystal form.
  • the seed crystal of the crystal form is prepared by the method of preparing each crystal form without adding a seed crystal in this application document.
  • the present invention also provides the preparation method of the pharmaceutically acceptable salt of the compound of formula (1):
  • the compound of formula (1) is reacted with an inorganic base in reaction solvent A.
  • the inorganic base is selected from potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium bicarbonate, calcium bicarbonate, potassium hydroxide, sodium hydroxide, Lithium hydroxide, magnesium hydroxide or calcium hydroxide.
  • the pharmaceutically acceptable salt of the compound of formula (1) is selected from potassium, sodium, lithium, magnesium, calcium salts of the compound of formula (1).
  • reaction solvent A is selected from one of alcohol solvents, ketone solvents, nitrile solvents or ester solvents, or any combination of two or more solvents.
  • the alcohol solvent is selected from one or any combination of two or more solvents selected from aliphatic alcohol solvents, alicyclic alcohol solvents and aromatic alcohol solvents; preferably, the aliphatic alcohol solvents
  • the solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol or glycerol; more preferably , the aliphatic alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, isobutanol or n-amyl alcohol; preferably, the alicyclic alcohol solvent is selected from cyclopentanol, cyclopentyl alcohol , cyclohexanol, cyclohexanol or cyclohexanol;
  • the ketone solvent is selected from acetone.
  • the nitrile solvent is selected from acetonitrile.
  • the ester solvent is a fatty ester solvent; preferably, the fatty ester solvent is selected from methyl formate, ethyl formate, propyl formate, isopropyl formate, methyl acetate, One or more of ethyl acetate, propyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl acetate, and isobutyl acetate Any combination of solvents; further preferably, the fatty ester solvent is selected from the one in ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, and isobutyl acetate Or any combination of two or more solvents;
  • the present invention also provides the preparation method of formula (1) compound potassium salt crystal form:
  • the compound of formula (1) is reacted with potassium salt in reaction solvent B.
  • the potassium salt is selected from potassium carbonate, potassium bicarbonate, or potassium hydroxide.
  • reaction solvent B is selected from alcohol solvents.
  • the alcohol-based solvent is selected from one or any combination of two or more solvents selected from aliphatic alcohol-based solvents, alicyclic alcohol-based solvents, and aromatic alcohol-based solvents.
  • the fatty alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-pentanol, n-hexanol, ethyl alcohol
  • methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-pentanol, n-hexanol, ethyl alcohol One or any combination of two or more solvents among glycol, propylene glycol or glycerol.
  • the fatty alcohol solvent is selected from one or any combination of two or more solvents selected from methanol, ethanol, n-propanol, isopropanol, isobutanol, and n-amyl alcohol.
  • the alicyclic alcohol solvent is selected from cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol or cyclohexanol.
  • the aromatic alcohol solvent is selected from benzyl alcohol, phenethyl alcohol, or phenylpropanol.
  • the present invention also provides a pharmaceutical composition, which contains crystal form A, crystal form B, crystal form C, crystal form D or pharmaceutically acceptable salt and crystal form thereof of the compound of formula (1), and one or more A second therapeutic agent, optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and/or diluents.
  • the present invention also provides a pharmaceutical preparation, which contains crystal form A, crystal form B, crystal form C, crystal form D or pharmaceutically acceptable salt and crystal form thereof of the compound of formula (1), and one or more Pharmaceutical carrier and/or diluent; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.
  • the pharmaceutical formulations described above are administered orally, parenterally, rectally or pulmonary, etc. to a patient or subject in need of such treatment.
  • conventional solid preparations such as tablets, capsules, pills, granules, etc.
  • oral liquid preparations such as oral solutions, oral suspensions, syrups, etc.
  • suitable fillers, binders, disintegrants, lubricants and the like can be added.
  • parenteral administration it can be prepared into injection, including injection solution, sterile powder for injection and concentrated solution for injection. When the injection is prepared, it can be produced by the conventional method in the existing pharmaceutical field.
  • the injection When the injection is prepared, no additive can be added, or an appropriate additive can be added according to the properties of the drug.
  • rectal administration it can be made into suppositories and the like.
  • pulmonary administration it can be made into inhalants or sprays.
  • the present invention also provides methods of treating and/or preventing KHK-mediated diseases and related diseases, comprising administering to a patient in need of such treatment an effective amount of 2-((1R,5S,6R)-3-(7,7- Difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-4-yl)-3 -Azabicyclo[3.1.0]hex-6-yl)acetic acid crystal form A, crystal form B, crystal form C, crystal form D or pharmaceutically acceptable salts and crystal forms thereof.
  • the KHK-mediated disease and related diseases are selected from endocrine disorders, urological diseases, metabolic diseases, non-alcoholic steatohepatitis, cirrhosis, fatty liver, hepatitis, liver failure, hereditary fructose intolerance Diseases, non-alcoholic fatty liver disease, hepatobiliary diseases, fibrotic diseases, cardiovascular and cerebrovascular diseases, immune inflammatory diseases, central nervous system diseases, gastrointestinal diseases and hyperproliferative diseases such as cancer.
  • the present invention also provides crystalline form A, crystalline form B, crystalline form C, crystalline form D or pharmaceutically acceptable salts of the compound of formula (1) and their crystalline forms in the preparation for the treatment and/or prevention of KHK-mediated diseases and related Use in medicine for disease.
  • the KHK-mediated disease and related diseases are selected from endocrine disorders, urological diseases, metabolic diseases, non-alcoholic steatohepatitis, cirrhosis, fatty liver, hepatitis, liver failure, hereditary fructose intolerance Diseases, non-alcoholic fatty liver disease, hepatobiliary diseases, fibrotic diseases, cardiovascular and cerebrovascular diseases, immune inflammatory diseases, central nervous system diseases, gastrointestinal diseases and hyperproliferative diseases such as cancer.
  • the present invention also provides crystalline form A, crystalline form B, crystalline form C, crystalline form D or pharmaceutically acceptable salts and crystalline forms thereof of the compound of formula (1) for the treatment and/or prevention of KHK-mediated diseases and related disease.
  • the KHK-mediated disease and related diseases are selected from endocrine disorders, urological diseases, metabolic diseases, non-alcoholic steatohepatitis, cirrhosis, fatty liver, hepatitis, liver failure, hereditary fructose intolerance Diseases, non-alcoholic fatty liver disease, hepatobiliary diseases, fibrotic diseases, cardiovascular and cerebrovascular diseases, immune inflammatory diseases, central nervous system diseases, gastrointestinal diseases and hyperproliferative diseases such as cancer.
  • the present invention also provides a crystal form A, a crystal form B, a crystal form C, a crystal form D or a pharmaceutically acceptable salt of the compound of the formula (1) and a composition of the crystal form and one or more other drugs, these other
  • the drug and the crystalline form A, crystalline form B, crystalline form C, crystalline form D or pharmaceutically acceptable salts and crystalline forms thereof of the compound of formula (1) are administered simultaneously or sequentially for the treatment and/or prevention of KHK-mediated diseases and related diseases.
  • the KHK-mediated disease and related diseases are selected from endocrine disorders, urological diseases, metabolic diseases, non-alcoholic steatohepatitis, cirrhosis, fatty liver, hepatitis, liver failure, hereditary fructose intolerance Diseases, non-alcoholic fatty liver disease, hepatobiliary diseases, fibrotic diseases, cardiovascular and cerebrovascular diseases, immune inflammatory diseases, central nervous system diseases, gastrointestinal diseases and hyperproliferative diseases such as cancer.
  • an "effective amount” refers to an amount sufficient to achieve the desired therapeutic or prophylactic effect, eg, an amount to achieve relief of symptoms associated with the disease to be treated.
  • Treatment refers to alleviation or elimination of the targeted disease state or disorder. If a subject receives a therapeutic amount of said crystalline form or a pharmaceutical composition thereof according to the methods described herein, the subject exhibits one or more signs and symptoms that are observable and/or detectable decreased or improved, the subject was successfully "treated”. It is also to be understood that the treatment of the disease state or disorder includes not only complete treatment, but also that complete treatment is not achieved, but some biologically or medically relevant result is achieved.
  • crystal form A The main advantages of the crystal form A, crystal form B, crystal form C, crystal form D, pharmaceutically acceptable salts and crystal forms of the compound of formula (1) of the present invention include:
  • crystal form A, crystal form B, crystal form C, crystal form D, pharmaceutically acceptable salts and crystal forms thereof provided by the present invention have good properties, which are convenient for detection, preparation, transportation and storage;
  • crystal form A, crystal form B, crystal form C, crystal form D, pharmaceutically acceptable salt and crystal form thereof provided by the present invention have high purity, less residual solvent, high solubility, good stability and easy quality control ;
  • the crystal form A, crystal form B, crystal form C, crystal form D, pharmaceutically acceptable salts and crystal forms thereof provided by the present invention all have a good inhibitory effect on KHK kinase, and can be used for the treatment and/or prevention of KHK-mediated induced and related diseases.
  • Fig. 1 is an X-ray powder diffraction pattern of the crystal form A of the compound of formula (1), where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • Figure 2 is a differential scanning calorimetry (DSC) thermogram of the crystal form A of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), the abscissa represents temperature, The unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 3 is the thermogravimetric analysis (TG) curve and derivative thermogravimetric analysis (DTG) curve of the crystal form A of the compound of formula (1), the abscissa is temperature (°C), the left ordinate represents weight (%), the right The side ordinate represents the weight loss rate (%) versus temperature.
  • TG thermogravimetric analysis
  • TMG derivative thermogravimetric analysis
  • Fig. 4 is an X-ray powder diffraction pattern of the crystal form B of the compound of formula (1), where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • Figure 5 is a differential scanning calorimetry (DSC) thermogram of the crystal form B of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), the abscissa represents temperature, The unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 6 is the thermogravimetric analysis (TG) curve and derivative thermogravimetric analysis (DTG) curve of the crystal form B of the compound of formula (1), the abscissa is temperature (°C), the left ordinate represents weight (%), the right The side ordinate represents the weight loss rate (%) versus temperature.
  • TG thermogravimetric analysis
  • TMG derivative thermogravimetric analysis
  • Figure 8 is a differential scanning calorimetry (DSC) thermogram of the crystal form C of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), the abscissa represents temperature, The unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 9 is the thermogravimetric analysis (TG) curve and derivative thermogravimetric analysis (DTG) curve of the crystal form C of the compound of formula (1), the abscissa is temperature (°C), the left ordinate represents weight (%), the right The side ordinate represents the weight loss rate (%) versus temperature.
  • TG thermogravimetric analysis
  • TMG derivative thermogravimetric analysis
  • 10 is an X-ray powder diffraction pattern of the crystal form D of the compound of formula (1), the ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle (2 ⁇ ).
  • Figure 11 is a differential scanning calorimetry (DSC) thermogram of the crystal form D of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), the abscissa represents temperature, The unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 12 is the thermogravimetric analysis (TG) curve and derivative thermogravimetric analysis (DTG) curve of the crystal form D of the compound of formula (1), the abscissa is temperature (°C), the left ordinate represents weight (%), the right The side ordinate represents the weight loss rate (%) versus temperature.
  • TG thermogravimetric analysis
  • TMG derivative thermogravimetric analysis
  • Figure 13 is an X-ray powder diffraction pattern of the potassium salt crystal form I of the compound of formula (1), where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • Figure 14 is a differential scanning calorimetry (DSC) thermogram of the potassium salt crystal form I of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), and the abscissa represents temperature (temperature). ), the unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 15 is the thermogravimetric analysis (TG) curve and derivative thermogravimetric analysis (DTG) curve of potassium salt crystal form I of the compound of formula (1), the abscissa is temperature (°C), and the left ordinate represents weight (%) , the right ordinate represents the relationship between weight loss rate (%) and temperature.
  • TG thermogravimetric analysis
  • TSG derivative thermogravimetric analysis
  • 16 is an X-ray powder diffraction pattern of the potassium salt crystal form II of the compound of formula (1), where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • Figure 17 is a differential scanning calorimetry (DSC) thermogram of the potassium salt crystal form II of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), and the abscissa represents temperature (temperature). ), the unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 17-1 is a thermogravimetric analysis (TG) curve of potassium salt crystal form II of the compound of formula (1), the abscissa is temperature (°C), and the ordinate is weight (%).
  • TG thermogravimetric analysis
  • Figure 19 is a differential scanning calorimetry (DSC) thermogram of the magnesium salt crystal form of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), and the abscissa represents temperature (temperature) , the unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 20 is an X-ray powder diffraction pattern of the calcium salt crystal form I of the compound of formula (1).
  • the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • Figure 21 is an X-ray powder diffraction pattern of the calcium salt crystal form II of the compound of formula (1), where the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2 ⁇ ).
  • Figure 22 is a differential scanning calorimetry (DSC) thermogram of the calcium salt crystal form II of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), and the abscissa represents temperature (temperature). ), the unit is (°C).
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TG) curve of calcium salt crystal form II of the compound of formula (1), the abscissa is temperature (° C.), and the ordinate is weight (%).
  • Figure 25 is a differential scanning calorimetry (DSC) thermogram of the sodium salt crystal form I of the compound of formula (1), the ordinate represents heat flow, the unit is (W/g), and the abscissa represents temperature (temperature). ), the unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 26 is a thermogravimetric analysis (TG) curve of the sodium salt crystal form I of the compound of formula (1), the abscissa is temperature (°C), and the ordinate is weight (%).
  • TG thermogravimetric analysis
  • DMSO dimethyl sulfoxide
  • PE petroleum ether
  • EA ethyl acetate
  • DAST diethylaminosulfur trifluoride
  • NMP N-methylpyrrolidone
  • DBN 1,5-diazabicyclo[4.3.0]non-5-ene
  • THF tetrahydrofuran
  • DIEA N,N-diisopropylethylamine
  • IPAc isopropyl acetate
  • 2-oxoadipic acid (10.0 g, 62.5 mmol) was added to a solution of DBN (9.3 g, 74.9 mmol) in acetone (100 mL), and dimethyl sulfate (7.9 g, 62.6 mmol) was added dropwise.
  • DBN 9.3 g, 74.9 mmol
  • dimethyl sulfate 7.9 g, 62.6 mmol
  • step method two solid 20.8g, add 500ml three-necked round-bottomed flask, add 210ml of ethyl acetate, turn on stirring, be warming up to 70 °C of feed liquid temperature, the system is clarified and solid is completely dissolved, close the oil bath heating, Naturally cooled to 10-25° C., filtered and air-dried to obtain 12.6 g of solid with a yield of 60.6%.
  • step (12) of the above-mentioned preparation example the added 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylazetidine) Alk-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid methyl
  • the amount of ester is 200.07g, obtain wet product, add ethanol (1800ml), add water (3600ml) after dissolving, separate out solid, suction filter and dry to obtain solid (184.3g).
  • Embodiment 9 the preparation of formula (1) compound calcium salt
  • crystal structures of the present invention are not limited to crystal structures that provide X-ray powder diffraction patterns identical to those depicted in the accompanying drawings disclosed in this application, substantially the same X-ray powder diffraction patterns as those disclosed in the accompanying drawings. Any crystal structure of a ray powder diffraction pattern is included within the scope of the present invention.
  • X-ray reflection parameters Cu, K ⁇ ; Incident slit: 0.6mm; Divergence slit: 8mm; Scanning mode: Continuous;
  • Scanning range 3.0 to 45.0 degrees; sampling step size: 0.02 degrees; scanning time per step: 0.3s; detector angle: 2.0 degrees.
  • the X-ray powder diffraction pattern of Form A of the compound of formula (1) is shown in Figure 1, and the crystal form has peaks at the following diffraction angles 2 ⁇ (°): 6.9 ⁇ 0.2°, 8.0 ⁇ 0.2°, 9.4 ⁇ 0.2 °, 10.2 ⁇ 0.2°, 10.5 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.2 ⁇ 0.2°, 15.1 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.9 ⁇ 0.2 °, 19.5 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.0 ⁇ 0.2°, 23.1 ⁇ 0.2°, 25.3 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound of formula (1) is shown in Figure 4, and the crystal form has peaks at the following diffraction angles 2 ⁇ (°): 6.4 ⁇ 0.2°, 8.3 ⁇ 0.2°, 10.0 ⁇ 0.2 °, 12.7 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.6 ⁇ 0.2°, 17.7 ⁇ 0.2°, 20.6 ⁇ 0.2°, 22.0 ⁇ 0.2°.
  • Form C by X-ray powder diffraction using Cu-K ⁇ radiation, expressed in 2 ⁇ angles (°), has characteristic peaks at 8.5 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.7 ⁇ 0.2°, 18.5 ⁇ 0.2°; also There are characteristic peaks at 13.0 ⁇ 0.2°, 13.4 ⁇ 0.2°, 13.8 ⁇ 0.2°, and 16.8 ⁇ 0.2°; there are also characteristic peaks at 19.2 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.1 ⁇ 0.2°, and 22.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form C of the compound of formula (1) is shown in Figure 7, and the crystal form has peaks at the following diffraction angles 2 ⁇ (°): 8.5 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.7 ⁇ 0.2 °, 13.0 ⁇ 0.2°, 13.4 ⁇ 0.2°, 13.8 ⁇ 0.2°, 16.8 ⁇ 0.2°, 18.5 ⁇ 0.2°, 19.2 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.1 ⁇ 0.2°, 22.1 ⁇ 0.2°.
  • Form D by X-ray powder diffraction using Cu-K ⁇ radiation at 6.4 ⁇ 0.2°, 10.0 ⁇ 0.2°, 12.7 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.6 ⁇ 0.2°, 25.5
  • ⁇ 0.2° there are characteristic peaks at 14.9 ⁇ 0.2°, 15.6 ⁇ 0.2°, 20.6 ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystalline form D of the compound of formula (1) is shown in Figure 10, and the crystalline form has peaks at the following diffraction angles 2 ⁇ (°): 6.4 ⁇ 0.2°, 8.3 ⁇ 0.2°, 10.0 ⁇ 0.2 °, 12.7 ⁇ 0.2°, 14.9 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.6 ⁇ 0.2°, 25.5 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the potassium salt crystal form I of the compound of formula (1) is shown in Figure 13, and the crystal form has peaks at the following diffraction angles 2 ⁇ (°): 4.8 ⁇ 0.2°, 5.9 ⁇ 0.2°, 7.1 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.8 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.3 ⁇ 0.2°, 25.0 ⁇ 0.2°.
  • Assay conditions Purge with nitrogen at 50 ml/min, collect data at a heating rate of 10°C/min between 25°C and 230°C, plot with endothermic peaks pointing down.
  • the crystal form A of the compound of formula (1) exhibits an endothermic peak in the range of 167°C to 173°C, and its differential scanning calorimetry analysis diagram is basically shown in FIG. 2 .
  • the crystalline form B of the compound of formula (1) has an endothermic peak in the range of 167°C to 173°C, and its differential scanning calorimetry analysis diagram is basically shown in FIG. 5 .
  • the crystal form C of the compound of formula (1) exhibits an endothermic peak in the range of 170°C to 175°C, and its differential scanning calorimetry analysis diagram is basically as shown in FIG. 8 .
  • the crystal form D of the compound of formula (1) has an endothermic peak in the range of 165°C to 170°C, and its differential scanning calorimetry analysis diagram is basically as shown in FIG. 11 .
  • the potassium salt crystal form I of the compound of formula (1) exhibits an endothermic peak in the range of 174°C to 180°C, and its differential scanning calorimetry analysis diagram is basically as shown in FIG. 14 .
  • the actually measured onset and maximum temperatures have a certain degree of variability depending on the measurement parameters and the heating rate.
  • Test Conditions Purge with nitrogen gas at 60 ml/min, and collect data at a heating rate of 10°C/min between room temperature and 400°C.
  • the crystalline form A of the compound of formula (1) has no weight loss in the range below 200°C, and its TG curve is shown in FIG. 3 .
  • the crystalline form B of the compound of formula (1) has no weight loss in the range below 200°C, and its TG curve is shown in FIG. 6 .
  • the crystalline form C of the compound of formula (1) has no weight loss in the range below 200°C, and its TG curve is shown in FIG. 9 .
  • the crystalline form D of the compound of formula (1) has no weight loss in the range below 200°C, and its TG curve is shown in FIG. 12 .
  • the potassium salt crystal form I of the compound of formula (1) has weight loss below 100° C., which is adsorbed water, and its TG curve is shown in FIG. 15 .
  • Test conditions D/max-2500 diffractometer (Rigaku, Japan);
  • the range of 2 ⁇ is 2° ⁇ 40°, and the scanning speed is 8°/min;
  • the X-ray powder diffraction pattern of the potassium salt crystal form II of the compound of formula (1) is shown in Figure 16, and the crystal form has peaks at the following diffraction angles 2 ⁇ (°): 4.7 ⁇ 0.2°, 5.1 ⁇ 0.2°, 6.5 ⁇ 0.2°, 7.9 ⁇ 0.2°, 8.3 ⁇ 0.2°, 10.3 ⁇ 0.2°, 11.0 ⁇ 0.2°, 12.1 ⁇ 0.2°, 13.0 ⁇ 0.2°, 17.6 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.4 ⁇ 0.2°, 24.1 ⁇ 0.2°, 24.5 ⁇ 0.2°.
  • the solid state thermal properties of the potassium salt form II of the compound of formula (1) were investigated by differential scanning calorimetry (DSC).
  • the temperature range is 303.15 ⁇ 473.15K, and the heating rate is 10K or 5K/min.
  • the potassium salt crystal form II of the compound of formula (1) has an endothermic peak in the range of 155°C to 165°C, and its differential scanning calorimetry analysis diagram is basically as shown in FIG. 17 .
  • the actually measured onset and maximum temperatures have a certain degree of variability depending on the measurement parameters and the heating rate.
  • Test Conditions Purge with nitrogen gas at 60 ml/min, and collect data at a heating rate of 10°C/min between room temperature and 300°C.
  • the potassium salt crystal form II of the compound of formula (1) loses 8.5% in weight below 200°C, and its TG curve is shown in Figure 17-1.
  • Test conditions D/max-2500 diffractometer (Rigaku, Japan);
  • the range of 2 ⁇ is 2° ⁇ 40°, and the scanning speed is 8°/min;
  • X-ray powder diffraction of magnesium salt crystal form expressed in 2 ⁇ angle (°) has characteristic peaks at 18.8 ⁇ 0.2°, 23.8 ⁇ 0.2°, 26.3 ⁇ 0.2°, 29.5 ⁇ 0.2°; also There are characteristic peaks at 23.0 ⁇ 0.2°, 25.9 ⁇ 0.2°, 31.5 ⁇ 0.2°, 32.0 ⁇ 0.2°, 38.1 ⁇ 0.2°, 39.0 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the magnesium salt crystal form of the compound of formula (1) is shown in Figure 18, and the crystal form has peaks at the following diffraction angles 2 ⁇ (°): 18.8 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.8 ⁇ 0.2°, 25.9 ⁇ 0.2°, 26.3 ⁇ 0.2°, 29.5 ⁇ 0.2°, 31.5 ⁇ 0.2°, 32.0 ⁇ 0.2°, 38.1 ⁇ 0.2°, 39.0 ⁇ 0.2°.
  • the temperature range is 303.15 ⁇ 473.15K, and the heating rate is 10K or 5K/min.
  • the magnesium salt crystal form of the compound of formula (1) has an endothermic peak in the range of 165°C to 180°C, and its differential scanning calorimetry analysis diagram is basically shown in FIG. 19 .
  • the actually measured onset and maximum temperatures have a certain degree of variability depending on the measurement parameters and the heating rate.
  • Test conditions D/max-2500 diffractometer (Rigaku, Japan);
  • the range of 2 ⁇ is 2° ⁇ 40°, and the scanning speed is 8°/min;
  • X-ray powder diffraction of calcium salt form I in 2 ⁇ angles (°) using Cu-K ⁇ radiation at 15.8 ⁇ 0.2°, 16.1 ⁇ 0.2°, 26.3 ⁇ 0.2°, 28.0 ⁇ 0.2°, 30.2 ⁇ 0.2° , 31.2 ⁇ 0.2° have characteristic peaks, and their X-ray powder diffraction patterns are shown in FIG. 20 .
  • X-ray reflection parameters Cu, K ⁇ ; Incident slit: 0.6mm; Divergence slit: 8mm; Scanning mode: Continuous;
  • Scanning range 3.0 to 45.0 degrees; sampling step size: 0.02 degrees; scanning time per step: 0.3s; detector angle: 2.0 degrees.
  • X-ray powder diffraction of calcium salt form II in 2 ⁇ angles (°) using Cu-K ⁇ radiation at 3.9 ⁇ 0.2°, 6.0 ⁇ 0.2°, 8.1 ⁇ 0.2°, 11.1 ⁇ 0.2°, 16.0 ⁇ 0.2° , 17.4 ⁇ 0.2°, and 19.0 ⁇ 0.2° have characteristic peaks, and their X-ray powder diffraction patterns are shown in FIG. 21 .
  • the solid state thermal properties of the calcium salt form II of the compound of formula (1) were investigated by differential scanning calorimetry (DSC).
  • Assay conditions Purge with nitrogen at 50 ml/min, collect data at a heating rate of 10°C/min between 25°C and 320°C.
  • the calcium salt crystal form II of the compound of formula (1) has a small endothermic peak at around 80 °C, and an exothermic peak at around 200 °C and 280 °C.
  • Comprehensive experimental observation found that the calcium salt has turned black at 200 °C, So the calcium salt melts at 200°C and further decomposes at 280°C. Its differential scanning calorimetry analysis diagram is basically shown in Figure 22.
  • the actually measured onset and maximum temperatures have a certain degree of variability depending on the measurement parameters and the heating rate.
  • Test Conditions Purge with nitrogen gas at 60 ml/min, and collect data at a heating rate of 10°C/min between room temperature and 300°C.
  • the calcium salt crystal form II of the compound of formula (1) has weight loss below 250°C, and its TG curve is shown in FIG. 23 .
  • X-ray reflection parameters Cu, K ⁇ ; Incident slit: 0.6mm; Divergence slit: 8mm; Scanning mode: Continuous;
  • Scanning range 3.0 to 45.0 degrees; sampling step size: 0.02 degrees; scanning time per step: 0.3s; detector angle: 2.0 degrees.
  • the X-ray powder diffraction pattern of the sodium salt crystal form I of the compound of formula (1) is shown in Figure 24, and the crystal form has peaks at the following diffraction angles 2 ⁇ (°): 3.9 ⁇ 0.2°, 4.5 ⁇ 0.2°, 7.8 ⁇ 0.2°, 8.5 ⁇ 0.2°, 9.1 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.7 ⁇ 0.2°, 14.2 ⁇ 0.2°, 16.8 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.6 ⁇ 0.2°, 20.4 ⁇ 0.2°, 30.5 ⁇ 0.2°, 34.7 ⁇ 0.2°.
  • the solid state thermal properties of the sodium salt form I of the compound of formula (1) were investigated by differential scanning calorimetry (DSC).
  • Assay conditions Purge with nitrogen at 50 ml/min, collect data at a heating rate of 10°C/min between 25°C and 220°C.
  • the differential scanning calorimetry analysis of the sodium salt crystal form I of the compound of formula (1) is basically as shown in FIG. 25 .
  • the actual measured onset and maximum temperatures have a certain degree of variability depending on the measurement parameters and the heating rate.
  • Test Conditions Purge with nitrogen gas at 60 ml/min, and collect data at a heating rate of 10°C/min between room temperature and 300°C.
  • the sodium salt crystal form I of the compound of formula (1) has weight loss below 200°C, and its TG curve is shown in FIG. 26 .
  • crystal structures of the present invention are not limited to crystal structures that provide X-ray powder diffraction patterns identical to those depicted in the accompanying drawings disclosed in this application, substantially the same X-ray powder diffraction patterns as those disclosed in the accompanying drawings. Any crystal structure of a ray powder diffraction pattern is included within the scope of the present invention.
  • the crystal form A of the compound of formula (1) was prepared according to the method in Example 1.
  • the closed mouth (polyethylene bag + composite film bag) is used to meet the illumination requirements for sampling and testing.
  • ICH Q1B stability test photostability test of new APIs and preparations.
  • Determination of related substances Determination by high performance liquid chromatography in accordance with the 2015 edition of the Chinese Pharmacopoeia Four General Principles 0512.
  • Moisture determination According to the 2015 edition of the Chinese Pharmacopoeia, four general rules 0832 Moisture determination method first method (Fischer's method) 2 coulometric titration method.
  • DSC measurement Precisely weigh an appropriate amount of sample into the Standard pan, place the lid on the sample pan in the DSC furnace, and place a blank pan of the same type in the reference position.
  • the heating program is as follows:
  • the crystal form A of the compound of formula (1) has a slight increase in total related substances under the conditions of high temperature 105°C and 60°C, 25°CRH92.5% open/closed, 40°CRH75% open/closed, other inspection items such as Moisture, XRD, DSC stability is good. It is illustrated that the crystal form A of the compound of formula (1) is relatively stable under the above conditions, which is convenient for the preparation, transportation and storage of medicines, and is more conducive to ensuring the effectiveness and safety of medicines.
  • the crystal form B of the compound of formula (1) was prepared according to the method of Example 2.
  • the closed mouth (polyethylene bag + composite film bag) is used to meet the illumination requirements for sampling and testing.
  • ICH Q1B stability test photostability test of new APIs and preparations.
  • Determination of related substances Determination by high performance liquid chromatography in accordance with the 2015 edition of the Chinese Pharmacopoeia Four General Principles 0512.
  • Moisture determination According to the 2015 edition of the Chinese Pharmacopoeia, four general rules 0832 Moisture determination method first method (Fischer's method) 2 coulometric titration method.
  • XRD measurement determined according to the 2015 edition of "Chinese Pharmacopoeia” four general rules 0451 X-ray diffraction method - the second method powder X-ray diffraction method.
  • DSC measurement Precisely weigh an appropriate amount of sample into the Standard pan, place the lid on the sample pan in the DSC furnace, and place a blank pan of the same type in the reference position.
  • the heating program is as follows:
  • the crystal form B of formula (1) has a slight increase in total related substances under the conditions of high temperature 105 °C, 60 °C and 25 °C RH92.5% open/closed conditions, and other inspection items such as moisture, XRD, DSC, etc. have good stability; Under the condition of 40°CRH75% for 1 month, the related substances, moisture, XRD and DSC stability are all good; it shows that the crystal form B of the compound of formula (1) is relatively stable under the above conditions, which is convenient for the preparation, transportation and storage of medicines , more conducive to ensuring the effectiveness and safety of drug use.
  • the crystal form C of the compound of formula (1) was prepared according to the method of Example 3.
  • the closed mouth (polyethylene bag + composite film bag) is used to meet the illumination requirements for sampling and testing.
  • ICH Q1B stability test photostability test of new APIs and preparations.
  • Determination of related substances Determination by high performance liquid chromatography in accordance with the 2015 edition of the Chinese Pharmacopoeia Four General Principles 0512.
  • Moisture determination According to the 2015 edition of the Chinese Pharmacopoeia, four general rules 0832 Moisture determination method first method (Fischer's method) 2 coulometric titration method.
  • XRD measurement determined according to the 2015 edition of "Chinese Pharmacopoeia” four general rules 0451 X-ray diffraction method - the second method powder X-ray diffraction method.
  • DSC measurement Precisely weigh an appropriate amount of sample into the Standard pan, place the lid on the sample pan in the DSC furnace, and place a blank pan of the same type in the reference position.
  • the heating program is as follows:
  • the crystal form C of the compound of formula (1) has a slight increase in the total related substances at high temperature of 105°C for 5 days and 60°C for 10 days; 25°CRH92.5% for 10 days and 40°CRH75% for 1 month under open/closed conditions
  • the material, content, moisture, XRD and other stability are good.
  • the crystal form D of the compound of formula (1) was prepared according to the method of Example 4.
  • the closed mouth (polyethylene bag + composite film bag) is used to meet the illumination requirements for sampling and testing.
  • ICH Q1B stability test photostability test of new APIs and preparations.
  • Determination of related substances Determination by high performance liquid chromatography in accordance with the 2015 edition of the Chinese Pharmacopoeia Four General Principles 0512.
  • Moisture determination According to the 2015 edition of the Chinese Pharmacopoeia, four general rules 0832 Moisture determination method first method (Fischer's method) 2 coulometric titration method.
  • XRD measurement determined according to the 2015 edition of "Chinese Pharmacopoeia” four general rules 0451 X-ray diffraction method - the second method powder X-ray diffraction method.
  • DSC measurement Precisely weigh an appropriate amount of sample into the Standard pan, place the lid on the sample pan in the DSC furnace, and place a blank pan of the same type in the reference position.
  • the heating program is as follows:
  • the crystal form D of the compound of formula (1) has a slight increase in the total related substances at a high temperature of 105 °C, and other inspection items such as moisture, XRD, DSC, etc. have good stability; place 1 under the condition of 40 °C RH75% open/closed The stability of total related substances, moisture, XRD and DSC are all good; it shows that the crystal form D of the compound of formula (1) is relatively stable under the above conditions. Stable, convenient for the preparation, transportation and storage of medicines, and more conducive to ensuring the effectiveness and safety of medicines.
  • the potassium salt crystal form II of the compound of formula (1) was prepared according to the method of method 3 of Example 5.
  • Determination of related substances Determination by high performance liquid chromatography in accordance with the 2015 edition of the Chinese Pharmacopoeia Four General Principles 0512.
  • Potassium salt crystal form II of the compound of formula (1) under the conditions of 60°C for 10 days, 92.5%RH for 10 days, and 40°C for 75%RH for 1 month, the properties and related substances are basically the same as 0 days, indicating that formula (1)
  • the potassium salt crystal form II of the compound is relatively stable under the above conditions, which is convenient for the preparation, transportation and storage of medicines, and is more conducive to ensuring the effectiveness and safety of medicines.
  • the calcium salt crystal form II of the compound of formula (1) for testing was prepared according to the method of Example 9, Method Three.
  • the calcium salt crystal form II of the compound of formula (1) was placed at RH80% for 1 day, the weight increased by 1.38%, and it was slightly hygroscopic.
  • the amorphous form of the compound of formula (1) was prepared according to the method 1 of the preparation example.
  • the closed mouth (polyethylene bag + composite film bag) is used to meet the illumination requirements for sampling and testing.
  • ICH Q1B stability test photostability test of new APIs and preparations.
  • Determination of related substances Determination by high performance liquid chromatography in accordance with the 2015 edition of the Chinese Pharmacopoeia Four General Principles 0512.
  • Moisture determination According to the 2015 edition of the Chinese Pharmacopoeia, four general rules 0832 Moisture determination method first method (Fischer's method) 2 coulometric titration method.
  • the amorphous compound of formula (1) was placed under the condition of open/closed mouth at high temperature of 60°C for 10 days, and the total related substances increased significantly, and the moisture stability was good; slightly increased, and the moisture increased significantly; placed under 40°CRH75% open/closed conditions for 1 month, the total related substances and moisture increased significantly, indicating the amorphous and crystal form A and crystal form B of the compound of formula (1). Compared with crystalline form C and crystalline form D, the stability under the above conditions is poor.
  • Test sample compound of formula (1), see the preparation example for its chemical name and preparation method.
  • Control drug PF-06835919, prepared by the method in the reference (US15/381,295).
  • KHK-C kinase reaction is 1 nM KHK-C, 100 ⁇ M ATP, 200 ⁇ M D-Fructose, HEPES 50 mM, MgCl 2 10 mM, Brij35 0.01%, and DMSO final concentration is 1%.
  • test compounds were 10000nM, 3333.33nM, 1111.11nM, 370.37nM, 123.457nM, 41.15nM, 13.71nM, 4.572nM, 1.524nM, 0.508nM, 0.169nM.
  • control drug is 1000nM, 333.33nM, 111.11nM, 37.037nM, 12.346nM, 4.115nM, 1.371nM, 0.4572nM, 0.1524nM, 0.0508nM, 0.0169nM.
  • Lum HC represents: the luminescence signal intensity of High control (adding the same volume of DMSO as the compound to be tested in the reaction system);
  • Lum LC means: luminescence signal intensity of Low control (control drug 1 ⁇ M);
  • Lum cpd means: means the luminescence signal intensity of the test compound
  • Curve fitting was performed using software, and IC50 was calculated.
  • the compound of formula (1) of the present invention can effectively inhibit the activity of KHK-C kinase and is an effective KHK-C kinase inhibitor.
  • Test sample compound of formula (1), see the preparation example for its chemical name and preparation method.
  • Control drug PF-06835919, prepared by the method in the reference (US15/381,295).
  • HepG2 cells in logarithmic growth phase were collected and counted using a platelet counter. Cell viability was detected by trypan blue exclusion method to ensure cell viability was above 90%.
  • HepG2 cells in a 96-well plate were cultured overnight at 37° C., 5% CO 2 , and 95% humidity.
  • the cells in the 96-well plate to which the drug has been added are placed under the conditions of 37° C., 5% CO 2 , and 95% humidity, and incubated for 30 minutes.
  • the medium in the 96-well plate was removed, and the cells in the plate were washed three times with cold DPBS (200 ⁇ l/well), then 30 ⁇ L of cold 10 mM ammonium acetate (pH 7.4) was added to each well to lyse the cells (hypotonic). After lysing on ice for 5 min, the cells were fully pipetted, and the cell lysate was taken for LC-MS analysis.
  • KHK-C kinase The expression level of KHK-C kinase in the liver is the highest. At the same time, KHK-C kinase can specifically metabolize fructose and generate fructose-1-phosphate. It can be seen from the above experimental results that the compound of formula (1) of the present invention can effectively inhibit D -Fructose induces the production of fructose-1-phosphate in HepG2 cells and is a potent KHK-C inhibitor.

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Abstract

本发明涉及一种己酮糖激酶抑制剂的晶型、可药用盐及其制备方法、药物组合物及应用。具体地涉及作为己酮糖激酶抑制剂的式(1)化合物的晶型、可药用盐及其晶型，其制备方法，包含晶型、可药用盐及其晶型的药物组合物，以及式(1)化合物的晶型、可药用盐及其晶型在制备用于预防和/或治疗KHK介导的疾病及相关疾病的药物中的应用。

Description

己酮糖激酶抑制剂的盐、晶型及其用途 技术领域
本发明涉及一种己酮糖激酶抑制剂的晶型、可药用盐，及其制备方法，药物组合物，以及其在制备用于治疗和/或预防KHK介导的疾病及相关疾病的药物中的应用。
背景技术
NAFLD/NASH是代谢综合征的肝脏表现。饮食以及生活方式的改变导致西方国家和许多亚洲国家肥胖和代谢综合征的流行，从而导致NAFLD的发病率显著增加，已成为颇受关注的公共健康问题之一。非酒精性脂肪肝炎(nonalcoholic steatohepatitis,NASH)是单纯性脂肪肝进一步发展的结果，其病理表现为脂质沉积、炎性细胞浸润、肝组织坏死和纤维化病变，进一步病变为更严重的肝硬化和肝细胞癌(HCC)。NAFLD不仅会影响患者的肝胆系统，还与胰岛素抵抗、血脂紊乱、动脉粥样硬化、脂肪栓塞、血液系统疾病等密切相关(Friedman SL等，Nat Med,2018,24:908-22)。因为代谢综合症的所有组分均与肝脏脂肪含量有关，所以存在代谢综合征的患者应该评估NAFLD风险。2型糖尿病患者伴随胰岛素抵抗、肥胖、血脂异常、肝脏酶学异常，有2型糖尿病风险的人群NAFLD的流行亦较高。
由于饮料和加工食品中糖添加(通常是蔗糖和高果糖玉米糖浆)不断增加，导致现代人饮食中果糖的含量增加。高果糖摄入已被证明会引起许多不良代谢作用，它在肥胖和代谢综合征的发展中具有一定的作用，如体重增加，高脂血症，高血压和胰岛素抵抗((a)Elliott SS,Keim NL,Stern JS,Teff K,Havel PJ.Fructose,weight gain,and the insulin resistance syn-drome.(b)Bray GA.Soft drink consumption and obesity:it is all about fructose.Current opinion in lipidology.2010；21(1):51–7.(c)The American journal of clinical nutrition.2002；76(5):911–22.and cardiovascular disease.The American journal of clinical nutrition.2007；86(4):899–906.)。果糖促进了NAFLD的发生、发展，加剧了NAFLD的发展和恶化(侍洪斌等，果糖与非酒精性脂肪肝的关联性研究，Medical Recapitulate 2017 23(9),1685-1689)。同时，高果糖摄入会增加NASH和进展期肝纤维化的风险(《2016年欧洲肝病学会、欧洲糖尿病学会和欧洲肥胖学会临床实践指南:非酒精性脂肪性肝病》)。不同于葡萄糖，果糖的代谢不受负反馈调控。果糖相对于其他碳水化合物优先代谢，其代谢产生各种反应和信号代谢物，促进代谢疾病进展。在没有KHK的情况下，果糖消耗引起的体重增加和胰岛素抵抗被阻断(George Marek,1 Varinderpal Pannu,1 Prashanth Shanmugham,1 Brianna Pancione,1 Dominic Mascia,1 Sean Crosson,1 Takuji Ishimoto,2 and Yuri Y.Sautin1；Adiponectin Resistance and Proinflammatory  Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via Ketohexokinase-Dependent Pathway；Diabetes 2015；64:508–518)。降低糖/HFCS(高果糖玉米糖浆)的摄入量和/或阻断尿酸的产生，有助于减少NAFLD及其肝硬化和慢性肝病的下游并发症(Thomas Jensen等，Fructose and Sugar:A Major Mediator of Nonalcoholic Fatty Liver Disease,J Hepatol.2018 May；68(5):1063–1075.)。同时，人类基因诱变导致基本的果糖糖尿症，是一种罕见的无害的异常，其特征在于在摄入含果糖的食物后尿液中出现果糖。T2D、肥胖及NAFLD/NASH及诸如心血管疾病及脑卒中等相关代谢类疾病的高患病率已导致对预防性保健及治疗性干预两者的需求增大。
己酮糖激酶(又称果糖激酶)为果糖代谢的基本酶。肝脏中KHK酶在ATP(三磷酸腺苷)的协助下磷酸化果糖C1位，产生果糖-1-磷酸(F1P)，进入正常代谢路径；同时ATP下游产生尿酸。两个替代性mRNA剪切体表达的人源性己酮糖激酶(hKHK)编码两个不同区域异构体酶KHK-A和KHK-C。KHK-C具有更低的Km值，更高的Kcat，高于405倍的催化效率，说明KHK-C对果糖磷酸化的亲和力和能力明显比KHK-A高。虽然KHK-A表达广泛，KHK-C分布于肝脏、肾脏、肠，但是KHK-C是体内果糖的主要代谢位点。
在人体内，葡萄糖通过多元醇通路经过中间体山梨糖醇转化为果糖，产生内源性果糖(Mingule A等，Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome,Nat Commun.2013；4:2434.)，并且此通路的活性随高血糖症增加。研究表明敲除KHK小鼠被保护免受葡萄糖诱导的体重增加、胰岛素抗性及脂肪变性，表明在高血糖病况下，内源性产生的果糖可促成胰岛素抗性及脂肪变性(Lanaspa,M.A等人，Nature Comm.4,2434,2013)。果糖是唯一在其代谢过程中产生尿酸的常见碳水化合物，同时果糖还会刺激氨基酸前体合成尿酸。因此，推测抑制KHK对其中涉及内源性或摄入果糖中的任一或两者的改变的许多疾病有益处。
肝果糖激酶缺乏症是果糖尿症的基础。与这种良性条件相反，醛缩酶B(果糖经KHK代谢途径中的下一种酶)的缺乏导致F1P在果糖摄入中的累积，并且可能导致细胞ATP的致死性消耗(遗传性果糖不耐受)。在果糖代谢路径中，紧接着KHK步骤下游负责分解F1P的酶为醛缩酶(ALDOB)，该酶的缺失导致遗传性果糖不耐受症(HFI)。在20000人中约有1人患病的罕见病症，该突变导致F1P积累、ATP损耗后尿酸形成增加，其组合造成低血糖症、高尿酸血症及乳酸性酸中毒，以及其他代谢紊乱。HFI阻断了果糖的下游代谢而导致急性症状，诸如呕吐、严重低血糖症、腹泻及腹痛，进而导致长期生长缺陷、肝及肾受损及潜在地死亡(Ali M等人，J.Med.Genet.1998年5月：35(5)；353-365)。患者在诊断之前通常经历 一年生存，且唯一治疗方式为避免饮食中的果糖。而体内葡萄糖经过多元醇通路转化为内源性果糖并在体内代谢，对这种治疗方式也是一种挑战。大部分食品中果糖的存在对饮食提出了挑战。除了物理症状，许多患者由于其不同寻常的饮食需面对情感及社会的孤立，同时需要严格遵守饮食限制(HFI-INFO Discussion Board,http；//hfiinfo.proboards.com.2015年12月14日访问)。此外，含有果糖、山梨糖醇或转化糖的输注还会危及患者生命。此病症有高度未满足的临床需求。
Figure PCTCN2021108515-appb-000001
晶型的研究在药物研发过程中发挥着重要的作用，同一药物的不同晶型在溶解度、稳定性、生物利用度等方面存在着显著的差异，为了更好地控制药物的质量，满足制剂、生产、运输等情况的要求，我们对式(1)化合物的晶型进行了研究，以期发现具有良好性质的晶型。
发明内容
本发明涉及式(1)所示的己酮糖激酶抑制剂2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁烷-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型。本发明还涉及晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型的制备方法，包含晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型的药物组合物，以及这些化合物的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型在制备用于预防和/或治疗KHK介导的疾病及相关疾病的药物中的应用。
本发明提供了一种式(1)化合物的晶型A，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在8.0±0.2°、9.4±0.2°、10.5±0.2°、12.7±0.2°、19.5±0.2°、21.2±0.2°处有特征峰：
Figure PCTCN2021108515-appb-000002
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式 (1)化合物的晶型A在包含上述特征峰的基础上，还在10.2±0.2°、13.6±0.2°、14.2±0.2°、15.8±0.2°、17.2±0.2°、25.3±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的晶型A在包含上述特征峰的基础上，还在6.9±0.2°、15.1±0.2°、16.6±0.2°、18.9±0.2°、22.0±0.2°、23.1±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的晶型A具有基本如图1所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的晶型A，其差示扫描量热分析图在大约167℃至173℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的晶型A，其差示扫描量热分析图在170℃±2℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的晶型A，其差示扫描量热分析图基本如图2所示。
在一些实施方案中，所述的式(1)化合物的晶型A，由热重分析所测定，其在200℃以下没有失重；在一些实施方案中，所述的式(1)化合物的晶型A，其具有基本如图3所示的热重分析图。
本发明提供了一种式(1)化合物的晶型B，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在6.4±0.2°、10.0±0.2°、12.7±0.2°、15.5±0.2°、17.6±0.2°、22.0±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的晶型B在包含上述特征峰的基础上，还在8.3±0.2°、16.5±0.2°、17.7±0.2°、20.6±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的晶型B具有基本如图4所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的晶型B，其差示扫描量热分析图在大约167℃至173℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的晶型B，其差示扫描量热分析图在169℃±2℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的晶型B，其差示扫描量热分析图基本如图5所示。
在一些实施方案中，所述的式(1)化合物的晶型B，由热重分析所测定，其在200℃以下没有失重；在一些实施方案中，所述的式(1)化合物的晶型B，其具有基本如图6所示的热重分析图。
本发明提供了一种式(1)化合物的晶型C，使用Cu-Kα辐射，以2θ角度表示的X-射线 粉末衍射，在8.5±0.2°、9.9±0.2°、10.7±0.2°、18.5±0.2°处有特征峰：
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的晶型C在包含上述特征峰的基础上，还在13.0±0.2°、13.4±0.2°、13.8±0.2°、16.8±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的晶型C在包含上述特征峰的基础上，还在19.2±0.2°、20.7±0.2°、21.1±0.2°、22.1±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的晶型C具有基本如图7所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的晶型C，其差示扫描量热分析图在大约170℃至175℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的晶型C，其差示扫描量热分析图在172℃±2℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的晶型C，其差示扫描量热分析图基本如图8所示。
在一些实施方案中，所述的式(1)化合物的晶型C，由热重分析所测定，其在200℃以下没有失重；在一些实施方案中，所述的式(1)化合物的晶型C，其具有基本如图9所示的热重分析图。
本发明提供了一种式(1)化合物的晶型D，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在6.4±0.2°、10.0±0.2°、12.7±0.2°、17.7±0.2°、18.6±0.2°、25.5±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的晶型D在包含上述特征峰的基础上，还在14.9±0.2°、15.6±0.2°、20.6±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的晶型D在包含上述特征峰的基础上，还在8.3±0.2°、16.5±0.2°、19.1±0.2°、20.2±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的晶型D具有如图10所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的晶型D，其差示扫描量热分析图在大约165℃至170℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的晶型D，其差示扫描量热分析图在167℃±2℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的晶型D，其差示扫描量热分析图基本如图11所示。
在一些实施方案中，所述的式(1)化合物的晶型D，由热重分析所测定，其在200℃以下没有失重；在一些实施方案中，所述的式(1)化合物的晶型D，其具有基本如图12所示的热重分析图。
本发明还提供了一种式(1)化合物的可药用的盐，所述的可药用的盐选自式(1)化合物与无机碱或有机碱形成的碱加成盐。
在一些实施方案中，所述的碱加成盐选自钾盐、钠盐、锂盐、镁盐或钙盐。
在一些实施方案中，所述的无机碱选自碳酸钾、碳酸钠、碳酸镁、碳酸钙、碳酸氢钠、碳酸氢钾、碳酸氢镁、碳酸氢钙、氢氧化钾、氢氧化钠、氢氧化锂、氢氧化镁或氢氧化钙。
在一些实施方案中，所述的有机碱选自甲醇钠、乙醇钾、乙酸钾、叔丁醇钾或叔丁醇钠。在一些实施方案中，所述的钾盐的晶型I，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在4.8±0.2°、5.9±0.2°、7.1±0.2°、8.3±0.2°、11.8±0.2°、15.5±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的钾盐晶型I在包含上述特征峰的基础上，还在14.6±0.2°、16.6±0.2°、17.9±0.2°、18.8±0.2°、19.6±0.2°、21.5±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的钾盐晶型I在包含上述特征峰的基础上，还在13.0±0.2°、14.2±0.2°、23.3±0.2°、25.0±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的钾盐晶型I具有基本如图13所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的钾盐晶型I，其差示扫描量热分析图在大约174℃至180℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的钾盐的晶型I，其差示扫描量热分析图在176℃±2℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的钾盐的晶型I，其差示扫描量热分析图基本如图14所示。
在一些实施方案中，所述的式(1)化合物的钾盐晶型I，由热重分析所测定，其在100℃以下有失重；在一些实施方案中，所述的式(1)化合物的钾盐晶型I，其具有基本如图15所示的热重分析图。
在一些实施方案中，所述的钾盐的晶型II，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在4.7±0.2°、6.5±0.2°、7.9±0.2°、10.3±0.2°、11.0±0.2°、12.1±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的钾盐晶型II在包含上述特征峰的基础上，还在5.1±0.2°、13.0±0.2°、20.1±0.2°、 21.4±0.2°、22.4±0.2°、24.1±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的钾盐晶型II在包含上述特征峰的基础上，还在8.3±0.2°、17.6±0.2°、19.5±0.2°、20.6±0.2°、21.1±0.2°、24.5±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的钾盐晶型II具有基本如图16所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的钾盐晶型II，其差示扫描量热分析图在大约155℃至165℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的钾盐晶型II，其差示扫描量热分析图在160℃±2℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的钾盐晶型II，其差示扫描量热分析图基本如图17所示。
在一些实施方案中，所述的式(1)化合物的钾盐晶型II，由热重分析所测定，其在200℃以下有失重在一些实施方案中，所述的式(1)化合物的钾盐晶型II，其具有基本如图17-1所示的热重分析图。
在一些实施方案中，所述镁盐的晶型，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在18.8±0.2°、23.8±0.2°、26.3±0.2°、29.5±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的镁盐晶型在包含上述特征峰的基础上，还在23.0±0.2°、25.9±0.2°、31.5±0.2°、32.0±0.2°、38.1±0.2°、39.0±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的镁盐晶型具有基本如图18所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的镁盐晶型，其差示扫描量热分析图在大约165℃至180℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的镁盐晶型，其差示扫描量热分析图在170℃±2℃范围内具有吸热峰；在一些实施方案中，所述的式(1)化合物的镁盐晶型，其差示扫描量热分析图基本如图19所示。
在一些实施方案中，所述钙盐的晶型I，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在15.8±0.2°、16.1±0.2°、26.3±0.2°、28.0±0.2°、30.2±0.2°、31.2±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的钙盐晶型I具有基本如图20所示的X-射线粉末衍射图。
在一些实施方案中，所述钙盐的晶型II，其使用Cu-Kα辐射，以2θ角度表示的X-射线 粉末衍射，在3.9±0.2°、6.0±0.2°、8.1±0.2°、11.1±0.2°、16.0±0.2°、17.4±0.2°、19.0±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的钙盐晶型II具有基本如图21所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的钙盐晶型II，其差示扫描量热分析图基本如图22所示。
在一些实施方案中，所述的式(1)化合物的钙盐晶型II，由热重分析所测定，其在250℃以下有失重；在一些实施方案中，所述的式(1)化合物的钙盐晶型II，其具有基本如图23所示的热重分析图。
在一些实施方案中，所述钠盐的晶型I，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在3.9±0.2°、4.5±0.2°、7.8±0.2°、9.1±0.2°、11.8±0.2°、12.7±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的钠盐晶型I在包含上述特征峰的基础上，还在8.5±0.2°、10.5±0.2°、14.2±0.2°、16.8±0.2°、17.9±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，所述的式(1)化合物的钠盐晶型I在包含上述特征峰的基础上，还在18.6±0.2°、20.4±0.2°、30.5±0.2°、34.7±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，所述的式(1)化合物的钠盐晶型I具有基本如图24所示的X-射线粉末衍射图。
在一些实施方案中，所述的式(1)化合物的钠盐晶型I，其差示扫描量热分析图基本如图25所示。
在一些实施方案中，所述的式(1)化合物的钠盐晶型I，由热重分析所测定，其在200℃以下有失重；
在一些实施方案中，所述的式(1)化合物的钠盐晶型I，其具有基本如图26所示的热重分析图。
本发明还提供式(1)化合物的晶型A的制备方法。
将式(1)化合物与有机溶剂一(作为溶剂)混合，加热至第一温度，降温至35℃以下，过滤，干燥而得到所述式(1)化合物的晶型A。
在一些实施方案中，式(1)化合物的晶型A的制备方法还包括在降温至35℃以下之后， 进一步滴加另一种溶剂，过滤，干燥而得到所述化合物的晶型A。
在一些实施方案中，所述的另一种溶剂为醚类溶剂，选自乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环。
在一些实施方案中，所述的第一温度选自40℃-95℃，例如50℃-70℃，例如50℃-80℃，例如50℃-90℃，例如60℃-70℃，例如60℃-80℃，例如60℃-90℃，例如70℃-80℃，例如70℃-90℃，例如65℃-95℃，例如65℃-90℃，例如65℃-75℃，例如85℃-95℃，在一些实施方案中，所述的第一温度是指加热至溶液溶清时的温度。
在一些实施方案中，所述的有机溶剂一为酯类溶剂。
在一些实施方案中，所述酯类溶剂为脂肪酯类溶剂。
在一些实施方案中，所述脂肪酯类溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯中的一种或者两种以上溶剂的任意组合。
在一些实施方案中，所述脂肪酯类溶剂选自甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丙酯、乙酸丁酯、乙酸异丁酯中的一种或者两种以上溶剂的任意组合。
所述“两种以上溶剂的任意组合”是指上述有机溶剂一按照一定比例混合形成的溶剂。包括但不限于以下具体实例：乙酸乙酯/甲酸甲酯、乙酸乙酯/甲酸乙酯、乙酸乙酯/甲酸丙酯、乙酸乙酯/乙酸甲酯、乙酸乙酯/乙酸丙酯、乙酸乙酯/乙酸异丙酯、乙酸乙酯/乙酸异丁酯、甲酸乙酯/乙酸甲酯、甲酸乙酯/乙酸丙酯、甲酸乙酯/乙酸异丙酯、乙酸甲酯/乙酸丙酯、乙酸甲酯/乙酸异丙酯等。
在一些实施方案中，所述的式(1)化合物与所述的有机溶剂一的重量比为1:6-1:12，例如1:7-1:12，例如1:8-1:12，例如1:9-1:12，例如1:10-1:12，例如1:11-1:12，例如1:7-1:11，例如1:8-1:11，例如1:9-1:11，例如1:10-1:11，例如1:7-1:10，例如1:8-1:10，例如1:8-1:9，例如1:8、1:9、1:10、1:11、1:12等。
在一些实施方案中，所述的“35℃以下”为5℃-35℃，例如10℃-35℃，例如10℃-30℃，例如10℃-25℃。
在一些实施方案中，式(1)化合物的晶型A的制备方法可以表述为：
将式(1)化合物与酯类溶剂混合，加热至料液温度60℃-90℃，降温至10℃-35℃，过滤，干燥而得到所述化合物的晶型A。
在一些实施方案中，式(1)化合物的晶型A的制备方法可以表述为：
将式(1)化合物与酯类溶剂混合，加热至料液温度60℃-90℃，降温至10℃-35℃，加 入异丙醚，搅拌，过滤，干燥而得到所述化合物的晶型A。
本发明还提供式(1)化合物的晶型B的制备方法。
将式(1)化合物与有机溶剂二(作为溶剂)混合，搅拌，加热至第二温度，降温至10℃-30℃，过滤，干燥而得到所述式(1)化合物的晶型B。
在一些实施方案中，所述的有机溶剂二为醇类溶剂。
在一些实施方案中，所述醇类溶剂选自脂肪醇类溶剂、脂环醇类溶剂及芳香醇类溶剂中的一种或者两种以上溶剂的任意组合。
在一些实施方案中，所述脂肪醇类溶剂选自乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正戊醇、正己醇、乙二醇、丙二醇或丙三醇。
在一些实施方案中，所述的脂肪醇类溶剂选自乙醇、正丙醇、异丙醇、异丁醇、正戊醇。
在一些实施方案中，所述的脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇或环己乙醇。
在一些实施方案中，所述芳香醇类溶剂选自苯甲醇、苯乙醇或苯丙醇。
所述“两种以上溶剂的任意组合”是指上述有机溶剂二按照一定比例混合形成的溶剂。包括但不限于以下具体实例：乙醇/丙醇、乙醇/异丙醇、乙醇/正丁醇、乙醇/异丁醇、乙醇/叔丁醇、乙醇/正戊醇、乙醇/环戊醇、乙醇/苯甲醇、乙醇/叔丁醇等。
在一些实施方案中，所述的式(1)化合物与所述的有机溶剂二的重量比为1:7-1:13，例如1:8-1:13，例如1:9-1:13，例如1:10-1:13，例如1:11-1:13，例如1:12-1:13，例如1:7-1:12，例如1:8-1:12，例如1:9-1:12，例如1:10-1:12，例如1:11-1:12，例如1:7-1:11，例如1:8-1:11，例如1:9-1:11，例如1:10-1:11，例如1:7-1:10，例如1:8-1:10，例如1:8-1:9，例如1:8、1:9、1:10、1:11、1:12等。
在一些实施方案中，所述的第二温度选自40℃-80℃，例如50℃-60℃，例如50℃-70℃，例如50℃-80℃，例如60℃-70℃，例如60℃-80℃，例如70℃-80℃，例如55℃-65℃，例如60℃-65℃，在一些实施方案中，所述的第二温度是指加热至溶液溶清时的温度。
在一些实施方案中，所述的降温是指通过空气浴搅拌降温、自然降温等。
在一些实施方案中，所述的空气浴的温度为20℃-30℃，例如25℃-30℃，例如26℃-30℃，例如27℃-30℃，例如28℃-30℃，例如29℃-30℃。
本发明还提供式(1)化合物的晶型C的制备方法。
将式(1)化合物与有机溶剂三(作为溶剂)混合，加热至第三温度，降温10h-25h，过滤，干燥，转入100℃-140℃烘箱1-5h，得到所述式(1)化合物的晶型C。
在一些实施方案中，所述的有机溶剂三是指甲醇。
在一些实施方案中，所述的式(1)化合物与所述的有机溶剂三的重量比为1:2-1:8，例如1:3-1:8，例如1:4-1:8，例如1:5-1:8，例如1:6-1:8，例如1:7-1:8，例如1:2-1:7，例如1:3-1:7，例如1:4-1:7，例如1:5-1:7，例如1:6-1:7，例如1:2-1:6，例如1:3-1:6，例如1:4-1:6，例如1:5-1:6，例如1:2-1:5，例如1:3-1:5，例如1:4-1:5，例如1:2-1:4，例如1:3-1:4，例如1:2-1:3，例如1:4、1:5、1:6、1:7等。
在一些实施方案中，所述的第三温度选自40℃-80℃，例如50℃-60℃，例如50℃-70℃，例如50℃-80℃，例如60℃-70℃，例如60℃-80℃，例如70℃-80℃，例如50℃-65℃，例如55℃-60℃，例如60℃-65℃，在一些实施方案中，所述的第三温度是指加热至溶液溶清时的温度。
在一些实施方案中，晶型C的制备方法可以表述为：
将式(1)化合物与甲醇混合，加热至50℃-65℃，降温15h-20h，过滤，干燥，转入120℃-130℃烘箱1-3h，得到所述式(1)化合物的晶型C。
本发明还提供式(1)化合物的晶型D的制备方法。
将式(1)化合物与有机溶剂四(作为溶剂)混合，溶解后加水，过滤，得固体，加入有机溶剂五，加热回流10-25h，优选15-25h，过滤，干燥，得到所述式(1)化合物的晶型D。
在一些实施方案中，所述有机溶剂四为至少与水微溶的有机溶剂，例如与水互溶的有机溶剂。
在一些实施方案中，有机溶剂四为醇类溶剂。
在一些实施方案中，所述醇类溶剂选自脂肪醇类溶剂、脂环醇类溶剂及芳香醇类溶剂中的一种或者两种以上溶剂的任意组合。
在一些实施方案中，所述脂肪醇类溶剂选自乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正戊醇、正己醇、乙二醇、丙二醇或丙三醇。
在一些实施方案中，所述的脂肪醇类溶剂选自乙醇、正丙醇、异丙醇、异丁醇、正戊醇。
在一些实施方案中，所述的脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇或环己乙醇。
在一些实施方案中，所述芳香醇类溶剂选自苯甲醇、苯乙醇或苯丙醇。
在一些实施方案中，有机溶剂四与水的体积比选自1:6-6:1，例如1:5-5:1，例如1:4-4:1，例如1:3-3:1，例如1:2-2:1，例如4:5-5:4，例如1:2，例如1:1，例如3:2，例如3:4，例如3:5，例如4:3，例如4:5，例如2:3，例如5:3，例如5:4，例如5:6，例如5:7，例如5:8，例如5:9，例如6:5，例如6:7，例如6:10，例如6:11，例如7:4，例如7:5，例如7:6，例如7:8，例如7:9， 例如7:10，例如7:11，例如7:12，例如7:13，例如8:5，例如8:7，例如8:9，例如8:11，例如8:13，例如8:14，例如8:15，例如9:5，例如9:7，例如9:8，例如9:10，例如9:11，例如9:13，例如9:14，例如9:16，例如9:17。
在一些实施方案中，式(1)化合物与有机溶剂四的重量比为1:7-1:13，例如1:8-1:13，例如1:9-1:13，例如1:10-1:13，例如1:11-1:13，例如1:12-1:13，例如1:8-1:12，例如1:9-1:12，例如1:10-1:12，例如1:11-1:12，例如1:8-1:11，例如1:9-1:11，例如1:10-1:11，例如1:8-1:10，例如1:9-1:10，例如1:8-1:9，例如1:5，例如1:6，例如1:7，例如1:8，例如1:9，例如1:10，例如1:11，例如1:12，例如1:13，例如1:14，例如1:15。
在一些实施方案中，有机溶剂五为醚类溶剂，选自乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环。在一些实施方案中，在制备晶型A、晶型B、晶型C或晶型D的方法中所述的过滤可以通过抽滤的方法来进行。
在一些实施方案中，在制备晶型A、晶型B、晶型C或晶型D的过程中还包括搅拌的步骤。在一些实施方案中，搅拌为机械搅拌或者人工搅拌。在一些实施方案中，搅拌为机械搅拌。
在一些实施方案中，上述制备晶型A、晶型B、晶型C或晶型D的方法所述的干燥可通过减压干燥、烘箱烘干、自然晾干或者通风干燥来进行，干燥温度不超过60℃，例如30℃-55℃，例如35℃-50℃。
在一些实施方案中，还包括在降温过程中分别加入该晶型A、晶型B、晶型C或晶型D的晶种的步骤，以利于各晶型的形成和析出，所述的各晶型的晶种是通过本申请文件中不加晶种制备各晶型的方法制备所得的。
本发明还提供式(1)化合物的可药用盐的制备方法：
将式(1)化合物与无机碱在反应溶剂A中进行反应。
在某些实施方案中，所述的无机碱选自碳酸钾、碳酸钠、碳酸镁、碳酸钙、碳酸氢钾、碳酸氢钠、碳酸氢镁、碳酸氢钙、氢氧化钾、氢氧化钠、氢氧化锂、氢氧化镁或氢氧化钙。
在某些实施方案中，式(1)化合物的可药用盐选自式(1)化合物的钾盐、钠盐、锂盐、镁盐、钙盐。
在某些实施方案中，所述的反应溶剂A选自醇类溶剂、酮类溶剂、腈类溶剂或酯类溶剂中的一种或者两种以上溶剂的任意组合。
在某些实施方案中，所述醇类溶剂选自脂肪醇类溶剂、脂环醇类溶剂及芳香醇类溶剂中的一种或者两种以上溶剂的任意组合；优选地，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正戊醇、正己醇、乙二醇、丙二醇或丙三醇； 更优选地，所述的脂肪醇类溶剂选自甲醇、乙醇、正丙醇、异丙醇、异丁醇或正戊醇；优选地，所述的脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇或环己乙醇；优选地，所述芳香醇类溶剂选自苯甲醇、苯乙醇或苯丙醇；
在某些实施方案中，所述的酮类溶剂选自丙酮。
在某些实施方案中，所述的腈类溶剂选自乙腈。
在某些实施方案中，所述酯类溶剂为脂肪酯类溶剂；优选地，所述脂肪酯类溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯中的一种或者两种以上溶剂的任意组合；进一步优选地，所述脂肪酯类溶剂选自甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丙酯、乙酸丁酯、乙酸异丁酯中的一种或者两种以上溶剂的任意组合；
本发明还提供了式(1)化合物钾盐晶型的制备方法：
将式(1)化合物与钾盐在反应溶剂B中进行反应。
在某些实施方案中，所述的钾盐选自碳酸钾、碳酸氢钾或氢氧化钾。
在某些实施方案中，所述的反应溶剂B选自醇类溶剂。
在某些实施方案中，所述醇类溶剂选自脂肪醇类溶剂、脂环醇类溶剂及芳香醇类溶剂中的一种或者两种以上溶剂的任意组合。
在某些实施方案中，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正戊醇、正己醇、乙二醇、丙二醇或丙三醇中的一种或者两种以上溶剂的任意组合。
在某些实施方案中，所述的脂肪醇类溶剂选自甲醇、乙醇、正丙醇、异丙醇、异丁醇、正戊醇中的一种或者两种以上溶剂的任意组合。
在一些实施方案中，所述的脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇或环己乙醇。
在一些实施方案中，所述芳香醇类溶剂选自苯甲醇、苯乙醇或苯丙醇。
为了分析所获得的结晶，通常采用X射线衍射结晶分析方法。
用X-射线粉末衍射测定本发明的晶型时，有时由于测定的仪器或测定的条件，对于测得的峰而言会稍有测定误差，在误差范围内的光谱峰的结晶也涵盖在本发明的结晶中。因此在确定结晶结构时，应该将此误差考虑在内，因此本申请人在确定2θ角度时考虑了误差范围在±0.2°之内。另外，特定结晶形式的不同样品的X射线粉末衍射(XRPD)主峰是相同的，但次峰可以变化。
本发明还提供了一种药物组合物，其含有前述式(1)化合物的晶型A、晶型B、晶型C、晶型D或可药用盐及其晶型，及一种或多种第二治疗剂，任选地，所述药物组合物还包含一种或多种药用载体和/或稀释剂。
本发明还提供了一种药物制剂，其含有前述式(1)化合物的晶型A、晶型B、晶型C、晶型D或可药用盐及其晶型，及一种或多种药用载体和/或稀释剂；所述药物制剂为临床上或药学上可接受的任一剂型。
在本发明的一些实施方式中，上述药物制剂以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
本发明还提供治疗和/或预防KHK介导的疾病及相关疾病的方法，其包括向需要此治疗的患者给予有效量的2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁烷-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸的晶型A、晶型B、晶型C、晶型D或可药用盐及其晶型。
在一个实施方案中，KHK介导的疾病及相关疾病选自内分泌失调病、泌尿类疾病、代谢类疾病、非酒精性脂肪肝炎、肝硬化、脂肪肝、肝炎、肝脏衰竭、遗传性果糖不耐受症、非酒精性脂肪肝病、肝胆类疾病、纤维化疾病、心脑血管类疾病、免疫炎症类疾病、中枢神经类疾病、胃肠道类疾病和过度增殖性疾病诸如癌症。
本发明还提供式(1)化合物的晶型A、晶型B、晶型C、晶型D或可药用盐及其晶型在制备用于治疗和/或预防KHK介导的疾病及相关疾病的药物中的用途。
在一个实施方案中，KHK介导的疾病及相关疾病选自内分泌失调病、泌尿类疾病、代谢类疾病、非酒精性脂肪肝炎、肝硬化、脂肪肝、肝炎、肝脏衰竭、遗传性果糖不耐受症、非酒精性脂肪肝病、肝胆类疾病、纤维化疾病、心脑血管类疾病、免疫炎症类疾病、中枢神经类疾病、胃肠道类疾病和过度增殖性疾病诸如癌症。
本发明还提供了式(1)化合物的晶型A、晶型B、晶型C、晶型D或可药用盐及其晶型，用于治疗和/或预防KHK介导的疾病及相关疾病。
在一个实施方案中，KHK介导的疾病及相关疾病选自内分泌失调病、泌尿类疾病、代谢类疾病、非酒精性脂肪肝炎、肝硬化、脂肪肝、肝炎、肝脏衰竭、遗传性果糖不耐受症、非酒精性脂肪肝病、肝胆类疾病、纤维化疾病、心脑血管类疾病、免疫炎症类疾病、中枢神经类疾病、胃肠道类疾病和过度增殖性疾病诸如癌症。
本发明还提供式(1)化合物的晶型A、晶型B、晶型C、晶型D或可药用盐及其晶型与一种或多种其他药物的组合物，可将这些其他药物与式(1)化合物的晶型A、晶型B、晶型C、晶型D或可药用盐及其晶型同时或相继给药，用于治疗和/或预防KHK介导的疾病及相关疾病。
在一个实施方案中，KHK介导的疾病及相关疾病选自内分泌失调病、泌尿类疾病、代谢类疾病、非酒精性脂肪肝炎、肝硬化、脂肪肝、肝炎、肝脏衰竭、遗传性果糖不耐受症、非酒精性脂肪肝病、肝胆类疾病、纤维化疾病、心脑血管类疾病、免疫炎症类疾病、中枢神经类疾病、胃肠道类疾病和过度增殖性疾病诸如癌症。
在本公开中除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。同时，为了更好地理解本发明，下面提供部分术语的定义和解释。
本文中所述的“有效量”是指足以实现所需治疗或预防效果的量，例如，实现减轻与待治疗疾病相关的症状的量。
本文中所述的“治疗”是指减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的所述晶型或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
本发明式(1)化合物的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型的主要优点包括：
(1)本发明提供的化合物2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁烷-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型的制备方法操作简便，适合工业化生产；
(2)本发明提供的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型具有良好的性状，便于检测、制剂、运输和储藏；
(3)本发明提供的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型的纯度高、残留溶剂少，溶解度较高，稳定性好，质量易控；
(4)本发明提供的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型具有优异的生物利用度；
(5)本发明提供的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型对KHK激酶均具有良好的抑制作用，可用于治疗和/或预防KHK介导的疾病及相关疾病。
附图说明
图1是式(1)化合物的晶型A的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图2是式(1)化合物的晶型A的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图3是式(1)化合物的晶型A的热重分析(TG)曲线和微商热重分析(DTG)曲线，横坐标为温度(℃)，左侧纵坐标表示重量(％)，右侧纵坐标表示失重速率(％)与温度的关系。
图4是式(1)化合物的晶型B的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图5是式(1)化合物的晶型B的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图6是式(1)化合物的晶型B的热重分析(TG)曲线和微商热重分析(DTG)曲线，横坐标为温度(℃)，左侧纵坐标表示重量(％)，右侧纵坐标表示失重速率(％)与温度的关系。
图7是式(1)化合物的晶型C的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图8是式(1)化合物的晶型C的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图9是式(1)化合物的晶型C的热重分析(TG)曲线和微商热重分析(DTG)曲线，横坐标为温度(℃)，左侧纵坐标表示重量(％)，右侧纵坐标表示失重速率(％)与温度的关系。
图10是式(1)化合物的晶型D的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图11是式(1)化合物的晶型D的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图12是式(1)化合物的晶型D的热重分析(TG)曲线和微商热重分析(DTG)曲线，横坐标为温度(℃)，左侧纵坐标表示重量(％)，右侧纵坐标表示失重速率(％)与温度的关系。
图13是式(1)化合物的钾盐晶型I的X-射线粉末衍射图谱，纵坐标表示衍射强度 (intensity)，横坐标表示衍射角度(2θ)。
图14是式(1)化合物的钾盐晶型I的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图15是式(1)化合物的钾盐晶型I的热重分析(TG)曲线和微商热重分析(DTG)曲线，横坐标为温度(℃)，左侧纵坐标表示重量(％)，右侧纵坐标表示失重速率(％)与温度的关系。
图16是式(1)化合物的钾盐晶型II的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图17是式(1)化合物的钾盐晶型II的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图17-1是式(1)化合物的钾盐晶型II的热重分析(TG)曲线，横坐标为温度(℃)，纵坐标表示重量(％)。
图18是式(1)化合物的镁盐晶型的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图19是式(1)化合物的镁盐晶型的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图20是式(1)化合物的钙盐晶型I的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图21是式(1)化合物的钙盐晶型II的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图22是式(1)化合物的钙盐晶型II的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图23是式(1)化合物的钙盐晶型II的热重分析(TG)曲线，横坐标为温度(℃)，纵坐标表示重量(％)。
图24是式(1)化合物的钠盐晶型I的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图25是式(1)化合物的钠盐晶型I的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图26是式(1)化合物的钠盐晶型I的热重分析(TG)曲线，横坐标为温度(℃)，纵坐标表示重量(％)。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
下述缩写所代表的定义如下：
DMSO：二甲基亚砜；PE：石油醚；EA：乙酸乙酯；DAST：二乙胺基三氟化硫；
NMP：N-甲基吡咯烷酮；DBN：1,5-二氮杂双环[4.3.0]壬-5-烯；
THF：四氢呋喃；DIEA：N,N-二异丙基乙胺；IPAc：乙酸异丙酯
制备例
(1)1-乙基2,4-二甲基1-氧代丁烷-1,2,4-三羧酸酯的制备
Figure PCTCN2021108515-appb-000003
将金属钠(4.3g,186.9mmol)加入到乙醇(200mL)中，完全溶解后，旋干，悬浮于四氢呋喃(200mL)中，将草酸二乙酯(27.4g,187.5mmol)缓慢加入到溶液中，随后加入戊二酸二甲酯(30.0g,187.3mmol)，25℃下反应16小时，TLC检测反应(Rf＝0.5,PE:EA＝1:1)，旋干，加入水(300mL)和甲基叔丁基醚(200mL)，分液，水相调节pH＝1，3×200ml乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，旋干，剩余物直接用于下一步。
(2)2-氧代己二酸的制备
Figure PCTCN2021108515-appb-000004
将1-乙基2,4-二甲基1-氧代丁烷-1,2,4-三羧酸酯(上步粗品)加入到4N盐酸(230mL,920mmol)中，加热至65℃，6小时，旋干，得到化合物21.0g，两步产率：70.0％。
(3)6-甲氧基-5,6-二氧代己酸的制备
Figure PCTCN2021108515-appb-000005
0℃下，将2-氧代己二酸(10.0g,62.5mmol)加入到DBN(9.3g,74.9mmol)的丙酮(100mL)溶液中，逐滴加入硫酸二甲酯(7.9g,62.6mmol)，25℃，16小时，旋干，加入水(50mL)， 调节pH＝2-3，3×100ml乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，旋干，剩余物直接用于下一步。
(4)2-氧代己二酸二甲酯的制备
Figure PCTCN2021108515-appb-000006
将6-甲氧基-5,6-二氧代己酸(上步粗品)溶于二氯甲烷(100mL)中，加入2滴N,N-二甲基甲酰胺，0℃，加入草酰氯(15.9g,125.2mmol)，25℃，16小时，旋干，0℃，将甲醇(40mL)加入到剩余物中，25℃，2小时，旋干，剩余物柱层析(PE:EA＝5:1)得产物(7.9g,两步产率：66.9％)。
(5)2,2-二氟己二酸二甲酯的制备
Figure PCTCN2021108515-appb-000007
2-氧代己二酸二甲酯(4.8g,25.5mmol)溶于氯仿(50mL)加入到DAST中，25℃反应48小时，加入水淬灭反应，3×100ml乙酸乙酯萃取，合并有机相，浓缩，柱层析(乙酸乙酯：石油醚＝1:3)得产物(2.0g,37.0％)。
(6)3,3-二氟-2-氧代环戊烷-1-羧酸甲酯的制备
Figure PCTCN2021108515-appb-000008
氢化钠(60％)(0.57g,14.2mmol)溶于THF(40mL)中，加入2,2-二氟己二酸二甲酯(2.0g,9.5mmol)的THF溶液(10mL)，20℃反应16小时，加入水淬灭反应，调节pH＝5-6，3×100ml乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，直接用于下一步(产物1.6g，产率：94.1％)。
(7)7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-醇的制备
Figure PCTCN2021108515-appb-000009
3,3-二氟-2-氧代环戊烷-1-羧酸甲酯(2.4g,13.5mmol)溶于水中(40mL)，加入甲基异 硫脲硫酸盐(3.8g,20.2mmol)，碳酸钠(2.85g,26.9mmol)，25℃反应16小时，用1N盐酸调pH＝2，3×100ml乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得2.4g粗品直接用于下步反应。
(8)4-氯-7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊二烯并[d]嘧啶的制备
Figure PCTCN2021108515-appb-000010
7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-醇(2.4g粗品)、溶于三氯氧磷(5mL)/1,2-二氯乙烷(10mL)中，110℃反应16h，浓缩，饱和碳酸氢钠调节pH＝7-8，3×80ml乙酸乙酯萃取，合并有机相，浓缩，柱层析(乙酸乙酯：石油醚＝1:10)，得化合物1.4g，两步产率：43.8％。
(9)2-((1R,5S,6s)-3-(7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸甲酯的制备
Figure PCTCN2021108515-appb-000011
4-氯-7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊二烯并[d]嘧啶(200mg,0.84mmol)溶于NMP(5mL)中，加入2-((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)乙酸甲酯(160mg,1.03mmol)，碳酸钾(260mg,1.88mmol)，90℃反应16小时，加入水，3×50ml乙酸乙酯萃取，合并有机相，浓缩，粗品直接用于下一步。
(10)2-((1R,5S,6s)-3-(7,7-二氟-2-(甲基磺酰基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸甲酯的制备
Figure PCTCN2021108515-appb-000012
2-((1R,5S,6s)-3-(7,7-二氟-2-(甲硫基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸甲酯(上步粗品)溶于二氯甲烷(10mL)中，加入间氯过氧苯甲酸(80％)(400mg,1.85mmol)，20℃反应3小时。加入饱和碳酸钠溶液，分液，水相用2×30ml二氯甲烷萃取，合并有机相，旋干，柱层析(乙酸乙酯：石油醚＝3:1)，得化合物160mg， 两步产率：48.6％。
(11)2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁烷-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸甲酯的制备
Figure PCTCN2021108515-appb-000013
2-((1R,5S,6s)-3-(7,7-二氟-2-(甲基磺酰基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸甲酯(100mg,0.26mmol)，溶于NMP(3mL)，加入DIEA(0.5ml)，(S)-2-甲基氮杂环丁烷三氟乙酸盐(107mg,0.58mmol)，160℃微波反应2小时，加入水，2×30ml乙酸乙酯萃取，合并有机相，旋干，柱层析(乙酸乙酯：石油醚＝1:1)，得化合物60mg，产率：61.4％。
(12)2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁烷-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸的制备(式(1)化合物的制备)
方法一：
Figure PCTCN2021108515-appb-000014
2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁烷-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己-6-基)乙酸甲酯(60mg,0.16mmol)，溶于MeOH/THF/H 2O(3/3/3mL)中，加入NaOH(26mg,0.65mmol)，25℃反应3小时。用1N盐酸调节pH＝5，浓缩，柱层析(ACN/H 2O＝40:60)得到式(1)化合物(38mg,65.8％)。分子式：C 18H 22F 2N 4O 2分子量：364.4LC-MS(M/e)：365.0(M+H +) 1HNMR(400MHz,MeOD):δ:4.38-4.43(m,1H),3.98-4.05(m,3H),3.84-3.91(m,1H),3.61-3.68(m,2H),3.04-3.09(m,2H),2.31-2.48(m,3H),2.30(d,J＝7.2Hz,2H),1.90-1.96(m,1H),1.56(s,2H),1.48(d,J＝6.4Hz,3H),0.85-0.89(m,1H)。
方法二：
向2L三口瓶中加入水(150ml)，氢氧化锂一水合物(33.3g,0.792mol)和甲醇(1.35L)，搅拌稀释后加入2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁烷-1-基)-6,7-二氢-5H-环戊二烯 并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己烷-6-基)乙酸甲酯(150g,0.396mol)，搅拌分散，升温至35℃反应2-3小时。旋蒸浓缩除去溶剂，所得剩余物加水(1500ml)搅拌溶解，加入二氯甲烷(200ml×2)萃取，所得水相40℃旋转蒸发除去残留溶剂，用2N盐酸调节pH至4.4-5.0，析出大量固体，过滤，水(2L)淋洗，晾干得141.3g固体，收率97.8％。
1HNMR(400MHz,DMSO):δ:12.08(s,br,1H),4.24-4.29(m,1H),3.75-3.88(m,4H),3.59(s,2H),2.99-3.02(m,2H),2.20-2.38(m,3H),2.21(d,J＝7.2Hz,2H),1.86-1.88(m,1H),1.52(s,2H),1.40(d,J＝6.0Hz,3H),0.74-0.77(m,1H)。
实施例1：晶型A的制备
方法一：
取上述制备例第(12)步方法二固体20.8g，加入500ml三口圆底烧瓶，加入乙酸乙酯210ml，开启搅拌，升温至料液温度70℃，体系澄清固体全溶，关闭油浴加热，自然降温至10-25℃，过滤，晾干，得到固体12.6g，收率60.6％。
方法二：
取上述通过制备例第(12)步方法二所得到的固体10.0g，加入250ml三口圆底烧瓶，加入乙酸异丙酯100ml，开启搅拌，升温至料液温度89℃，回流，体系澄清固体全溶，缓慢降温至35℃以下，关闭油浴加热，20-30℃滴加入异丙醚50ml，继续搅拌16h，T＝11℃下过滤，50℃下烘干，得到固体8.12g。
实施例2：晶型B的制备
取上述制备例第(12)步方法二固体22.6g，加入500ml三口瓶，加入乙醇230ml搅拌分散，升温，T＝63℃时体系澄清，固体溶解。转移至27.6℃空气浴搅拌降温析晶。T＝29℃时析出大量白色固体，继续搅拌2.5h，过滤。固体晾干，得到12.2g，收率54.0％。
实施例3：晶型C的制备
取上述制备例第(12)步方法二固体15.0g加入到250ml三口瓶中，加入甲醇75ml，转入60℃油浴升温溶解。T＝55℃时体系溶解，关闭加热缓慢降温18h，过滤。物料于通风处晾干2h，转入125℃烘箱转晶2h，2h后取出，得到固体10.7g，收率71.3％。
实施例4：晶型D的制备
按照上述制备例第(12)步方法二，加入的2-((1R,5S,6R)-3-(7,7-二氟-2-((S)-2-甲基氮杂环丁烷-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-氮杂双环[3.1.0]己烷-6-基)乙酸甲酯的量为200.07g，得到湿品，加入乙醇(1800ml)，溶解后加水(3600ml)，析出固体，抽滤晾干得固体(184.3g)，取该干燥固体5g加入至100ml单口瓶，加入异丙醚50ml，加热回流19h。过滤， 晾干，得到固体4.69g，收率93.8％。
实施例5：式(1)化合物钾盐的制备
方法一：
取氢氧化钾0.46g(8.2mmol)加入50ml单口圆底烧瓶，加入乙醇15ml搅拌溶解固体。体系澄清后加入式(1)化合物3.0g(8.2mmol)，体系瞬间澄清，逐渐析出固体，搅拌16h，过滤，晾干得固体0.48g，经XRD检测为钾盐晶型I。
方法二：
分别取碳酸氢钾(0.27g)或碳酸钾(0.19g)置于容器内，加入10ml乙醇。搅拌，保持温度在25℃，搅拌速率为500rpm。加入式(1)化合物1.0g，6h后抽滤，将产品放置在50℃真空干燥箱中干燥1h，经XRD检测为钾盐晶型II。
方法三：
取式(1)化合物3.02g置于容器中，加入0.6656g碳酸钾，再加入60mL乙醇，搅拌，保持温度25℃，6小时后抽滤，产品常温下干燥1天，经XRD检测为钾盐晶型II。
实施例6：式(1)化合物钠盐的制备
方法一：
取氢氧化钠0.33g(8.2mmol)加入50ml单口圆底烧瓶，加入乙醇15ml搅拌溶解固体。体系澄清后加入式(1)化合物3.0g(8.2mmol)，体系瞬间澄清，15min析出固体，体系变粘稠无法搅拌，补加乙醇15ml搅拌16h后过滤，晾干得固体1.25g。
方法二：
取碳酸氢钠0.23g置于容器内，加入15ml丙酮/乙腈/乙酸丁酯。搅拌，保持温度在25℃，搅拌速率为500rpm。加入式(1)化合物0.5g，12h后抽滤，将产品放置在50℃真空干燥箱中干燥1h。
方法三：
取式(1)化合物4.03g置于容器内，加入0.916g碳酸氢钠，再加入36mL异丁醇，保持温度25℃，搅拌，7h后过滤，产品放在50℃烘箱中干燥1天得钠盐，经XRD检测为钠盐晶型I。
实施例7：式(1)化合物锂盐的制备
取氢氧化锂一水合物0.57g(13.7mmol)，加入100ml单口瓶，加入乙醇50ml搅拌溶解，25min后固体颗粒溶解，乙醇体系呈浅白色。取式(1)化合物5.0g(13.7mmol)加入单口瓶，体系乳白色浑浊状，之后以肉眼可见速度迅速变清。搅拌反应2.5h后体系变粘稠，无法搅拌。 转入80℃油浴升温回流，体系黏度无明显改善，补加乙醇50ml，更换250ml单口烧瓶，体系可正常搅拌。回流搅拌1h后关闭加热，搅拌1h过滤。固体晾干，得2.95g。
实施例8：式(1)化合物镁盐的制备
方法一：
取式(1)化合物5.0g(13.7mmol)加入250ml单口瓶，加入乙醇50ml转入60℃油浴，料液体系马上澄清，加入氢氧化镁0.40g(6.9mmol)保温搅拌，体系呈乳白色浑浊状，搅拌2h后体系浑浊减轻，但仍不澄清。关闭加热继续搅拌19h，过滤，60℃鼓风干燥2h，得产物0.73g。
方法二：
取碳酸镁0.12g置于容器内，加入6ml乙醇，再加入2ml甲酸。搅拌，保持温度在25℃，搅拌速率为500rpm。加入式(1)化合物1.0g，5h后抽滤，将产品放置在50℃真空干燥箱中干燥1h，经XRD检测为镁盐晶型。
实施例9：式(1)化合物钙盐的制备
方法一：
取式(1)化合物5.0g(13.7mmol)加入250ml单口瓶，加入乙醇50ml转入60℃油浴，料液体系马上澄清，加入氢氧化钙0.51g(6.9mmol)保温搅拌，体系呈乳白色浑浊状，搅拌2h后体系浑浊依旧无明显变化。关闭加热继续搅拌19h，过滤，60℃鼓风干燥2h，得产物3.78g。
方法二：
取碳酸钙0.14g置于容器内，加入6ml乙醇，再加入2ml甲酸。保持温度在25℃，搅拌，搅拌速率为500rpm。加入式(1)化合物1.0g，5h后抽滤，将产品放置在50℃真空干燥箱中干燥1h，经XRD检测为钙盐晶型I。
方法三：
取式(1)化合物2.0g置于结晶器内，加入乙醇30ml，混合均匀。取0.2g氢氧化钙于容器中，加入15ml水，混合均匀，将此悬浮液倒入结晶器中。搅拌，保持温度在25℃。4h内降温至10℃，抽滤，将产品放置在常温下干燥1天，经XRD检测为钙盐晶型II。
对采用实施例1、实施例2、实施例3、实施例4、实施例5方法一中所列举的方法制得的晶型，进行X-射线粉末衍射测定、差示扫描量热法测定和热重分析：
X-射线粉末衍射测定
本发明的晶体结构不限于提供与本申请公开的附图中所绘的X-射线粉末衍射图完全相同的X-射线粉末衍射图的晶体结构，与附图中公开的那些基本相同的X-射线粉末衍射图的任 何晶体结构都包含在本发明的范围内。
X-射线粉末衍射测定的条件：
X射线反射参数：Cu，Kα；入射狭缝：0.6mm；发散狭缝：8mm；扫描模式：连续；
扫描范围：3.0～45.0度；取样步长：0.02度；每步扫描时间：0.3s；探测器角度：2.0度。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的晶型A在8.0±0.2°、9.4±0.2°、10.5±0.2°、12.7±0.2°、19.5±0.2°、21.2±0.2°处有特征峰；还在10.2±0.2°、13.6±0.2°、14.2±0.2°、15.8±0.2°、17.2±0.2°、25.3±0.2°处有特征峰；还在6.9±0.2°、15.1±0.2°、16.6±0.2°、18.9±0.2°、22.0±0.2°、23.1±0.2°处有特征峰。
式(1)化合物的晶型A的X-射线粉末衍射图谱示于图1中，该晶型在以下衍射角度2θ(°)处有峰：6.9±0.2°、8.0±0.2°、9.4±0.2°、10.2±0.2°、10.5±0.2°、12.7±0.2°、13.6±0.2°、14.2±0.2°、15.1±0.2°、15.8±0.2°、16.6±0.2°、17.2±0.2°、18.9±0.2°、19.5±0.2°、21.2±0.2°、22.0±0.2°、23.1±0.2°、25.3±0.2°。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的晶型B在6.4±0.2°、10.0±0.2°、12.7±0.2°、15.5±0.2°、17.6±0.2°、22.0±0.2°处有特征峰；还在8.3±0.2°、16.5±0.2°、17.7±0.2°、20.6±0.2°处有特征峰。
式(1)化合物的晶型B的X-射线粉末衍射图谱示于图4中，该晶型在以下衍射角度2θ(°)处有峰：6.4±0.2°、8.3±0.2°、10.0±0.2°、12.7±0.2°、15.5±0.2°、16.5±0.2°、17.6±0.2°、17.7±0.2°、20.6±0.2°、22.0±0.2°。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的晶型C在8.5±0.2°、9.9±0.2°、10.7±0.2°、18.5±0.2°处有特征峰；还在13.0±0.2°、13.4±0.2°、13.8±0.2°、16.8±0.2°处有特征峰；还在19.2±0.2°、20.7±0.2°、21.1±0.2°、22.1±0.2°处有特征峰。
式(1)化合物的晶型C的X-射线粉末衍射图谱示于图7中，该晶型在以下衍射角度2θ(°)处有峰：8.5±0.2°、9.9±0.2°、10.7±0.2°、13.0±0.2°、13.4±0.2°、13.8±0.2°、16.8±0.2°、18.5±0.2°、19.2±0.2°、20.7±0.2°、21.1±0.2°、22.1±0.2°。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的晶型D在6.4±0.2°、10.0±0.2°、12.7±0.2°、17.7±0.2°、18.6±0.2°、25.5±0.2°处有特征峰；还在14.9±0.2°、15.6±0.2°、20.6±0.2°处有特征峰；还在8.3±0.2°、16.5±0.2°、19.1±0.2°、20.2±0.2°处有特征峰。
式(1)化合物的晶型D的X-射线粉末衍射图谱示于图10中，该晶型在以下衍射角度2θ(°)处有峰：6.4±0.2°、8.3±0.2°、10.0±0.2°、12.7±0.2°、14.9±0.2°、15.6±0.2°、16.5±0.2°、17.7±0.2°、18.6±0.2°、19.1±0.2°、20.2±0.2°、20.6±0.2°、25.5±0.2°。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的钾盐晶型I在4.8±0.2°、5.9±0.2°、 7.1±0.2°、8.3±0.2°、11.8±0.2°、15.5±0.2°处有特征峰；还在14.6±0.2°、16.6±0.2°、17.9±0.2°、18.8±0.2°、19.6±0.2°、21.5±0.2°处有特征峰；还在13.0±0.2°、14.2±0.2°、23.3±0.2°、25.0±0.2°处有特征峰。
式(1)化合物的钾盐晶型I的X-射线粉末衍射图谱示于图13中，该晶型在以下衍射角度2θ(°)处有峰：4.8±0.2°、5.9±0.2°、7.1±0.2°、8.3±0.2°、11.8±0.2°、13.0±0.2°、14.2±0.2°、14.6±0.2°、15.5±0.2°、16.6±0.2°、17.9±0.2°、18.8±0.2°、19.6±0.2°、21.5±0.2°、23.3±0.2°、25.0±0.2°。
差示扫描量热法
通过差示扫描量热法(DSC)研究式(1)化合物的晶型A、晶型B、晶型C、晶型D、钾盐晶型I的固态热性能。
测定条件：用氮气以50毫升/分钟吹扫，在25℃至230℃之间以10℃/分钟加热速率收集数据，在吸热峰朝下的情况下绘图。
式(1)化合物的晶型A在167℃至173℃范围内出现吸热峰，其差示扫描量热分析图基本如图2所示。
式(1)化合物的晶型B在167℃至173℃范围内出现吸热峰，其差示扫描量热分析图基本如图5所示。
式(1)化合物的晶型C在170℃至175℃范围内出现吸热峰，其差示扫描量热分析图基本如图8所示。
式(1)化合物的晶型D在165℃至170℃范围内出现吸热峰，其差示扫描量热分析图基本如图11所示。
式(1)化合物的钾盐晶型I在174℃至180℃范围内出现吸热峰，其差示扫描量热分析图基本如图14所示。
在DSC测定中，根据测量参数及加热速率，实际测得的开始温度和最高温度具有一定程度的可变性。
热重分析
测试条件：用氮气以60毫升/分钟吹扫，在室温至400℃之间以10℃/分钟加热速率收集数据。
式(1)化合物的晶型A在低于200℃范围内没有失重，其TG曲线显示于图3中。
式(1)化合物的晶型B在低于200℃范围内没有失重，其TG曲线显示于图6中。
式(1)化合物的晶型C在低于200℃范围内没有失重，其TG曲线显示于图9中。
式(1)化合物的晶型D在低于200℃范围内没有失重，其TG曲线显示于图12中。
式(1)化合物的钾盐晶型I在100℃以下有失重，为吸附水，其TG曲线显示于图15中。
对采用实施例5方法二、方法三所列举的方法制得的钾盐晶型II，进行X-射线粉末衍射测定、差示扫描量热法测定和热重分析：
X-射线粉末衍射测定
测试条件：D/max-2500衍射仪(Rigaku、日本)；
2θ的范围2°～40°，扫描速度8°/min；
电压40千伏，电流100毫安。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的钾盐晶型II在4.7±0.2°、6.5±0.2°、7.9±0.2°、10.3±0.2°、11.0±0.2°、12.1±0.2°处有特征峰；还在5.1±0.2°、13.0±0.2°、20.1±0.2°、21.4±0.2°、22.4±0.2°、24.1±0.2°处有特征峰；还在8.3±0.2°、17.6±0.2°、19.5±0.2°、20.6±0.2°、21.1±0.2°、24.5±0.2°处有特征峰。
式(1)化合物的钾盐晶型II的X-射线粉末衍射图谱示于图16中，该晶型在以下衍射角度2θ(°)处有峰：4.7±0.2°、5.1±0.2°、6.5±0.2°、7.9±0.2°、8.3±0.2°、10.3±0.2°、11.0±0.2°、12.1±0.2°、13.0±0.2°、17.6±0.2°、19.5±0.2°、20.1±0.2°、20.6±0.2°、21.1±0.2°、21.4±0.2°、22.4±0.2°、24.1±0.2°、24.5±0.2°。
差示扫描量热法
通过差示扫描量热法(DSC)研究式(1)化合物的钾盐晶型II的固态热性能。
测定条件：Mettler Toledo DSCF,Greifensee,瑞士
氮气保护，温度范围303.15～473.15K，升温速率为10K或5K/min。
式(1)化合物的钾盐晶型II在155℃至165℃范围内出现吸热峰，其差示扫描量热分析图基本如图17所示。
在DSC测定中，根据测量参数及加热速率，实际测得的开始温度和最高温度具有一定程度的可变性。
热重分析
测试条件：用氮气以60毫升/分钟吹扫，在室温至300℃之间以10℃/分钟加热速率收集数据。
式(1)化合物的钾盐晶型II在200以下℃失重8.5％，其TG曲线显示于图17-1中。
对采用实施例8方法二所列举的方法制得的镁盐晶型，进行X-射线粉末衍射测定、差示扫描量热法测定：
X-射线粉末衍射测定
测试条件：D/max-2500衍射仪(Rigaku、日本)；
2θ的范围2°～40°，扫描速度8°/min；
电压40千伏，电流100毫安。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的镁盐晶型在18.8±0.2°、23.8±0.2°、26.3±0.2°、29.5±0.2°处有特征峰；还在23.0±0.2°、25.9±0.2°、31.5±0.2°、32.0±0.2°、38.1±0.2°、39.0±0.2°处有特征峰。
式(1)化合物的镁盐晶型的X-射线粉末衍射图谱示于图18中，该晶型在以下衍射角度2θ(°)处有峰：18.8±0.2°、23.0±0.2°、23.8±0.2°、25.9±0.2°、26.3±0.2°、29.5±0.2°、31.5±0.2°、32.0±0.2°、38.1±0.2°、39.0±0.2°。
差示扫描量热法
通过差示扫描量热法(DSC)研究式(1)化合物的镁盐晶型的固态热性能。
测定条件：Mettler Toledo DSC,Greifensee,瑞士
氮气保护，温度范围303.15～473.15K，升温速率为10K或5K/min。
式(1)化合物的镁盐晶型在165℃至180℃范围内出现吸热峰，其差示扫描量热分析图基本如图19所示。
在DSC测定中，根据测量参数及加热速率，实际测得的开始温度和最高温度具有一定程度的可变性。
对采用实施例9方法二所列举的方法制得的钙盐晶型I，进行X-射线粉末衍射测定。
X-射线粉末衍射测定
测试条件：D/max-2500衍射仪(Rigaku、日本)；
2θ的范围2°～40°，扫描速度8°/min；
电压40千伏，电流100毫安。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的钙盐晶型I在15.8±0.2°、16.1±0.2°、26.3±0.2°、28.0±0.2°、30.2±0.2°、31.2±0.2°处有特征峰，其X-射线粉末衍射图谱示于图20中。
对采用实施例9方法三所列举的方法制得的钙盐晶型II，进行X-射线粉末衍射测定、差示扫描量热法测定和热重分析。
X-射线粉末衍射测定
X-射线粉末衍射测定的条件：
X射线反射参数：Cu，Kα；入射狭缝：0.6mm；发散狭缝：8mm；扫描模式：连续；
扫描范围：3.0～45.0度；取样步长：0.02度；每步扫描时间：0.3s；探测器角度：2.0度。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的钙盐晶型II在3.9±0.2°、6.0±0.2°、 8.1±0.2°、11.1±0.2°、16.0±0.2°、17.4±0.2°、19.0±0.2°处有特征峰，其X-射线粉末衍射图谱示于图21中。
差示扫描量热法测定
通过差示扫描量热法(DSC)研究式(1)化合物的钙盐晶型II的固态热性能。
测定条件：用氮气以50毫升/分钟吹扫，在25℃至320℃之间以10℃/分钟加热速率收集数据。
式(1)化合物的钙盐晶型II在80℃左右有一个小的吸热峰，在200℃和280℃左右出现放热峰，综合实验观察发现钙盐在200℃时已变成黑色，所以钙盐在200℃时熔化，后在280℃时进一步分解。其差示扫描量热分析图基本如图22所示。
在DSC测定中，根据测量参数及加热速率，实际测得的开始温度和最高温度具有一定程度的可变性。
热重分析
测试条件：用氮气以60毫升/分钟吹扫，在室温至300℃之间以10℃/分钟加热速率收集数据。
式(1)化合物的钙盐晶型II，在250℃以下有失重，其TG曲线显示于图23中。
对采用实施例6方法三所列举的方法制得的钠盐晶型I，进行X-射线粉末衍射测定、差示扫描量热法测定和热重分析。
X-射线粉末衍射测定
X-射线粉末衍射测定的条件：
X射线反射参数：Cu，Kα；入射狭缝：0.6mm；发散狭缝：8mm；扫描模式：连续；
扫描范围：3.0～45.0度；取样步长：0.02度；每步扫描时间：0.3s；探测器角度：2.0度。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的钠盐晶型I在3.9±0.2°、4.5±0.2°、7.8±0.2°、9.1±0.2°、11.8±0.2°、12.7±0.2°处有特征峰；还在8.5±0.2°、10.5±0.2°、14.2±0.2°、16.8±0.2°、17.9±0.2°处有特征峰，还在18.6±0.2°、20.4±0.2°、30.5±0.2°、34.7±0.2°处有特征峰。
式(1)化合物的钠盐晶型I的X-射线粉末衍射图谱示于图24中，该晶型在以下衍射角度2θ(°)处有峰：3.9±0.2°、4.5±0.2°、7.8±0.2°、8.5±0.2°、9.1±0.2°、10.5±0.2°、11.8±0.2°、12.7±0.2°、14.2±0.2°、16.8±0.2°、17.9±0.2°、18.6±0.2°、20.4±0.2°、30.5±0.2°、34.7±0.2°。
差示扫描量热法测定
通过差示扫描量热法(DSC)研究式(1)化合物的钠盐晶型I的固态热性能。
测定条件：用氮气以50毫升/分钟吹扫，在25℃至220℃之间以10℃/分钟加热速率收集数据。
式(1)化合物的钠盐晶型I，其差示扫描量热分析图基本如图25所示。
在DSC测定中，根据测量参数及加热速率，实际测得的开始温度和最高温度具有一定程度的可变性。
热重分析
测试条件：用氮气以60毫升/分钟吹扫，在室温至300℃之间以10℃/分钟加热速率收集数据。
式(1)化合物的钠盐晶型I，在200℃以下有失重，其TG曲线显示于图26中。
本发明的晶体结构不限于提供与本申请公开的附图中所绘的X-射线粉末衍射图完全相同的X-射线粉末衍射图的晶体结构，与附图中公开的那些基本相同的X-射线粉末衍射图的任何晶体结构都包含在本发明的范围内。
实施例10式(1)化合物的晶型A的稳定性考察
1、供试品
式(1)化合物的晶型A，按照实施例1中的方法制备。
2、考察条件
2.1式(1)化合物的晶型A的考察条件：
在105℃条件下放置5天，敞口，于第5天取样检测；
在60℃条件下放置10天，敞口/闭口，于第10天取样检测；
在25℃RH92.5％条件下放置10天，敞口/闭口，于第10天取样检测；
在40℃RH75％条件下放置1个月，敞口/闭口，于1个月取样检测；
在光照条件下，采用闭口(聚乙烯袋+复合膜袋)，达到照度要求取样检测。
照度要求：ICH Q1B稳定性试验：新原料药和制剂的光稳定性试验。
3、测定方法
有关物质测定：按照《中国药典》2015年版四部通则0512高效液相色谱法测定。
水分测定：按照《中国药典》2015年版四部通则0832水分测定法第一法(费休氏法)2库仑滴定法测定。
XRD测定：按照《中国药典》2015年版四部通则0451X射线衍射法-第二法粉末X射线衍射法测定。
DSC测定：精密称量适量样品于Standard盘中，加盖后置于DSC炉中样品盘位置，参 比位置放置同种类型的空白盘，升温程序如下：
1.Equilibrate at 25℃；
2.Ramp10℃ to 200℃。
4、试验结果
式(1)化合物的晶型A的稳定性数据如下表所示。
表1晶型A稳定性考察结果
Figure PCTCN2021108515-appb-000015
5、试验结论
式(1)化合物的晶型A，在高温105℃条件下和60℃、25℃RH92.5％开/闭口、40℃RH75％开/闭口条件下总有关物质略有增加，其他检查项如水分、XRD、DSC稳定性良好。说明了式(1)化合物的晶型A在上述条件下较为稳定，便于药品的制备、运输和储藏，更利于保证药物使用的有效性和安全性。
实施例11式(1)化合物晶型B的稳定性考察
1、供试品
式(1)化合物的晶型B，按照实施例2的方法制备。
2、考察条件
2.1式(1)化合物的晶型B的考察条件：
在105℃条件下放置5天，敞口，于第5天取样检测；
在60℃条件下放置10天，敞口/闭口，于第10天取样检测；
在25℃RH92.5％条件下放置10天，敞口/闭口，于第10天取样检测；
在40℃RH75％条件下放置1个月，敞口/闭口，于1个月取样检测；
在光照条件下，采用闭口(聚乙烯袋+复合膜袋)，达到照度要求取样检测。
照度要求：ICH Q1B稳定性试验：新原料药和制剂的光稳定性试验。
3、测定方法
有关物质测定：按照《中国药典》2015年版四部通则0512高效液相色谱法测定。
水分测定：按照《中国药典》2015年版四部通则0832水分测定法第一法(费休氏法)2库仑滴定法测定。
XRD测定：按照《中国药典》2015年版四部通则0451X射线衍射法-第二法粉末X射线衍射法测定。
DSC测定：精密称量适量样品于Standard盘中，加盖后置于DSC炉中样品盘位置，参比位置放置同种类型的空白盘，升温程序如下：
1.Equilibrate at 25℃；
2.Ramp10℃to 200℃。
4、试验结果
式(1)化合物的晶型B的稳定性数据如下表所示。
表2晶型B稳定性考察结果
Figure PCTCN2021108515-appb-000016
5、试验结论
式(1)的晶型B在高温105℃、60℃条件下和25℃RH92.5％开/闭口条件下总有关物质略有增加，其他检查项如水分、XRD、DSC等稳定性良好；在40℃RH75％条件下放置1个月有关物质、水分、XRD、DSC稳定性均良好；说明了式(1)化合物的晶型B在上述条件下较为稳定，便于药品的制备、运输和储藏，更利于保证药物使用的有效性和安全性。
实施例12式(1)化合物的晶型C的稳定性考察
1、供试品
式(1)化合物的晶型C，按照实施例3的方法制备。
2、考察条件
2.1式(1)化合物的晶型C的考察条件：
在105℃条件下放置5天，敞口，于第5天取样检测；
在60℃条件下放置10天，敞口/闭口，于第10天取样检测；
在25℃RH92.5％条件下放置10天，敞口/闭口，于第10天取样检测；
在40℃RH75％条件下放置1个月，敞口/闭口，于1个月取样检测；
在光照条件下，采用闭口(聚乙烯袋+复合膜袋)，达到照度要求取样检测。
照度要求：ICH Q1B稳定性试验：新原料药和制剂的光稳定性试验。
3、测定方法
有关物质测定：按照《中国药典》2015年版四部通则0512高效液相色谱法测定。
水分测定：按照《中国药典》2015年版四部通则0832水分测定法第一法(费休氏法)2库仑滴定法测定。
XRD测定：按照《中国药典》2015年版四部通则0451X射线衍射法-第二法粉末X射线衍射法测定。
DSC测定：精密称量适量样品于Standard盘中，加盖后置于DSC炉中样品盘位置，参比位置放置同种类型的空白盘，升温程序如下：
1.Equilibrate at 25℃；2.Ramp10℃to 200℃。
4、试验结果
式(1)化合物的晶型C的稳定性数据如下表所示。
表3晶型C稳定性考察结果
Figure PCTCN2021108515-appb-000017
5、试验结论
式(1)化合物的晶型C在高温105℃5天、60℃10天总有关物质略有增加；25℃RH92.5％10 天和40℃RH75％放置1个月开/闭口条件下有关物质、含量、水分、XRD等稳定性良好。
实施例13式(1)化合物的晶型D的稳定性考察
1、供试品
式(1)化合物的晶型D，按照实施例4的方法制备。
2、考察条件
2.1式(1)化合物的晶型D的考察条件：
在105℃条件下放置5天，敞口，于第5天取样检测；
在60℃条件下放置10天，敞口/闭口，于第10天取样检测；
在25℃RH92.5％条件下放置10天，敞口/闭口，于第10天取样检测；
在40℃RH75％条件下放置1个月，敞口/闭口，于1个月取样检测；
在光照条件下，采用闭口(聚乙烯袋+复合膜袋)，达到照度要求取样检测。
照度要求：ICH Q1B稳定性试验：新原料药和制剂的光稳定性试验。
3、测定方法
有关物质测定：按照《中国药典》2015年版四部通则0512高效液相色谱法测定。
水分测定：按照《中国药典》2015年版四部通则0832水分测定法第一法(费休氏法)2库仑滴定法测定。
XRD测定：按照《中国药典》2015年版四部通则0451X射线衍射法-第二法粉末X射线衍射法测定。
DSC测定：精密称量适量样品于Standard盘中，加盖后置于DSC炉中样品盘位置，参比位置放置同种类型的空白盘，升温程序如下：
1.Equilibrate at 25℃；
2.Ramp10℃to 200℃。
4、试验结果
式(1)化合物的晶型D的稳定性数据如下表所示。
表4晶型D稳定性考察结果
Figure PCTCN2021108515-appb-000018
Figure PCTCN2021108515-appb-000019
5、试验结论
式(1)化合物的晶型D在高温105℃条件下总有关物质略有增加，其他检查项如含水分、XRD、DSC等稳定性良好；在40℃RH75％开/闭口条件下放置1个月、60℃和25℃RH92.5％开/闭口条件下放置10天，总有关物质、水分、XRD、DSC稳定性均良好；说明了式(1)化合物的晶型D在上述条件下较为稳定，便于药品的制备、运输和储藏，更利于保证药物使用的有效性和安全性。
实施例14式(1)化合物的钾盐晶型II的稳定性考察
1、供试品
式(1)化合物的钾盐晶型II，按照实施例5方法三的方法制备。
2、考察条件
2.1式(1)化合物的钾盐晶型II的考察条件：
在60℃条件下放置10天，低密度聚乙烯袋包装，于第10天取样检测；
在25℃RH92.5％条件下放置10天，低密度聚乙烯袋包装，于第10天取样检测；
在40℃RH75％条件下放置1个月，低密度聚乙烯袋包装，于1个月取样检测。
3、测定方法
有关物质测定：按照《中国药典》2015年版四部通则0512高效液相色谱法测定。
4、试验结果
式(1)化合物的钾盐晶型II的稳定性数据如下表所示。
表5钾盐晶型II的稳定性考察结果
Figure PCTCN2021108515-appb-000020
5、试验结论
式(1)化合物的钾盐晶型II，在60℃10天、92.5％RH10天、40℃75％RH 1个月条件下，性状、有关物质与0天基本一致，说明了式(1)化合物的钾盐晶型II在上述条件下较为稳 定，便于药品的制备、运输和储藏，更利于保证药物使用的有效性和安全性。
实施例15式(1)化合物的钙盐晶型II的引湿性考察
1、供试品 式(1)化合物的钙盐晶型II，按照实施例9方法三的方法制备。
2、考察条件 RH80％放置1天，开口。
3、实验结果
式(1)化合物的钙盐晶型II，在RH80％放置1天，增重1.38％，略有引湿性。
实施例16对比试验—式(1)化合物无定型的稳定性研究
1、供试品
式(1)化合物的无定型，按照制备例的方法一制备。
2、考察条件
2.1式(1)化合物的无定型的考察条件：
在60℃条件下放置10天，敞口/闭口，于第10天取样检测；
在25℃RH92.5％条件下放置10天，敞口/闭口，于第10天取样检测；
在40℃RH75％条件下放置1个月，敞口/闭口，于1个月取样检测；
在光照条件下，采用闭口(聚乙烯袋+复合膜袋)，达到照度要求取样检测。
照度要求：ICH Q1B稳定性试验：新原料药和制剂的光稳定性试验。
3、测定方法
有关物质测定：按照《中国药典》2015年版四部通则0512高效液相色谱法测定。
水分测定：按照《中国药典》2015年版四部通则0832水分测定法第一法(费休氏法)2库仑滴定法测定。
4、试验结果
式(1)化合物的无定型的稳定性数据如下表所示。
表5无定型稳定性考察结果
Figure PCTCN2021108515-appb-000021
5、试验结论
式(1)化合物的无定型在高温60℃开/闭口条件下放置10天总有关物质增加明显，水分稳定性良好；在25℃RH92.5％开/闭口条件下放置10天，总有关物质略有增加，水分增加明显；在40℃RH75％开/闭口条件下放置1个月，总有关物质、水分均增加明显，说明了式(1)化合物的无定型与晶型A、晶型B、晶型C、晶型D相比，在上述条件下的稳定性较差。
实验例1式(1)化合物的体外KHK激酶抑制活性实验
供试品：式(1)化合物，其化学名称和制备方法请见制备例。
对照药：PF-06835919，参考文献(US15/381,295)中的方法制备。
实验试剂：
Figure PCTCN2021108515-appb-000022
实验耗材：
Figure PCTCN2021108515-appb-000023
实验仪器：
Figure PCTCN2021108515-appb-000024
1、化合物稀释
1)使用DMSO配制本发明化合物及对照药至10mM，作为试验储备液。
2)将本发明化合物储备液10倍稀释至1mM，然后，3倍梯度稀释本发明化合物至11个浓度，最高浓度为1mM，将对照药储备液100倍稀释至0.1mM，然后，3倍梯度稀释对照药至11个浓度，最高浓度为0.1mM。
3)使用Echo550分别转移0.1μL稀释后的本发明化合物及对照药至384孔板，每个浓度设定2个复孔，1000rpm离心1min。
2、酶反应实验
1)加入5μL KHK-C激酶工作液至384孔板，1000rpm离心1min，然后，室温25℃孵育15min。
2)加入5μL底物工作液至384孔板，启动激酶反应，1000rpm离心1min，室温25℃孵育60min。
3)KHK-C激酶反应终浓度为1nM KHK-C，100μM ATP，200μM D-Fructose，HEPES 50mM，MgCl 2 10mM，Brij35 0.01％，DMSO终浓度为1％。
4)测试化合物终浓度为10000nM、3333.33nM、1111.11nM、370.37nM、123.457nM、41.15nM、13.71nM、4.572nM、1.524nM、0.508nM、0.169nM。
5)对照药终浓度为1000nM、333.33nM、111.11nM、37.037nM、12.346nM、4.115nM、1.371nM、0.4572nM、0.1524nM、0.0508nM、0.0169nM。
3、反应终止及检测
1)加入10μL ADP Glo试剂，1000rpm离心1min，室温25℃孵育40min。
2)加入20μL激酶检测试剂，1000rpm离心1min，室温25℃孵育40min。
3)反应结束后，在Envision上读取荧光值LUM。
4、数据分析
使用如下公式计算抑制率inhibition(％inh)：
Figure PCTCN2021108515-appb-000025
其中，Lum HC表示：High control(反应体系中加入与待测化合物相同体积的DMSO)的发光信号强度；
Lum LC表示：Low control(对照药1μM)的发光信号强度；
Lum cpd表示：表示供试品化合物的发光信号强度；
采用软件进行曲线拟合，计算得出IC 50。
实验结果：
表6本发明式(1)化合物对KHK-C抑制活性
Figure PCTCN2021108515-appb-000026
Figure PCTCN2021108515-appb-000027
从上述实验结果可以看出，本发明的式(1)化合物能够有效抑制KHK-C激酶活性，是有效的KHK-C激酶抑制剂。
实验例2式(1)化合物的体外细胞抑制活性实验
供试品：式(1)化合物，其化学名称和制备方法请见制备例。
对照药：PF-06835919，参考文献(US15/381,295)中的方法制备。
实验试剂：
Reagent Vendor Cat No.
MEM培养基 Gibco 10370-021
HepG2肝癌细胞系 ATCC HB-8065
丙酮酸钠 Gibco 11360-070
谷氨酰胺 Gibco 35050-061
胎牛血清(FBS) Gibco 10091-148
DPBS缓冲液 Gibco 14200-075
0.25％胰酶(含EDTA) Gibco 25200-072
DMSO Sigma D4540
青链霉素 Gibco 10378016
醋酸铵 TEDIA AS0139-028
D-fructose sigma F3510-100G
实验仪器：
Instrument Vendor Cat No.
CO 2培养箱 SANYO MCO-15A4
生物安全柜 上海力申科技仪器有限公司 1200A2
冷冻离心机 Eppendorf Centrifuge5840R
显微镜 Nikon TS100-F
实验方法：
1、细胞培养和接种
1)收集处于对数生长期的HepG2细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。
2)调整HepG2细胞浓度，分别加入81μL无FBS的基础培养基(饥饿处理)细胞悬液至96孔板中，试验孔细胞接种量为5×10 4个。
3)将96孔板中的HepG2细胞置于37℃、5％CO 2、95％湿度条件下培养过夜。
2、加药
1)加药前，向96孔板试验孔中加入9μL FBS，停止饥饿处理。
2)配制10倍化合物溶液，最高浓度为100μM，8个浓度，3倍梯度稀释，在接种有细胞的 96孔板中每孔加入10μL药物溶液，每个药物浓度设置三个复孔，溶剂对照组加入10μL 1％DMSO溶液，设置3个复孔。
3)将已加入药物的96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下，孵育30min。
4)配制11倍D-Fructose溶液，浓度为220mM，在接种有HepG2细胞的96孔板中每孔加入10μL D-Fructose溶液，设置3个复孔，溶剂对照组加入10μL 11％DPBS溶液，设置3个复孔。
5)将已加入D-fructose的96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下孵育3h。
3、样本处理
将96孔板中的培养基去除，用冷的DPBS(200μl/孔)洗孔板中的细胞，洗3次，然后，每孔加入30μL冷的10mM醋酸铵(pH 7.4)裂解细胞(低渗裂解)，冰上裂解5min之后，充分吹打细胞，取细胞裂解液进行LC-MS分析。
4、数据分析
使用GraphPad Prism 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算EC50值。
5、实验结果：
表7本发明式(1)化合物在细胞中对D-Fructose诱导HepG2细胞果糖-1-磷酸产生的抑制作用
Figure PCTCN2021108515-appb-000028
肝脏中KHK-C激酶表达量最高，同时，KHK-C激酶可特异性地代谢果糖，生成果糖-1-磷酸，从上述实验结果可以看出，本发明的式(1)化合物能够有效抑制D-Fructose诱导HepG2细胞产生果糖-1-磷酸，是有效的KHK-C抑制剂。

Claims (11)

  1. 式(1)化合物的晶型、可药用盐及其晶型，其特征在于，
    式(1)化合物的晶型A，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在8.0±0.2°、9.4±0.2°、10.5±0.2°、12.7±0.2°、19.5±0.2°、21.2±0.2°处有特征峰；优选还在10.2±0.2°、13.6±0.2°、14.2±0.2°、15.8±0.2°、17.2±0.2°、25.3±0.2°处有特征峰；进一步优选还在6.9±0.2°、15.1±0.2°、16.6±0.2°、18.9±0.2°、22.0±0.2°、23.1±0.2°处有特征峰；更进一步优选其X-射线粉末衍射图谱基本如图1所示；
    式(1)化合物的晶型B，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在6.4±0.2°、10.0±0.2°、12.7±0.2°、15.5±0.2°、17.6±0.2°、22.0±0.2°处有特征峰；优选还在8.3±0.2°、16.5±0.2°、17.7±0.2°、20.6±0.2°处有特征峰；更进一步优选其X-射线粉末衍射图谱基本如图4所示；
    式(1)化合物的晶型C，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在8.5±0.2°、9.9±0.2°、10.7±0.2°、18.5±0.2°处有特征峰；优选还在13.0±0.2°、13.4±0.2°、13.8±0.2°、16.8±0.2°处有特征峰；进一步优选还在19.2±0.2°、20.7±0.2°、21.1±0.2°、22.1±0.2°处有特征峰，更进一步优选其X-射线粉末衍射图谱基本如图7所示；
    式(1)化合物的晶型D，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在6.4±0.2°、10.0±0.2°、12.7±0.2°、17.7±0.2°、18.6±0.2°、25.5±0.2°处有特征峰；优选还在14.9±0.2°、15.6±0.2°、20.6±0.2°、处有特征峰；进一步优选还在8.3±0.2°、16.5±0.2°、19.1±0.2°、20.2±0.2°处有特征峰，更进一步优选其X-射线粉末衍射图谱基本如图10所示；
    式(1)化合物的可药用盐，选自式(1)化合物与无机碱或有机碱形成的碱加成盐；优选地，所述的碱加成盐选自钾盐、钠盐、锂盐、镁盐或钙盐；
    优选地，所述的钾盐的晶型I，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在4.8±0.2°、5.9±0.2°、7.1±0.2°、8.3±0.2°、11.8±0.2°、15.5±0.2°处有特征峰；优选还在14.6±0.2°、16.6±0.2°、17.9±0.2°、18.8±0.2°、19.6±0.2°、21.5±0.2°处有特征峰；进一步优选还在13.0±0.2°、14.2±0.2°、23.3±0.2°、25.0±0.2°处有特征峰；更进一步优选其X-射线粉末衍射图谱基本如图13所示；
    优选地，所述的钾盐的晶型II，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在4.7±0.2°、6.5±0.2°、7.9±0.2°、10.3±0.2°、11.0±0.2°、12.1±0.2°处有特征峰；优选还在5.1±0.2°、13.0±0.2°、20.1±0.2°、21.4±0.2°、22.4±0.2°、24.1±0.2°处有特征峰；进一步优选还在8.3±0.2°、17.6±0.2°、19.5±0.2°、20.6±0.2°、21.1±0.2°、24.5±0.2°处有特征峰；更进一步优选其X-射线粉末衍射图谱基本如图16所示；
    优选地，所述的镁盐的晶型，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在18.8±0.2°、23.8±0.2°、26.3±0.2°、29.5±0.2°处有特征峰；优选还在23.0±0.2°、25.9±0.2°、 31.5±0.2°、32.0±0.2°、38.1±0.2°、39.0±0.2°处有特征峰；更进一步优选其X-射线粉末衍射图谱基本如图18所示；
    优选地，所述的钙盐的晶型I，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在15.8±0.2°、16.1±0.2°、26.3±0.2°、28.0±0.2°、30.2±0.2°、31.2±0.2°处有特征峰，优选其X-射线粉末衍射图谱基本如图20所示；
    优选地，所述的钙盐的晶型II，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在3.9±0.2°、6.0±0.2°、8.1±0.2°、11.1±0.2°、16.0±0.2°、17.4±0.2°、19.0±0.2°处有特征峰；优选其X-射线粉末衍射图谱基本如图21所示；
    优选地，所述的钠盐的晶型I，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在3.9±0.2°、4.5±0.2°、7.8±0.2°、9.1±0.2°、11.8±0.2°、12.7±0.2°处有特征峰；优选还在8.5±0.2°、10.5±0.2°、14.2±0.2°、16.8±0.2°、17.9±0.2°处有特征峰；进一步优选还在18.6±0.2°、20.4±0.2°、30.5±0.2°、34.7±0.2°处有特征峰；更进一步优选其X-射线粉末衍射图谱基本如图24所示；
    Figure PCTCN2021108515-appb-100001
  2. 如权利要求1所述的晶型、可药用盐及其晶型，其特征在于，
    所述的晶型A，其差示扫描量热分析图在167℃至173℃范围内具有吸热峰，优选在170℃±2℃具有吸热峰，进一步优选晶型A的差示扫描量热分析图基本如图2所示；
    所述的晶型B，其差示扫描量热分析图在167℃至173℃范围内具有吸热峰，优选在169℃±2℃具有吸热峰，进一步优选晶型B的差示扫描量热分析图基本如图5所示；
    所述的晶型C，其差示扫描量热分析图在170℃至175℃范围内具有吸热峰，优选在172℃±2℃具有吸热峰，进一步优选晶型C的差示扫描量热分析图基本如图8所示；
    所述的晶型D，其差示扫描量热分析图在165℃至170℃范围内具有吸热峰，优选在167℃±2℃具有吸热峰，进一步优选晶型D的差示扫描量热分析图基本如图11所示；
    钾盐的晶型I的差示扫描量热分析图在174℃至180℃范围内具有吸热峰，优选在176℃±2℃具有吸热峰，进一步优选钾盐晶型I的差示扫描量热分析图基本如图14所示；
    钾盐的晶型II的差示扫描量热分析图在155℃至165℃范围内具有吸热峰，优选在160℃±2℃具有吸热峰，进一步优选钾盐晶型II的差示扫描量热分析图基本如图17所示；
    镁盐的晶型的差示扫描量热分析图在165℃至180℃范围内具有吸热峰，优选在170℃± 2℃具有吸热峰，进一步优选镁盐晶型的差示扫描量热分析图基本如图19所示。
  3. 如权利要求1或2所述的晶型、可药用盐及其晶型，其特征在于，
    所述的晶型A，由热重分析所测定，其在200℃以下没有失重，优选地，晶型A的热重分析图基本如图3所示；
    所述的晶型B，由热重分析所测定，其在200℃以下没有失重，优选地，晶型B的热重分析图基本如图6所示；
    所述的晶型C，由热重分析所测定，其在200℃以下没有失重，优选地，晶型C的热重分析图基本如图9所示；
    所述的晶型D，由热重分析所测定，其在200℃以下没有失重，优选地，晶型D的热重分析图基本如图12所示。
  4. 如权利要求1-3任一项所述的晶型、可药用盐及其晶型的制备方法，其特征在于，
    所述的晶型A的制备方法为：将式(1)化合物与有机溶剂一混合，加热至第一温度，降温至35℃以下，过滤，干燥而得到所述式(1)化合物的晶型A；
    所述的晶型B的制备方法为：将式(1)化合物与有机溶剂二混合，加热至第二温度，降温至10℃-30℃，过滤，干燥而得到所述式(1)化合物的晶型B；
    所述的晶型C的制备方法为：将式(1)化合物与有机溶剂三混合，加热至第三温度，降温10h-25h，过滤，干燥，转入100℃-140℃烘箱1-5h，得到所述式(1)化合物的晶型C；
    所述的晶型D的制备方法为：将式(1)化合物与有机溶剂四混合，溶解后加水，过滤，得固体，加入有机溶剂五，加热回流10-25h，过滤，干燥，得到所述式(1)化合物的晶型D；
    所述的式(1)化合物的可药用盐的制备方法为：将式(1)化合物与无机碱在反应溶剂A中进行成盐反应。
  5. 如权利要求4所述的制备方法，其特征在于，所述的第一温度选自40℃-95℃，优选65℃-90℃；
    所述的第二温度选自40℃-80℃，优选60℃-70℃；
    所述的第三温度选自40℃-80℃，优选50℃-65℃。
  6. 如权利要求4或5所述的制备方法，其特征在于，
    所述的有机溶剂一为酯类溶剂；优选地，所述酯类溶剂为脂肪酯类溶剂；优选地，所述脂肪酯类溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯中的一种或者两种以上溶剂的任意组合，优选地，所述脂肪酯类溶剂选自甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丙酯、乙酸丁酯、乙酸异丁酯中的一种或者两种以上溶 剂的任意组合；
    所述的有机溶剂二和有机溶剂四分别独立地选自醇类溶剂；
    优选地，所述醇类溶剂分别独立地选自脂肪醇类溶剂、脂环醇类溶剂及芳香醇类溶剂中的一种或者两种以上溶剂的任意组合；
    优选地，所述脂肪醇类溶剂分别独立地选自乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正戊醇、正己醇、乙二醇、丙二醇或丙三醇；优选地，所述的脂肪醇类溶剂选自乙醇、正丙醇、异丙醇、异丁醇、正戊醇；
    优选地，所述的脂环醇类溶剂分别独立地选自环戊醇、环戊甲醇、环己醇、环己甲醇或环己乙醇；
    优选地，所述芳香醇类溶剂分别独立地选自苯甲醇、苯乙醇或苯丙醇；
    所述的有机溶剂三为甲醇；
    所述的有机溶剂五为醚类溶剂，优选地，所述醚类溶剂选自乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环。
  7. 如权利要求4所述的制备方法，其特征在于，
    所述的反应溶剂A选自醇类溶剂、酮类溶剂、腈类溶剂或酯类溶剂中的一种或者两种以上溶剂的任意组合；
    优选地，所述醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正戊醇、正己醇、乙二醇、丙二醇或丙三醇；优选地，所述的醇类溶剂选自甲醇、乙醇、正丙醇、异丙醇、异丁醇或正戊醇；
    优选地，所述酮类溶剂选自丙酮；
    优选地，所述腈类溶剂选自乙腈；
    优选的，所述酯类溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯中的一种或者两种以上溶剂的任意组合；
    所述的无机碱选自碳酸钾、碳酸钠、碳酸镁、碳酸钙、碳酸氢钾、碳酸氢钠、碳酸氢镁、碳酸氢钙、氢氧化钾、氢氧化钠、氢氧化锂、氢氧化镁或氢氧化钙。
  8. 一种药物制剂，其含有权利要求1-3中任一项所述的式(1)化合物的晶型A、晶型B、晶型C、晶型D、可药用盐及其晶型，及一种或多种药用载体和/或稀释剂；所述药物制剂为临床上或药学上可接受的任一剂型。
  9. 一种药物组合物，其含有如权利要求1-3中任一项所述的式(1)化合物的晶型、可药 用盐及其晶型，以及一种或多种第二治疗活性剂；任选地，所述药物组合物还包含一种或多种药用载体和/或稀释剂。
  10. 权利要求1-3中任一项所述的式(1)化合物的晶型、可药用盐及其晶型、权利要求8所述的药物组合物在制备用于治疗和/或预防KHK介导的疾病及相关疾病的药物中的用途。
  11. 如权利要求10所述的用途，其中，所述KHK介导的疾病及相关疾病选自内分泌失调病、泌尿类疾病、代谢类疾病、非酒精性脂肪肝炎、肝硬化、脂肪肝、肝炎、肝脏衰竭、遗传性果糖不耐受症、非酒精性脂肪肝病、肝胆类疾病、纤维化疾病、心脑血管类疾病、免疫炎症类疾病、中枢神经类疾病、胃肠道类疾病和过度增殖性疾病诸如癌症。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023151473A1 (zh) * 2022-02-09 2023-08-17 上海研健新药研发有限公司 一种khk抑制剂，其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102939283A (zh) * 2010-04-22 2013-02-20 詹森药业有限公司 可用作己酮糖激酶抑制剂的吲唑化合物
CN108473469A (zh) * 2015-12-29 2018-08-31 辉瑞公司 作为己酮糖激酶抑制剂的被取代的3-氮杂双环[3.1.0]己烷
WO2020156445A1 (zh) * 2019-01-29 2020-08-06 山东轩竹医药科技有限公司 己酮糖激酶抑制剂及其用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI810550B (zh) * 2020-04-20 2023-08-01 南韓商Ｌｇ化學股份有限公司 3-氮雜二環烷基衍生物及包含其之醫藥組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102939283A (zh) * 2010-04-22 2013-02-20 詹森药业有限公司 可用作己酮糖激酶抑制剂的吲唑化合物
CN108473469A (zh) * 2015-12-29 2018-08-31 辉瑞公司 作为己酮糖激酶抑制剂的被取代的3-氮杂双环[3.1.0]己烷
WO2020156445A1 (zh) * 2019-01-29 2020-08-06 山东轩竹医药科技有限公司 己酮糖激酶抑制剂及其用途

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
ALI M ET AL., J. MED. GENET., vol. 35, no. 5, May 1998 (1998-05-01), pages 353 - 365
BRAY GA: "Soft drink consumption and obesity: it is all about fructose", CURRENT OPINION IN LIPIDOLOGY, vol. 21, no. 1, 2010, pages 51 - 7
FRIEDMAN SL ET AL., NAT MED, vol. 24, 2018, pages 908 - 22
GEORGE MAREKVARINDERPAL PANNUPRASHANTH SHANMUGHAMBRIANNA PANCIONEDOMINIC MASCIASEAN CROSSONTAKUJI ISHIMOTOYURI Y. SAUTINL: "Adiponectin Resistance and Proinflammatory Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via Ketohexokinase-Dependent Pathway", DIABETES, vol. 64, 2015, pages 508 - 518
LANASPA, M.A ET AL., NATURE COMM, vol. 4, 2013, pages 2434
MINGULE A ET AL.: "Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome", NAT COMMUN, vol. 4, 2013, pages 2434
See also references of EP4190776A4
SHI HONGBIN ET AL.: "Study on association between fructose and nonalcoholic fatty liver disease", MEDICAL RECAPITULATE, vol. 23, no. 9, 2017, pages 1685 - 1689
THE AMERICAN JOURNAL OF CLINICAL NUTRITION, vol. 76, no. 5, 2002, pages 911 - 22
THE AMERICAN JOURNAL OF CLINICAL NUTRITION, vol. 86, no. 4, 2007, pages 899 - 906
THOMAS JENSEN ET AL.: "Fructose and Sugar: A Major Mediator of Nonalcoholic Fatty Liver Disease", J HEPATOL, vol. 68, no. 5, May 2018 (2018-05-01), pages 1063 - 1075, XP085372173, DOI: 10.1016/j.jhep.2018.01.019

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023151473A1 (zh) * 2022-02-09 2023-08-17 上海研健新药研发有限公司 一种khk抑制剂，其制备方法和应用

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