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WO2025237405A1 - Compound, and preparation method therefor and use thereof - Google Patents

Compound, and preparation method therefor and use thereof

Info

Publication number
WO2025237405A1
WO2025237405A1 PCT/CN2025/095415 CN2025095415W WO2025237405A1 WO 2025237405 A1 WO2025237405 A1 WO 2025237405A1 CN 2025095415 W CN2025095415 W CN 2025095415W WO 2025237405 A1 WO2025237405 A1 WO 2025237405A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
crystal form
acid
characteristic peaks
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/095415
Other languages
French (fr)
Chinese (zh)
Inventor
石瑛
葛广存
张小兵
杨方龙
王思勤
金磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changchun Genescience Pharmaceutical Co Ltd
Original Assignee
Changchun Genescience Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changchun Genescience Pharmaceutical Co Ltd filed Critical Changchun Genescience Pharmaceutical Co Ltd
Publication of WO2025237405A1 publication Critical patent/WO2025237405A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This invention belongs to the field of compounds, specifically relating to a compound, its preparation method, and its application.
  • the melanocortin-4 receptor is a member of the melanocortin receptor family (MCRs), belonging to the class A G protein-coupled receptor (GPCR) subfamily. Composed of five members (MC1R-MC5R), it mediates various physiological functions in the human body.
  • MCRs melanocortin receptor family
  • GPCR G protein-coupled receptor
  • MC4R is a seven-transmembrane GPCR, primarily expressed in the hypothalamus, hippocampus, and thalamus, and is a central regulator of body weight and energy homeostasis.
  • MC4R is an unusual GPCR because it has both endogenous agonists and endogenous antagonists. Given the important role of the MC4R signaling pathway in regulating food intake, energy balance, and growth, MC4R has become a target for treating obesity.
  • the MC4R agonist Setmelanotide has been approved by the FDA for patients with POMC deficiency, leptin receptor deficiency, and other forms of severe hereditary obesity.
  • This invention provides a compound having the structure shown in Formula A:
  • X represents acid
  • n is a number from 0.5 to 4.
  • the acid is an inorganic acid or an organic acid.
  • the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.
  • the organic acid is selected from one or more of methanesulfonic acid, ethanesulfonic acid, aspartic acid, citric acid, maleic acid, fumaric acid, L-malic acid, L-tartaric acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, etc.
  • X represents sulfuric acid, methanesulfonic acid, ethanesulfonic acid, or maleic acid.
  • n is a number from 0.6 to 3, for example, 0.7, 0.8, 0.87, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8 or 2.9.
  • n is a number from 0.7 to 1.3.
  • n is a number from 0.9 to 2.2.
  • n is a number from 0.9 to 1.3.
  • n is a number from 0.9 to 1.3.
  • the compound is any one of the following compounds:
  • the present invention also provides a method for preparing the compound shown in formula A, comprising: reacting the compound shown in formula (I) with X to obtain the compound shown in formula A;
  • X and n have the limitations shown above.
  • the reaction is carried out in a first organic solvent
  • the first organic solvent is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane.
  • the reaction temperature is 40–60°C, for example 45°C, 50°C, or 55°C.
  • the present invention also provides solid forms of compounds of formula A, including amorphous and crystalline forms, such as crystalline and amorphous forms of compounds of formula A-I (e.g., formula A-1), crystalline and amorphous forms of compounds of formula A-II (e.g., formula A-2), crystalline and amorphous forms of compounds of formula A-III (e.g., formula A-3), crystalline and amorphous forms of compounds of formula A-IV (e.g., formula A-4), and crystalline and amorphous forms of compounds of formula A-V (e.g., formula A-5).
  • amorphous and crystalline forms such as crystalline and amorphous forms of compounds of formula A-I (e.g., formula A-1), crystalline and amorphous forms of compounds of formula A-II (e.g., formula A-2), crystalline and amorphous forms of compounds of formula A-III (e.g., formula A-3), crystalline and amorphous forms of compounds of formula A-
  • the crystal form of the compound of formula A-I (e.g., formula A-1) has an XRPD pattern as shown in FIG3.
  • the crystal form of the compound of formula A-I has an endothermic peak with an initial temperature of 100-108°C and a peak temperature greater than 0 and less than 10°C.
  • the crystal form of the compound of formula A-I e.g., formula A-1
  • the crystal form of the compound of formula A-I has an endothermic peak with an initial temperature of 102-106°C and a peak temperature greater than 0 and less than 8°C.
  • the crystal form of the compound of formula A-I has an endothermic peak with an initial temperature of 104.3°C and a peak temperature greater than 5.44°C.
  • the crystal form of the compound of formula A-I (e.g., formula A-1) has a DSC spectrum substantially as shown in FIG4.
  • the crystal form of the compound of formula A-I (e.g., formula A-1) loses no more than 2.0 wt% at room temperature to about 130°C, for example, a weight loss of 1.2 to 1.9 wt%.
  • the crystal form of the compound of formula A-I (e.g., formula A-1) has a TGA spectrum as shown in FIG5.
  • the crystal form of the compound of formula A-I (e.g., formula A-1) is amorphous.
  • the crystal form of the compound of formula A-II exhibits characteristic peaks in X-ray powder diffraction at 15.0 ⁇ 0.20°, 18.3 ⁇ 0.20°, 19.8 ⁇ 0.20°, 21.3 ⁇ 0.20°, and 23.7 ⁇ 0.20° when measured by Cu-K ⁇ radiation, expressed in 2 ⁇ angles; further, characteristic peaks may also be observed at 16.6 ⁇ 0.20°, 20.5 ⁇ 0.20°, and 23.7 ⁇ 0.20°.
  • Characteristic peaks are present at 2 ⁇ 0.20°, 26.2 ⁇ 0.20° and/or 27.7 ⁇ 0.20°; further, characteristic peaks may also be present at 11.0 ⁇ 0.20°, 12.1 ⁇ 0.20°, 13.0 ⁇ 0.20°, 13.8 ⁇ 0.20°, 24.7 ⁇ 0.20°, 26.9 ⁇ 0.20°, 30.2 ⁇ 0.20°, 31.7 ⁇ 0.20° and/or 33.5 ⁇ 0.20°.
  • the crystal form of the compound of formula A-II (e.g., formula A-2) is determined by Cu-K ⁇ radiation, and X-ray powder diffraction, expressed in 2 ⁇ angles, is performed at 11.0 ⁇ 0.20°, 12.1 ⁇ 0.20°, 13.0 ⁇ 0.20°, 13.8 ⁇ 0.20°, 15.0 ⁇ 0.20°, 16.6 ⁇ 0.20°, and 18.3 ⁇ 0.20°.
  • Characteristic peaks are present at 19.8 ⁇ 0.20°, 20.5 ⁇ 0.20°, 21.3 ⁇ 0.20°, 23.2 ⁇ 0.20°, 23.7 ⁇ 0.20°, 24.7 ⁇ 0.20°, 26.2 ⁇ 0.20°, 26.9 ⁇ 0.20°, 27.7 ⁇ 0.20°, 30.2 ⁇ 0.20°, 31.7 ⁇ 0.20°, and 33.5 ⁇ 0.20°.
  • the crystal form of the compound of formula A-II (e.g., formula A-2) has an XRPD pattern as shown in FIG6.
  • the crystal form of the compound of formula A-II (e.g., formula A-2) has XRPD characteristic peaks as shown in Table 8, with an angle error of ⁇ 0.20°.
  • the crystal form of the compound of formula A-II (e.g., formula A-2) has one, two, or three peaks as follows:
  • An endothermic peak with an initial temperature of 20-30°C and a peak temperature difference greater than 0 and less than 10°C for example, an endothermic peak with an initial temperature of 22-27°C and a peak temperature difference greater than 2 and less than 8°C; for example, an endothermic peak with an initial temperature of 25.62°C and a peak temperature difference of 6.54°C.
  • An endothermic peak with an initial temperature of 133-145°C and a peak temperature greater than 0 and less than 10°C from the initial temperature for example, an endothermic peak with an initial temperature of 125-143°C and a peak temperature greater than 2 and less than 8°C from the initial temperature; for example, an endothermic peak with an initial temperature of 139.58°C and a peak temperature greater than 5.22°C from the initial temperature.
  • An endothermic peak with an initial temperature of 145-155°C and a peak temperature difference greater than 0 and less than 20°C for example, an endothermic peak with an initial temperature of 147-153°C and a peak temperature difference greater than 8 and less than 15°C; for example, an endothermic peak with an initial temperature of 149.58°C and a peak temperature difference of 12.57°C.
  • the crystal form of the compound of formula A-II (e.g., formula A-2) has a DSC spectrum substantially as shown in FIG7.
  • the crystal form of the compound of formula A-II loses no more than 1.0 wt% at room temperature to about 140°C, preferably no more than 0.9 wt% or 0.8 wt%, for example 0.3 to 0.8 wt%.
  • the crystal form of the compound of formula A-II (e.g., formula A-2) has a TGA spectrum substantially as shown in FIG8.
  • the crystal form of the compound of formula A-II (e.g., formula A-2) is a hydrate.
  • the crystal form of the compound of formula A-III (e.g., formula A-3) is obtained by Cu-K ⁇ radiation, and X-ray powder diffraction in 2 ⁇ angles shows characteristic peaks at 15.9 ⁇ 0.20°, 19.6 ⁇ 0.20°, 21.5 ⁇ 0.20°, 22.1 ⁇ 0.20°, 24.8 ⁇ 0.20°, and 26.5 ⁇ 0.20°; further, characteristic peaks may also be present at 17.1 ⁇ 0.20°, 18.1 ⁇ 0.20°, 20.1 ⁇ 0.20°, 23.5 ⁇ 0.20°, and/or 24.4 ⁇ 0.20°; further, characteristic peaks may also be present at 14.6 ⁇ 0.20°, 17.6 ⁇ 0.20°, 28.1 ⁇ 0.20°, 30.5 ⁇ 0.20°, and/or 32.9 ⁇ 0.20°.
  • the crystal form of the compound of formula A-III (e.g., formula A-3) is determined by Cu-K ⁇ radiation, and X-ray powder diffraction, expressed in 2 ⁇ angles, is performed at 3.1 ⁇ 0.20°, 4.4 ⁇ 0.20°, 14.6 ⁇ 0.20°, 15.9 ⁇ 0.20°, 17.1 ⁇ 0.20°, 17.6 ⁇ 0.20°, 18.1 ⁇ 0.20°, 19.6 ⁇ 0.20°, and 20.2 ⁇ Characteristic peaks are present at 0.20°, 21.5 ⁇ 0.20°, 22.1 ⁇ 0.20°, 23.5 ⁇ 0.20°, 24.4 ⁇ 0.20°, 24.8 ⁇ 0.20°, 26.5 ⁇ 0.20°, 28.1 ⁇ 0.20°, 28.7 ⁇ 0.20°, 30.5 ⁇ 0.20°, 31.0 ⁇ 0.20°, 32.0 ⁇ 0.20°, 32.9 ⁇ 0.20°, and 33.4 ⁇ 0.20°.
  • the crystal form of the compound of formula A-III (e.g., formula A-3) has an XRPD pattern as shown in FIG9.
  • the crystal form of the compound of formula A-III (e.g., formula A-3) has XRPD characteristic peaks as shown in Table 9, with a 2 ⁇ angle error of ⁇ 0.20°.
  • the crystal form of the compound of formula A-III (e.g., formula A-3) has an endothermic peak with an initial temperature of 180-192°C and a peak temperature greater than 0 and less than 10°C; for example, an endothermic peak with an initial temperature of 183-190°C and a peak temperature greater than 2 and less than 5°C; exemplaryly, an endothermic peak with an initial temperature of 186.63°C and a peak temperature greater than 3.02°C.
  • the crystal form of the compound of formula A-III (e.g., formula A-3) has a DSC spectrum substantially as shown in FIG10.
  • the crystal form of the compound of formula A-III loses no more than 1.0 wt% at room temperature to about 170°C, preferably no more than 0.9 wt%, 0.7 wt%, or 0.5 wt%.
  • the crystal form of the compound of formula A-III (e.g., formula A-3) has a TGA spectrum substantially as shown in FIG11.
  • the crystal form of the compound of formula A-III (e.g., formula A-3) is anhydrous.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) exhibits characteristic peaks in X-ray powder diffraction at 12.8 ⁇ 0.20°, 16.5 ⁇ 0.20°, 17.5 ⁇ 0.20°, 21.3 ⁇ 0.20°, 22.3 ⁇ 0.20°, and 26.6 ⁇ 0.20° when measured using Cu-K ⁇ radiation at 20° angles; further, characteristic peaks can also be observed at 10.8 ⁇ 0.20°.
  • Characteristic peaks are present at 0°, 19.6 ⁇ 0.20°, 20.6 ⁇ 0.20°, 23.1 ⁇ 0.20°, 27.1 ⁇ 0.20° and/or 28.8 ⁇ 0.20°; further, characteristic peaks may also be present at 13.8 ⁇ 0.20°, 25.1 ⁇ 0.20°, 27.6 ⁇ 0.20°, 28.2 ⁇ 0.20°, 29.7 ⁇ 0.20° and/or 34.8 ⁇ 0.20°.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) is characterized by X-ray powder diffraction at 10.8 ⁇ 0.20°, 12.8 ⁇ 0.20°, 13.8 ⁇ 0.20°, 16.5 ⁇ 0.20°, 17.5 ⁇ 0.20°, 19.6 ⁇ 0.20°, 20.6 ⁇ 0.20°, 21.3 ⁇ 0.20°, 22.3 ⁇ 0.20°, 23.1 ⁇ 0.20°, 25.1 ⁇ 0.20°, 26.6 ⁇ 0.20°, 27.1 ⁇ 0.20°, 27.6 ⁇ 0.20°, 28.2 ⁇ 0.20°, 28.8 ⁇ 0.20°, 29.7 ⁇ 0.20°, and 34.8 ⁇ 0.20° when measured using Cu-K ⁇ radiation.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) has an XRPD pattern as shown in FIG13.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) has XRPD characteristic peaks as shown in Table 10, with a 2 ⁇ angle error of ⁇ 0.20°.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) has an endothermic peak with an initial temperature of 170-180°C and a peak temperature greater than 0 and less than 10°C; for example, an endothermic peak with an initial temperature of 172-178°C and a peak temperature greater than 0 and less than 5°C; exemplaryly, an endothermic peak with an initial temperature of 175.78°C and a peak temperature greater than 1.4°C.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) has a DSC spectrum substantially as shown in FIG14.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) loses no more than 0.5 wt% at room temperature to about 160°C, preferably no more than 0.3 wt%, 0.2 wt%, or 0.1 wt%.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) has a TGA spectrum substantially as shown in FIG15.
  • the crystal form of the compound of formula A-IV (e.g., formula A-4) is anhydrous.
  • the crystal form of the compounds of formulas A-V (e.g., formula A-5) is determined by Cu-K ⁇ radiation, and X-ray powder diffraction, expressed in 2 ⁇ angles, shows characteristic peaks at 6.3 ⁇ 0.20°, 13.0 ⁇ 0.20°, 15.8 ⁇ 0.20°, 18.1 ⁇ 0.20°, 18.9 ⁇ 0.20°, and 23.3 ⁇ 0.20°; furthermore, characteristic peaks may also be observed at 7.2 ⁇ 0.20°, 8.5 ⁇ 0.20°, 13.9 ⁇ 0.20°, and 16.9 ⁇ 0.20°.
  • Characteristic peaks are present at 20.9 ⁇ 0.20°, 21.7 ⁇ 0.20°, 22.7 ⁇ 0.20°, 24.3 ⁇ 0.20°, 25.6 ⁇ 0.20° and/or 27.5 ⁇ 0.20°; further, characteristic peaks may also be present at 9.3 ⁇ 0.20°, 10.6 ⁇ 0.20°, 11.3 ⁇ 0.20°, 12.1 ⁇ 0.20°, 26.3 ⁇ 0.20°, 27.8 ⁇ 0.20°, 28.7 ⁇ 0.20° and/or 29.4 ⁇ 0.20°.
  • the crystal form of the compounds of formulas A-V (e.g., formula A-5) is determined by Cu-K ⁇ radiation, and X-ray powder diffraction, expressed in 2 ⁇ angles, is performed at 6.3 ⁇ 0.20°, 7.2 ⁇ 0.20°, 8.5 ⁇ 0.20°, 9.3 ⁇ 0.20°, 10.6 ⁇ 0.20°, 11.3 ⁇ 0.20°, 12.1 ⁇ 0.20°, 13.0 ⁇ 0.20°, 13.9 ⁇ 0.20°, and 15.8 ⁇ 0.20°.
  • Characteristic peaks are present at 20°, 16.9 ⁇ 0.20°, 18.1 ⁇ 0.20°, 18.9 ⁇ 0.20°, 20.9 ⁇ 0.20°, 21.7 ⁇ 0.20°, 22.7 ⁇ 0.20°, 23.3 ⁇ 0.20°, 24.3 ⁇ 0.20°, 25.6 ⁇ 0.20°, 26.3 ⁇ 0.20°, 27.5 ⁇ 0.20°, 27.8 ⁇ 0.20°, 28.7 ⁇ 0.20°, and 29.4 ⁇ 0.20°.
  • the crystal form of the compound of formula A-V (e.g., formula A-5) has an XRPD pattern as shown in FIG17.
  • the crystal form of the compound of formula A-V (e.g., formula A-5) has XRPD characteristic peaks as shown in Table 11, with a 2 ⁇ angle error of ⁇ 0.20°.
  • the crystal form of the compound of formula A-V (e.g., formula A-5) has an endothermic peak with an initial temperature of 115-130°C and a peak temperature greater than 0 and less than 3°C; for example, an endothermic peak with an initial temperature of 118-125°C and a peak temperature greater than 0 and less than 1°C; exemplaryly, an endothermic peak with an initial temperature of 121.65°C and a peak temperature less than 0.33°C.
  • the crystal form of the compound of formula A-V (e.g., formula A-5) has a DSC spectrum substantially as shown in FIG18.
  • the crystal form of the compound of formula A-V loses no more than 2.5 wt% at room temperature to about 130°C, preferably no more than 2.3 wt%, 2.2 wt%, or 2.1 wt%, for example, 1.5 to 2.3 wt%.
  • the crystal form of the compound of formula A-V (e.g., formula A-5) has a TGA spectrum as shown in FIG19.
  • the crystal form of the compound of formula A-V (e.g., formula A-5) is anhydrous.
  • the present invention also provides a method for preparing the crystal form of the compound shown in Formula A, comprising mixing the compound shown in Formula (I) with X and a first organic solvent, stirring to dissolve, adding a second organic solvent to form a suspension, adding a third organic solvent, continuing to stir, then cooling to room temperature and stirring, and after post-treatment, obtaining the crystal form;
  • X and the first organic solvent are as defined above.
  • the first organic solvent, the second organic solvent, and/or the third organic solvent may be the same or different.
  • the second organic solvent is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane, for example, isopropyl ether.
  • the third organic solvent is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane, for example, isopropyl ether.
  • the volume ratio of the first organic solvent, the second organic solvent and the third organic solvent is 1:(0.5-10):(1-10), for example 1:(1-5):(2-8).
  • the mass-to-volume ratio of the compound represented by formula (I) to the first organic solvent is 50 to 500 mg/ml, for example, 150 to 300 mg/ml.
  • the temperature of the stirring and dissolving process is 40 to 60°C, for example, 45°C, 50°C or 55°C.
  • the mixture is stirred for 1 to 6 hours, for example, 2 to 4 hours.
  • the stirring time at room temperature is not less than 1 day, for example, 1 to 3 days.
  • the present invention also provides a method for preparing the crystal form of the compound represented by formulas A-IV (e.g., formula A-4), comprising mixing the compound represented by formula (I) with ethanesulfonic acid and 4-methyl-2-pentanone, stirring at 40-60°C (e.g., 50°C) for 1-6 hours (e.g., 2-4 hours), cooling to room temperature and continuing to stir for at least 1 day (e.g., 2 days, 3 days or more); the resulting solid is centrifuged and dried to obtain the compound represented by formulas A-IV (e.g., formula A-4);
  • the equivalence ratio of the ethanesulfonic acid to the compound shown in formula (I) is 1.0 to 2.5, for example 1.1 to 2.4, such as 1.2, 1.3, 1.4, 2.0, 2.1, 2.2, and 2.3.
  • the present invention also provides a method for preparing the crystal form of the compound represented by formulas A-IV (e.g., formula A-4), comprising mixing the compound represented by formula (I) with ethanesulfonic acid and 4-methyl-2-pentanone, stirring at 40-60°C (e.g., 50°C) for 1-6 hours (e.g., 2-4 hours), cooling to room temperature and continuing to stir for at least 1 day (e.g., 2 days, 3 days or more), then cooling to 0-6°C (e.g., 5°C) and continuing to stir for at least 1 day (e.g., 1 day, 2 days or more); the resulting solid is centrifuged and dried to obtain the compound represented by formulas A-IV (e.g., formula A-4);
  • the equivalence ratio of the ethanesulfonic acid to the compound shown in formula (I) is 1.0 to 2.5, for example 1.1 to 2.4, such as 1.2, 1.3, 1.4, 2.0, 2.1, 2.2, and 2.3.
  • the present invention also provides a method for preparing the crystal form of the compound represented by formulas A-IV (e.g., formula A-4), comprising mixing the compound represented by formula (I) with ethanesulfonic acid and 4-methyl-2-pentanone, stirring at 40-60°C (e.g., 50°C) for 1-6 hours (e.g., 2-4 hours), cooling and stirring (e.g., first cooling to room temperature and stirring for at least 1 day; if no solid precipitates, then cooling to 0-6°C and continuing to stir for at least 1 day), if no solid precipitates, adding isopropyl ether to the mixture at room temperature and stirring until solid precipitates; the obtained solid is centrifuged and dried to obtain the compound represented by formulas A-IV (e.g., formula A-4);
  • the equivalence ratio of the ethanesulfonic acid to the compound shown in formula (I) is 1.0 to 2.5, for example 1.1 to 2.4, such as 1.2, 1.3, 1.4, 2.0, 2.1, 2.2, and 2.3.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound shown in Formula A above and/or the solid form (e.g., crystal form) of the compound shown in Formula A.
  • the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may further contain additional therapeutic agents, used in combination with the compound shown in Formula A or a crystal form of the compound shown in Formula A.
  • the present invention also provides the use of the compound of Formula A, the solid form (e.g., crystal form) of the compound of Formula A, or the pharmaceutical composition thereof in the preparation of a medicament for the diagnosis, prevention, and/or treatment of MC4R receptor-mediated diseases or conditions.
  • the compound of Formula A the solid form (e.g., crystal form) of the compound of Formula A, or the pharmaceutical composition thereof in the preparation of a medicament for the diagnosis, prevention, and/or treatment of MC4R receptor-mediated diseases or conditions.
  • the drug is an MC4R antagonist.
  • the disease or condition is cachexia (cachexia associated with cancer, cachexia associated with acquired immunodeficiency syndrome (AIDS), cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with treatment of other chronic diseases); anorexia or anorexia nervosa (anorexia in the elderly, anorexia associated with chemotherapy and/or radiotherapy); nausea and vomiting; weight loss (involuntary weight loss); growth retardation; sarcopenia; muscle atrophy; muscle weakness; fragility; osteoporosis; bone disease (bone loss); pain (neuropathic pain); anxiety (post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition-related obesity (such as sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (inflammatory diseases associated with anorexia or cachexia, sarcopenia or muscle atrophy).
  • cachexia cachexia associated with cancer, cachexia associated with acquired immunodeficiency syndrome (AIDS), cachexia associated with congestive heart failure (
  • the present invention also provides a method for diagnosing, preventing and/or treating MC4R receptor-mediated diseases or conditions, the method comprising administering, alone to a patient requiring such treatment, a therapeutically effective amount of the compound of Formula A, a solid form (e.g., a crystal form) of the compound of Formula A, or a pharmaceutical composition thereof.
  • the disease or ailment has the same limitations as described above.
  • the compound shown in Formula A has good biological activity and solubility, and has the potential to be developed into a drug.
  • the crystal form of the compound shown in Formula A has low hygroscopicity, good solubility, chemical stability and/or physical stability, and has the potential to be developed into a drug.
  • crystal form refers to a crystal form that has the same chemical composition but a different spatial arrangement of molecules and/or ions that form crystals, including single crystals.
  • single crystals can be obtained when n is approximately 0.9 (such as when a compound and an acid form a salt in a 1:1 molar ratio).
  • amorphous refers to a solid form of molecules and/or ions that are not crystalline. Amorphous solids do not exhibit definite X-ray powder diffraction patterns with clear maximum values.
  • X-ray powder diffraction pattern substantially as shown means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the major peaks shown in the X-ray powder diffraction pattern appear in the X-ray powder diffraction pattern; the major peaks refer to peaks with a relative intensity greater than 10%, preferably greater than 20%, and more preferably greater than 30%, with the highest peak as a reference (the relative intensity of the highest peak is specified as 100%).
  • pharmaceutically acceptable excipient refers to an excipient that does not cause significant irritation to the organism and does not impair the biological activity and properties of the active compound.
  • patient refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.
  • therapeutic effective amount refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and/or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptom of the disease, disorder, or symptom (i.e., reversal of the pathology and/or symptom).
  • prevention of disease e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or
  • two or more refers to two, three or more kinds.
  • room temperature refers to a temperature of 20-25°C.
  • n is an approximation with an error range of ⁇ 0.2, preferably ⁇ 0.1. Taking an n value of approximately 0.9 as an example, this represents a range of n values from 0.7 to 1.1, preferably from 0.8 to 1.0.
  • Figure 1 shows the XRPD spectrum of the compound represented by formula (I);
  • FIG. 1 shows the NMR spectrum of the compound represented by formula (I);
  • Figure 3 shows the XRPD pattern of the crystal form of compound A-1 (denoted as crystal form A);
  • Figure 4 shows the DSC spectrum of the crystal form of compound A-1
  • Figure 5 shows the TGA spectrum of the crystal form of compound A-1
  • Figure 6 shows the XRPD pattern of the crystal form of compound A-2 (denoted as crystal form B);
  • Figure 7 shows the DSC spectrum of the crystal form of compound A-2
  • Figure 8 shows the TGA spectrum of the crystal form of compound A-2
  • Figure 9 shows the XRPD pattern of the crystal form (denoted as crystal form C) of compound A-3;
  • Figure 10 shows the DSC spectrum of the crystal form of compound A-3
  • FIG 11 shows the TGA spectrum of the crystal form of compound A-3
  • Figure 12 shows the NMR spectrum of the crystal form of compound A-3
  • Figure 13 shows the XRPD pattern of the crystal form (denoted as crystal form D) of compound A-4;
  • Figure 14 shows the DSC spectrum of the crystal form of compound A-4
  • Figure 15 shows the TGA spectrum of the crystal form of compound A-4
  • Figure 16 shows the NMR spectrum of the crystal form of compound A-4
  • Figure 17 shows the XRPD pattern of the crystal form (denoted as crystal form E) of compound A-5;
  • Figure 18 shows the DSC spectrum of the crystal form of compound A-5
  • Figure 19 shows the TGA spectrum of the crystal form of compound A-5
  • Figure 20 shows the NMR spectrum of the crystal form of compound A-5
  • Figure 21 shows the DVS diagram of the crystal form of compound A-3
  • Figure 22 shows the DVS diagram of the crystal form of compound A-4
  • Figure 23 shows the DVS diagram of the crystal form of compound A-5.
  • Patent application PCT/CN2023/132220 (filed on November 17, 2023, publication number WO2024104452A1) discloses the compound shown in formula (I), and all contents involved in that patent application are added to this invention by reference.
  • the system was extracted with ethyl acetate (2 ⁇ 300 mL), and the organic phases were combined.
  • the aqueous phase was then adjusted to pH 6 with hydrochloric acid (2 M), and extracted with methanol/dichloromethane (1/5) (4 ⁇ 500 mL).
  • the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give the title compound 1j (42 g, crude product). The crude product was not further purified and was directly fed into the next step.
  • Step 2 6-Chloro-2-methyl-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborane-2-yl)pyridine 1c
  • Step 2 1 g of (S)-7-amino-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester
  • Step 7 (R)-1-((S)-7-((5-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-6-methylpyridin-2-yl)amino)-5-azaspiro[2.4]hept-5-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)prop-1-one (I)
  • the crude product was purified by high-performance liquid chromatography (column specifications: Kinetex 5 ⁇ m EVO C18, 30*150 mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 39% B to 54% B over 10 minutes); and then lyophilized with a mixed solvent of acetonitrile/water (1 v/4 v) to give the compound of formula (I) (approximately 46.67 mg).
  • a signal peak for methanesulfonic acid was observed at 2.3 ppm. Based on the integration results, the molar ratio of the compound shown in formula (I) to methanesulfonic acid was approximately 1:1.6, i.e., n ⁇ 1.6.
  • a signal peak for mesylate was observed at 2.39 ppm. Based on the integration results, the ratio of the compound shown in formula (I) to mesylate was approximately 1:1, i.e., n ⁇ 1.
  • the molar ratio of the compound shown in formula (I) to ethyl sulfonic acid is about 1:0.9, that is, n ⁇ 0.9.
  • a signal peak of maleic acid was observed at 6.21 ppm. Based on the integration results, the molar ratio of the compound shown in formula (I) to maleic acid was approximately 1:0.9, i.e., n ⁇ 0.9.
  • Test Example 1 In vitro cell viability test
  • ⁇ Cell culture medium DMEM, 10% fetal bovine serum 1*PS, 200 ⁇ g/ml hygromycin
  • the cells are suspended in experimental buffer and then seeded into 384-well cell culture plates.
  • %Inhibiiton (Signalcmpd-SignalAve_VC)/(SignalAve_PC-SignalAve_VC) ⁇ 100.
  • SignalAve_VC Signal value of the negative control
  • SignalAve_PC Signal value of the positive control
  • %inhibition The percentage of inhibition rate.
  • Test Example 2 Pharmacokinetic Study of the Test Compound in Male SD Rats
  • test substance On the day of administration, the test substance was prepared using a solvent formulation of 5% DMSO + 5% Solutol + 90% Saline, and the prepared solution was kept on standby.
  • the intravenous injection (IV) group received a dose of 1 mg/kg at a concentration of 0.2 mg/mL
  • the oral gavage (PO) group received a dose of 2 mg/kg at a concentration of 0.2 mg/mL.
  • Animals in the oral group were required to fast overnight but had free access to water and were allowed to eat again 4 hours after administration. Fasting was not required for the intravenous group.
  • IV intravenously
  • PO orally
  • blood was collected intravenously at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration.
  • PO group blood was collected intravenously at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration.
  • Approximately 0.20 mL of blood was collected.
  • Blood collection tubes were anticoagulated with K2-EDTA. Plasma was obtained by centrifugation within 1 hour of blood collection (centrifugation conditions: 6800g, 6 minutes, 2-8°C). Samples were stored at -80°C before analysis.
  • the concentration of the test substance in the plasma of male SD rats was determined using a validated LC-MS/MS method.
  • the compound shown in formula (I) exhibits favorable pharmacokinetic properties in male SD rats, which enhances the drug-likeness of the compound.
  • the solid samples obtained in the experiment were analyzed using an ARL Equinox 100 X-ray powder diffractometer. The 2 ⁇ scanning angle ranged from 0° to 35°.
  • the testing method was Cu target K ⁇ radiation, voltage 40 kV, current 0.9 mA, and the sample disk was a zero-background sample disk.
  • thermogravimetric analyzer was a METTLER TOLEDO TGA2 (METTLER TOLEDO, US). 2-10 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C/min, with nitrogen purging at 50 mL/min at the sample location and 20 mL/min at the balance location.
  • the differential scanning calorimeter was a METTLER TOLEDO DSC3 (METTLER TOLEDO, US). 1-5 mg samples were accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10 °C/min, with nitrogen purging at a rate of 40 mL/min.
  • Dynamic moisture adsorption-desorption analysis was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations ranging from 0% to 95% to 0%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm/dt method, with a dm/dt value less than 0.002% maintained for 10 minutes as the endpoint, or each gradient maintained for a maximum of 180 minutes. After the test, XRPD analysis was performed on the samples to confirm whether the solid morphology had changed.
  • the high-performance liquid chromatographs used were Waters Arc HPLC (normal phase) and Agilent 1260II (reversed phase), and the test conditions are shown in Tables 6 and 7.
  • Compound A-1 was characterized by XRPD, and its XRPD spectrum is shown in Figure 3. This is designated as crystal form A. DSC and TGA tests were performed on crystal form A (see Figures 4 and 5). The results showed that crystal form A has an endothermic peak with an initial temperature of 104.30°C and a peak temperature of 109.74°C. Its weight loss from room temperature to approximately 130°C is about 1.7 wt%, indicating that it is an anhydrous compound.
  • Compound A-2 was characterized by XRPD, and its XRPD spectrum is shown in Figure 6.
  • the XRPD analysis is shown in Table 8, and it is designated as crystal form B.
  • DSC and TGA tests were performed on crystal form B (see Figures 7-8). The results showed that crystal form B has three endothermic peaks: an endothermic peak with an initial temperature of 25.62°C and a peak temperature of 32.16°C; an endothermic peak with an initial temperature of 139.58°C and a peak temperature of 144.80°C; and an endothermic peak with an initial temperature of 149.58°C and a peak temperature of 162.15°C.
  • the weight loss from room temperature to approximately 140°C is approximately 0.6 wt%, indicating that it is a hydrate.
  • the NMR results of the product show that the integration results are basically consistent with those of the free state; there is a signal peak of methanesulfonic acid at 2.35 ppm. According to the integration results, the ratio of the compound shown in formula (I) to methanesulfonic acid is approximately 1:1.
  • the product was characterized by XRPD, and its XRPD spectrum is shown in Figure 9.
  • the XRPD analysis is shown in Table 9, and it is denoted as crystal form C.
  • DSC and TGA tests were performed on crystal form C (see Figures 10 and 11). The results showed that crystal form C has an endothermic peak with an onset temperature of 186.63°C and a peak temperature of 189.65°C; the weight loss from room temperature to about 170°C is about 0.48wt%, indicating that it is an anhydrous product.
  • the NMR results of the product show that there is a signal peak of ethyl sulfonic acid at 1.07 ppm. According to the integration results, the molar ratio of the compound shown in formula (I) to ethyl sulfonic acid is about 1:0.9.
  • the product was characterized by XRPD, and its XRPD spectrum is shown in Figure 13.
  • the XRPD analysis is shown in Table 10, and it is denoted as crystal form D.
  • DSC and TGA tests were performed on crystal form D (see Figures 14-15), which showed that crystal form D has an endothermic peak with an onset temperature of 175.78°C and a peak temperature of 177.18°C; the weight loss in the range of room temperature to about 160°C is about 0.06wt%, indicating that it is an anhydrous product.
  • the NMR results of the product show that the integration results are basically consistent with those of the free state; there is a signal peak of maleic acid at 6.21 ppm and a signal peak of isopropyl ether at 1.72 ppm.
  • the molar ratio of the compound shown in formula (I) to maleic acid is about 1:0.9, and the molar ratio of the compound to isopropyl ether is 1:0.14.
  • the product was characterized by XRPD, and its XRPD spectrum is shown in Figure 17.
  • the XRPD analysis is shown in Table 11, and it is denoted as crystal form E.
  • DSC and TGA analysis of crystal form E showed that crystal form E has an endothermic peak with an onset temperature of 121.65°C and a peak temperature of 121.98°C; the weight loss at room temperature to about 130°C is about 2.0 wt%, indicating that it is an anhydrous product.
  • Crystal form C gains approximately 0.86% weight upon moisture absorption at 80% RH, and loses only 0.009% weight upon returning to 0% RH, indicating that crystal form C has slight hygroscopic properties.
  • the crystal form of crystal form C remains unchanged after DVS testing.
  • Crystal form D gains approximately 1.69% weight upon moisture absorption at 80% RH, and loses only 0.023% weight upon returning to 0% RH, indicating that crystal form D has slight hygroscopic properties.
  • the crystal form of crystal form D remains unchanged after DVS testing.
  • Crystal form E exhibits a moisture absorption weight gain of approximately 2.65% at 80% RH, and a weight loss of only 0.264% upon returning to 0% RH, indicating that crystal form E is hygroscopic.
  • the crystal form of crystal form E remains unchanged after DVS testing.
  • the preparation process of the biological medium is shown in Table 17.
  • Samples of different crystal forms were added to the biological medium and water and stirred at 37°C for 24 hours. Samples were taken at 0.5 hours, 2 hours, and 24 hours.
  • the sampled solutions were filtered through a 0.22 ⁇ m aqueous filter membrane. Some samples with higher concentrations were appropriately diluted with diluent.
  • the signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, the pH value of the supernatant after 24 hours was tested. The test results are shown in Table 18.

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Abstract

Provided in the present invention are a compound, and a preparation method therefor and the use thereof. The compound has a structure as shown in formula (A), wherein X represents an acid, and n is a number from 0.5 to 4. The compound exhibits an excellent biological activity and solubility, and has promising drug development prospects.

Description

一种化合物及其制备方法和应用A compound, its preparation method and application

本申请要求享有2024年5月17日向中国国家知识产权局提交的，专利申请号为202410619690.2，发明名称为“一种化合物及其制备方法和应用”的在先申请的优先权权益；所述在先申请的全文通过引用的方式结合于本申请中。This application claims priority to an earlier application filed on May 17, 2024, with China National Intellectual Property Administration, patent application number 202410619690.2, entitled "A compound and its preparation method and application"; the entire contents of the earlier application are incorporated herein by reference.

技术领域Technical Field

本发明属于化合物领域，具体涉及一种化合物及其制备方法和应用。This invention belongs to the field of compounds, specifically relating to a compound, its preparation method, and its application.

背景技术Background Technology

黑皮质素4受体(melanocortin-4 receptor，MC4R)是黑皮质素受体家族(MCRs)的成员，属于A类G蛋白偶联受体(GPCR)亚家族，由5个成员(MC1R-MC5R)组成，介导人体多种生理功能。MC4R是一个七次跨膜GPCR，主要在下丘脑、海马和丘脑表达，是机体体重和能量稳态的中心调控者。The melanocortin-4 receptor (MC4R) is a member of the melanocortin receptor family (MCRs), belonging to the class A G protein-coupled receptor (GPCR) subfamily. Composed of five members (MC1R-MC5R), it mediates various physiological functions in the human body. MC4R is a seven-transmembrane GPCR, primarily expressed in the hypothalamus, hippocampus, and thalamus, and is a central regulator of body weight and energy homeostasis.

MC4R是一个非同寻常的GPCR，因为既存在其内源性激动剂又有其内源性拮抗剂。基于MC4R信号通路参与调节摄食、能量平衡和生长的重要功能，MC4R成为治疗肥胖的靶点，MC4R激动剂Setmelanotide已经FDA获批上市用于POMC缺乏、瘦素受体缺乏和其他形式的严重遗传性肥胖的患者。MC4R is an unusual GPCR because it has both endogenous agonists and endogenous antagonists. Given the important role of the MC4R signaling pathway in regulating food intake, energy balance, and growth, MC4R has become a target for treating obesity. The MC4R agonist Setmelanotide has been approved by the FDA for patients with POMC deficiency, leptin receptor deficiency, and other forms of severe hereditary obesity.

现有技术中虽然已公开了几种小分子MC4R拮抗剂，但获得理化性质、生物利用度、生物活性等更适宜成药的新型小分子MC4R拮抗剂，是本领域亟待解决的技术问题。Although several small molecule MC4R antagonists have been disclosed in the prior art, obtaining novel small molecule MC4R antagonists with more suitable physicochemical properties, bioavailability, and biological activity for drug development is a technical problem that urgently needs to be solved in this field.

发明内容Summary of the Invention

本发明提供一种化合物，其具有如式A所示的结构：
This invention provides a compound having the structure shown in Formula A:

其中，X代表酸，n为0.5～4的数。Where X represents acid, and n is a number from 0.5 to 4.

根据本发明的实施方案，所述酸为无机酸或有机酸，例如所述无机酸选自盐酸、硫酸、磷酸、氢溴酸等中的一种或两种以上，例如所述有机酸选自甲磺酸、乙磺酸、天冬氨酸、柠檬酸、马来酸、富马酸、L-苹果酸、L-酒石酸、丙二酸、草酸、苯磺酸、甲苯磺酸等中的一种或两种以上。示例性地，X代表硫酸、甲磺酸、乙磺酸或马来酸。According to embodiments of the present invention, the acid is an inorganic acid or an organic acid. For example, the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc., and the organic acid is selected from one or more of methanesulfonic acid, ethanesulfonic acid, aspartic acid, citric acid, maleic acid, fumaric acid, L-malic acid, L-tartaric acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, etc. Exemplarily, X represents sulfuric acid, methanesulfonic acid, ethanesulfonic acid, or maleic acid.

根据本发明的实施方案，所述n为0.6～3的数，例如为0.7、0.8、0.87、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8或2.9。According to an embodiment of the present invention, n is a number from 0.6 to 3, for example, 0.7, 0.8, 0.87, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8 or 2.9.

根据本发明的一种实施方案，当X代表硫酸时，n为0.7～1.3的数。According to one embodiment of the present invention, when X represents sulfuric acid, n is a number from 0.7 to 1.3.

根据本发明的一种实施方案，当X代表甲磺酸时，n为0.9～2.2的数。According to one embodiment of the present invention, when X represents methanesulfonic acid, n is a number from 0.9 to 2.2.

根据本发明的一种实施方案，当X代表乙磺酸时，n为0.9～1.3的数。According to one embodiment of the present invention, when X represents ethanesulfonic acid, n is a number from 0.9 to 1.3.

根据本发明的一种实施方案，当X代表马来酸时，n为0.9～1.3的数。According to one embodiment of the present invention, when X represents maleic acid, n is a number from 0.9 to 1.3.

根据本发明示例性的方案，所述化合物为如下任一化合物：According to an exemplary embodiment of the present invention, the compound is any one of the following compounds:

n为0.6～3的数，例如0.7～1.3或0.8～1.0的数，示例性n＝0.8、0.87、0.9、1.0、1.1或1.2； n is a number between 0.6 and 3, for example, a number between 0.7 and 1.3 or a number between 0.8 and 1.0, such as n = 0.8, 0.87, 0.9, 1.0, 1.1 or 1.2;

n为1.4～2.2的数，例如1.5～2.0或1.5～1.8的数，示例性n＝1.4、1.5、1.6、1.7、1.8、1.9、2.0或2.1； n is a number between 1.4 and 2.2, such as a number between 1.5 and 2.0 or a number between 1.5 and 1.8, for example n = 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 or 2.1;

n为大于等于0.9且小于1.4的数，例如0.9～1.1的数，示例性n＝0.9、1.0、1.1、1.2或1.3； n is a number greater than or equal to 0.9 and less than 1.4, for example, a number between 0.9 and 1.1, such as n = 0.9, 1.0, 1.1, 1.2 or 1.3;

n为0.6～3的数，例如0.7～1.3或0.8～1.1的数，示例性n＝0.8、0.9、1.0、1.1或1.2； n is a number between 0.6 and 3, for example, a number between 0.7 and 1.3 or between 0.8 and 1.1, such as n = 0.8, 0.9, 1.0, 1.1 or 1.2;

n为0.6～3的数，例如0.7～1.3或0.8～1.0的数，示例性n＝0.8、0.9、1.0、1.1或1.2。 n is a number between 0.6 and 3, for example, a number between 0.7 and 1.3 or between 0.8 and 1.0, with examples n = 0.8, 0.9, 1.0, 1.1 or 1.2.

本发明还提供了制备式A所示化合物的方法，包括：式(I)所示化合物与X反应，得到所述式A所示化合物；
The present invention also provides a method for preparing the compound shown in formula A, comprising: reacting the compound shown in formula (I) with X to obtain the compound shown in formula A;

所述X和n具有如上文所示的限定。X and n have the limitations shown above.

根据本发明的实施方案，所述反应在第一有机溶剂中进行，例如所述第一有机溶剂选自甲基异丁基酮、乙酸异丙酯、甲醇、异丙醚、正庚烷中的一种或两种以上。According to an embodiment of the present invention, the reaction is carried out in a first organic solvent, for example, the first organic solvent is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane.

根据本发明的实施方案，所述反应的温度为40～60℃，例如45℃、50℃或55℃。According to an embodiment of the present invention, the reaction temperature is 40–60°C, for example 45°C, 50°C, or 55°C.

本发明还提供式A所示化合物的固体形态，包括无定形和晶型，例如包括式A-I(例如式A-1)化合物的晶型和无定形，式A-II(例如式A-2)化合物的晶型和无定形，式A-III(例如式A-3)化合物的晶型和无定形，式A-IV(例如式A-4)化合物的晶型和无定形、以及式A-V(例如式A-5)化合物的晶型和无定形。The present invention also provides solid forms of compounds of formula A, including amorphous and crystalline forms, such as crystalline and amorphous forms of compounds of formula A-I (e.g., formula A-1), crystalline and amorphous forms of compounds of formula A-II (e.g., formula A-2), crystalline and amorphous forms of compounds of formula A-III (e.g., formula A-3), crystalline and amorphous forms of compounds of formula A-IV (e.g., formula A-4), and crystalline and amorphous forms of compounds of formula A-V (e.g., formula A-5).

根据本发明的实施方案，所述式A-I(例如式A-1)化合物的晶型具有基本如图3所示的XRPD图谱。According to an embodiment of the present invention, the crystal form of the compound of formula A-I (e.g., formula A-1) has an XRPD pattern as shown in FIG3.

根据本发明的实施方案，所述式A-I(例如式A-1)化合物的晶型具有一个起始温度为100～108℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；例如，式A-I(例如式A-1)化合物的晶型具有一个起始温度为102～106℃、峰值温度与起始温度差值大于0且小于8℃的吸热峰；示例性地，所述式A-I(例如式A-1)化合物的晶型具有一个起始温度为104.3℃、峰值温度与起始温度差值为5.44℃的吸热峰。According to an embodiment of the present invention, the crystal form of the compound of formula A-I (e.g., formula A-1) has an endothermic peak with an initial temperature of 100-108°C and a peak temperature greater than 0 and less than 10°C. For example, the crystal form of the compound of formula A-I (e.g., formula A-1) has an endothermic peak with an initial temperature of 102-106°C and a peak temperature greater than 0 and less than 8°C. Exemplarily, the crystal form of the compound of formula A-I (e.g., formula A-1) has an endothermic peak with an initial temperature of 104.3°C and a peak temperature greater than 5.44°C.

根据本发明示例性的实施方案，所述式A-I(例如式A-1)化合物的晶型具有基本如图4所示的DSC图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-I (e.g., formula A-1) has a DSC spectrum substantially as shown in FIG4.

根据本发明的实施方案，所述式A-I(例如式A-1)化合物的晶型在室温～约130℃失重不超过2.0wt％，例如失重为1.2～1.9wt％。According to an embodiment of the present invention, the crystal form of the compound of formula A-I (e.g., formula A-1) loses no more than 2.0 wt% at room temperature to about 130°C, for example, a weight loss of 1.2 to 1.9 wt%.

根据本发明示例性的实施方案，所述式A-I(例如式A-1)化合物的晶型具有基本如图5所示的TGA图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-I (e.g., formula A-1) has a TGA spectrum as shown in FIG5.

根据本发明的实施方案，所述式A-I(例如式A-1)化合物的晶型为无水晶型。According to an embodiment of the present invention, the crystal form of the compound of formula A-I (e.g., formula A-1) is amorphous.

根据本发明的实施方案，所述式A-II(例如式A-2)化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在15.0±0.20°、18.3±0.20°、19.8±0.20°、21.3±0.20°和23.7±0.20°处具有特征峰；进一步地，还可以在16.6±0.20°、20.5±0.20°、23.2±0.20°、26.2±0.20°和/或27.7±0.20°处具有特征峰；进一步地，还可以在11.0±0.20°、12.1±0.20°、13.0±0.20°、13.8±0.20°、24.7±0.20°、26.9±0.20°、30.2±0.20°、31.7±0.20°和/或33.5±0.20°处具有特征峰。According to an embodiment of the invention, the crystal form of the compound of formula A-II (e.g., formula A-2) exhibits characteristic peaks in X-ray powder diffraction at 15.0±0.20°, 18.3±0.20°, 19.8±0.20°, 21.3±0.20°, and 23.7±0.20° when measured by Cu-Kα radiation, expressed in 2θ angles; further, characteristic peaks may also be observed at 16.6±0.20°, 20.5±0.20°, and 23.7±0.20°. Characteristic peaks are present at 2±0.20°, 26.2±0.20° and/or 27.7±0.20°; further, characteristic peaks may also be present at 11.0±0.20°, 12.1±0.20°, 13.0±0.20°, 13.8±0.20°, 24.7±0.20°, 26.9±0.20°, 30.2±0.20°, 31.7±0.20° and/or 33.5±0.20°.

根据本发明示例性的实施方案，所述式A-II(例如式A-2)化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.0±0.20°、12.1±0.20°、13.0±0.20°、13.8±0.20°、15.0±0.20°、16.6±0.20°、18.3±0.20°、19.8±0.20°、20.5±0.20°、21.3±0.20°、23.2±0.20°、23.7±0.20°、24.7±0.20°、26.2±0.20°、26.9±0.20°、27.7±0.20°、30.2±0.20°、31.7±0.20°和33.5±0.20°处具有特征峰。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-II (e.g., formula A-2) is determined by Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, is performed at 11.0±0.20°, 12.1±0.20°, 13.0±0.20°, 13.8±0.20°, 15.0±0.20°, 16.6±0.20°, and 18.3±0.20°. Characteristic peaks are present at 19.8±0.20°, 20.5±0.20°, 21.3±0.20°, 23.2±0.20°, 23.7±0.20°, 24.7±0.20°, 26.2±0.20°, 26.9±0.20°, 27.7±0.20°, 30.2±0.20°, 31.7±0.20°, and 33.5±0.20°.

根据本发明的实施方案，所述式A-II(例如式A-2)化合物的晶型具有基本如图6所示的XRPD图谱。According to an embodiment of the present invention, the crystal form of the compound of formula A-II (e.g., formula A-2) has an XRPD pattern as shown in FIG6.

根据本发明的实施方案，所述式A-II(例如式A-2)化合物的晶型具有基本如表8所示的XRPD特征峰，20角度误差为±0.20°。According to an embodiment of the present invention, the crystal form of the compound of formula A-II (e.g., formula A-2) has XRPD characteristic peaks as shown in Table 8, with an angle error of ±0.20°.

根据本发明的实施方案，所述式A-II(例如式A-2)化合物的晶型具有如下一个、两个或三个峰：According to an embodiment of the present invention, the crystal form of the compound of formula A-II (e.g., formula A-2) has one, two, or three peaks as follows:

(1)起始温度为20～30℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；例如，起始温度为22～27℃、峰值温度与起始温度差值大于2且小于8℃的吸热峰；示例性地，起始温度为25.62℃、峰值温度与起始温度差值为6.54℃的吸热峰；(1) An endothermic peak with an initial temperature of 20-30°C and a peak temperature difference greater than 0 and less than 10°C; for example, an endothermic peak with an initial temperature of 22-27°C and a peak temperature difference greater than 2 and less than 8°C; for example, an endothermic peak with an initial temperature of 25.62°C and a peak temperature difference of 6.54°C.

(2)起始温度为133～145℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；例如，起始温度为125～143℃、峰值温度与起始温度差值大于2且小于8℃的吸热峰；示例性地，起始温度为139.58℃、峰值温度与起始温度差值为5.22℃的吸热峰；(2) An endothermic peak with an initial temperature of 133-145℃ and a peak temperature greater than 0 and less than 10℃ from the initial temperature; for example, an endothermic peak with an initial temperature of 125-143℃ and a peak temperature greater than 2 and less than 8℃ from the initial temperature; for example, an endothermic peak with an initial temperature of 139.58℃ and a peak temperature greater than 5.22℃ from the initial temperature.

(3)起始温度为145～155℃、峰值温度与起始温度差值大于0且小于20℃的吸热峰；例如，起始温度为147～153℃、峰值温度与起始温度差值大于8且小于15℃的吸热峰；示例性地，起始温度为149.58℃、峰值温度与起始温度差值为12.57℃的吸热峰；(3) An endothermic peak with an initial temperature of 145-155℃ and a peak temperature difference greater than 0 and less than 20℃; for example, an endothermic peak with an initial temperature of 147-153℃ and a peak temperature difference greater than 8 and less than 15℃; for example, an endothermic peak with an initial temperature of 149.58℃ and a peak temperature difference of 12.57℃.

根据本发明示例性的实施方案，所述式A-II(例如式A-2)化合物的晶型具有基本如图7所示的DSC图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-II (e.g., formula A-2) has a DSC spectrum substantially as shown in FIG7.

根据本发明的实施方案，所述式A-II(例如式A-2)化合物的晶型在室温～约140℃失重不超过1.0wt％，优选失重不超过0.9wt％或0.8wt％，例如为0.3～0.8wt％。According to embodiments of the present invention, the crystal form of the compound of formula A-II (e.g., formula A-2) loses no more than 1.0 wt% at room temperature to about 140°C, preferably no more than 0.9 wt% or 0.8 wt%, for example 0.3 to 0.8 wt%.

根据本发明示例性的实施方案，所述式A-II(例如式A-2)化合物的晶型具有基本如图8所示的TGA图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-II (e.g., formula A-2) has a TGA spectrum substantially as shown in FIG8.

根据本发明的实施方案，所述式A-II(例如式A-2)化合物的晶型为水合物。According to an embodiment of the present invention, the crystal form of the compound of formula A-II (e.g., formula A-2) is a hydrate.

根据本发明的实施方案，所述式A-III(例如式A-3)化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在15.9±0.20°、19.6±0.20°、21.5±0.20°、22.1±0.20°、24.8±0.20°和26.5±0.20°处具有特征峰；进一步地，还可以在17.1±0.20°、18.1±0.20°、20.1±0.20°、23.5±0.20°和/或24.4±0.20°处具有特征峰；进一步地，还可以在14.6±0.20°、17.6±0.20°、28.1±0.20°、30.5±0.20°和/或32.9±0.20°处具有特征峰。According to an embodiment of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) is obtained by Cu-Kα radiation, and X-ray powder diffraction in 2θ angles shows characteristic peaks at 15.9±0.20°, 19.6±0.20°, 21.5±0.20°, 22.1±0.20°, 24.8±0.20°, and 26.5±0.20°; further, characteristic peaks may also be present at 17.1±0.20°, 18.1±0.20°, 20.1±0.20°, 23.5±0.20°, and/or 24.4±0.20°; further, characteristic peaks may also be present at 14.6±0.20°, 17.6±0.20°, 28.1±0.20°, 30.5±0.20°, and/or 32.9±0.20°.

根据本发明示例性的实施方案，所述式A-III(例如式A-3)化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.1±0.20°、4.4±0.20°、14.6±0.20°、15.9±0.20°、17.1±0.20°、17.6±0.20°、18.1±0.20°、19.6±0.20°、20.2±0.20°、21.5±0.20°、22.1±0.20°、23.5±0.20°、24.4±0.20°、24.8±0.20°、26.5±0.20°、28.1±0.20°、28.7±0.20°、30.5±0.20°、31.0±0.20°、32.0±0.20°、32.9±0.20°和33.4±0.20°处具有特征峰。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) is determined by Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, is performed at 3.1±0.20°, 4.4±0.20°, 14.6±0.20°, 15.9±0.20°, 17.1±0.20°, 17.6±0.20°, 18.1±0.20°, 19.6±0.20°, and 20.2± Characteristic peaks are present at 0.20°, 21.5±0.20°, 22.1±0.20°, 23.5±0.20°, 24.4±0.20°, 24.8±0.20°, 26.5±0.20°, 28.1±0.20°, 28.7±0.20°, 30.5±0.20°, 31.0±0.20°, 32.0±0.20°, 32.9±0.20°, and 33.4±0.20°.

根据本发明的实施方案，所述式A-III(例如式A-3)化合物的晶型具有基本如图9所示的XRPD图谱。According to an embodiment of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) has an XRPD pattern as shown in FIG9.

根据本发明的实施方案，所述式A-III(例如式A-3)化合物的晶型具有基本如表9所示的XRPD特征峰，2θ角度误差为±0.20°。According to an embodiment of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) has XRPD characteristic peaks as shown in Table 9, with a 2θ angle error of ±0.20°.

根据本发明的实施方案，所述式A-III(例如式A-3)化合物的晶型具有一个起始温度为180～192℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；例如，起始温度为183～190℃、峰值温度与起始温度差值大于2且小于5℃的吸热峰；示例性地，起始温度为186.63℃、峰值温度与起始温度差值为3.02℃的吸热峰。According to an embodiment of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) has an endothermic peak with an initial temperature of 180-192°C and a peak temperature greater than 0 and less than 10°C; for example, an endothermic peak with an initial temperature of 183-190°C and a peak temperature greater than 2 and less than 5°C; exemplaryly, an endothermic peak with an initial temperature of 186.63°C and a peak temperature greater than 3.02°C.

根据本发明示例性的实施方案，所述式A-III(例如式A-3)化合物的晶型具有基本如图10所示的DSC图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) has a DSC spectrum substantially as shown in FIG10.

根据本发明的实施方案，所述式A-III(例如式A-3)化合物的晶型在室温～约170℃失重不超过1.0wt％，优选失重不超过0.9wt％、0.7wt％或0.5wt％。According to embodiments of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) loses no more than 1.0 wt% at room temperature to about 170°C, preferably no more than 0.9 wt%, 0.7 wt%, or 0.5 wt%.

根据本发明示例性的实施方案，所述式A-III(例如式A-3)化合物的晶型具有基本如图11所示的TGA图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) has a TGA spectrum substantially as shown in FIG11.

根据本发明的实施方案，所述式A-III(例如式A-3)化合物的晶型为无水物。According to an embodiment of the present invention, the crystal form of the compound of formula A-III (e.g., formula A-3) is anhydrous.

根据本发明的实施方案，所述式A-IV(例如式A-4)化合物的晶型使用Cu-Kα辐射，以20角度表示的X-射线粉末衍射在12.8±0.20°、16.5±0.20°、17.5±0.20°、21.3±0.20°、22.3±0.20°和26.6±0.20°处具有特征峰；进一步地，还可以在10.8±0.20°、19.6±0.20°、20.6±0.20°、23.1±0.20°、27.1±0.20°和/或28.8±0.20°处具有特征峰；进一步地，还可以在13.8±0.20°、25.1±0.20°、27.6±0.20°、28.2±0.20°、29.7±0.20°和/或34.8±0.20°处具有特征峰。According to embodiments of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) exhibits characteristic peaks in X-ray powder diffraction at 12.8±0.20°, 16.5±0.20°, 17.5±0.20°, 21.3±0.20°, 22.3±0.20°, and 26.6±0.20° when measured using Cu-Kα radiation at 20° angles; further, characteristic peaks can also be observed at 10.8±0.20°. Characteristic peaks are present at 0°, 19.6±0.20°, 20.6±0.20°, 23.1±0.20°, 27.1±0.20° and/or 28.8±0.20°; further, characteristic peaks may also be present at 13.8±0.20°, 25.1±0.20°, 27.6±0.20°, 28.2±0.20°, 29.7±0.20° and/or 34.8±0.20°.

根据本发明示例性的实施方案，所述式A-IV(例如式A-4)化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在10.8±0.20°、12.8±0.20°、13.8±0.20°、16.5±0.20°、17.5±0.20°、19.6±0.20°、20.6±0.20°、21.3±0.20°、22.3±0.20°、23.1±0.20°、25.1±0.20°、26.6±0.20°、27.1±0.20°、27.6±0.20°、28.2±0.20°、28.8±0.20°、29.7±0.20°和34.8±0.20°处具有特征峰。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) is characterized by X-ray powder diffraction at 10.8±0.20°, 12.8±0.20°, 13.8±0.20°, 16.5±0.20°, 17.5±0.20°, 19.6±0.20°, 20.6±0.20°, 21.3±0.20°, 22.3±0.20°, 23.1±0.20°, 25.1±0.20°, 26.6±0.20°, 27.1±0.20°, 27.6±0.20°, 28.2±0.20°, 28.8±0.20°, 29.7±0.20°, and 34.8±0.20° when measured using Cu-Kα radiation.

根据本发明的实施方案，所述式A-IV(例如式A-4)化合物的晶型具有基本如图13所示的XRPD图谱。According to an embodiment of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) has an XRPD pattern as shown in FIG13.

根据本发明的实施方案，所述式A-IV(例如式A-4)化合物的晶型具有基本如表10所示的XRPD特征峰，2θ角度误差为±0.20°。According to an embodiment of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) has XRPD characteristic peaks as shown in Table 10, with a 2θ angle error of ±0.20°.

根据本发明的实施方案，所述式A-IV(例如式A-4)化合物的晶型具有一个起始温度为170～180℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；例如，起始温度为172～178℃、峰值温度与起始温度差值大于0且小于5℃的吸热峰；示例性地，起始温度为175.78℃、峰值温度与起始温度差值为1.4℃的吸热峰。According to an embodiment of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) has an endothermic peak with an initial temperature of 170-180°C and a peak temperature greater than 0 and less than 10°C; for example, an endothermic peak with an initial temperature of 172-178°C and a peak temperature greater than 0 and less than 5°C; exemplaryly, an endothermic peak with an initial temperature of 175.78°C and a peak temperature greater than 1.4°C.

根据本发明示例性的实施方案，所述式A-IV(例如式A-4)化合物的晶型具有基本如图14所示的DSC图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) has a DSC spectrum substantially as shown in FIG14.

根据本发明的实施方案，所述式A-IV(例如式A-4)化合物的晶型在室温～约160℃失重不超过0.5wt％，优选失重不超过0.3wt％、0.2wt％或0.1wt％。According to embodiments of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) loses no more than 0.5 wt% at room temperature to about 160°C, preferably no more than 0.3 wt%, 0.2 wt%, or 0.1 wt%.

根据本发明示例性的实施方案，所述式A-IV(例如式A-4)化合物的晶型具有基本如图15所示的TGA图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) has a TGA spectrum substantially as shown in FIG15.

根据本发明的实施方案，所述式A-IV(例如式A-4)化合物的晶型为无水物。According to an embodiment of the present invention, the crystal form of the compound of formula A-IV (e.g., formula A-4) is anhydrous.

根据本发明的实施方案，所述式A-V(例如式A-5)化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在6.3±0.20°、13.0±0.20°、15.8±0.20°、18.1±0.20°、18.9±0.20°和23.3±0.20°处具有特征峰；进一步地，还可以在7.2±0.20°、8.5±0.20°、13.9±0.20°、16.9±0.20°、20.9±0.20°、21.7±0.20°、22.7±0.20°、24.3±0.20°、25.6±0.20°和/或27.5±0.20°处具有特征峰；进一步地，还可以在9.3±0.20°、10.6±0.20°、11.3±0.20°、12.1±0.20°、26.3±0.20°、27.8±0.20°、28.7±0.20°和/或29.4±0.20°处具有特征峰。According to an embodiment of the invention, the crystal form of the compounds of formulas A-V (e.g., formula A-5) is determined by Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, shows characteristic peaks at 6.3±0.20°, 13.0±0.20°, 15.8±0.20°, 18.1±0.20°, 18.9±0.20°, and 23.3±0.20°; furthermore, characteristic peaks may also be observed at 7.2±0.20°, 8.5±0.20°, 13.9±0.20°, and 16.9±0.20°. Characteristic peaks are present at 20.9±0.20°, 21.7±0.20°, 22.7±0.20°, 24.3±0.20°, 25.6±0.20° and/or 27.5±0.20°; further, characteristic peaks may also be present at 9.3±0.20°, 10.6±0.20°, 11.3±0.20°, 12.1±0.20°, 26.3±0.20°, 27.8±0.20°, 28.7±0.20° and/or 29.4±0.20°.

根据本发明示例性的实施方案，所述式A-V(例如式A-5)化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在6.3±0.20°、7.2±0.20°、8.5±0.20°、9.3±0.20°、10.6±0.20°、11.3±0.20°、12.1±0.20°、13.0±0.20°、13.9±0.20°、15.8±0.20°、16.9±0.20°、18.1±0.20°、18.9±0.20°、20.9±0.20°、21.7±0.20°、22.7±0.20°、23.3±0.20°、24.3±0.20°、25.6±0.20°、26.3±0.20°、27.5±0.20°、27.8±0.20°、28.7±0.20°和29.4±0.20°处具有特征峰。According to an exemplary embodiment of the present invention, the crystal form of the compounds of formulas A-V (e.g., formula A-5) is determined by Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, is performed at 6.3±0.20°, 7.2±0.20°, 8.5±0.20°, 9.3±0.20°, 10.6±0.20°, 11.3±0.20°, 12.1±0.20°, 13.0±0.20°, 13.9±0.20°, and 15.8±0.20°. Characteristic peaks are present at 20°, 16.9±0.20°, 18.1±0.20°, 18.9±0.20°, 20.9±0.20°, 21.7±0.20°, 22.7±0.20°, 23.3±0.20°, 24.3±0.20°, 25.6±0.20°, 26.3±0.20°, 27.5±0.20°, 27.8±0.20°, 28.7±0.20°, and 29.4±0.20°.

根据本发明的实施方案，所述式A-V(例如式A-5)化合物的晶型具有基本如图17所示的XRPD图谱。According to an embodiment of the present invention, the crystal form of the compound of formula A-V (e.g., formula A-5) has an XRPD pattern as shown in FIG17.

根据本发明的实施方案，所述式A-V(例如式A-5)化合物的晶型具有基本如表11所示的XRPD特征峰，2θ角度误差为±0.20°。According to an embodiment of the present invention, the crystal form of the compound of formula A-V (e.g., formula A-5) has XRPD characteristic peaks as shown in Table 11, with a 2θ angle error of ±0.20°.

根据本发明的实施方案，所述式A-V(例如式A-5)化合物的晶型具有一个起始温度为115～130℃、峰值温度与起始温度差值大于0且小于3℃的吸热峰；例如，起始温度为118～125℃、峰值温度与起始温度差值大于0且小于1℃的吸热峰；示例性地，起始温度为121.65℃、峰值温度与起始温度差值为0.33℃的吸热峰。According to an embodiment of the present invention, the crystal form of the compound of formula A-V (e.g., formula A-5) has an endothermic peak with an initial temperature of 115-130°C and a peak temperature greater than 0 and less than 3°C; for example, an endothermic peak with an initial temperature of 118-125°C and a peak temperature greater than 0 and less than 1°C; exemplaryly, an endothermic peak with an initial temperature of 121.65°C and a peak temperature less than 0.33°C.

根据本发明示例性的实施方案，所述式A-V(例如式A-5)化合物的晶型具有基本如图18所示的DSC图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-V (e.g., formula A-5) has a DSC spectrum substantially as shown in FIG18.

根据本发明的实施方案，所述式A-V(例如式A-5)化合物的晶型在室温～约130℃失重不超过2.5wt％，优选失重不超过2.3wt％、2.2wt％或2.1wt％，例如失重1.5～2.3wt％。According to embodiments of the present invention, the crystal form of the compound of formula A-V (e.g., formula A-5) loses no more than 2.5 wt% at room temperature to about 130°C, preferably no more than 2.3 wt%, 2.2 wt%, or 2.1 wt%, for example, 1.5 to 2.3 wt%.

根据本发明示例性的实施方案，所述式A-V(例如式A-5)化合物的晶型具有基本如图19所示的TGA图谱。According to an exemplary embodiment of the present invention, the crystal form of the compound of formula A-V (e.g., formula A-5) has a TGA spectrum as shown in FIG19.

根据本发明的实施方案，所述式A-V(例如式A-5)化合物的晶型为无水物。According to an embodiment of the present invention, the crystal form of the compound of formula A-V (e.g., formula A-5) is anhydrous.

本发明还提供所述式A所示化合物的晶型的制备方法，包括将式(I)所示化合物与X和第一有机溶剂混合，搅拌溶清，加入第二有机溶剂，形成悬浮液，再加入第三有机溶剂，继续搅拌，而后降至室温搅拌，经后处理，得到所述晶型；The present invention also provides a method for preparing the crystal form of the compound shown in Formula A, comprising mixing the compound shown in Formula (I) with X and a first organic solvent, stirring to dissolve, adding a second organic solvent to form a suspension, adding a third organic solvent, continuing to stir, then cooling to room temperature and stirring, and after post-treatment, obtaining the crystal form;

X和第一有机溶剂具有如上文所示的限定。X and the first organic solvent are as defined above.

根据本发明的实施方案，所述第一有机溶剂、第二有机溶剂和/或第三有机溶剂相同或不同。According to embodiments of the present invention, the first organic solvent, the second organic solvent, and/or the third organic solvent may be the same or different.

根据本发明的实施方案，所述第二有机溶剂选自甲基异丁基酮、乙酸异丙酯、甲醇、异丙醚、正庚烷中的一种或两种以上，例如异丙醚。According to an embodiment of the present invention, the second organic solvent is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane, for example, isopropyl ether.

根据本发明的实施方案，所述第三有机溶剂选自甲基异丁基酮、乙酸异丙酯、甲醇、异丙醚、正庚烷中的一种或两种以上，例如异丙醚。According to an embodiment of the present invention, the third organic solvent is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane, for example, isopropyl ether.

根据本发明的实施方案，所述第一有机溶剂、第二有机溶剂与第三有机溶剂的体积比为1：(0.5～10)：(1～10)，例如1：(1～5)：(2～8)。According to an embodiment of the present invention, the volume ratio of the first organic solvent, the second organic solvent and the third organic solvent is 1:(0.5-10):(1-10), for example 1:(1-5):(2-8).

根据本发明的实施方案，所述式(I)所示化合物与第一有机溶剂的质量体积比为50～500mg/ml，例如150～300mg/ml。According to an embodiment of the present invention, the mass-to-volume ratio of the compound represented by formula (I) to the first organic solvent is 50 to 500 mg/ml, for example, 150 to 300 mg/ml.

根据本发明的实施方案，所述搅拌溶清的温度为40～60℃，例如45℃、50℃或55℃。According to an embodiment of the present invention, the temperature of the stirring and dissolving process is 40 to 60°C, for example, 45°C, 50°C or 55°C.

根据本发明的实施方案，加入第三有机溶剂后搅拌1～6h，例如2～4h。According to an embodiment of the present invention, after adding the third organic solvent, the mixture is stirred for 1 to 6 hours, for example, 2 to 4 hours.

根据本发明的实施方案，所述室温搅拌的时间不低于1天，例如为1～3天。According to an embodiment of the present invention, the stirring time at room temperature is not less than 1 day, for example, 1 to 3 days.

本发明还提供所述式A-IV(例如式A-4)所示化合物的晶型的一种制备方法，包括将式(I)所示化合物与乙磺酸和4-甲基-2戊酮混合，40～60℃(例如50℃)搅拌1～6h(例如2～4h)，降至室温继续搅拌不低于1天(例如为2天、3天或更多天)；所得固体经离心、干燥，得到所述式A-IV(例如式A-4)所示化合物；The present invention also provides a method for preparing the crystal form of the compound represented by formulas A-IV (e.g., formula A-4), comprising mixing the compound represented by formula (I) with ethanesulfonic acid and 4-methyl-2-pentanone, stirring at 40-60°C (e.g., 50°C) for 1-6 hours (e.g., 2-4 hours), cooling to room temperature and continuing to stir for at least 1 day (e.g., 2 days, 3 days or more); the resulting solid is centrifuged and dried to obtain the compound represented by formulas A-IV (e.g., formula A-4);

优选地，所述乙磺酸与式(I)所示化合物的当量比为1.0～2.5，例如1.1～2.4，示例性为1.2、1.3、1.4、2.0、2.1、2.2、2.3。Preferably, the equivalence ratio of the ethanesulfonic acid to the compound shown in formula (I) is 1.0 to 2.5, for example 1.1 to 2.4, such as 1.2, 1.3, 1.4, 2.0, 2.1, 2.2, and 2.3.

本发明还提供所述式A-IV(例如式A-4)所示化合物的晶型的一种制备方法，包括将式(I)所示化合物与乙磺酸和4-甲基-2戊酮混合，40～60℃(例如50℃)搅拌1～6h(例如2～4h)，降至室温继续搅拌不低于1天(例如为2天、3天或更多天)，再降至0～6℃(例如5℃)继续搅拌不低于1天(例如为1天、2天或更多天)；所得固体经离心、干燥，得到所述式A-IV(例如式A-4)所示化合物；The present invention also provides a method for preparing the crystal form of the compound represented by formulas A-IV (e.g., formula A-4), comprising mixing the compound represented by formula (I) with ethanesulfonic acid and 4-methyl-2-pentanone, stirring at 40-60°C (e.g., 50°C) for 1-6 hours (e.g., 2-4 hours), cooling to room temperature and continuing to stir for at least 1 day (e.g., 2 days, 3 days or more), then cooling to 0-6°C (e.g., 5°C) and continuing to stir for at least 1 day (e.g., 1 day, 2 days or more); the resulting solid is centrifuged and dried to obtain the compound represented by formulas A-IV (e.g., formula A-4);

优选地，所述乙磺酸与式(I)所示化合物的当量比为1.0～2.5，例如1.1～2.4，示例性为1.2、1.3、1.4、2.0、2.1、2.2、2.3。Preferably, the equivalence ratio of the ethanesulfonic acid to the compound shown in formula (I) is 1.0 to 2.5, for example 1.1 to 2.4, such as 1.2, 1.3, 1.4, 2.0, 2.1, 2.2, and 2.3.

本发明还提供所述式A-IV(例如式A-4)所示化合物的晶型的一种制备方法，包括将式(I)所示化合物与乙磺酸和4-甲基-2戊酮混合，40～60℃(例如50℃)搅拌1～6h(例如2～4h)，降温搅拌(例如先降至室温搅拌不低于1天，若无固体析出，再降至0～6℃继续搅拌不低于1天)，如无固体析出，则在室温下向混合物中加入异丙醚，搅拌至固体析出；所得固体经离心、干燥，得到所述式A-IV(例如式A-4)所示化合物；The present invention also provides a method for preparing the crystal form of the compound represented by formulas A-IV (e.g., formula A-4), comprising mixing the compound represented by formula (I) with ethanesulfonic acid and 4-methyl-2-pentanone, stirring at 40-60°C (e.g., 50°C) for 1-6 hours (e.g., 2-4 hours), cooling and stirring (e.g., first cooling to room temperature and stirring for at least 1 day; if no solid precipitates, then cooling to 0-6°C and continuing to stir for at least 1 day), if no solid precipitates, adding isopropyl ether to the mixture at room temperature and stirring until solid precipitates; the obtained solid is centrifuged and dried to obtain the compound represented by formulas A-IV (e.g., formula A-4);

优选地，所述乙磺酸与式(I)所示化合物的当量比为1.0～2.5，例如1.1～2.4，示例性为1.2、1.3、1.4、2.0、2.1、2.2、2.3。Preferably, the equivalence ratio of the ethanesulfonic acid to the compound shown in formula (I) is 1.0 to 2.5, for example 1.1 to 2.4, such as 1.2, 1.3, 1.4, 2.0, 2.1, 2.2, and 2.3.

本发明还提供一种药物组合物，包含上述式A所示化合物和/或式A所示化合物的固体形态(例如晶型)。The present invention also provides a pharmaceutical composition comprising the compound shown in Formula A above and/or the solid form (e.g., crystal form) of the compound shown in Formula A.

根据本发明的实施方案，所述药物组合物还包含一种、两种或更多种药学上可接受的辅料。According to embodiments of the present invention, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable excipients.

根据本发明的实施方案，所述药物组合物中还可以含有另外的治疗剂，与式A所示化合物或式A所示化合物的晶型组合使用。According to embodiments of the present invention, the pharmaceutical composition may further contain additional therapeutic agents, used in combination with the compound shown in Formula A or a crystal form of the compound shown in Formula A.

本发明还提供上述式A所示化合物、式A所示化合物的固体形态(例如晶型)或所述药物组合物在制备药物中的应用，所述药物为诊断、预防和/或治疗MC4R受体介导的疾病或病症的药物。The present invention also provides the use of the compound of Formula A, the solid form (e.g., crystal form) of the compound of Formula A, or the pharmaceutical composition thereof in the preparation of a medicament for the diagnosis, prevention, and/or treatment of MC4R receptor-mediated diseases or conditions.

根据本发明的实施方案，所述药物为MC4R拮抗剂。According to an embodiment of the present invention, the drug is an MC4R antagonist.

根据本发明的实施方案，所述疾病或病症为恶病质(与癌症相关的恶病质、与获得性免疫缺陷综合征(AIDS)相关的恶病质、与充血性心力衰竭(CHF)相关的恶病质；与慢性肾病(CKD)相关的恶病质；与其他慢性疾病治疗相关的恶病质)；厌食或神经性厌食症(老年性厌食、与化疗和/或放疗相关的厌食)；恶心呕吐；体重减轻(非自愿体重减轻)；生长发育不全；肌少症；肌肉萎缩；肌肉无力；脆弱；骨质疏松症；骨疾病(骨丢失)；疼痛(神经病理性疼痛)；焦虑(创伤后应激障碍或PTSD)；抑郁症；高血压；营养不良肥胖(如慢性肥胖引起的肌肉减少症)；性功能障碍；和炎症性疾病(与厌食或恶病质、肌肉减少或肌肉萎缩相关的炎症性疾病)。According to embodiments of the present invention, the disease or condition is cachexia (cachexia associated with cancer, cachexia associated with acquired immunodeficiency syndrome (AIDS), cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with treatment of other chronic diseases); anorexia or anorexia nervosa (anorexia in the elderly, anorexia associated with chemotherapy and/or radiotherapy); nausea and vomiting; weight loss (involuntary weight loss); growth retardation; sarcopenia; muscle atrophy; muscle weakness; fragility; osteoporosis; bone disease (bone loss); pain (neuropathic pain); anxiety (post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition-related obesity (such as sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (inflammatory diseases associated with anorexia or cachexia, sarcopenia or muscle atrophy).

本发明还提供了一种用于诊断、预防和/或治疗MC4R受体介导的疾病或病症的方法，该方法包括向需要这种治疗的患者单独施用治疗有效量的上述式A所示化合物、式A所示化合物的固体形态(例如晶型)或药物组合物。The present invention also provides a method for diagnosing, preventing and/or treating MC4R receptor-mediated diseases or conditions, the method comprising administering, alone to a patient requiring such treatment, a therapeutically effective amount of the compound of Formula A, a solid form (e.g., a crystal form) of the compound of Formula A, or a pharmaceutical composition thereof.

根据本发明的实施方案，所述疾病或病症具有如上文相同的限定。According to an embodiment of the present invention, the disease or ailment has the same limitations as described above.

有益效果Beneficial effects

式A所示化合物具有良好的生物活性和溶解性，具备成药前景。The compound shown in Formula A has good biological activity and solubility, and has the potential to be developed into a drug.

式A所示化合物的晶型具有低引湿性、良好的溶解性、化学稳定性和/或物理稳定性，具备成药前景。The crystal form of the compound shown in Formula A has low hygroscopicity, good solubility, chemical stability and/or physical stability, and has the potential to be developed into a drug.

术语定义与说明Terminology Definitions and Explanations

术语“晶型”指具有相同化学组成但有不同的形成结晶的分子和/或离子的空间排布的晶型，包括单晶。例如，当n约为0.9(如化合物和酸按照摩尔比1：1成盐)时能够得到单晶。The term "crystal form" refers to a crystal form that has the same chemical composition but a different spatial arrangement of molecules and/or ions that form crystals, including single crystals. For example, single crystals can be obtained when n is approximately 0.9 (such as when a compound and an acid form a salt in a 1:1 molar ratio).

术语“无定形”指不是结晶的分子和/或离子的固体形式。无定形固体不显示确定的具有清晰最大值的X-射线粉末衍射图形。The term "amorphous" refers to a solid form of molecules and/or ions that are not crystalline. Amorphous solids do not exhibit definite X-ray powder diffraction patterns with clear maximum values.

术语“基本上如图所示的X-射线粉末衍射图谱”是指X-射线粉末衍射图所示的主要峰中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在X-射线粉末衍射图中；其主要峰指以最高峰作为参照(最高峰的相对强度指定为100％)，相对强度大于10％、优选大于20％、更优选大于30％的峰。The term "X-ray powder diffraction pattern substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the major peaks shown in the X-ray powder diffraction pattern appear in the X-ray powder diffraction pattern; the major peaks refer to peaks with a relative intensity greater than 10%, preferably greater than 20%, and more preferably greater than 30%, with the highest peak as a reference (the relative intensity of the highest peak is specified as 100%).

术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害活性化合物的生物活性及性能的辅料。The term "pharmaceuticalally acceptable excipient" refers to an excipient that does not cause significant irritation to the organism and does not impair the biological activity and properties of the active compound.

术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或病症的个体中缓解疾病、紊乱或疾病(即逆转病理和/或病症)。The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and/or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptom of the disease, disorder, or symptom (i.e., reversal of the pathology and/or symptom).

术语“两种以上”指两种、三种或更多种。The term "two or more" refers to two, three or more kinds.

术语“室温”指温度为20-25℃。The term "room temperature" refers to a temperature of 20-25°C.

式A所示化合物(例如式A-1化合物、式A-2化合物、式A-3化合物、式A-4化合物和A-5化合物)中的n值为约数，误差范围为±0.2，优选为±0.1。以n约为0.9为例，代表n取值范围为0.7～1.1，优选0.8～1.0。In the compounds represented by Formula A (e.g., compounds of Formula A-1, Formula A-2, Formula A-3, Formula A-4, and Formula A-5), the value of n is an approximation with an error range of ±0.2, preferably ±0.1. Taking an n value of approximately 0.9 as an example, this represents a range of n values from 0.7 to 1.1, preferably from 0.8 to 1.0.

附图说明Attached Figure Description

图1为式(I)所示化合物的XRPD图谱；Figure 1 shows the XRPD spectrum of the compound represented by formula (I);

图2为式(I)所示化合物的NMR图谱；Figure 2 shows the NMR spectrum of the compound represented by formula (I);

图3为式A-1化合物的晶型(记为晶型A)的XRPD图谱；Figure 3 shows the XRPD pattern of the crystal form of compound A-1 (denoted as crystal form A);

图4为式A-1化合物的晶型的DSC图谱；Figure 4 shows the DSC spectrum of the crystal form of compound A-1;

图5为式A-1化合物的晶型的TGA图谱；Figure 5 shows the TGA spectrum of the crystal form of compound A-1;

图6为式A-2化合物的晶型(记为晶型B)的XRPD图谱；Figure 6 shows the XRPD pattern of the crystal form of compound A-2 (denoted as crystal form B);

图7为式A-2化合物的晶型的DSC图谱；Figure 7 shows the DSC spectrum of the crystal form of compound A-2;

图8为式A-2化合物的晶型的TGA图谱；Figure 8 shows the TGA spectrum of the crystal form of compound A-2;

图9为式A-3化合物的晶型(记为晶型C)的XRPD图谱；Figure 9 shows the XRPD pattern of the crystal form (denoted as crystal form C) of compound A-3;

图10为式A-3化合物的晶型的DSC图谱；Figure 10 shows the DSC spectrum of the crystal form of compound A-3;

图11为式A-3化合物的晶型的TGA图谱；Figure 11 shows the TGA spectrum of the crystal form of compound A-3;

图12为式A-3化合物的晶型的NMR图谱；Figure 12 shows the NMR spectrum of the crystal form of compound A-3;

图13为式A-4化合物的晶型(记为晶型D)的XRPD图谱；Figure 13 shows the XRPD pattern of the crystal form (denoted as crystal form D) of compound A-4;

图14为式A-4化合物的晶型的DSC图谱；Figure 14 shows the DSC spectrum of the crystal form of compound A-4;

图15为式A-4化合物的晶型的TGA图谱；Figure 15 shows the TGA spectrum of the crystal form of compound A-4;

图16为式A-4化合物的晶型的NMR图谱；Figure 16 shows the NMR spectrum of the crystal form of compound A-4;

图17为式A-5化合物的晶型(记为晶型E)的XRPD图谱；Figure 17 shows the XRPD pattern of the crystal form (denoted as crystal form E) of compound A-5;

图18为式A-5化合物的晶型的DSC图谱；Figure 18 shows the DSC spectrum of the crystal form of compound A-5;

图19为式A-5化合物的晶型的TGA图谱；Figure 19 shows the TGA spectrum of the crystal form of compound A-5;

图20为式A-5化合物的晶型的NMR图谱；Figure 20 shows the NMR spectrum of the crystal form of compound A-5;

图21为式A-3化合物的晶型的DVS图；Figure 21 shows the DVS diagram of the crystal form of compound A-3;

图22为式A-4化合物的晶型的DVS图；Figure 22 shows the DVS diagram of the crystal form of compound A-4;

图23为式A-5化合物的晶型的DVS图。Figure 23 shows the DVS diagram of the crystal form of compound A-5.

具体实施方式Detailed Implementation

下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

专利申请PCT/CN2023/132220(申请日为2023年11月17日，公开号WO2024104452A1)记载了式(I)所示化合物，该专利申请中所涉及的所有内容均以引证的方式添加到本发明中。Patent application PCT/CN2023/132220 (filed on November 17, 2023, publication number WO2024104452A1) discloses the compound shown in formula (I), and all contents involved in that patent application are added to this invention by reference.

以下为实施例1-6所用的仪器、参数、表征及测试方法：The following are the instruments, parameters, characterization, and testing methods used in Examples 1-6:

(1)核磁分析(1H NMR)(1) Nuclear magnetic resonance analysis ( ¹H NMR)

将若干毫克固体样品溶解于二甲基亚砜-d6或氘代甲醇溶剂中，在Bruker AVANCE NEO 400(Bruker，GER)上进行核磁分析。Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 or deuterated methanol solvent and analyzed by nuclear magnetic resonance on a Bruker AVANCE NEO 400 (Bruker, GER).

(2)离子色谱仪器及方法(2) Ion chromatography instruments and methods

表1
Table 1

实施例1式(I)所示化合物的制备和表征Example 1: Preparation and characterization of the compound shown in formula (I)

(1)中间体1c的合成
(1) Synthesis of intermediate 1c

第一步(6-氯-2-甲基吡啶-3-基)硼酸1jStep 1 (6-chloro-2-methylpyridin-3-yl)boronic acid 1j

氮气保护下，在2升三口烧瓶中加入1c-a(50g)和四氢呋喃(500mL)，将体系降温至-78摄氏度。在-78摄氏度下滴加正丁基锂溶液(2.5mol/L，四氢呋喃/正己烷溶液，117mL)，滴加完毕后，-78摄氏度搅拌反应40分钟。然后在-78摄氏度下滴加硼酸三甲酯(50.33g)，维持-78摄氏度继续反应60分钟后，滴加饱和氯化铵水溶液(400mL)淬灭反应。体系用乙酸乙酯(2×300mL)萃取，合并有机相，水相再用盐酸(2M)调节到PH＝6，水相用甲醇/二氯甲烷(1/5)萃取(4×500毫升)。合并有机相无水硫酸钠干燥，浓缩得到标题化合物1j(42g，粗品)。粗品未进一步纯化，直接投下步。Under nitrogen protection, 1c-a (50 g) and tetrahydrofuran (500 mL) were added to a 2 L three-necked flask, and the system was cooled to -78 °C. A 2.5 mol/L tetrahydrofuran/n-hexane solution (117 mL) was added dropwise at -78 °C, and the reaction was stirred at -78 °C for 40 minutes. Then, trimethyl borate (50.33 g) was added dropwise at -78 °C, and the reaction was continued at -78 °C for 60 minutes. The reaction was then quenched by adding a saturated ammonium chloride aqueous solution (400 mL). The system was extracted with ethyl acetate (2 × 300 mL), and the organic phases were combined. The aqueous phase was then adjusted to pH 6 with hydrochloric acid (2 M), and extracted with methanol/dichloromethane (1/5) (4 × 500 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give the title compound 1j (42 g, crude product). The crude product was not further purified and was directly fed into the next step.

LC-MS：(ES，m/z)＝172.05[M+H]+LC-MS: (ES, m/z)=172.05[M+H]+

第二步 6-氯-2-甲基-3-(4，4,5,5-四乙基-1，3，2-二氧杂硼烷-2-基)吡啶1cStep 2: 6-Chloro-2-methyl-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborane-2-yl)pyridine 1c

将1j(17g)和3,4-二乙基已烷-3,4-二醇(15.56g)溶于二氯甲烷(170mL)溶液中，室温下反应12小时。反应混合物用水(150mL)稀释，二氯甲烷萃取(4×150mL)。合并有机相，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，乙酸乙酯/石油醚(0-15％)，得到标题化合物1c(20g)。1j (17 g) and 3,4-diethylhexane-3,4-diol (15.56 g) were dissolved in dichloromethane (170 mL) and reacted at room temperature for 12 hours. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (4 × 150 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to ethyl acetate/petroleum ether (0–15%) to give title compound 1c (20 g).

LC-MS：(ESI，m/z)＝310.50[M+H]+LC-MS: (ESI, m/z)=310.50[M+H]+

(2)中间体1g的合成
(2) Synthesis of intermediate 1g

第一步(S)-7-((叔丁氧基羰基)氨基)-5-氮杂螺[2.4]庚烷-5-羧酸苄酯11Step 1 (S)-7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester 11

在0摄氏度下，向1升三口烧瓶内加入1k(30g)和三乙胺(42.90g)溶在二氯甲烷(300mL)中，滴加氯甲酸苄酯(36.16g)。加入完毕后体系室温下继续搅拌2小时。反应混合物室温下用冰水(100mL)淬灭。反应混合物用乙酸乙酯萃取(3×300mL)。合并有机相，用饱和食盐水反洗(1×100mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，石油醚/乙酸乙酯(3：2)，得到标题化合物1l(46.0g)。At 0°C, 1kJ (30g) and triethylamine (42.90g) dissolved in dichloromethane (300mL) were added to a 1L three-necked flask, followed by dropwise addition of benzyl chloroformate (36.16g). After the addition was complete, the system was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water (100mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3×300mL). The combined organic phases were backwashed with saturated brine (1×100mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (3:2) to give the title compound 1L (46.0g).

LC-MS：(ES，m/z)＝347.10[M+H]+LC-MS: (ES, m/z)=347.10[M+H]+

第二步(S)-7-氨基-5-氮杂螺[2.4]庚烷-5-羧酸苄酯1gStep 2: 1 g of (S)-7-amino-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester

在0摄氏度下，向1升三口烧瓶内加入1l(46g)溶在1，4-二氧六环(100mL)中，滴加氯化氢的1，4-二氧六环(4M，150mL)溶液，加入完毕后体系室温下继续搅拌1小时。反应混合物室温下用饱和碳酸氢钠水溶液淬灭。反应混合物用乙酸乙酯萃取(3×500毫升)。合并有机相，用饱和食盐水反洗(1×300毫升)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩，得到标题化合物1g(28.0g)。At 0°C, 1 L (46 g) of a compound dissolved in 1,4-dioxane (100 mL) was added to a 1 L three-necked flask, followed by dropwise addition of a 4 M, 150 mL solution of 1,4-dioxane hydrogen chloride. The mixture was stirred at room temperature for 1 hour after the addition was complete. The reaction mixture was quenched at room temperature with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (3 × 500 mL). The combined organic phases were backwashed with saturated brine (1 × 300 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1 g (28.0 g) of the title compound.

LC-MS：(ES，m/z)＝247.05[M+H]+LC-MS: (ES, m/z)=247.05[M+H]+

(3)(R)-1-((S)-7-((5-(2-(二氟甲氧基)-1-甲基-1H-咪唑-4-基)-6-甲基吡啶-2-基)氨基)-5-氮杂螺[2.4]庚-5-基)-2-(5-氟-2-甲氧基吡啶-4-基)丙-1-酮式(I)
(3)(R)-1-((S)-7-((5-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-6-methylpyridin-2-yl)amino)-5-azaspiro[2.4]hept-5-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)prop-1-one (I)

第一步 4-溴-2-甲氧基-1-甲基-1H-咪唑1bStep 1 4-Bromo-2-methoxy-1-methyl-1H-imidazolium 1b

将化合物1a(3g)溶在无水甲醇(30mL)中，室温下缓慢滴加甲醇钠-甲醇溶液(30wt％，45g)，滴加完毕后升温至70℃继续搅拌过夜。然后将反应混合物冷却至室温，用水(100mL)稀释，随后混合物用乙酸乙酯萃取(3×100mL)。合并有机相，用饱和氯化钠溶液反洗(2×100mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩，得到标题化合物1b(1.1g)。Compound 1a (3 g) was dissolved in anhydrous methanol (30 mL), and a sodium methoxide-methanol solution (30 wt%, 45 g) was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 70 °C and the mixture was stirred overnight. The reaction mixture was then cooled to room temperature and diluted with water (100 mL). The mixture was then extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (2 × 100 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give title compound 1b (1.1 g).

LC-MS：(ESI，m/z)＝191.25[M+H]+LC-MS: (ESI, m/z)=191.25[M+H]+

第二步 6-氯-3-(2-甲氧基-1-甲基-1H-咪唑-4-基)-2-甲基吡啶1dStep 2: 6-Chloro-3-(2-methoxy-1-methyl-1H-imidazol-4-yl)-2-methylpyridine 1d

将1b(600mg)和1c(976mg)溶在1，4-二氧六环(6mL)和水(1.5mL)的混合溶液中，随后加入[1，1′-双(二叔丁基膦)二茂铁]二氯化钯(206mg)和磷酸钾(1.34g)，氮气置换三次并升温至80℃继续搅拌3小时。将反应混合物降温至室温后过滤，滤液用水(30mL)稀释，随后混合物用乙酸乙酯萃取(3×50mL)。合并有机相，用饱和氯化钠溶液反洗(2×30mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，洗脱剂为乙酸乙酯/石油醚(0-18％)，得到标题化合物1d(350mg)。Compound 1b (600 mg) and 1c (976 mg) were dissolved in a mixture of 1,4-dioxane (6 mL) and water (1.5 mL), followed by the addition of [1,1′-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (206 mg) and potassium phosphate (1.34 g). The mixture was purged three times with nitrogen and heated to 80 °C with stirring for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (30 mL), and the mixture was then extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (2 × 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (0–18%) as the eluent to give title compound 1d (350 mg).

LC-MS：(ESI，m/z)＝238.00[M+H]+LC-MS: (ESI, m/z)=238.00[M+H]+

第三步 4-(6-氯-2-甲基吡啶-3-基)-1-甲基-1H-咪唑-2-醇1eStep 3: 4-(6-chloro-2-methylpyridin-3-yl)-1-methyl-1H-imidazol-2-ol 1e

将1d(350mg)溶在四氢呋喃(4mL)中，随后加入稀盐酸溶液(1M，4mL)并升温至60℃继续搅拌1小时。将反应体系降温至室温后，用饱和碳酸氢钠溶液调整pH至弱酸性，随后混合物用乙酸乙酯萃取(3×30mL)。合并有机相，用饱和氯化钠溶液反洗(2×30mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩，得到标题化合物1e(300mg)。1d (350 mg) was dissolved in tetrahydrofuran (4 mL), followed by the addition of dilute hydrochloric acid solution (1 M, 4 mL) and the mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, the pH was adjusted to weakly acidic with saturated sodium bicarbonate solution, and the mixture was then extracted with ethyl acetate (3 × 30 mL). The combined organic phases were backwashed with saturated sodium chloride solution (2 × 30 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1e (300 mg).

LC-MS：(ESI，m/z)＝224.00[M+H]+LC-MS: (ESI, m/z)=224.00[M+H]+

第四步 6-氯-3-(2-(二氟甲氧基)-1-甲基-1H-咪唑-4-基)-2-甲基吡啶1fStep 4: 6-Chloro-3-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-2-methylpyridine 1f

将1e(300mg)溶在1，4-二氧六环(10mL)中，加入氢氧化钠溶液(20wt％，10mL)并升温至65℃后，通入一氯二氟甲烷气体并于65℃继续搅拌1小时。将反应体系降温至室温后，用水(30mL)稀释，随后混合物用乙酸乙酯萃取(3×50mL)。合并有机相，用饱和氯化钠溶液反洗(2×30mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，洗脱剂为乙酸乙酯/石油醚(0-18％)，得到标题化合物1f(230mg)。1e (300 mg) was dissolved in 1,4-dioxane (10 mL), sodium hydroxide solution (20 wt%, 10 mL) was added, and the mixture was heated to 65 °C. Dichlorofluoromethane gas was then introduced, and the mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The mixture was then extracted with ethyl acetate (3 × 50 mL). The combined organic phases were backwashed with saturated sodium chloride solution (2 × 30 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (0–18%) as the eluent to give the title compound 1f (230 mg).

LC-MS：(ESI，m/z)＝273.95[M+H]+7LC-MS: (ESI, m/z)=273.95[M+H]+7

第五步(S)-7-((5-(2-(二氟甲氧基)-1-甲基-1H-咪唑-4-基)-6-甲基吡啶-2-基)氨基)-5-氮杂螺[2.4]庚烷-5-羧酸苄酯1hStep 5 (S)-7-((5-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-6-methylpyridin-2-yl)amino)-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester 1h

将1f(200mg)和1g(198mg)溶在甲苯(2mL)中，随后加入三(二亚苄基丙酮)二钯(67mg)，2-二环己基膦-2′，6′-二甲氧基-联苯(60mg)和叔丁醇钠(140mg)，氮气置换三次并升温至90℃继续搅拌1小时。将反应混合物降温至室温后过滤，滤液用水(30mL)稀释，随后混合物用乙酸乙酯萃取(3×50mL)。合并有机相，用饱和氯化钠溶液反洗(2×30mL)，无水硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。所得残余物用硅胶柱层析纯化，洗脱剂为乙酸乙酯/石油醚(0-38％)，得到标题化合物1h(240mg)。1f (200 mg) and 1g (198 mg) were dissolved in toluene (2 mL), followed by the addition of tris(dibenzylacetone)dipalladium (67 mg), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (60 mg), and sodium tert-butoxide (140 mg). The mixture was purged three times with nitrogen and heated to 90 °C with stirring for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (30 mL), and the mixture was then extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (2 × 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (0–38%) as the eluent to give the title compound 1h (240 mg).

LC-MS：(ESI，m/z)＝484.10[M+H]+LC-MS: (ESI, m/z)=484.10[M+H]+

第六步(S)-N-(5-(2-(二氟甲氧基)-1-甲基-1H-咪唑-4-基)-6-甲基吡啶-2-基)-5-氮杂螺[2.4]庚-7-胺1iStep 6 (S)-N-(5-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-6-methylpyridin-2-yl)-5-azaspiro[2.4]hept-7-amine 1i

将1h(240mg)放入反应瓶中，室温下加入三氟乙酸(5mL)并升温至60℃继续搅拌1小时。将反应混合物减压浓缩得到标题化合物1i的三氟乙酸盐(180mg，粗品)。粗品未进一步纯化，直接投下步。1 h (240 mg) was placed in a reaction flask, and trifluoroacetic acid (5 mL) was added at room temperature. The mixture was then heated to 60 °C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate of the title compound 1i (180 mg, crude product). The crude product was not further purified and was directly added to the next step.

LC-MS：(ESI，m/z)＝350.05[M+H]+LC-MS: (ESI, m/z)=350.05[M+H]+

第七步(R)-1-((S)-7-((5-(2-(二氟甲氧基)-1-甲基-1H-咪唑-4-基)-6-甲基吡啶-2-基)氨基)-5-氮杂螺[2.4]庚-5-基)-2-(5-氟-2-甲氧基吡啶-4-基)丙-1-酮式(I)Step 7: (R)-1-((S)-7-((5-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-6-methylpyridin-2-yl)amino)-5-azaspiro[2.4]hept-5-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)prop-1-one (I)

将1i的三氟乙酸盐(90mg，粗品)和化合物1f(50mg)溶在N,N-二甲基乙酰胺(2mL)中，加入N,N-二异丙基乙胺(322mg)将体系调至碱性，随后加入1-丙基磷酸酐(50wt％的乙酸乙酯溶液，800mg)并在室温下继续搅拌1小时。将所得混合物过滤，滤饼用N,N-二甲基乙酰胺(2×1mL)洗涤。粗品通过高效液相(层析柱规格：Kinetex 5μm EVO C18，30*150mm；流动相A：水(10mmol/L碳酸氢铵)，流动相B：乙腈；流速：60毫升/分钟；梯度：10分钟内39％B到54％B；)纯化，再用乙腈/水(1v/4v)的混合溶剂冻干，得到式(I)所示化合物(约46.67mg)。The trifluoroacetate of 1i (90 mg, crude) and compound 1f (50 mg) were dissolved in N,N-dimethylacetamide (2 mL), and the system was adjusted to alkalinity by adding N,N-diisopropylethylamine (322 mg). Then, 1-propylphosphonic anhydride (50 wt% ethyl acetate solution, 800 mg) was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered, and the filter cake was washed with N,N-dimethylacetamide (2 × 1 mL). The crude product was purified by high-performance liquid chromatography (column specifications: Kinetex 5 μm EVO C18, 30*150 mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 39% B to 54% B over 10 minutes); and then lyophilized with a mixed solvent of acetonitrile/water (1 v/4 v) to give the compound of formula (I) (approximately 46.67 mg).

LC-MS：(ESI，m/z)＝530.90[M+H]+。LC-MS: (ESI, m/z)=530.90[M+H]+.

式(I)所示化合物的XRPD和NMR图谱如图1-2所示。The XRPD and NMR spectra of the compound shown in formula (I) are shown in Figures 1-2.

发明人实验发现，式A所示化合物的制备与酸和溶剂的选择相关。本申请制备得到的式A所示化合物的实施例具体如下所示。The inventors have experimentally discovered that the preparation of the compound shown in Formula A is related to the choice of acid and solvent. Examples of the compound shown in Formula A prepared in this application are shown below.

实施例2Example 2

将式(I)所示化合物40mg加入0.4mL甲基异丁基酮中，加入90μL硫酸的甲基异丁基酮溶液(H2SO4的浓度为1M)，50℃搅拌2小时后降至室温搅拌2天后，离心，固体50℃真空干燥，得到产物，即式A-1化合物。
Add 40 mg of the compound shown in formula (I) to 0.4 mL of methyl isobutyl ketone, add 90 μL of methyl isobutyl ketone solution of sulfuric acid ( H2SO4 concentration is 1M), stir at 50 °C for 2 hours, cool to room temperature and stir for 2 days, centrifuge, and dry the solid under vacuum at 50 °C to obtain the product, namely compound A-1.

NMR结果：1H NMR(400MHz，DMSO-d6)δ12.48(s，1H)，8.13(dd，J＝9.6，1.5Hz，1H)，7.81-7.19(m，2H)，7.01(s，1H)，6.70(dd，J＝9.1，4.9Hz，1H)，4.27-3.98(m，2H)，3.82(d，J＝4.4Hz，3H)，3.63-3.49(m，4H)，2.71-2.57(m，3H)，1.40-1.15(m，5H)，0.94-0.56(m，6H)；NMR results: 1 H NMR (400MHz, DMSO-d 6 )δ12.48 (s, 1H), 8.13 (dd, J=9.6, 1.5Hz, 1H), 7.81-7.19 (m, 2H), 7.01 (s, 1H), 6.70 (dd, J=9.1, 4.9Hz, 1H), 4.27- 3.98 (m, 2H), 3.82 (d, J=4.4Hz, 3H), 3.63-3.49 (m, 4H), 2.71-2.57 (m, 3H), 1.40-1.15 (m, 5H), 0.94-0.56 (m, 6H);

离子色谱测试结果计算得到，式A-1化合物中n≈0.87。Based on the ion chromatography test results, n≈0.87 in compound A-1.

实施例3Example 3

将式(I)所示化合物40mg加入0.6mL乙酸异丙酯中，加入166μL甲磺酸的乙酸异丙酯溶液(甲磺酸的浓度为1M)，50℃搅拌2小时后降至室温搅拌2天后，离心，固体50℃真空干燥，得到产物，即式A-2化合物。
Add 40 mg of the compound shown in formula (I) to 0.6 mL of isopropyl acetate, add 166 μL of isopropyl acetate solution of methanesulfonic acid (methanesulfonic acid concentration is 1M), stir at 50 °C for 2 hours, cool to room temperature and stir for 2 days, centrifuge, and dry the solid under vacuum at 50 °C to obtain the product, namely compound A-2.

NMR结果：1H NMR(400MHz，DMSO-d6)δ12.57(s，1H)，8.13(dd，J＝10.2，1.6Hz，1H)，7.80-7.19(m，2H)，7.13-6.90(m，1H)，6.70(dd，J＝9.3，4.9Hz，1H)，4.30-3.96(m，2H)，3.82(m，5H)，3.53(m，5H)，2.63(d，J＝4.8Hz，3H)，2.32(s，5H)，2.00(q，J＝6.9，6.3Hz，1H)，1.32(dd，J＝13.6，6.9Hz，3H)，0.95-0.61(m，4H).在2.3ppm处有甲磺酸的信号峰；根据积分结果计算，式(I)所示化合物和甲磺酸的摩尔比约为1：1.6，即n≈1.6。NMR results: 1 H NMR (400MHz, DMSO-d 6 )δ12.57 (s, 1H), 8.13 (dd, J=10.2, 1.6Hz, 1H), 7.80-7.19 (m, 2H), 7.13-6.90 (m, 1H), 6.70 (dd, J=9.3, 4.9Hz, 1H), 4.30-3.96 (m, 2H), 3.82 (m, 5H), 3.53 (m, 5H), 2.63 (d, J= 4.8 Hz, 3H), 2.32 s, 5H), 2.00 q, J = 6.9, 6.3 Hz, 1H), 1.32 dd, J = 13.6, 6.9 Hz, 3H), 0.95-0.61 m, 4H. A signal peak for methanesulfonic acid was observed at 2.3 ppm. Based on the integration results, the molar ratio of the compound shown in formula (I) to methanesulfonic acid was approximately 1:1.6, i.e., n≈1.6.

实施例4Example 4

将式(I)所示化合物211g，加入1L乙腈，缓慢滴加1.1eq甲磺酸的乙腈溶液(20mL)，室温搅拌1小时后，加入异丙醚1L，过滤，用异丙醚淋洗，浓缩干，用一定量的水(50V)溶解后冻干，得到式A-3化合物。
211 g of the compound shown in formula (I) was added to 1 L of acetonitrile, and 20 mL of acetonitrile solution of 1.1 eq methanesulfonic acid was slowly added dropwise. After stirring at room temperature for 1 hour, 1 L of isopropyl ether was added, filtered, washed with isopropyl ether, concentrated to dryness, dissolved in a certain amount of water (50 V), and freeze-dried to obtain compound A-3.

NMR结果：1H NMR(400MHz，DMSO-d6)δ8.29-8.03(m，2H)，7.79-7.25(m，2H)，7.03(dd，J＝17.8，9.4Hz，1H)，6.75-6.64(m，1H)，4.27-3.94(m，2H)，3.91-3.69(m，4H)，3.68-3.51(m，6H)，2.62(d，J＝6.2Hz，3H)，2.39(s，3H)，1.32(dd，J＝13.1，6.9Hz，3H)，0.92-0.58(m，5H).NMR results: 1 H NMR (400MHz, DMSO-d 6 )δ8.29-8.03 (m, 2H), 7.79-7.25 (m, 2H), 7.03 (dd, J=17.8, 9.4Hz, 1H), 6.75-6.64 (m, 1H), 4.27-3.94 (m, 2H), 3.91-3 .69 (m, 4H), 3.68-3.51 (m, 6H), 2.62 (d, J=6.2Hz, 3H), 2.39 (s, 3H), 1.32 (dd, J=13.1, 6.9Hz, 3H), 0.92-0.58 (m, 5H).

在2.39ppm处有甲磺酸的信号峰，根据积分结果计算，式(I)所示化合物和甲磺酸的比例约为1：1，即n≈1。A signal peak for mesylate was observed at 2.39 ppm. Based on the integration results, the ratio of the compound shown in formula (I) to mesylate was approximately 1:1, i.e., n≈1.

实施例5Example 5

将式(I)所示化合物40mg加入0.3mL甲基异丁基酮中，加入90μL乙磺酸的甲基异丁基酮溶液(乙磺酸的浓度为1M)，50℃搅拌2小时后浓缩后加一定量的水(50V)溶解，冻干，得到产物，即式A-4化合物。
Add 40 mg of the compound shown in formula (I) to 0.3 mL of methyl isobutyl ketone, add 90 μL of methyl isobutyl ketone solution of ethanesulfonic acid (concentration of ethanesulfonic acid is 1 M), stir at 50 °C for 2 hours, concentrate, add a certain amount of water (50 V) to dissolve, freeze dry to obtain the product, namely compound A-4.

NMR结果：1H NMR(400MHz，DMSO-d6)δ12.74(s，1H)，8.57(d，J＝46.9Hz，1H)，8.13(dd，J＝10.8，1.6Hz，2H)，7.54(td，J＝72.0，1.1Hz，2H)，7.03(s，1H)，6.70(dd，J＝6.5，4.9Hz，1H)，4.31-3.95(m，2H)，3.82(d，J＝4.9Hz，3H)，3.54(d，J＝2.6Hz，4H)，2.62(d，J＝5.5Hz，3H)，2.42(q，J＝7.4Hz，2H)，1.32(dd，J＝13.8，6.9Hz，3H)，1.24(s，1H)，1.07(t，J＝7.4Hz，3H)，0.92-0.58(m，4H).NMR results: 1 H NMR (400MHz, DMSO-d 6 ) δ12.74 (s, 1H), 8.57 (d, J = 46.9Hz, 1H), 8.13 (dd, J = 10.8, 1.6Hz, 2H), 7.54 (td, J = 7 2.0, 1.1Hz, 2H), 7.03 (s, 1H), 6.70 (dd, J=6.5, 4.9Hz, 1H), 4.31-3.95 (m, 2H), 3.82 (d , J=4.9Hz, 3H), 3.54 (d, J=2.6Hz, 4H), 2.62 (d, J=5.5Hz, 3H), 2.42 (q, J=7.4Hz, 2H), 1.32 (dd, J=13.8, 6.9Hz, 3H), 1.24 (s, 1H), 1.07 (t, J=7.4Hz, 3H), 0.92-0.58 (m, 4H).

在2.42ppm、1.07ppm处有乙基磺酸的信号峰，根据积分结果计算，式(I)所示化合物和乙基磺酸的摩尔比约为1：0.9，即n≈0.9。There are signal peaks of ethyl sulfonic acid at 2.42 ppm and 1.07 ppm. According to the integration results, the molar ratio of the compound shown in formula (I) to ethyl sulfonic acid is about 1:0.9, that is, n≈0.9.

实施例6Example 6

将式(I)所示化合物40mg加入0.6mL甲基异丁基酮或乙酸异丙酯中，加入10.6mg的马来酸，50℃搅拌2小时后降至室温搅拌2天后，离心，固体50℃真空干燥，得到产物，即式A-5化合物。
Add 40 mg of the compound shown in formula (I) to 0.6 mL of methyl isobutyl ketone or isopropyl acetate, add 10.6 mg of maleic acid, stir at 50 °C for 2 hours, cool to room temperature and stir for 2 days, centrifuge, and dry the solid under vacuum at 50 °C to obtain the product, namely compound A-5.

NMR结果：1H NMR(400MHz，DMSO-d6)δ8.12(dd，J＝8.7，1.6Hz，1H)，7.53(td，J＝72.2，0.9Hz，1H)，7.12(s，1H)，6.71(dd，J＝6.8，4.9Hz，1H)，6.60(s，1H)，6.21(s，2H)，4.29-3.96(m，2H)，3.82(d，J＝5.8Hz，3H)，3.79-3.43(m，6H)，2.47(s，3H)，1.41-1.13(m，4H)，1.04(d，J＝6.0Hz，2H)，0.92-0.77(m，1H)，0.74-0.45(m，2H).NMR results: 1H NMR (400MHz, DMSO-d6 ) )δ8.12 (dd, J=8.7, 1.6Hz, 1H), 7.53 (td, J=72.2, 0.9Hz, 1H), 7.12 (s, 1H), 6.71 (dd, J=6.8, 4.9Hz, 1H), 6.60 (s, 1H), 6.21 (s, 2H), 4.29-3.96 ( m, 2H), 3.82 (d, J=5.8Hz, 3H), 3.79-3.43 (m, 6H), 2.47 (s, 3H), 1.41-1. 13(m, 4H), 1.04(d, J=6.0Hz, 2H), 0.92-0.77(m, 1H), 0.74-0.45(m, 2H).

在6.21ppm处有马来酸的信号峰，根据积分结果计算，式(I)所示化合物和马来酸的摩尔比约为1：0.9，即n≈0.9。A signal peak of maleic acid was observed at 6.21 ppm. Based on the integration results, the molar ratio of the compound shown in formula (I) to maleic acid was approximately 1:0.9, i.e., n≈0.9.

测试例1体外细胞活性测试Test Example 1: In vitro cell viability test

a.实验耗材a. Laboratory consumables

表2
Table 2

b.实验步骤b. Experimental Procedure

√细胞系：flipin-293-MC4√ Cell line: flipin-293-MC4

√细胞培养基：DMEM，10％胎牛血清1*PS，200μg/ml潮霉素√ Cell culture medium: DMEM, 10% fetal bovine serum 1*PS, 200μg/ml hygromycin

√实验缓冲液：HBSS，20mM HEPES，0.1％BSA，500μM IBMX√ Experimental buffer: HBSS, 20mM HEPES, 0.1% BSA, 500μM IBMX

√阳性化合物：ML00253764√ Positive compound: ML00253764

c.拮抗剂检测c. Antagonist detection

1.细胞消化后悬浮在实验缓冲液中，然后种到384孔细胞实验板中。1. After digestion, the cells are suspended in experimental buffer and then seeded into 384-well cell culture plates.

2.向细胞板中加入式(I)所示化合物，37℃下孵育10分钟。2. Add the compound shown in formula (I) to the cell plate and incubate at 37°C for 10 minutes.

3.向细胞板中加入Melanotan I，37℃下孵育30分钟。3. Add Melanotan I to the cell plate and incubate at 37°C for 30 minutes.

4.融解EU cAMP tracer和ulight anti camp两个检测试剂，用试剂盒中裂解液进行稀释。4. Dissolve the EU cAMP tracer and ulight anti-camp test reagents and dilute them with the lysis buffer provided in the kit.

5.向细胞板中加入稀释好的检测试剂。室温下孵育1小时。5. Add the diluted test reagent to the cell plate. Incubate at room temperature for 1 hour.

6.用Envision读数。(激发光：340nm，发射光：615nm和665nm)6. Use Envision readings. (Excitation: 340nm, Emission: 615nm and 665nm)

d.数据分析d. Data Analysis

1.％Inhibition计算：1. % Inhibition Calculation:

％Inhibiiton＝(Signalcmpd-SignalAve_VC)/(SignalAve_PC-SignalAve_VC)×100.%Inhibiiton=(Signalcmpd-SignalAve_VC)/(SignalAve_PC-SignalAve_VC)×100.

Signalcmpd：化合物信号值；Signalcmpd: Compound signal value;

SignalAve_VC：阴性对照的信号值；SignalAve_VC: Signal value of the negative control;

SignalAve_PC：阳性对照的信号值；SignalAve_PC: Signal value of the positive control;

％inhibition：抑制率的百分比。%inhibition: The percentage of inhibition rate.

2.利用GraphPad非线性拟合公式计算化合物IC50：2. Calculate the IC50 of the compound using the GraphPad nonlinear fitting formula:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))

X：化合物浓度对数值；Y：抑制率的百分比X: Logarithm of compound concentration; Y: Percentage of inhibition rate

受试化合物拮抗MC4R的活性如表3所示。The antagonistic activities of the test compounds against MC4R are shown in Table 3.

表3
Table 3

测试例2受试化合物在SD雄性大鼠体内的药代动力学研究Test Example 2: Pharmacokinetic Study of the Test Compound in Male SD Rats

2.1实验方法2.1 Experimental Methods

给药当天采用5％DMSO+5％Solutol+90％Saline溶媒处方，对受试物进行配制，给药溶液配好后备用。On the day of administration, the test substance was prepared using a solvent formulation of 5% DMSO + 5% Solutol + 90% Saline, and the prepared solution was kept on standby.

静脉注射IV组给药剂量为1mg/kg，给药浓度为0.2mg/mL，口服灌胃PO组给药剂量为2mg/kg，给药浓度为0.2mg/mL。其中口服组动物需提前禁食过夜，自由饮水，并于给药后4小时还食，静脉组无需禁食。The intravenous injection (IV) group received a dose of 1 mg/kg at a concentration of 0.2 mg/mL, while the oral gavage (PO) group received a dose of 2 mg/kg at a concentration of 0.2 mg/mL. Animals in the oral group were required to fast overnight but had free access to water and were allowed to eat again 4 hours after administration. Fasting was not required for the intravenous group.

给药前称量动物体重，根据体重，计算给药量，并于给药当天IV和PO给药一次。IV组给药后在0.083、0.25、0.5、1.0、2.0、4.0、8.0和24h时间点通过静脉采血，PO组给药后在0.25、0.5、1.0、2.0、4.0、6.0、8.0和24h时间点静脉采血。取血量约0.20mL，采血管K2-EDTA抗凝，血液样本采集后1h内离心得血浆(离心条件：6800g，6分钟，2-8℃)，待测样品在分析前存放于-80℃冰箱内。Animals were weighed before administration, and the dosage was calculated based on their weight. The animals were administered intravenously (IV) and orally (PO) once on the same day. For the IV group, blood was collected intravenously at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration. For the PO group, blood was collected intravenously at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration. Approximately 0.20 mL of blood was collected. Blood collection tubes were anticoagulated with K2-EDTA. Plasma was obtained by centrifugation within 1 hour of blood collection (centrifugation conditions: 6800g, 6 minutes, 2-8℃). Samples were stored at -80℃ before analysis.

运用已验证的LC-MS/MS方法检测SD雄性大鼠血浆中受试物浓度。The concentration of the test substance in the plasma of male SD rats was determined using a validated LC-MS/MS method.

2.2实验结果2.2 Experimental Results

本发明中化合物在SD雄性大鼠体内的药代动力学研究通过以上的实验进行测定，结果见表4。The pharmacokinetic studies of the compounds in this invention in male SD rats were conducted using the experiments described above, and the results are shown in Table 4.

表4受试化合物在SD雄性大鼠体内的药代动力学研究实验结果(IV 1mpk/PO 2mpk)
Table 4. Pharmacokinetic study results of the test compounds in male SD rats (IV 1 mpk/PO 2 mpk)

2.3实验结论2.3 Experimental Conclusions

式(I)所示化合物在SD雄性大鼠体内具有良好的药代动力学性质，提升了化合物的成药性。The compound shown in formula (I) exhibits favorable pharmacokinetic properties in male SD rats, which enhances the drug-likeness of the compound.

测试例3溶解度测试Test Example 3: Solubility Test

分别称量式(I)所示化合物、式A-4化合物、式A-5化合物9.5mg，加入4mL水中，在37℃下搅拌24h，然后使用HPLC测量溶液的信号峰面积，最后根据峰面积、原料的HPLC标准曲线和稀释倍数计算溶液中化合物的浓度，结果见表5。Weigh 9.5 mg of the compound shown in formula (I), compound A-4, and compound A-5 respectively, add them to 4 mL of water, stir at 37 °C for 24 h, and then use HPLC to measure the signal peak area of the solution. Finally, calculate the concentration of the compound in the solution based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. The results are shown in Table 5.

表5溶解度结果
Table 5 Solubility Results

实施例7-11以及测试例4-6所用的仪器、参数、表征及测试方法如下：The instruments, parameters, characterization, and testing methods used in Examples 7-11 and Test Examples 4-6 are as follows:

(1)X射线粉末衍射(XRPD)(1) X-ray powder diffraction (XRPD)

实验所得固体样品用X射线粉末衍射仪ARL Equinox 100进行分析。2θ扫描角度从0°到35°。测试方法为Cu靶Kα射线，电压40kV，电流0.9mA，样品盘为零背景样品盘。The solid samples obtained in the experiment were analyzed using an ARL Equinox 100 X-ray powder diffractometer. The 2θ scanning angle ranged from 0° to 35°. The testing method was Cu target Kα radiation, voltage 40 kV, current 0.9 mA, and the sample disk was a zero-background sample disk.

(2)热重分析(TGA)(2) Thermogravimetric analysis (TGA)

热重分析仪的型号为METTLER TOLEDO TGA2(METTLER TOLEDO，US)。将2-10mg样品置于已平衡的开口铝制样品盘中，在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为50mL/min，天平处氮气吹扫速度为20mL/min。The thermogravimetric analyzer was a METTLER TOLEDO TGA2 (METTLER TOLEDO, US). 2-10 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C/min, with nitrogen purging at 50 mL/min at the sample location and 20 mL/min at the balance location.

(3)差示扫描量热分析(DSC)(3) Differential Scanning Calorimetry (DSC)

差示扫描量热分析仪的型号为METTLER TOLEDO DSC3(METTLER TOLEDO，US)。1-5mg样品经精确称重后置于扎孔的DSC Tzero样品盘中，以10℃/min的速率加热至最终温度，炉内氮气吹扫速度为40mL/min。The differential scanning calorimeter was a METTLER TOLEDO DSC3 (METTLER TOLEDO, US). 1-5 mg samples were accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10 °C/min, with nitrogen purging at a rate of 40 mL/min.

(4)动态水分吸脱附分析(DVS)(4) Dynamic moisture adsorption-desorption analysis (DVS)

动态水分吸脱附分析采用DVS Intrinsic(SMS，UK)进行测定。测试采用梯度模式，湿度变化为0％-95％-0％，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点，或每个梯度最长维持180分钟。测试完成后，对样品进行XRPD分析确认固体形态是否发生变化。Dynamic moisture adsorption-desorption analysis was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations ranging from 0% to 95% to 0%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm/dt method, with a dm/dt value less than 0.002% maintained for 10 minutes as the endpoint, or each gradient maintained for a maximum of 180 minutes. After the test, XRPD analysis was performed on the samples to confirm whether the solid morphology had changed.

(5)高效液相色谱(HPLC)(5) High Performance Liquid Chromatography (HPLC)

高效液相色谱型号为Waters Arc HPLC(正相)和Agilent 1260II(反相)，测试条件如表6和表7所示。The high-performance liquid chromatographs used were Waters Arc HPLC (normal phase) and Agilent 1260II (reversed phase), and the test conditions are shown in Tables 6 and 7.

表6 HPLC测试条件(反相)

Table 6 HPLC Test Conditions (Reversed Phase)

表7 HPLC测试条件(正相)
Table 7 HPLC Test Conditions (Normal Phase)

实施例7式A-1化合物的晶型Example 7 Crystal form of compound A-1

对式A-1化合物进行XRPD表征，其XRPD谱图如图3所示，将其记为晶型A。对晶型A进行DSC、TGA测试(参见图4～图5)，结果显示晶型A具有一个起始温度为104.30℃、峰值温度为109.74℃的吸热峰，在室温～约130℃失重约为1.7wt％，判断其为无水物。Compound A-1 was characterized by XRPD, and its XRPD spectrum is shown in Figure 3. This is designated as crystal form A. DSC and TGA tests were performed on crystal form A (see Figures 4 and 5). The results showed that crystal form A has an endothermic peak with an initial temperature of 104.30℃ and a peak temperature of 109.74℃. Its weight loss from room temperature to approximately 130℃ is about 1.7 wt%, indicating that it is an anhydrous compound.

实施例8式A-2化合物的晶型Example 8: Crystal form of compound A-2

对式A-2化合物进行XRPD表征，其XRPD谱图如图6所示，XRPD解析如表8所示，将其记为晶型B。对晶型B进行DSC、TGA测试(参见图7～图8)，结果显示晶型B具有三个吸热峰：起始温度为25.62℃、峰值温度为32.16℃的吸热峰，起始温度为139.58℃、峰值温度为144.80℃的吸热峰；起始温度为149.58℃、峰值温度为162.15℃的吸热峰；在室温～约140℃失重约为0.6wt％，判断其为水合物。Compound A-2 was characterized by XRPD, and its XRPD spectrum is shown in Figure 6. The XRPD analysis is shown in Table 8, and it is designated as crystal form B. DSC and TGA tests were performed on crystal form B (see Figures 7-8). The results showed that crystal form B has three endothermic peaks: an endothermic peak with an initial temperature of 25.62℃ and a peak temperature of 32.16℃; an endothermic peak with an initial temperature of 139.58℃ and a peak temperature of 144.80℃; and an endothermic peak with an initial temperature of 149.58℃ and a peak temperature of 162.15℃. The weight loss from room temperature to approximately 140℃ is approximately 0.6 wt%, indicating that it is a hydrate.

表8

Table 8

实施例9式A-3化合物的晶型Example 9 Crystal form of compound A-3

将式(I)所示化合物700mg加入3mL甲醇，加入1.59ml 1M甲磺酸甲醇溶液，在50℃搅拌溶清后，加入3mL异丙醚，形成悬浮液，向悬浮液中加入15mL异丙醚，在50℃搅拌2小时后，降至室温条件下搅拌1天，过滤，固体在35℃烘箱中干燥，得到产物。Add 700 mg of the compound shown in formula (I) to 3 mL of methanol, add 1.59 mL of 1 M methanesulfonic acid methanol solution, stir at 50 °C until dissolved, add 3 mL of isopropyl ether to form a suspension, add 15 mL of isopropyl ether to the suspension, stir at 50 °C for 2 hours, then cool to room temperature and stir for 1 day, filter, and dry the solid in an oven at 35 °C to obtain the product.

产物的NMR结果(参见图12)显示，积分结果与游离态基本一致；在2.35ppm处有甲磺酸的信号峰，根据积分结果计算，式(I)所示化合物和甲磺酸的比例约为1：1。The NMR results of the product (see Figure 12) show that the integration results are basically consistent with those of the free state; there is a signal peak of methanesulfonic acid at 2.35 ppm. According to the integration results, the ratio of the compound shown in formula (I) to methanesulfonic acid is approximately 1:1.

对产物进行XRPD表征，其XRPD谱图如图9所示，XRPD解析如表9所示，将其记为晶型C。对晶型C进行DSC、TGA测试(参见图10～图11)，结果显示晶型C具有起始温度为186.63℃、峰值温度为189.65℃的吸热峰；在室温～约170℃失重约为0.48wt％，判断其为无水物。The product was characterized by XRPD, and its XRPD spectrum is shown in Figure 9. The XRPD analysis is shown in Table 9, and it is denoted as crystal form C. DSC and TGA tests were performed on crystal form C (see Figures 10 and 11). The results showed that crystal form C has an endothermic peak with an onset temperature of 186.63℃ and a peak temperature of 189.65℃; the weight loss from room temperature to about 170℃ is about 0.48wt%, indicating that it is an anhydrous product.

表9
Table 9

实施例10式A-4化合物的晶型Example 10 Crystal form of compound A-4

将式(I)所示化合物700mg加入3mL甲醇中，加入1.59ml 1M乙磺酸甲醇溶液，在50℃搅拌溶清，加入9mL异丙醚，形成悬浮液，再加入9mL异丙醚，在50℃搅拌2小时后，降至室温条件下搅拌1天，过滤，固体在35℃烘箱中干燥，得到产物。700 mg of the compound shown in formula (I) was added to 3 mL of methanol, followed by 1.59 mL of 1 M ethanesulfonic acid methanol solution. The mixture was stirred at 50 °C until dissolved, and then 9 mL of isopropyl ether was added to form a suspension. The mixture was then stirred at 50 °C for 2 hours, cooled to room temperature, and stirred for 1 day. The mixture was filtered, and the solid was dried in an oven at 35 °C to obtain the product.

产物的NMR结果(参见图16)显示，在1.07ppm处有乙基磺酸的信号峰，根据积分结果计算，式(I)所示化合物和乙基磺酸的摩尔比约为1：0.9。The NMR results of the product (see Figure 16) show that there is a signal peak of ethyl sulfonic acid at 1.07 ppm. According to the integration results, the molar ratio of the compound shown in formula (I) to ethyl sulfonic acid is about 1:0.9.

对产物进行XRPD表征，其XRPD谱图如图13所示，XRPD解析如表10所示，将其记为晶型D。对晶型D进行DSC、TGA测试(参见图14～15)，显示晶型D具有起始温度为175.78℃、峰值温度为177.18℃的吸热峰；在室温～约160℃失重约为0.06wt％，判断其为无水物。The product was characterized by XRPD, and its XRPD spectrum is shown in Figure 13. The XRPD analysis is shown in Table 10, and it is denoted as crystal form D. DSC and TGA tests were performed on crystal form D (see Figures 14-15), which showed that crystal form D has an endothermic peak with an onset temperature of 175.78℃ and a peak temperature of 177.18℃; the weight loss in the range of room temperature to about 160℃ is about 0.06wt%, indicating that it is an anhydrous product.

表10
Table 10

此外，发明人还制备获得了式A-4化合物的单晶，经结构解析，其中n＝1，晶型即为晶型D。In addition, the inventors also prepared single crystals of the compound of formula A-4. After structural analysis, it was found that n=1 and the crystal form is crystal form D.

实施例11式A-5化合物的晶型Example 11 Crystal form of compound A-5

将式(I)所示化合物700mg加入186mg马来酸中，再加入3mL甲醇，在50℃搅拌溶清，而后加入6mL异丙醚，形成悬浮液，再加入12mL异丙醚，在50℃搅拌2小时后，降至室温条件下搅拌1天，过滤，固体在35℃烘箱中干燥，得到产物。700 mg of the compound shown in formula (I) was added to 186 mg of maleic acid, followed by 3 mL of methanol. The mixture was stirred at 50 °C until dissolved, and then 6 mL of isopropyl ether was added to form a suspension. Then, 12 mL of isopropyl ether was added and stirred at 50 °C for 2 hours. The mixture was then cooled to room temperature and stirred for 1 day. The mixture was filtered, and the solid was dried in an oven at 35 °C to obtain the product.

产物的NMR结果(参见图20)显示，积分结果与游离态基本一致；在6.21ppm处有马来酸的信号峰，在1.72ppm处有异丙醚的信号峰，根据积分结果计算，式(I)所示化合物和马来酸的摩尔比约为1：0.9，化合物和异丙醚的摩尔比为1：0.14。The NMR results of the product (see Figure 20) show that the integration results are basically consistent with those of the free state; there is a signal peak of maleic acid at 6.21 ppm and a signal peak of isopropyl ether at 1.72 ppm. According to the integration results, the molar ratio of the compound shown in formula (I) to maleic acid is about 1:0.9, and the molar ratio of the compound to isopropyl ether is 1:0.14.

对产物进行XRPD表征，其XRPD谱图如图17所示，XRPD解析如表11所示，将其记为晶型E。对晶型E进行DSC、TGA检测(参见图18～19)，显示晶型E具有起始温度为121.65℃、峰值温度为121.98℃的吸热峰；在室温～约130℃失重约为2.0wt％，判断其为无水物。The product was characterized by XRPD, and its XRPD spectrum is shown in Figure 17. The XRPD analysis is shown in Table 11, and it is denoted as crystal form E. DSC and TGA analysis of crystal form E (see Figures 18-19) showed that crystal form E has an endothermic peak with an onset temperature of 121.65℃ and a peak temperature of 121.98℃; the weight loss at room temperature to about 130℃ is about 2.0 wt%, indicating that it is an anhydrous product.

表11
Table 11

实施例12Example 12

将式(I)所示化合物(即无定形原料)40mg，加入甲醇/4-甲基-2-戊酮/醋酸异丙酯中，加入1.2eq或2.2eq对应的酸，50℃搅拌2小时后降至室温搅拌2天后，将有固体析出的离心，固体50℃真空干燥，得到产物；若无足量固体析出则降温至5℃继续搅拌1天；若仍无固体析出，则恢复至室温并加入一定量的反溶剂，搅拌一定时间后离心，固体50℃真空干燥，得到产物。结果如表12-15所示。40 mg of the compound shown in formula (I) (i.e., the amorphous raw material) was added to methanol/4-methyl-2-pentanone/isopropyl acetate, along with 1.2 eq or 2.2 eq of the corresponding acid. After stirring at 50°C for 2 hours, the mixture was cooled to room temperature and stirred for 2 days. Any solid precipitated was centrifuged, and the solid was dried under vacuum at 50°C to obtain the product. If no sufficient solid precipitated, the temperature was lowered to 5°C and stirring continued for 1 day. If no solid still precipitated, the mixture was restored to room temperature, and a certain amount of antisolvent was added. After stirring for a certain period, the mixture was centrifuged, and the solid was dried under vacuum at 50°C to obtain the product. The results are shown in Tables 12-15.

表12溶剂悬浮法1
Table 12 Solvent Suspension Method 1

表13溶剂悬浮法2

Table 13 Solvent Suspension Method 2

表14溶剂悬浮法3
Table 14 Solvent Suspension Method 3

表15溶析正滴法

Table 15. Dissolution Titration Method

测试例4引湿性测试Test Example 4 Hygroscopicity Test

对晶型C、晶型D、晶型E进行动态水分吸脱附分析，结果分别如图21～23和表16所示。Dynamic water adsorption-desorption analysis was performed on crystal forms C, D, and E, and the results are shown in Figures 21-23 and Table 16, respectively.

晶型C在80％RH下，吸湿增重约为0.86％，再回到0％湿度下失重0.009％，表明晶型C略有引湿性。晶型C经DVS测试后晶型不变。Crystal form C gains approximately 0.86% weight upon moisture absorption at 80% RH, and loses only 0.009% weight upon returning to 0% RH, indicating that crystal form C has slight hygroscopic properties. The crystal form of crystal form C remains unchanged after DVS testing.

晶型D在80％RH下，吸湿增重约为1.69％，再回到0％湿度下失重0.023％，表明晶型D略有引湿性。晶型D经DVS测试后晶型不变。Crystal form D gains approximately 1.69% weight upon moisture absorption at 80% RH, and loses only 0.023% weight upon returning to 0% RH, indicating that crystal form D has slight hygroscopic properties. The crystal form of crystal form D remains unchanged after DVS testing.

晶型E在80％RH下，吸湿增重约为2.65％，再回到0％湿度下失重0.264％，表明晶型E有引湿性。晶型E经DVS测试后晶型不变。Crystal form E exhibits a moisture absorption weight gain of approximately 2.65% at 80% RH, and a weight loss of only 0.264% upon returning to 0% RH, indicating that crystal form E is hygroscopic. The crystal form of crystal form E remains unchanged after DVS testing.

表16
Table 16

测试例5溶解度测试Test Example 5: Solubility Test

生物介质的配制过程如表17所示。不同晶型的样品加入生物介质和水中在37℃搅拌24h，分别于0.5h，2h和24h取样，将取样的溶液用0.22μm水系滤膜过滤，对部分浓度较高的样品用稀释剂进行适当稀释，用HPLC测量溶液的信号峰面积，最后根据峰面积、原料的HPLC标准曲线和稀释倍数计算溶液中化合物的浓度。此外，取24h上清液测试其pH值。测试结果如表18所示。The preparation process of the biological medium is shown in Table 17. Samples of different crystal forms were added to the biological medium and water and stirred at 37°C for 24 hours. Samples were taken at 0.5 hours, 2 hours, and 24 hours. The sampled solutions were filtered through a 0.22 μm aqueous filter membrane. Some samples with higher concentrations were appropriately diluted with diluent. The signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, the pH value of the supernatant after 24 hours was tested. The test results are shown in Table 18.

表17生物介质的配制过程
Table 17 Preparation process of biological media

表18
Table 18

测试例6稳定性测试Test Example 6 Stability Test

晶型C、晶型D和晶型E在高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)条件下进行稳定性研究，于第5天取样进行XRPD表征和HPLC测试，结果如表19所示。Stability studies were conducted on crystal forms C, D, and E under high temperature (60℃), high humidity (25℃/92.5%RH), and light (25℃/4500Lux) conditions. Samples were taken on day 5 for XRPD characterization and HPLC testing. The results are shown in Table 19.

表19
Table 19

以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims (15)

一种化合物，其特征在于，所述化合物具有如式A所示的结构：
A compound characterized in that the compound has a structure as shown in Formula A:
其中，X代表酸，n为0.5～4的数。Where X represents acid, and n is a number from 0.5 to 4. 根据权利要求1所述的化合物，其特征在于，所述酸为无机酸或有机酸；The compound according to claim 1, wherein the acid is an inorganic acid or an organic acid; 优选地，所述无机酸选自盐酸、硫酸、磷酸、氢溴酸中的一种或两种以上；Preferably, the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; 优选地，所述有机酸选自甲磺酸、乙磺酸、天冬氨酸、柠檬酸、马来酸、富马酸、L-苹果酸、L-酒石酸、丙二酸、草酸、苯磺酸、甲苯磺酸中的一种或两种以上。Preferably, the organic acid is selected from one or more of methanesulfonic acid, ethanesulfonic acid, aspartic acid, citric acid, maleic acid, fumaric acid, L-malic acid, L-tartaric acid, malonic acid, oxalic acid, benzenesulfonic acid, and toluenesulfonic acid. 根据权利要求1所述的化合物，其特征在于，X代表硫酸、甲磺酸、乙磺酸或马来酸；The compound according to claim 1, wherein X represents sulfuric acid, methanesulfonic acid, ethanesulfonic acid, or maleic acid; 和/或，所述n为0.6～3的数。And/or, the n is a number from 0.6 to 3. 根据权利要求1所述的化合物，其特征在于，当X代表硫酸时，n为0.7～1.3的数；The compound according to claim 1 is characterized in that, when X represents sulfuric acid, n is a number from 0.7 to 1.3; 当X代表甲磺酸时，n为0.9～2.2的数；When X represents methanesulfonic acid, n is a number ranging from 0.9 to 2.2; 当X代表乙磺酸时，n为0.9～1.3的数；When X represents ethanesulfonic acid, n is a number ranging from 0.9 to 1.3; 当X代表马来酸时，n为0.9～1.3的数。When X represents maleic acid, n is a number ranging from 0.9 to 1.3. 权利要求1-4任一项所述化合物的制备方法，其特征在于，所述制备方法包括：式(I)所示化合物与X反应，得到所述化合物；
A method for preparing the compound according to any one of claims 1-4, characterized in that the preparation method comprises: reacting the compound of formula (I) with X to obtain the compound;
优选地，所述反应在第一有机溶剂中进行，所述第一有机溶剂选自甲基异丁基酮、乙酸异丙酯、甲醇、异丙醚、正庚烷中的一种或两种以上；Preferably, the reaction is carried out in a first organic solvent, which is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane. 和/或，所述反应的温度为40～60℃。And/or, the temperature of the reaction is 40–60°C. 权利要求1-4任一项所述化合物的固体形态，其特征在于，所述固体形态包括无定形和晶型；The solid form of the compound according to any one of claims 1-4 is characterized in that the solid form includes amorphous and crystalline forms; 优选地，所述固体形态包括式A-I化合物的晶型和无定形，式A-II化合物的晶型和无定形，式A-III化合物的晶型和无定形，式A-IV化合物的晶型和无定形、以及式A-V化合物的晶型和无定形；Preferably, the solid form includes the crystalline and amorphous forms of compounds of formula A-I, the crystalline and amorphous forms of compounds of formula A-II, the crystalline and amorphous forms of compounds of formula A-III, the crystalline and amorphous forms of compounds of formula A-IV, and the crystalline and amorphous forms of compounds of formula A-V. n为0.6～3的数，例如0.7～1.3或0.8～1.0的数； n is a number between 0.6 and 3, for example, a number between 0.7 and 1.3 or a number between 0.8 and 1.0; n为1.4～2.2的数，例如1.5～2.0或1.5～1.8的数； n is a number between 1.4 and 2.2, for example, a number between 1.5 and 2.0 or a number between 1.5 and 1.8; n为大于等于0.9且小于1.4的数，例如0.9～1.1的数； n is a number greater than or equal to 0.9 and less than 1.4, for example, a number between 0.9 and 1.1; n为0.6～3的数，例如0.7～1.3或0.8～1.1的数； n is a number between 0.6 and 3, for example, a number between 0.7 and 1.3 or a number between 0.8 and 1.1; n为0.6～3的数，例如0.7～1.3或0.8～1.0的数。 n is a number between 0.6 and 3, for example, a number between 0.7 and 1.3 or a number between 0.8 and 1.0. 根据权利要求6所述的固体形态，其特征在于，所述式A-I化合物的晶型具有基本如图3所示的XRPD图谱；优选地，所述式A-I化合物的晶型为无水晶型。According to claim 6, the solid form of the compound of formula A-I is characterized in that the crystal form has an XRPD pattern as shown in Figure 3; preferably, the crystal form of the compound of formula A-I is an amorphous form. 根据权利要求6所述的固体形态，其特征在于，所述式A-II化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在15.0±0.20°、18.3±0.20°、19.8±0.20°、21.3±0.20°和23.7±0.20°处具有特征峰；进一步地，还在16.6±0.20°、20.5±0.20°、23.2±0.20°、26.2±0.20°和/或27.7±0.20°处具有特征峰；进一步地，还在11.0±0.20°、12.1±0.20°、13.0±0.20°、13.8±0.20°、24.7±0.20°、26.9±0.20°、30.2±0.20°、31.7±0.20°和/或33.5±0.20°处具有特征峰；According to claim 6, the solid form of the compound of formula A-II is characterized by X-ray powder diffraction at 15.0±0.20°, 18.3±0.20°, 19.8±0.20°, 21.3±0.20°, and 23.7±0.20° using Cu-Kα radiation and expressed in 2θ angles, exhibiting characteristic peaks; furthermore, characteristic peaks are also observed at 16.6±0.20°, 20.5±0.20°, and 23.7±0.20°. Characteristic peaks are present at 0.2±0.20°, 26.2±0.20° and/or 27.7±0.20°; further, characteristic peaks are also present at 11.0±0.20°, 12.1±0.20°, 13.0±0.20°, 13.8±0.20°, 24.7±0.20°, 26.9±0.20°, 30.2±0.20°, 31.7±0.20° and/or 33.5±0.20°. 优选地，所述式A-II化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.0±0.20°、12.1±0.20°、13.0±0.20°、13.8±0.20°、15.0±0.20°、16.6±0.20°、18.3±0.20°、19.8±0.20°、20.5±0.20°、21.3±0.20°、23.2±0.20°、23.7±0.20°、24.7±0.20°、26.2±0.20°、26.9±0.20°、27.7±0.20°、30.2±0.20°、31.7±0.20°和33.5±0.20°处具有特征峰；Preferably, the crystal form of the compound of formula A-II, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 11.0±0.20°, 12.1±0.20°, 13.0±0.20°, 13.8±0.20°, 15.0±0.20°, 16.6±0.20°, 18.3±0.20°, 19.8±0.20°, 20.5±0.20°, 21.3±0.20°, 23.2±0.20°, 23.7±0.20°, 24.7±0.20°, 26.2±0.20°, 26.9±0.20°, 27.7±0.20°, 30.2±0.20°, 31.7±0.20°, and 33.5±0.20° in terms of angle 2θ. 优选地，所述式A-II化合物的晶型具有基本如图6所示的XRPD图谱；Preferably, the crystal form of the compound of formula A-II has an XRPD pattern as shown in Figure 6; 优选地，所述式A-II化合物的晶型具有基本如表8所示的XRPD特征峰，2θ角度误差为±0.20°；Preferably, the crystal form of the compound of formula A-II has XRPD characteristic peaks as shown in Table 8, with a 2θ angle error of ±0.20°; 优选地，所述式A-II化合物的晶型具有如下一个、两个或三个峰：Preferably, the crystal form of the compound of formula A-II has one, two, or three peaks as follows: (1)起始温度为20～30℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；(1) An endothermic peak with an initial temperature of 20-30℃ and a peak temperature difference between the initial temperature and the peak temperature greater than 0 and less than 10℃; (2)起始温度为133～145℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；(2) An endothermic peak with an initial temperature of 133-145℃ and a peak temperature difference between the initial temperature and the peak temperature greater than 0 and less than 10℃. (3)起始温度为145～155℃、峰值温度与起始温度差值大于0且小于20℃的吸热峰；(3) An endothermic peak with an initial temperature of 145-155℃ and a peak temperature difference between the initial temperature and the peak temperature greater than 0 and less than 20℃. 优选地，所述式A-II化合物的晶型具有基本如图7所示的DSC图谱；Preferably, the crystal form of the compound of formula A-II has a DSC spectrum basically as shown in Figure 7; 优选地，所述式A-II化合物的晶型在室温～约140℃失重不超过1.0wt％，优选失重不超过0.9wt％或0.8wt％；Preferably, the crystal form of the compound of formula A-II loses no more than 1.0 wt% at room temperature to about 140°C, and more preferably no more than 0.9 wt% or 0.8 wt%. 优选地，所述式A-II化合物的晶型具有基本如图8所示的TGA图谱；Preferably, the crystal form of the compound of formula A-II has a TGA spectrum as shown in Figure 8; 优选地，所述式A-II化合物的晶型为水合物。Preferably, the crystal form of the compound of formula A-II is a hydrate. 根据权利要求6所述的固体形态，其特征在于，所述式A-III化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在15.9±0.20°、19.6±0.20°、21.5±0.20°、22.1±0.20°、24.8±0.20°和26.5±0.20°处具有特征峰；进一步地，还在17.1±0.20°、18.1±0.20°、20.1±0.20°、23.5±0.20°和/或24.4±0.20°处具有特征峰；进一步地，还在14.6±0.20°、17.6±0.20°、28.1±0.20°、30.5±0.20°和/或32.9±0.20°处具有特征峰；According to claim 6, the solid form of the compound of formula A-III is characterized by the following X-ray powder diffraction, expressed in 2θ angles, using Cu-Kα radiation, exhibiting characteristic peaks at 15.9±0.20°, 19.6±0.20°, 21.5±0.20°, 22.1±0.20°, 24.8±0.20°, and 26.5±0.20°; further, characteristic peaks are also present at 17.1±0.20°, 18.1±0.20°, 20.1±0.20°, 23.5±0.20°, and/or 24.4±0.20°; further, characteristic peaks are also present at 14.6±0.20°, 17.6±0.20°, 28.1±0.20°, 30.5±0.20°, and/or 32.9±0.20°. 优选地，所述式A-III化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.1±0.20°、4.4±0.20°、14.6±0.20°、15.9±0.20°、17.1±0.20°、17.6±0.20°、18.1±0.20°、19.6±0.20°、20.2±0.20°、21.5±0.20°、22.1±0.20°、23.5±0.20°、24.4±0.20°、24.8±0.20°、26.5±0.20°、28.1±0.20°、28.7±0.20°、30.5±0.20°、31.0±0.20°、32.0±0.20°、32.9±0.20°和33.4±0.20°处具有特征峰；Preferably, the crystal form of the compound of formula A-III is determined by Cu-Kα radiation, and X-ray powder diffraction is performed at angles of 2θ at 3.1±0.20°, 4.4±0.20°, 14.6±0.20°, 15.9±0.20°, 17.1±0.20°, 17.6±0.20°, 18.1±0.20°, 19.6±0.20°, 20.2±0.20°, and 21. Characteristic peaks are present at 5±0.20°, 22.1±0.20°, 23.5±0.20°, 24.4±0.20°, 24.8±0.20°, 26.5±0.20°, 28.1±0.20°, 28.7±0.20°, 30.5±0.20°, 31.0±0.20°, 32.0±0.20°, 32.9±0.20°, and 33.4±0.20°. 优选地，所述式A-III化合物的晶型具有基本如图9所示的XRPD图谱。Preferably, the crystal form of the compound of formula A-III has an XRPD pattern as shown in Figure 9. 优选地，所述式A-III化合物的晶型具有基本如表9所示的XRPD特征峰，2θ角度误差为±0.20°；Preferably, the crystal form of the compound of formula A-III has XRPD characteristic peaks as shown in Table 9, with a 2θ angle error of ±0.20°; 优选地，所述式A-III化合物的晶型具有一个起始温度为180～192℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；Preferably, the crystal form of the compound of formula A-III has an endothermic peak with an initial temperature of 180-192°C and a peak temperature greater than 0 and less than 10°C from the initial temperature. 优选地，所述式A-III化合物的晶型具有基本如图10所示的DSC图谱；Preferably, the crystal form of the compound of formula A-III has a DSC spectrum basically as shown in Figure 10; 优选地，所述式A-III化合物的晶型在室温～约170℃失重不超过1.0wt％，优选失重不超过0.9wt％、0.7wt％或0.5wt％；Preferably, the crystal form of the compound of formula A-III loses no more than 1.0 wt% at room temperature to about 170°C, and more preferably no more than 0.9 wt%, 0.7 wt%, or 0.5 wt%. 优选地，所述式A-III化合物的晶型具有基本如图11所示的TGA图谱；Preferably, the crystal form of the compound of formula A-III has a TGA spectrum as shown in Figure 11; 优选地，所述式A-III化合物的晶型为无水物。Preferably, the crystal form of the compound of formula A-III is anhydrous. 根据权利要求6所述的固体形态，其特征在于，所述式A-IV化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在12.8±0.20°、16.5±0.20°、17.5±0.20°、21.3±0.20°、22.3±0.20°和26.6±0.20°处具有特征峰；进一步地，还在10.8±0.20°、19.6±0.20°、20.6±0.20°、23.1±0.20°、27.1±0.20°和/或28.8±0.20°处具有特征峰；进一步地，还在13.8±0.20°、25.1±0.20°、27.6±0.20°、28.2±0.20°、29.7±0.20°和/或34.8±0.20°处具有特征峰；According to claim 6, the solid form of the compound of formula A-IV is characterized by X-ray powder diffraction at 12.8±0.20°, 16.5±0.20°, 17.5±0.20°, 21.3±0.20°, 22.3±0.20°, and 26.6±0.20° when irradiated with Cu-Kα radiation; further, at 10.8±0.20°. Characteristic peaks are present at 20°, 19.6±0.20°, 20.6±0.20°, 23.1±0.20°, 27.1±0.20° and/or 28.8±0.20°; further, characteristic peaks are also present at 13.8±0.20°, 25.1±0.20°, 27.6±0.20°, 28.2±0.20°, 29.7±0.20° and/or 34.8±0.20°. 优选地，所述式A-IV化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在10.8±0.20°、12.8±0.20°、13.8±0.20°、16.5±0.20°、17.5±0.20°、19.6±0.20°、20.6±0.20°、21.3±0.20°、22.3±0.20°、23.1±0.20°、25.1±0.20°、26.6±0.20°、27.1±0.20°、27.6±0.20°、28.2±0.20°、28.8±0.20°、29.7±0.20°和34.8±0.20°处具有特征峰；Preferably, the crystal form of the compound of formula A-IV, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at angles of 2θ at 10.8±0.20°, 12.8±0.20°, 13.8±0.20°, 16.5±0.20°, 17.5±0.20°, 19.6±0.20°, 20.6±0.20°, 21.3±0.20°, 22.3±0.20°, 23.1±0.20°, 25.1±0.20°, 26.6±0.20°, 27.1±0.20°, 27.6±0.20°, 28.2±0.20°, 28.8±0.20°, 29.7±0.20°, and 34.8±0.20°. 优选地，所述式A-IV化合物的晶型具有基本如图13所示的XRPD图谱；Preferably, the crystal form of the compound of formula A-IV has an XRPD pattern as shown in Figure 13; 优选地，所述式A-IV化合物的晶型具有基本如表10所示的XRPD特征峰，2θ角度误差为±0.20°；Preferably, the crystal form of the compound of formula A-IV has XRPD characteristic peaks as shown in Table 10, with a 2θ angle error of ±0.20°; 优选地，所述式A-IV化合物的晶型具有一个起始温度为170～180℃、峰值温度与起始温度差值大于0且小于10℃的吸热峰；Preferably, the crystal form of the compound of formula A-IV has an endothermic peak with an initial temperature of 170-180°C and a peak temperature greater than 0 and less than 10°C from the initial temperature. 优选地，所述式A-IV化合物的晶型具有基本如图14所示的DSC图谱；Preferably, the crystal form of the compound of formula A-IV has a DSC spectrum basically as shown in Figure 14; 优选地，所述式A-IV化合物的晶型在室温～约160℃失重不超过0.5wt％，优选失重不超过0.3wt％、0.2wt％或0.1wt％；Preferably, the crystal form of the compound of formula A-IV loses no more than 0.5 wt% at room temperature to about 160°C, and more preferably no more than 0.3 wt%, 0.2 wt%, or 0.1 wt%. 优选地，所述式A-IV化合物的晶型具有基本如图15所示的TGA图谱；Preferably, the crystal form of the compound of formula A-IV has a TGA spectrum as shown in Figure 15; 优选地，所述式A-IV化合物的晶型为无水物。Preferably, the crystal form of the compound of formula A-IV is anhydrous. 根据权利要求6所述的固体形态，其特征在于，所述式A-V化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在6.3±0.20°、13.0±0.20°、15.8±0.20°、18.1±0.20°、18.9±0.20°和23.3±0.20°处具有特征峰；进一步地，还在7.2±0.20°、8.5±0.20°、13.9±0.20°、16.9±0.20°、20.9±0.20°、21.7±0.20°、22.7±0.20°、24.3±0.20°、25.6±0.20°和/或27.5±0.20°处具有特征峰；进一步地，还在9.3±0.20°、10.6±0.20°、11.3±0.20°、12.1±0.20°、26.3±0.20°、27.8±0.20°、28.7±0.20°和/或29.4±0.20°处具有特征峰；According to claim 6, the solid form of the compound of formula A-V is characterized by X-ray powder diffraction at 6.3±0.20°, 13.0±0.20°, 15.8±0.20°, 18.1±0.20°, 18.9±0.20°, and 23.3±0.20° using Cu-Kα radiation and expressed in 2θ angles, exhibiting characteristic peaks; furthermore, characteristic peaks are also observed at 7.2±0.20°, 8.5±0.20°, 13.9±0.20°, and 16.9±0.20°. Characteristic peaks are present at 20.9±0.20°, 21.7±0.20°, 22.7±0.20°, 24.3±0.20°, 25.6±0.20° and/or 27.5±0.20°; further, characteristic peaks are also present at 9.3±0.20°, 10.6±0.20°, 11.3±0.20°, 12.1±0.20°, 26.3±0.20°, 27.8±0.20°, 28.7±0.20° and/or 29.4±0.20°. 优选地，所述式A-V化合物的晶型使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在6.3±0.20°、7.2±0.20°、8.5±0.20°、9.3±0.20°、10.6±0.20°、11.3±0.20°、12.1±0.20°、13.0±0.20°、13.9±0.20°、15.8±0.20°、16.9±0.20°、18.1±0.20°、18.9±0.20°、20.9±0.20°、21.7±0.20°、22.7±0.20°、23.3±0.20°、24.3±0.20°、25.6±0.20°、26.3±0.20°、27.5±0.20°、27.8±0.20°、28.7±0.20°和29.4±0.20°处具有特征峰；Preferably, the crystal form of the A-V compound is determined using Cu-Kα radiation, with X-ray powder diffraction at angles of 2θ at 6.3±0.20°, 7.2±0.20°, 8.5±0.20°, 9.3±0.20°, 10.6±0.20°, 11.3±0.20°, 12.1±0.20°, 13.0±0.20°, 13.9±0.20°, 15.8±0.20°, and 16.9±0.20°. Characteristic peaks are present at 0.20°, 18.1±0.20°, 18.9±0.20°, 20.9±0.20°, 21.7±0.20°, 22.7±0.20°, 23.3±0.20°, 24.3±0.20°, 25.6±0.20°, 26.3±0.20°, 27.5±0.20°, 27.8±0.20°, 28.7±0.20°, and 29.4±0.20°. 优选地，所述式A-V化合物的晶型具有基本如图17所示的XRPD图谱；Preferably, the crystal form of the compound of formula A-V has an XRPD pattern as shown in Figure 17; 优选地，所述式A-V化合物的晶型具有基本如表11所示的XRPD特征峰，2θ角度误差为±0.20°；Preferably, the crystal form of the compound of formula A-V has XRPD characteristic peaks as shown in Table 11, with a 2θ angle error of ±0.20°; 优选地，所述式A-V化合物的晶型具有一个起始温度为115～130℃、峰值温度与起始温度差值大于0且小于3℃的吸热峰；Preferably, the crystal form of the compound of formula A-V has an endothermic peak with an initial temperature of 115-130°C and a peak temperature greater than 0 and less than 3°C from the initial temperature. 优选地，所述式A-V化合物的晶型具有基本如图18所示的DSC图谱；Preferably, the crystal form of the compound of formula A-V has a DSC spectrum basically as shown in Figure 18; 优选地，所述式A-V化合物的晶型在室温～约130℃失重不超过2.5wt％，优选失重不超过2.3wt％、2.2wt％或2.1wt％；Preferably, the crystal form of the A-V compound loses no more than 2.5 wt% at room temperature to about 130°C, and more preferably no more than 2.3 wt%, 2.2 wt%, or 2.1 wt%. 优选地，所述式A-V化合物的晶型具有基本如图19所示的TGA图谱；Preferably, the crystal form of the compound of formula A-V has a TGA spectrum as shown in Figure 19; 优选地，所述式A-V化合物的晶型为无水物。Preferably, the crystal form of the compound of formula A-V is anhydrous. 权利要求6～11任一项中的晶型的制备方法，其特征在于，包括将式(I)所示化合物与X和第一有机溶剂混合，搅拌溶清，加入第二有机溶剂，形成悬浮液，再加入第三有机溶剂，继续搅拌，而后降至室温搅拌，经后处理，得到所述晶型；The method for preparing the crystal form according to any one of claims 6 to 11 is characterized in that it includes mixing the compound shown in formula (I) with X and a first organic solvent, stirring to dissolve, adding a second organic solvent to form a suspension, adding a third organic solvent, continuing to stir, then cooling to room temperature and stirring, and after post-treatment, obtaining the crystal form; 优选地，所述第一有机溶剂、第二有机溶剂和/或第三有机溶剂相同或不同；Preferably, the first organic solvent, the second organic solvent, and/or the third organic solvent are the same or different; 优选地，所述第二有机溶剂选自甲基异丁基酮、乙酸异丙酯、甲醇、异丙醚、正庚烷中的一种或两种以上；Preferably, the second organic solvent is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane; 优选地，所述第三有机溶剂选自甲基异丁基酮、乙酸异丙酯、甲醇、异丙醚、正庚烷中的一种或两种以上；Preferably, the third organic solvent is selected from one or more of methyl isobutyl ketone, isopropyl acetate, methanol, isopropyl ether, and n-heptane; 优选地，所述第一有机溶剂、第二有机溶剂与第三有机溶剂的体积比为1:(0.5～10)：(1～10)；Preferably, the volume ratio of the first organic solvent, the second organic solvent, and the third organic solvent is 1:(0.5-10):(1-10); 优选地，所述搅拌溶清的温度为40～60℃；Preferably, the temperature for stirring and dissolving is 40–60°C; 优选地，加入第三有机溶剂后搅拌1～6h；Preferably, the mixture is stirred for 1–6 hours after the addition of the third organic solvent; 优选地，所述室温搅拌的时间不低于1天。Preferably, the stirring time at room temperature is not less than 1 day. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-4任一项所述化合物或权利要求6～11任一项所述的固体形态。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the compound according to any one of claims 1-4 or the solid form according to any one of claims 6-11. 权利要求1-4任一项所述化合物、权利要求6～11任一项所述的固体形态或权利要求13所述药物组合物在制备药物中的应用，所述药物为诊断、预防和/或治疗MC4R受体介导的疾病或病症的药物；The use of the compound of any one of claims 1-4, the solid form of any one of claims 6-11, or the pharmaceutical composition of claim 13 in the preparation of a medicament, wherein the medicament is a medicament for diagnosing, preventing, and/or treating MC4R receptor-mediated diseases or conditions; 优选地，所述疾病或病症为恶病质(与癌症相关的恶病质、与获得性免疫缺陷综合征(AIDS)相关的恶病质、与充血性心力衰竭(CHF)相关的恶病质；与慢性肾病(CKD)相关的恶病质；与其他慢性疾病治疗相关的恶病质)；厌食或神经性厌食症(老年性厌食、与化疗和/或放疗相关的厌食)；恶心呕吐；体重减轻(非自愿体重减轻)；生长发育不全；肌少症；肌肉萎缩；肌肉无力；脆弱；骨质疏松症；骨疾病(骨丢失)；疼痛(神经病理性疼痛)；焦虑(创伤后应激障碍或PTSD)；抑郁症；高血压；营养不良肥胖(如慢性肥胖引起的肌肉减少症)；性功能障碍；和炎症性疾病(与厌食或恶病质、肌肉减少或肌肉萎缩相关的炎症性疾病)。Preferably, the disease or condition is cachexia (cachexia associated with cancer, cachexia associated with acquired immunodeficiency syndrome (AIDS), cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with treatment of other chronic diseases); anorexia or anorexia nervosa (anorexia in the elderly, anorexia associated with chemotherapy and/or radiotherapy); nausea and vomiting; weight loss (involuntary weight loss); growth retardation; sarcopenia; muscle atrophy; muscle weakness; fragility; osteoporosis; bone disease (bone loss); pain (neuropathic pain); anxiety (post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition-related obesity (such as sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (inflammatory diseases associated with anorexia or cachexia, sarcopenia or muscle atrophy). 用于诊断、预防和/或治疗MC4R受体介导的疾病或病症的方法，其特征在于，所述方法包括向需要这种治疗的患者单独施用治疗有效量的权利要求1-4任一项所述化合物、权利要求6～11任一项所述的固体形态或权利要求13所述药物组合物；A method for diagnosing, preventing and/or treating MC4R receptor-mediated diseases or conditions, characterized in that the method comprises administering, to a patient in need of such treatment, a therapeutically effective amount of the compound of any one of claims 1-4, the solid form of any one of claims 6-11, or the pharmaceutical composition of claim 13; 优选地，所述疾病或病症为恶病质(与癌症相关的恶病质、与获得性免疫缺陷综合征(AIDS)相关的恶病质、与充血性心力衰竭(CHF)相关的恶病质；与慢性肾病(CKD)相关的恶病质；与其他慢性疾病治疗相关的恶病质)；厌食或神经性厌食症(老年性厌食、与化疗和/或放疗相关的厌食)；恶心呕吐；体重减轻(非自愿体重减轻)；生长发育不全；肌少症；肌肉萎缩；肌肉无力；脆弱；骨质疏松症；骨疾病(骨丢失)；疼痛(神经病理性疼痛)；焦虑(创伤后应激障碍或PTSD)；抑郁症；高血压；营养不良肥胖(如慢性肥胖引起的肌肉减少症)；性功能障碍；和炎症性疾病(与厌食或恶病质、肌肉减少或肌肉萎缩相关的炎症性疾病)。Preferably, the disease or condition is cachexia (cachexia associated with cancer, cachexia associated with acquired immunodeficiency syndrome (AIDS), cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with treatment of other chronic diseases); anorexia or anorexia nervosa (anorexia in the elderly, anorexia associated with chemotherapy and/or radiotherapy); nausea and vomiting; weight loss (involuntary weight loss); growth retardation; sarcopenia; muscle atrophy; muscle weakness; fragility; osteoporosis; bone disease (bone loss); pain (neuropathic pain); anxiety (post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition-related obesity (such as sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (inflammatory diseases associated with anorexia or cachexia, sarcopenia or muscle atrophy).
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US20090291940A1 (en) * 2006-04-04 2009-11-26 Taisho Pharmaceutical Co., Ltd. Aminopyrrolidine compound
WO2023105387A1 (en) * 2021-12-06 2023-06-15 Pfizer Inc. Melanocortin 4 receptor antagonists and uses thereof
CN117736206A (en) * 2022-09-21 2024-03-22 长春金赛药业有限责任公司 Urea derivatives as MC4R antagonists, pharmaceutical compositions and pharmaceutical applications thereof
WO2024104452A1 (en) * 2022-11-17 2024-05-23 长春金赛药业有限责任公司 Mc4r antagonist compound, pharmaceutical composition and pharmaceutical use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090291940A1 (en) * 2006-04-04 2009-11-26 Taisho Pharmaceutical Co., Ltd. Aminopyrrolidine compound
WO2023105387A1 (en) * 2021-12-06 2023-06-15 Pfizer Inc. Melanocortin 4 receptor antagonists and uses thereof
CN117736206A (en) * 2022-09-21 2024-03-22 长春金赛药业有限责任公司 Urea derivatives as MC4R antagonists, pharmaceutical compositions and pharmaceutical applications thereof
WO2024104452A1 (en) * 2022-11-17 2024-05-23 长春金赛药业有限责任公司 Mc4r antagonist compound, pharmaceutical composition and pharmaceutical use thereof

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