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WO2024027723A1 - Crystal form, salt type and composition of pyridazine compound and preparation method therefor - Google Patents

Crystal form, salt type and composition of pyridazine compound and preparation method therefor Download PDF

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Publication number
WO2024027723A1
WO2024027723A1 PCT/CN2023/110617 CN2023110617W WO2024027723A1 WO 2024027723 A1 WO2024027723 A1 WO 2024027723A1 CN 2023110617 W CN2023110617 W CN 2023110617W WO 2024027723 A1 WO2024027723 A1 WO 2024027723A1
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Prior art keywords
compound
formula
crystal form
preparation
angles
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PCT/CN2023/110617
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French (fr)
Chinese (zh)
Inventor
贺海鹰
赵乐乐
孙建军
吴艾米丽媛媛
曹兰
童海骏
赵亚男
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南京明德新药研发有限公司
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Publication of WO2024027723A1 publication Critical patent/WO2024027723A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a crystal form, salt form, composition and preparation method of a pyridazine compound, specifically disclosing the A crystal form, salt form and composition of the compound of formula (I), and the B form of the compound of formula (II). Preparation methods and applications of crystal forms and Form C of the compound of formula (III).
  • the NLRP3 inflammasome is a multi-protein complex that plays an important role in the development of innate immunity and inflammation-related diseases.
  • the NLRP3 inflammasome consists of NOD-like receptors (NLRs), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase 1 (Caspase-1) composition.
  • NLRs NOD-like receptors
  • ASC apoptosis-associated speck-like protein containing a CARD
  • Caspase-1 caspase 1
  • Exogenous pathogens or endogenous risk factors such as mitochondrial reactive oxygen species, oxidized mitochondrial DNA, ⁇ -amyloid or ⁇ -synuclein can activate NLRP3.
  • Activated NLRP3, ASC and Caspase-1 form the activated NLRP3 inflammasome, which further hydrolyzes IL-1 ⁇ precursor (pro-IL-1 ⁇ ) and IL-18 precursor (pro-IL-18) through Caspase-1. It releases active cytokines IL-1 ⁇ and IL-18. The secretion of these cytokines can lead to pyroptosis or neuronal damage.
  • NLRP3 inflammasome plays an important role in the development of various autoimmune diseases, cardiovascular diseases, neurodegenerative diseases and tumors (Nature Reviews Drug Discovery, 2018, 17(8):588-606.).
  • NLRP3 inhibitors There are currently no drug molecules for NLRP3 inhibitors on the market.
  • the preclinical compound MCC950 has a significant inhibitory effect on NLRP3 (Sci. Transl. Med. 10, eaah4066 (2016)).
  • Drugs such as OLT-1177, Inzomelid, Selnoflast and IFM-2427 are in the clinical research stage.
  • the development of NLRP3 inhibitors has broad application prospects.
  • the present invention also provides the A crystal form of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.20°, 16.53 ⁇ 0.20° and 18.12 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.20°, 13.48 ⁇ 0.20°, 16.53 ⁇ 0.20°, 18.12 ⁇ 0.20°, 21.44 ⁇ 0.20° and 24.06 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.20°, 12.72 ⁇ 0.20°, 13.48 ⁇ 0.20°, 16.53 ⁇ 0.20°, 18.12 ⁇ 0.20°, 21.44 ⁇ 0.20°, 24.06 ⁇ 0.20° and 25.55 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.20°, 8.41 ⁇ 0.20°, 12.72 ⁇ 0.20°, 13.48 ⁇ 0.20°, 14.72 ⁇ 0.20°, 15.92 ⁇ 0.20°, 16.53 ⁇ 0.20°, 16.89 ⁇ 0.20°, 18.12 ⁇ 0.20°, 21.44 ⁇ 0.20°, 24.06 ⁇ 0.20°, 25.55 ⁇ 0.20° and 27.12 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.10°, 8.41 ⁇ 0.10°, 12.72 ⁇ 0.10°, 13.48 ⁇ 0.10°, 14.72 ⁇ 0.10°, 15.92 ⁇ 0.10°, 16.53 ⁇ 0.10°, 16.89 ⁇ 0.10°, 18.12 ⁇ 0.10°, 21.44 ⁇ 0.10°, 24.06 ⁇ 0.10°, 25.55 ⁇ 0.10° and 27.12 ⁇ 0.10°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.20°, 8.41 ⁇ 0.20°, 12.16 ⁇ 0.20°, 12.72 ⁇ 0.20°, 13.48 ⁇ 0.20° ⁇ 14.72 ⁇ 0.20° ⁇ 15.92 ⁇ 0.20° ⁇ 16.53 ⁇ 0.20° ⁇ 16.89 ⁇ 0.20° ⁇ 17.37 ⁇ 0.20° ⁇ 18.12 ⁇ 0.20° ⁇ 21.44 ⁇ 0.20° ⁇ 24.06 ⁇ 0.20° ⁇ 24.84 ⁇ 0.20° ⁇ 25.55 ⁇ 0.20°, 27.12 ⁇ 0.20° and 29.03 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.10°, 8.41 ⁇ 0.10°, 12.16 ⁇ 0.10°, 12.72 ⁇ 0.10°, 13.48 ⁇ 0.10° ⁇ 14.72 ⁇ 0.10° ⁇ 15.92 ⁇ 0.10° ⁇ 16.53 ⁇ 0.10° ⁇ 16.89 ⁇ 0.10° ⁇ 17.37 ⁇ 0.10° ⁇ 18.12 ⁇ 0.10° ⁇ 21.44 ⁇ 0.10° ⁇ 24.06 ⁇ 0.10° ⁇ 24.84 ⁇ 0.10° ⁇ 25.55 ⁇ 0.10°, 27.12 ⁇ 0.10° and 29.03 ⁇ 0.10°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.20°, 8.41 ⁇ 0.20°, 11.58 ⁇ 0.20°, 12.16 ⁇ 0.20°, 12.72 ⁇ 0.20° ⁇ 13.07 ⁇ 0.20° ⁇ 13.48 ⁇ 0.20° ⁇ 14.72 ⁇ 0.20° ⁇ 15.92 ⁇ 0.20° ⁇ 16.53 ⁇ 0.20° ⁇ 16.89 ⁇ 0.20° ⁇ 17.37 ⁇ 0.20° ⁇ 18.12 ⁇ 0.20° ⁇ 18.43 ⁇ 0.20° ⁇ 19.11 ⁇ 0.20° ⁇ 21.24 ⁇ 0.20° ⁇ 21.44 ⁇ 0.20° ⁇ 22.41 ⁇ 0.20° ⁇ 23.02 ⁇ 0.20° ⁇ 23.23 ⁇ 0.20° ⁇ 23.52 ⁇ 0.20° ⁇ 24.06 ⁇ 0.20° ⁇ 24.84 ⁇ 0.20° ⁇ 25.34 ⁇ 0.20° ⁇ 25.55 ⁇ 0.20° ⁇ 26.08 ⁇ 0.20° ⁇ 26.49 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.10°, 8.41 ⁇ 0.10°, 11.58 ⁇ 0.10°, 12.16 ⁇ 0.10°, 12.72 ⁇ 0.10° ⁇ 13.07 ⁇ 0.10° ⁇ 13.48 ⁇ 0.10° ⁇ 14.72 ⁇ 0.10° ⁇ 15.92 ⁇ 0.10° ⁇ 16.53 ⁇ 0.10° ⁇ 16.89 ⁇ 0.10° ⁇ 17.37 ⁇ 0.10° ⁇ 18.12 ⁇ 0.10° ⁇ 18.43 ⁇ 0.10° ⁇ 19.11 ⁇ 0.10° ⁇ 21.24 ⁇ 0.10° ⁇ 21.44 ⁇ 0.10° ⁇ 22.41 ⁇ 0.10° ⁇ 23.02 ⁇ 0.10° ⁇ 23.23 ⁇ 0.10° ⁇ 23.52 ⁇ 0.10° ⁇ 24.06 ⁇ 0.10° ⁇ 24.84 ⁇ 0.10° ⁇ 25.34 ⁇ 0.10° ⁇ 25.55 ⁇ 0.10° ⁇ 26.08 ⁇ 0.10° ⁇ 26.49 ⁇ 0.10°
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80, 8.41, 11.58, 12.16, 12.72, 13.07, 13.48, 14.72, 15.92, 16.53, 16.89, 17.37, 18.12, 18.43, 19.11, 21.24, 21.44, 22.41, 23.02, 23.23, 23.52, 24.06, 24.84, 25.34, 25.55, 26.08, 26.49, 26.89, 27.12, 27.92, 28.62, 29. 03, 29.75, 30.10, 31.21, 32.10, 32.89, 33.26, 34.45, 35.64, 36.06, 37.24, 38.84.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.20°, 16.53 ⁇ 0.20°, and/or 18.12 ⁇ 0.20°, and/or 5.80 ⁇ 0.20°, and/or 11.58 ⁇ 0.20°, and/or 12.16 ⁇ 0.20°, and/or 12.72 ⁇ 0.20°, and/or 13.07 ⁇ 0.20°, and/or 13.48 ⁇ 0.20°, and/or 14.72 ⁇ 0.20 °, and/or 15.92 ⁇ 0.20°, and/or 16.89 ⁇ 0.20°, and/or 17.37 ⁇ 0.20°, and/or 18.43 ⁇ 0.20°, and/or 19.11 ⁇ 0.20°, and/or 21.24 ⁇ 0.20°, and/or 21.44 ⁇ 0.20°, and/or 22.41 ⁇ 0.20°, and/or 23.02 ⁇ 0.20°, and/or 23.23 ⁇ 0.20°, and/or 23.52 ⁇ 0.20
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.10°, 16.53 ⁇ 0.10°, and/or 18.12 ⁇ 0.10°, and/or 5.80 ⁇ 0.10°, and/or 11.58 ⁇ 0.10°, and/or 12.16 ⁇ 0.10°, and/or 12.72 ⁇ 0.10°, and/or 13.07 ⁇ 0.10°, and/or 13.48 ⁇ 0.10°, and/or 14.72 ⁇ 0.10 °, and/or 15.92 ⁇ 0.10°, and/or 16.89 ⁇ 0.10°, and/or 17.37 ⁇ 0.10°, and/or 18.43 ⁇ 0.10°, and/or 19.11 ⁇ 0.10°, and/or 21.24 ⁇ 0.10°, and/or 21.44 ⁇ 0.10°, and/or 22.41 ⁇ 0.10°, and/or 23.02 ⁇ 0.10°, and/or 23.23 ⁇ 0.10°, and/or 23.52 ⁇ 0.10
  • the XRPD pattern of the above-mentioned crystal form A is basically as shown in Figure 1.
  • the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak starting point at 164.0 ⁇ 5°C.
  • the DSC pattern of the above-mentioned crystal form A is shown in Figure 2.
  • thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 1.25% at 150.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form A is shown in Figure 3.
  • the present invention also provides compounds of formula (II), whose structural formula is as follows:
  • the present invention also provides the B crystal form of the compound of formula (II), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 8.11 ⁇ 0.20°, 14.59 ⁇ 0.20°, 19.11 ⁇ 0.20° and 21.75 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 8.11 ⁇ 0.20°, 13.89 ⁇ 0.20°, 14.59 ⁇ 0.20°, 15.31 ⁇ 0.20°, 19.11 ⁇ 0.20°, 21.75 ⁇ 0.20°, 24.94 ⁇ 0.20° and 25.73 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 8.11 ⁇ 0.20°, 13.89 ⁇ 0.20°, 14.59 ⁇ 0.20°, 15.31 ⁇ 0.20°, 16.62 ⁇ 0.20°, 19.11 ⁇ 0.20°, 21.75 ⁇ 0.20°, 22.23 ⁇ 0.20°, 24.94 ⁇ 0.20°, 25.73 ⁇ 0.20°, 26.22 ⁇ 0.20°, 27.88 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 7.66 ⁇ 0.20°, 8.11 ⁇ 0.20°, 13.89 ⁇ 0.20°, 14.59 ⁇ 0.20° ⁇ 15.31 ⁇ 0.20° ⁇ 16.62 ⁇ 0.20° ⁇ 17.65 ⁇ 0.20° ⁇ 18.35 ⁇ 0.20° ⁇ 19.11 ⁇ 0.20° ⁇ 21.75 ⁇ 0.20° ⁇ 22.23 ⁇ 0.20° ⁇ 24.94 ⁇ 0.20° ⁇ 25.73 ⁇ 0.20° ⁇ 26.22 ⁇ 0.20°, 27.88 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 7.66 ⁇ 0.20°, 8.11 ⁇ 0.20°, 11.34 ⁇ 0.20°, 12.21 ⁇ 0.20° ⁇ 13.89 ⁇ 0.20° ⁇ 14.59 ⁇ 0.20° ⁇ 14.84 ⁇ 0.20° ⁇ 15.31 ⁇ 0.20° ⁇ 16.20 ⁇ 0.20° ⁇ 16.62 ⁇ 0.20° ⁇ 17.44 ⁇ 0.20° ⁇ 17.65 ⁇ 0.20° ⁇ 18.35 ⁇ 0.20° ⁇ 19.11 ⁇ 0.20° ⁇ 19.84 ⁇ 0.20° ⁇ 20.43 ⁇ 0.20° ⁇ 21.75 ⁇ 0.20° ⁇ 22.23 ⁇ 0.20° ⁇ 22.46 ⁇ 0.20° ⁇ 23.50 ⁇ 0.20° ⁇ 24.36 ⁇ 0.20° ⁇ 24.94 ⁇ 0.20° ⁇ 25.73 ⁇ 0.20° ⁇ 26.22 ⁇ 0.20° ⁇ 27.43 ⁇ 0.20° ⁇ 27.88 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.10°, 7.66 ⁇ 0.10°, 8.11 ⁇ 0.10°, 11.34 ⁇ 0.10°, 12.21 ⁇ 0.10° ⁇ 13.89 ⁇ 0.10° ⁇ 14.59 ⁇ 0.10° ⁇ 14.84 ⁇ 0.10° ⁇ 15.31 ⁇ 0.10° ⁇ 16.20 ⁇ 0.10° ⁇ 16.62 ⁇ 0.10° ⁇ 17.44 ⁇ 0.10° ⁇ 17.65 ⁇ 0.10° ⁇ 18.35 ⁇ 0.10° ⁇ 19.11 ⁇ 0.10° ⁇ 19.84 ⁇ 0.10° ⁇ 20.43 ⁇ 0.10° ⁇ 21.75 ⁇ 0.10° ⁇ 22.23 ⁇ 0.10° ⁇ 22.46 ⁇ 0.10° ⁇ 23.50 ⁇ 0.10° ⁇ 24.36 ⁇ 0.10° ⁇ 24.94 ⁇ 0.10° ⁇ 25.73 ⁇ 0.10° ⁇ 26.22 ⁇ 0.10°, 27.43 ⁇ 0.10°, 27.88 ⁇ 0.10°
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22, 7.66, 8.11, 11.34, 12.21, 13.89, 14.59, 14.84, 15.31, 16.20, 16.62, 17.44, 17.65, 18.35, 19.11, 19.84, 20.43, 21.75, 22.23, 22.46, 23.50, 24.36, 24.94, 25.73, 26.22, 27.43, 27.88, 28.72, 29.14, 30.11, 30.64, 32. 04, 32.87, 33.46, 35.89, 38.78 and 39.28.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 8.11 ⁇ 0.20°, and/or 7.66 ⁇ 0.20°, and/or 11.34 ⁇ 0.20°, and/or 12.21 ⁇ 0.20°, and/or 13.89 ⁇ 0.20°, and/or 14.59 ⁇ 0.20°, and/or 14.84 ⁇ 0.20°, and/or 15.31 ⁇ 0.20°, and/or 16.20 ⁇ 0.20 °, and/or 16.62 ⁇ 0.20°, and/or 17.44 ⁇ 0.20°, and/or 17.65 ⁇ 0.20°, and/or 18.35 ⁇ 0.20°, and/or 19.11 ⁇ 0.20°, and/or 19.84 ⁇ 0.20°, and/or 20.43 ⁇ 0.20°, and/or 21.75 ⁇ 0.20°, and/or 22.23 ⁇ 0.20°, and/or 22.46 ⁇ 0.20°, and/or 23.50 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.10°, 8.11 ⁇ 0.10°, and/or 7.66 ⁇ 0.10°, and/or 11.34 ⁇ 0.10°, and/or 12.21 ⁇ 0.10°, and/or 13.89 ⁇ 0.10°, and/or 14.59 ⁇ 0.10°, and/or 14.84 ⁇ 0.10°, and/or 15.31 ⁇ 0.10°, and/or 16.20 ⁇ 0.10 °, and/or 16.62 ⁇ 0.10°, and/or 17.44 ⁇ 0.10°, and/or 17.65 ⁇ 0.10°, and/or 18.35 ⁇ 0.10°, and/or 19.11 ⁇ 0.10°, and/or 19.84 ⁇ 0.10°, and/or 20.43 ⁇ 0.10°, and/or 21.75 ⁇ 0.10°, and/or 22.23 ⁇ 0.10°, and/or 22.46 ⁇ 0.10°, and/or 23.50 ⁇ 0.10°
  • the XRPD pattern of the above-mentioned crystal form B is basically as shown in Figure 4.
  • the XRPD spectrum analysis data of the above-mentioned Form B is shown in Table 2.
  • the differential scanning calorimetry curve of the above-mentioned B crystal form has an endothermic peak at 153.7 ⁇ 3°C.
  • the DSC pattern of the above-mentioned B crystal form is shown in Figure 5.
  • thermogravimetric analysis curve of the above-mentioned B crystal form has a weight loss of 2.88% at 150.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned B crystal form is shown in Figure 6.
  • the present invention also provides a compound of formula (III), whose structural formula is as follows:
  • the present invention also provides the C crystal form of the compound of formula (III), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 13.19 ⁇ 0.20°, 15.22 ⁇ 0.20° and 20.59 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 13.19 ⁇ 0.20°, 15.22 ⁇ 0.20°, 15.80 ⁇ 0.20°, 16.25 ⁇ 0.20°, 18.12 ⁇ 0.20°, 20.59 ⁇ 0.20°, 21.63 ⁇ 0.20° and 26.50 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 13.19 ⁇ 0.20°, 15.22 ⁇ 0.20°, 15.80 ⁇ 0.20°, 16.25 ⁇ 0.20°, 18.12 ⁇ 0.20°, 20.59 ⁇ 0.20°, 21.63 ⁇ 0.20°, 24.11 ⁇ 0.20°, 26.50 ⁇ 0.20°, 27.75 ⁇ 0.20° and 28.15 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 9.30 ⁇ 0.20°, 13.19 ⁇ 0.20°, 15.22 ⁇ 0.20°, 15.80 ⁇ 0.20° ⁇ 16.25 ⁇ 0.20° ⁇ 18.12 ⁇ 0.20° ⁇ 20.59 ⁇ 0.20° ⁇ 21.63 ⁇ 0.20° ⁇ 24.11 ⁇ 0.20° ⁇ 24.91 ⁇ 0.20° ⁇ 25.87 ⁇ 0.20° ⁇ 26.50 ⁇ 0.20° ⁇ 27.75 ⁇ 0.20° ⁇ 28.15 ⁇ 0.20°, 30.73 ⁇ 0.20° and 31.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46, 9.30, 13.19, 15.22, 15.80, 16.25, 18.12, 20.59, 21.63, 24.11, 24.91, 25.87, 26.50, 27.75, 28.15, 30.73 and 31.74.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 15.22 ⁇ 0.20°, and/or 9.30 ⁇ 0.20°, and/or 13.19 ⁇ 0.20°, and/or 15.80 ⁇ 0.20°, and/or 16.25 ⁇ 0.20°, and/or 18.12 ⁇ 0.20°, and/or 20.59 ⁇ 0.20°, and/or 21.63 ⁇ 0.20°, and/or 24.11 ⁇ 0.20 °, and/or 24.91 ⁇ 0.20°, and/or 25.87 ⁇ 0.20°, and/or 26.50 ⁇ 0.20°, and/or 27.75 ⁇ 0.20°, and/or 28.15 ⁇ 0.20°, and/or 30.73 ⁇ 0.20°, and/or 31.74 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form C is basically as shown in Figure 7.
  • the differential scanning calorimetry curve of the above-mentioned crystal form C has endothermic peaks at 105.1 ⁇ 3°C and 216.0 ⁇ 3°C.
  • the DSC pattern of the above-mentioned C crystal form is shown in Figure 8.
  • the weight loss of the above-mentioned C crystal form in the thermogravimetric analysis curve reaches 8.22% at 150.0 ⁇ 3°C.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and pharmaceutically acceptable excipients;
  • the dosage form of the above-mentioned pharmaceutical composition is selected from capsules, granules, injections, pills, syrups, powders, ointments, emulsions, solutions, suspensions or tinctures, and other variables are as defined in the present invention.
  • the above-mentioned auxiliary materials are selected from excipients, fillers, binders, humectants, disintegrants, slow solvents, absorption accelerators, adsorbents, diluents, solubilizers, emulsifiers, lubricants, Wetting agents, glidants, suspending agents, flavoring agents, perfumes or mixtures thereof, other variables are as defined in the present invention.
  • the present invention also provides a preparation method of the compound of formula (I), which is prepared as follows:
  • R 1 is selected from H, CH 3 , Boc, Cbz, Bn and PMB;
  • R 1 is selected from Boc, Cbz, Bn and PMB
  • the preparation method of the compound of formula (I) is selected from:
  • the preparation method of the compound of formula (II-3) is selected from:
  • Method one includes:
  • Method two includes:
  • Method three includes:
  • R 1 is selected from H, CH 3 , Boc, Cbz, Bn and PMB;
  • R 2 is selected from Bn, PMB, PNB and MOM
  • R 4 is selected from CH 3 , MOM, Bn, SEM and Ac;
  • R 5 is selected from F, Cl, Br, I, OTf and OCH 2 CF 3 ;
  • R 31 is selected from B(OH) 2 ;, and BF 3K ;
  • R 6 is selected from F, Cl, Br and I.
  • R 7 is selected from Cl, Br, OTf, OCH 2 CF 3 and OTs.
  • the present invention also provides a method for preparing the compound of formula (I),
  • Step 1 React compound EE-3 to obtain compound EE-4,
  • Step 2 react compound EE-4 to obtain compound EE-5,
  • Step 3 React compound EE-5 and compound AA to obtain compound H-1,
  • Step 4 react compound H-1 to obtain the compound of formula (I),
  • the preparation method of the compound of formula (I) above includes the following steps: Step 1: react compound EE-3 with reagents A and B to obtain compound EE-4,
  • Reagent A is selected from the group consisting of methyl chloride, methyl bromide, methyl iodide and methoxymethyl methanesulfonate, with methyl chloride being preferred;
  • Reagent B is selected from potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen, lithium hexamethyldisilazide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium tert-butoxide , sodium tert-butoxide, sodium hydroxide, lithium hydroxide and potassium hydroxide, preferably potassium carbonate;
  • Solvent C is selected from DMF, DCM, THF, 2-MeTHF, EtOAc, i-PrOAc, NMP and dioxane, with DMF being preferred.
  • the preparation method of the compound of formula (I) above includes the following steps:
  • Step 2 React compound EE-4 with reagents D, E, F, and G to obtain compound EE-5,
  • Reagent D is selected from the group consisting of zonacol borane and zonacol borane, preferably zonacol borane;
  • Reagent E is selected from Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , bis(acetonitrile)palladium(II) dichloride, Pd(OAc) 2 and Pd 2 (dba) 3 , preferably Pd (OAc) 2 ;
  • Reagent F is selected from Sphos, Xphos, XantPhos and 2-(dicyclohexylphosphonium)biphenyl, preferably 2-(dicyclohexylphosphonium)biphenyl;
  • Reagent G is selected from potassium acetate, sodium acetate, TEA, DIPEA and potassium 2-ethylhexanoate, with TEA being preferred;
  • Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, with dioxane being preferred.
  • the preparation method of the compound of formula (I) above includes the following steps:
  • Step 3 React compound EE-5 and compound AA with reagents I and J to obtain compound H-1,
  • Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, preferably dioxane;
  • Reagent I is selected from Pd(OAc) 2 -BINAP, Pd 2 (dba) 3 -Xphos, Brettphos-Pd-G3, Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 CH 2 Cl 2 and Pd(OAc) 2 -Sphos, preferably Pd(dppf)Cl 2 CH 2 Cl 2 ;
  • Reagent J is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , KOAc, KF and TEA, preferably K 2 CO 3 .
  • the preparation method of the compound of formula (I) above includes the following steps:
  • Step 4 React compound H-1 and reagent K to obtain the compound of formula (I),
  • Reagent K is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably hydrochloric acid.
  • the preparation method of the compound of formula (I) above includes the following steps:
  • Step 1 React compound EE-3 with reagents A and B to obtain compound EE-4,
  • Step 2 React compound EE-4 with reagents D, E, F, and G to obtain compound EE-5,
  • Step 3 React compound EE-5 and compound AA with reagents I and J to obtain compound H-1,
  • Step 4 React compound H-1 and reagent K to obtain the compound of formula (I),
  • Reagent A is selected from the group consisting of methyl chloride, methyl bromide, methyl iodide and methoxymethyl methanesulfonate, with methyl chloride being preferred;
  • Reagent B is selected from potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen, lithium hexamethyldisilazide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium tert-butoxide , sodium tert-butoxide, sodium hydroxide, lithium hydroxide and potassium hydroxide, preferably potassium carbonate;
  • Solvent C is selected from DMF, DCM, THF, 2-MeTHF, EtOAc, i-PrOAc, NMP and dioxane, preferably DMF;
  • Reagent D is selected from the group consisting of zonacol borane and zonacol borane, preferably zonacol borane;
  • Reagent E is selected from Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , bis(acetonitrile)palladium(II) dichloride, Pd(OAc) 2 and Pd 2 (dba) 3 , preferably Pd (OAc) 2 ;
  • Reagent F is selected from Sphos, Xphos, XantPhos and 2-(dicyclohexylphosphonium)biphenyl, preferably 2-(dicyclohexylphosphonium)biphenyl;
  • Reagent G is selected from potassium acetate, sodium acetate, TEA, DIPEA and potassium 2-ethylhexanoate, with TEA being preferred;
  • Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, preferably dioxane;
  • Reagent I is selected from Pd(OAc) 2 -BINAP, Pd 2 (dba) 3 -Xphos, Brettphos-Pd-G3, Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 CH 2 Cl 2 and Pd(OAc) 2 -Sphos, preferably Pd(dppf)Cl 2 CH 2 Cl 2 ;
  • Reagent J is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , KOAc, KF and TEA, preferably K 2 CO 3 ;
  • Reagent K is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably hydrochloric acid.
  • the invention also provides a method for preparing the intermediate compound of formula (AA):
  • R 51 is selected from F, Cl, Br and I;
  • R 11 is selected from CH 3 , Boc, Cbz, Bn and PMB.
  • the invention also provides a method for preparing the intermediate compound of formula (AA):
  • the preparation method of the compound of formula (I) above is selected from:
  • Method one includes:
  • Method two includes:
  • Method three includes:
  • Method four includes:
  • Method five includes:
  • Method six includes:
  • Method seven includes:
  • Method eight includes:
  • Method nine includes:
  • Method ten includes:
  • Method 11 includes:
  • Method twelve includes:
  • Method thirteen includes:
  • Method fourteen includes:
  • the present invention also provides the above-mentioned compound A crystal form of the formula (I), the above-mentioned compound formula (II), the above-mentioned compound B crystal form of the formula (II), the above-mentioned pharmaceutical composition and the above-mentioned preparation method for the preparation and treatment of NLRP3 inflammation.
  • the above-mentioned NLRP3 inflammasome-related diseases are selected from NLRP3 inflammasome-related neuroinflammatory diseases (such as brain inflammation, brain injury) and neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease). Alzheimer's disease, multiple sclerosis).
  • NLRP3 inflammasome-related neuroinflammatory diseases such as brain inflammation, brain injury
  • neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease. Alzheimer's disease, multiple sclerosis.
  • the above-mentioned NLRP3 inflammasome-related diseases are selected from the group consisting of NLRP3 inflammasome-related neuroinflammatory diseases and neurodegenerative diseases.
  • the above-mentioned NLRP3 inflammasome-related neuroinflammatory disease is selected from brain inflammation and brain injury.
  • the above-mentioned neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease and multiple sclerosis.
  • the above-mentioned neurodegenerative disease is selected from Parkinson's disease and Alzheimer's disease.
  • the A crystal form of the compound of formula (I) and the B crystal form of the compound of formula (II) of the present invention are easy to obtain, and have relatively high physical and chemical stability. Well, it has high industrial application value and economic value.
  • the process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the following beneficial effects: the raw materials are cheap and easy to obtain, and overcome the shortcomings of difficulty in separation and purification and difficulty in industrialization.
  • the NLRP3 inhibitor provided by the invention can effectively inhibit the activity of NLRP3 inflammasome and the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1 ⁇ , and has good pharmacokinetic properties and can be used for NLRP3 inflammation.
  • composition means a mixture containing one or more compounds described herein, or physiologically acceptable salts or prodrugs thereof, and other chemical components, as well as other components such as physiologically acceptable carriers.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof described in this application can be a "pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof", and further, it can be “a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof”.
  • compound may also be “a pharmaceutical composition containing a compound of formula (III)”.
  • administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need may be “administering a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need”, and further , may be “administering a pharmaceutical composition containing a compound of formula (II) to an individual in need” or may be “administering a pharmaceutical composition containing a compound of formula (III) to an individual in need”.
  • terapéuticaally effective dose means an amount of a compound sufficient to effect treatment of a disease when administered to a human for the treatment of the disease.
  • solvate refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric solvent bound by non-covalent intermolecular forces.
  • the solvent is water, it is a hydrate.
  • treatment includes inhibiting, slowing, stopping or reversing existing symptoms or the progression or severity of a disease.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients.
  • they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, dragees, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • Boc represents tert-butoxycarbonyl
  • Cbz represents benzyloxycarbonyl
  • Bn represents benzyl
  • PMB p-methoxybenzyl
  • DCM represents dichloromethane
  • DMF represents N, N-bis Methylformamide
  • THF represents tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • EtOH represents ethanol
  • MeOH represents methanol
  • ACN (MeCN) represents acetonitrile
  • EtOAc represents ethyl acetate
  • H 2 O represents water
  • i-PrOH represents isopropyl alcohol
  • Acetone represents acetone
  • IPAc represents isopropyl acetate
  • 2-MeTHF represents 2-methyltetrahydrofuran
  • 1,4-Dioxane represents 1,4-dioxane
  • CHCl 3 represents chloroform
  • Toluene represents toluene
  • test parameters of the X-ray powder diffraction (X-ray powder diffractometer, XRPD) method of the present invention are shown in Table 4.
  • test parameters of the differential scanning calorimeter (DSC) method of the present invention are shown in Table 5.
  • thermogravimetric analyzer (TGA) method of the present invention are shown in Table 6.
  • test parameters of the dynamic vapor adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention are shown in Table 7.
  • FIG. 14 Single crystal X-ray diffraction (SC-XRD) three-dimensional structure ellipsoid diagram of the compound of formula (I).
  • the hydrochloride of compound AA-5 (85.0g, 283.69mmol) was dissolved in anhydrous methanol (850mL), and 37% formaldehyde aqueous solution (69.06g, 851mmol) was added to the reaction solution.
  • the reaction solution was heated at 20 The reaction was stirred at 20°C for 0.5 hours.
  • Sodium acetate borohydride (123.97g, 567mmol) was added in batches to the reaction solution at 20°C, and the reaction solution was stirred at 20°C for 11.5 hours.
  • the filtrate was concentrated under reduced pressure to remove dioxane and 2-methyltetrahydrofuran.
  • the remaining aqueous phase was adjusted to pH 4 with hydrochloric acid aqueous solution (1mol/L), extracted with 2-methyltetrahydrofuran (1000mL ⁇ 2), and the aqueous phase was adjusted to pH 10 with sodium hydroxide aqueous solution (1mol/L), and 2- Extract with methyltetrahydrofuran (1000mL ⁇ 1,700mL ⁇ 2), combine the organic phases, concentrate, dissolve the organic phase with 1400ml of dimethyltetrahydrofuran, add modified silica gel (LI-511, 50g) for palladium removal, and stir at 45°C for 6 hours, filter, continue adding modified silica gel (LI-511, 50g) for palladium removal to the filtrate, stir at 50°C for 12 hours, filter, add modified silica gel (LI-511, 50g) for palladium removal to the filtrate, stir at 50°C for 6 hours
  • the amorphous form of the compound of formula (I) was analyzed by high performance liquid chromatography (chromatographic column: Phenomenex C18 150 ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 1%-30%, 10 minutes ) to prepare the amorphous form of the compound of formula (III).
  • Acetone 0.5 mL was added to the amorphous form (50.2 mg) of the compound of formula (III), and the resulting suspension was stirred at room temperature for 3 days to obtain the C crystal form of the compound of formula (III).
  • the XRPD, DSC, TGA, and DVS detection results are shown in Figures 7, 8, 9, and 12 in sequence.
  • Example 7 Solid pre-stability test of crystal form A of compound of formula (I) and crystal form of compound B of formula (II)
  • Hygroscopicity evaluation classification table Note: ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • the DVS spectrum of the crystal form A of compound of formula (I) is shown in Figure 10.
  • the DVS results show that the sample absorbs moisture and gains weight by 0.1665% under the conditions of 25°C/80% RH, and the sample has no or almost no hygroscopicity. After completing the DVS test (0-95-0% RH), take out the sample and expose it to the air for XRPD testing. The results show that the crystal form has not changed before and after the DVS test.
  • the DVS spectrum of the crystalline form B of compound (II) is shown in Figure 11.
  • the DVS results showed that the sample gained 7.15% moisture and weight under the condition of 25°C/80%RH compared with the condition of 25°C/0%RH, and the sample was hygroscopic.
  • the DVS spectrum of the crystalline form C of compound (III) is shown in Figure 12.
  • the DVS results show that the sample has a hygroscopic weight gain of 21.09% under the condition of 25°C/80%RH compared with the condition of 25°C/0%RH.
  • the sample is extremely hygroscopic.
  • the crystal form of compound A of formula (I) has no or almost no hygroscopicity at 25 ⁇ 1°C and 80 ⁇ 2%RH, and the crystal form remains unchanged;
  • the crystal form of compound B of formula (II) has no or almost no hygroscopicity at 25 ⁇ 1°C and 80 ⁇ 2% RH. It is hygroscopic at 2% RH;
  • the crystal form C of the compound of formula (III) is extremely hygroscopic at 25 ⁇ 1°C and 80 ⁇ 2% RH.
  • MV average particle size calculated by volume
  • D10 Indicates the particle size corresponding to 10% of the particle size distribution (volume distribution);
  • D50 Indicates the particle size corresponding to 50% of the particle size distribution (volume distribution), also known as the median diameter;
  • D90 Indicates the particle size corresponding to 90% of the particle size distribution (volume distribution);
  • the PSD results of the crystal form of compound A of formula (I) are shown in Figure 13.
  • the volume average particle size of the crystal form of compound A of formula (I) is 12.05 microns.
  • the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform.
  • X-ray light source high-intensity micro-focus rotating anode light source, Cu target;
  • Goniometer four axes (Kappa, ⁇ , 2 ⁇ , ) goniometer;
  • Detector Large area photon II detector, the effective area of the detector is 14cm ⁇ 10cm, the distance between the detector and the sample is automatically adjustable by the motor.
  • This experiment used rat primary microglia to study the inhibitory activity of NLRP3 inhibitors on IL-1 ⁇ secretion in rat primary microglia.
  • the cerebral cortex was removed, digested and separated to obtain mixed glial cells, which were inoculated into culture bottles for culture. Change the medium every 3-4 days and culture for about 10 days. After the cells are completely confluent, shake at 37°C, collect microglia by centrifugation, inoculate them into a 96-well cell culture plate and culture them overnight. The cells were replaced with serum-free medium, 50ng/mL LPS was added for 3h, then different concentrations of compounds were added for 0.5h, and then 0.3 ⁇ g/mL Nigericin was added for 1h. Collect the supernatant and store it at -80°C or directly detect the release of IL-1 ⁇ by ELISA and follow the instructions of the kit.
  • Data processing uses the 10 ⁇ M positive compound group as the low value (L) and the DMSO group as the high value (H).
  • the compound of the present invention has significant inhibitory activity on the maturation and secretion of IL-1 ⁇ in rat primary microglia.
  • a central inflammation model was established by injecting LPS into the lateral ventricle of rats, and ELISA was used to evaluate the IL-1 ⁇ levels in cerebrospinal fluid to evaluate the in vivo efficacy of the test compounds.
  • SD male rats aged 10-14 weeks were anesthetized using isoflurane breathing; ensure that the animal's head does not move and adjust the brain surface to be flat; the rat's head is shaved, and a skin incision is made along the sagittal suture.
  • fontanelle position the glass electrode to the anterior fontanelle, reset each axis of the coordinate display to zero, and position according to the coordinates; slowly insert the needle to locate the lateral ventricle, inject 12.5 ⁇ g LPS, and give 5 mg/kg compound of formula (I) 2 hours later.
  • ATP was administered 3 hours later
  • cerebrospinal fluid was collected 3.5 hours later
  • IL-1 ⁇ inhibition level was evaluated by ELISA.
  • SD rats were selected and a Parkinson's disease (PD) model was established by injecting 6-hydroxydopamine (6-OHDA) through brain stereotaxy.
  • 6-OHDA 6-hydroxydopamine
  • the striatum was collected after treatment with the compound for 5 days, and IL-1 ⁇ was evaluated by ELISA. Inhibition level.
  • test substance compound of formula (I), 5, 10 mg/kg
  • vehicle control solvent stock solution
  • test compound had a significant inhibitory effect on striatal IL-1 ⁇ levels in the 6-hydroxydopamine-induced rat Parkinson model.
  • SD rats were selected to establish a Parkinson's disease (PD) model by injecting 6-hydroxydopamine (6-OHDA) through brain stereotaxy.
  • the compound was administered for 21 days and then related behavioral tests (balance beam test, rotarod test) were conducted. Test) and histological testing [tyrosine hydroxylase (TH), microglia marker (Iba1) immunofluorescence staining] to evaluate the efficacy of the compound to be tested.
  • SD rats were anesthetized with isoflurane breathing to ensure that the animal's head would not move and the brain surface should be adjusted to be flat.
  • the head of the rat was shaved, and a skin incision was made along the sagittal suture to expose the bregma.
  • Position the glass electrode to the bregma reset each axis of the coordinate display to zero, and locate the substantia nigra (SN) and striatum (Str) brain areas according to the coordinates; slowly insert the needle to locate SN and Str, wait 10 minutes, and then inject 0.4 ⁇ L Inject 6-OHDA at a rate of /min. After the drug is administered, stay for another 10 minutes and then slowly withdraw the needle.
  • Balance beam test training period put the animal on the balance beam to adapt for 10 minutes every day, and cross the balance beam twice for each training, for a total of 2 days; the formal test adapts to the environment for 30-60 minutes, place the animal on the balance beam, and record the animal passing the balance beam twice. number of foot slips. Evaluation criteria: The number of foot slides (feet leaving the upper surface of the balance beam) that successfully pass the balance beam twice.
  • Rotarod test muscle strength test: Before testing, animals are placed in the test room to adapt to the environment for 30-60 minutes; adaptation training: Each experimental animal is placed on the rotarod fatigue instrument for adaptive training for 5 minutes.
  • Formal testing The parameters of the rotary rod fatigue meter are set to a rotation speed of 20 rpm/min and a test time of 5 minutes. Rats are placed on the rotary rod in batches for testing. Result analysis: count the time each animal spent on the bar.
  • TH tyrosine hydroxylase
  • Iba1 microglia marker
  • results show that: compared with the compound group of formula (I) and the 6-OHDA modeling group, the rats in the compound group of formula (I) stay on the rod longer than the rats in the 6-OHDA modeling group, and the difference between the two is significant (p ⁇ 0.05) .
  • AD Alzheimer's Disease
  • Table 25 Grouping of experimental animals, model induction and drug administration and treatment
  • Animals were administered orally administered with vehicle or vehicle from the first day.
  • the vehicle group and oA ⁇ 1-42 modeling group were orally administered vehicle, and the third group was orally administered test compound solution twice a day with an interval of 8 hours.
  • Behavioral experiments were conducted on the eighth and tenth days, and the second dose was administered after the behavioral experiment.
  • tissue samples were taken from the mice 2 hours after the first administration.
  • Y maze test Place the mouse at the end of any arm of the Y maze and let it explore freely for 8 minutes.
  • the animal's movement trajectory and behavioral changes are recorded with video, and the following indicators are recorded: 1
  • the total number of entries (the total number of entries) : The number of times an animal enters the arms of the maze (taking all four legs of the mouse into the arms is considered as one arm entry); 2
  • One turn (an alternation): Enter all three arms of the Y maze consecutively once; 3*Number of turns (The number of maximum alternations): The total number of arm advances -2.
  • Mouse behavior was analyzed using the EthosVision-XT8.0 video analysis system.
  • Table 30 Analysis results of Tau protein phosphorylation levels and microglia activation in cortical brain areas 13 days after intracerebroventricular injection of oA ⁇ 1-42 Note: Data are expressed as Mean ⁇ SEM; *: compared with vehicle group, ****p ⁇ 0.0001; # : compared with oA ⁇ 1-42 modeling group, #### p ⁇ 0.0001.

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Abstract

Disclosed in the present invention are a crystal form, a salt type and a composition of a pyridazine compound and a preparation method therefor, and specifically disclosed are a method for preparing a crystal form A and a composition of the compound of formula (I), a crystal form B of the compound of formula (II) and a crystal form C of the compound of formula (III), and the use thereof.

Description

哒嗪类化合物的晶型、盐型、组合物及其制备方法Crystal forms, salt forms, compositions and preparation methods of pyridazine compounds
本申请主张如下优先权：This application claims the following priority rights:
CN202210918680.X，2022年08月01日；CN202210918680.X, August 1, 2022;
CN202210940251.2，2022年08月05日。CN202210940251.2, August 5, 2022.
技术领域Technical field
本发明涉及一种哒嗪类化合物的晶型、盐型、组合物及其制备方法，具体公开了式(I)化合物的A晶型、盐型、和组合物、式(Ⅱ)化合物的B晶型和式(Ⅲ)化合物的C晶型的制备方法和应用。The present invention relates to a crystal form, salt form, composition and preparation method of a pyridazine compound, specifically disclosing the A crystal form, salt form and composition of the compound of formula (I), and the B form of the compound of formula (II). Preparation methods and applications of crystal forms and Form C of the compound of formula (III).
背景技术Background technique
NLRP3炎性小体是一种多蛋白复合物，在先天免疫和炎症相关的疾病发生过程中具有重要作用。NLRP3炎性小体由NOD样受体(NOD-like receptors,NLRs)、凋亡相关的斑点样蛋白(apoptosis-associated speck-like protein containing a CARD,ASC)和半胱氨酸天冬氨酸蛋白酶1(Caspase-1)组成。外源性病原体或内源性危险因素如线粒体活性氧、氧化的线粒体DNA、β-淀粉样蛋白或α-突触核蛋白等均可激活NLRP3。活化的NLRP3与ASC和Caspase-1组成活化的NLRP3炎性小体，进一步通过Caspase-1水解IL-1β前体(pro-IL-1β)、IL-18前体(pro-IL-18)，使其释放具有活性的细胞因子IL-1β、IL-18。这些细胞因子的分泌可导致细胞焦亡(pyroptosis)或神经元损伤。NLRP3炎性小体在多种自身免疫性疾病、心血管疾病、神经退行性疾病和肿瘤发生的过程中扮演着重要角色(Nature Reviews Drug Discovery,2018,17(8):588-606.)。The NLRP3 inflammasome is a multi-protein complex that plays an important role in the development of innate immunity and inflammation-related diseases. The NLRP3 inflammasome consists of NOD-like receptors (NLRs), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase 1 (Caspase-1) composition. Exogenous pathogens or endogenous risk factors such as mitochondrial reactive oxygen species, oxidized mitochondrial DNA, β-amyloid or α-synuclein can activate NLRP3. Activated NLRP3, ASC and Caspase-1 form the activated NLRP3 inflammasome, which further hydrolyzes IL-1β precursor (pro-IL-1β) and IL-18 precursor (pro-IL-18) through Caspase-1. It releases active cytokines IL-1β and IL-18. The secretion of these cytokines can lead to pyroptosis or neuronal damage. NLRP3 inflammasome plays an important role in the development of various autoimmune diseases, cardiovascular diseases, neurodegenerative diseases and tumors (Nature Reviews Drug Discovery, 2018, 17(8):588-606.).
NLRP3抑制剂目前还没有药物分子上市，临床前化合物MCC950对NLRP3有显著的抑制作用(Sci.Transl.Med.10,eaah4066(2018))。OLT-1177、Inzomelid、Selnoflast和IFM-2427等药物处于临床研究阶段。开发NLRP3抑制剂具有广泛的应用前景。
There are currently no drug molecules for NLRP3 inhibitors on the market. The preclinical compound MCC950 has a significant inhibitory effect on NLRP3 (Sci. Transl. Med. 10, eaah4066 (2018)). Drugs such as OLT-1177, Inzomelid, Selnoflast and IFM-2427 are in the clinical research stage. The development of NLRP3 inhibitors has broad application prospects.
发明内容Contents of the invention
本发明还提供式(I)化合物的A晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：8.41±0.20°、16.53±0.20°和18.12±0.20°；
The present invention also provides the A crystal form of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2θ angles: 8.41±0.20°, 16.53±0.20° and 18.12±0.20°;
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.41±0.20°、13.48±0.20°、16.53±0.20°、18.12±0.20°、21.44±0.20°和24.06±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 8.41±0.20°, 13.48±0.20°, 16.53±0.20°, 18.12±0.20°, 21.44± 0.20° and 24.06±0.20°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.41±0.20°、12.72±0.20°、13.48±0.20°、16.53±0.20°、18.12±0.20°、21.44±0.20°、24.06±0.20°和25.55±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 8.41±0.20°, 12.72±0.20°, 13.48±0.20°, 16.53±0.20°, 18.12± 0.20°, 21.44±0.20°, 24.06±0.20° and 25.55±0.20°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80±0.20°、 8.41±0.20°、12.72±0.20°、13.48±0.20°、14.72±0.20°、15.92±0.20°、16.53±0.20°、16.89±0.20°、18.12±0.20°、21.44±0.20°、24.06±0.20°、25.55±0.20°和27.12±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.80±0.20°, 8.41±0.20°, 12.72±0.20°, 13.48±0.20°, 14.72±0.20°, 15.92±0.20°, 16.53±0.20°, 16.89±0.20°, 18.12±0.20°, 21.44±0.20°, 24.06±0.20°, 25.55±0.20° and 27.12±0.20°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80±0.10°、8.41±0.10°、12.72±0.10°、13.48±0.10°、14.72±0.10°、15.92±0.10°、16.53±0.10°、16.89±0.10°、18.12±0.10°、21.44±0.10°、24.06±0.10°、25.55±0.10°和27.12±0.10°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 5.80±0.10°, 8.41±0.10°, 12.72±0.10°, 13.48±0.10°, 14.72± 0.10°, 15.92±0.10°, 16.53±0.10°, 16.89±0.10°, 18.12±0.10°, 21.44±0.10°, 24.06±0.10°, 25.55±0.10° and 27.12±0.10°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80±0.20°、8.41±0.20°、12.16±0.20°、12.72±0.20°、13.48±0.20°、14.72±0.20°、15.92±0.20°、16.53±0.20°、16.89±0.20°、17.37±0.20°、18.12±0.20°、21.44±0.20°、24.06±0.20°、24.84±0.20°、25.55±0.20°、27.12±0.20°和29.03±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 5.80±0.20°, 8.41±0.20°, 12.16±0.20°, 12.72±0.20°, 13.48± 0.20°、14.72±0.20°、15.92±0.20°、16.53±0.20°、16.89±0.20°、17.37±0.20°、18.12±0.20°、21.44±0.20°、24.06±0.20°、24.84±0.20°、25.55± 0.20°, 27.12±0.20° and 29.03±0.20°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80±0.10°、8.41±0.10°、12.16±0.10°、12.72±0.10°、13.48±0.10°、14.72±0.10°、15.92±0.10°、16.53±0.10°、16.89±0.10°、17.37±0.10°、18.12±0.10°、21.44±0.10°、24.06±0.10°、24.84±0.10°、25.55±0.10°、27.12±0.10°和29.03±0.10°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 5.80±0.10°, 8.41±0.10°, 12.16±0.10°, 12.72±0.10°, 13.48± 0.10°、14.72±0.10°、15.92±0.10°、16.53±0.10°、16.89±0.10°、17.37±0.10°、18.12±0.10°、21.44±0.10°、24.06±0.10°、24.84±0.10°、25.55± 0.10°, 27.12±0.10° and 29.03±0.10°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80±0.20°、8.41±0.20°、11.58±0.20°、12.16±0.20°、12.72±0.20°、13.07±0.20°、13.48±0.20°、14.72±0.20°、15.92±0.20°、16.53±0.20°、16.89±0.20°、17.37±0.20°、18.12±0.20°、18.43±0.20°、19.11±0.20°、21.24±0.20°、21.44±0.20°、22.41±0.20°、23.02±0.20°、23.23±0.20°、23.52±0.20°、24.06±0.20°、24.84±0.20°、25.34±0.20°、25.55±0.20°、26.08±0.20°、26.49±0.20°、26.89±0.20°、27.12±0.20°、27.92±0.20°、28.62±0.20°、29.03±0.20°、29.75±0.20°、30.10±0.20°、31.21±0.20°、32.10±0.20°、32.89±0.20°、33.26±0.20°、34.45±0.20°、35.64±0.20°、36.06±0.20°、37.24±0.20°和38.84±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 5.80±0.20°, 8.41±0.20°, 11.58±0.20°, 12.16±0.20°, 12.72± 0.20°、13.07±0.20°、13.48±0.20°、14.72±0.20°、15.92±0.20°、16.53±0.20°、16.89±0.20°、17.37±0.20°、18.12±0.20°、18.43±0.20°、19.11± 0.20°、21.24±0.20°、21.44±0.20°、22.41±0.20°、23.02±0.20°、23.23±0.20°、23.52±0.20°、24.06±0.20°、24.84±0.20°、25.34±0.20°、25.55± 0.20°、26.08±0.20°、26.49±0.20°、26.89±0.20°、27.12±0.20°、27.92±0.20°、28.62±0.20°、29.03±0.20°、29.75±0.20°、30.10±0.20°、31.21± 0.20°, 32.10±0.20°, 32.89±0.20°, 33.26±0.20°, 34.45±0.20°, 35.64±0.20°, 36.06±0.20°, 37.24±0.20° and 38.84±0.20°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80±0.10°、8.41±0.10°、11.58±0.10°、12.16±0.10°、12.72±0.10°、13.07±0.10°、13.48±0.10°、14.72±0.10°、15.92±0.10°、16.53±0.10°、16.89±0.10°、17.37±0.10°、18.12±0.10°、18.43±0.10°、19.11±0.10°、21.24±0.10°、21.44±0.10°、22.41±0.10°、23.02±0.10°、23.23±0.10°、23.52±0.10°、24.06±0.10°、24.84±0.10°、25.34±0.10°、25.55±0.10°、26.08±0.10°、26.49±0.10°、26.89±0.10°、27.12±0.10°、27.92±0.10°、28.62±0.10°、29.03±0.10°、29.75±0.10°、30.10±0.10°、31.21±0.10°、32.10±0.10°、32.89±0.10°、33.26±0.10°、34.45±0.10°、35.64±0.10°、36.06±0.10°、37.24±0.10°和38.84±0.10°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 5.80±0.10°, 8.41±0.10°, 11.58±0.10°, 12.16±0.10°, 12.72± 0.10°、13.07±0.10°、13.48±0.10°、14.72±0.10°、15.92±0.10°、16.53±0.10°、16.89±0.10°、17.37±0.10°、18.12±0.10°、18.43±0.10°、19.11± 0.10°、21.24±0.10°、21.44±0.10°、22.41±0.10°、23.02±0.10°、23.23±0.10°、23.52±0.10°、24.06±0.10°、24.84±0.10°、25.34±0.10°、25.55± 0.10°、26.08±0.10°、26.49±0.10°、26.89±0.10°、27.12±0.10°、27.92±0.10°、28.62±0.10°、29.03±0.10°、29.75±0.10°、30.10±0.10°、31.21± 0.10°, 32.10±0.10°, 32.89±0.10°, 33.26±0.10°, 34.45±0.10°, 35.64±0.10°, 36.06±0.10°, 37.24±0.10° and 38.84±0.10°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80、8.41、11.58、12.16、12.72、13.07、13.48、14.72、15.92、16.53、16.89、17.37、18.12、18.43、19.11、21.24、21.44、22.41、23.02、23.23、23.52、24.06、24.84、25.34、25.55、26.08、26.49、26.89、27.12、27.92、28.62、29.03、29.75、30.10、31.21、32.10、32.89、33.26、34.45、35.64、36.06、37.24、38.84。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 5.80, 8.41, 11.58, 12.16, 12.72, 13.07, 13.48, 14.72, 15.92, 16.53, 16.89, 17.37, 18.12, 18.43, 19.11, 21.24, 21.44, 22.41, 23.02, 23.23, 23.52, 24.06, 24.84, 25.34, 25.55, 26.08, 26.49, 26.89, 27.12, 27.92, 28.62, 29. 03, 29.75, 30.10, 31.21, 32.10, 32.89, 33.26, 34.45, 35.64, 36.06, 37.24, 38.84.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.41±0.20°、16.53±0.20°、和/或18.12±0.20°、和/或5.80±0.20°、和/或11.58±0.20°、和/或12.16±0.20°、和/或12.72±0.20°、和/或13.07±0.20°、和/或13.48±0.20°、和/或14.72±0.20°、和/或15.92±0.20°、和/或16.89±0.20°、和/或17.37±0.20°、和/或18.43±0.20°、和/或19.11±0.20°、和/或21.24±0.20°、和/或21.44±0.20°、和/或22.41±0.20°、和/或23.02±0.20°、和/或23.23±0.20°、和/或23.52±0.20°、和/或24.06±0.20°、和/或24.84±0.20°、和/或25.34±0.20°、和/或25.55±0.20°、和/或26.08±0.20°、和/或26.49±0.20°、和/或26.89±0.20°、和/或27.12±0.20°、 和/或27.92±0.20°、和/或28.62±0.20°、和/或29.03±0.20°、和/或29.75±0.20°、和/或30.10±0.20°、和/或31.21±0.20°、和/或32.10±0.20°、和/或32.89±0.20°、和/或33.26±0.20°、和/或34.45±0.20°、和/或35.64±0.20°、和/或36.06±0.20°、和/或37.24±0.20°、和/或38.84±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 8.41±0.20°, 16.53±0.20°, and/or 18.12±0.20°, and/or 5.80 ±0.20°, and/or 11.58±0.20°, and/or 12.16±0.20°, and/or 12.72±0.20°, and/or 13.07±0.20°, and/or 13.48±0.20°, and/or 14.72±0.20 °, and/or 15.92±0.20°, and/or 16.89±0.20°, and/or 17.37±0.20°, and/or 18.43±0.20°, and/or 19.11±0.20°, and/or 21.24±0.20°, and/or 21.44±0.20°, and/or 22.41±0.20°, and/or 23.02±0.20°, and/or 23.23±0.20°, and/or 23.52±0.20°, and/or 24.06±0.20°, and/ or 24.84±0.20°, and/or 25.34±0.20°, and/or 25.55±0.20°, and/or 26.08±0.20°, and/or 26.49±0.20°, and/or 26.89±0.20°, and/or 27.12 ±0.20°, and/or 27.92±0.20°, and/or 28.62±0.20°, and/or 29.03±0.20°, and/or 29.75±0.20°, and/or 30.10±0.20°, and/or 31.21±0.20°, and/or Or 32.10±0.20°, and/or 32.89±0.20°, and/or 33.26±0.20°, and/or 34.45±0.20°, and/or 35.64±0.20°, and/or 36.06±0.20°, and/or 37.24 ±0.20°, and/or 38.84±0.20°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.41±0.10°、16.53±0.10°、和/或18.12±0.10°、和/或5.80±0.10°、和/或11.58±0.10°、和/或12.16±0.10°、和/或12.72±0.10°、和/或13.07±0.10°、和/或13.48±0.10°、和/或14.72±0.10°、和/或15.92±0.10°、和/或16.89±0.10°、和/或17.37±0.10°、和/或18.43±0.10°、和/或19.11±0.10°、和/或21.24±0.10°、和/或21.44±0.10°、和/或22.41±0.10°、和/或23.02±0.10°、和/或23.23±0.10°、和/或23.52±0.10°、和/或24.06±0.10°、和/或24.84±0.10°、和/或25.34±0.10°、和/或25.55±0.10°、和/或26.08±0.10°、和/或26.49±0.10°、和/或26.89±0.10°、和/或27.12±0.10°、和/或27.92±0.10°、和/或28.62±0.10°、和/或29.03±0.10°、和/或29.75±0.10°、和/或30.10±0.10°、和/或31.21±0.10°、和/或32.10±0.10°、和/或32.89±0.10°、和/或33.26±0.10°、和/或34.45±0.10°、和/或35.64±0.10°、和/或36.06±0.10°、和/或37.24±0.10°、和/或38.84±0.10°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 8.41±0.10°, 16.53±0.10°, and/or 18.12±0.10°, and/or 5.80 ±0.10°, and/or 11.58±0.10°, and/or 12.16±0.10°, and/or 12.72±0.10°, and/or 13.07±0.10°, and/or 13.48±0.10°, and/or 14.72±0.10 °, and/or 15.92±0.10°, and/or 16.89±0.10°, and/or 17.37±0.10°, and/or 18.43±0.10°, and/or 19.11±0.10°, and/or 21.24±0.10°, and/or 21.44±0.10°, and/or 22.41±0.10°, and/or 23.02±0.10°, and/or 23.23±0.10°, and/or 23.52±0.10°, and/or 24.06±0.10°, and/or or 24.84±0.10°, and/or 25.34±0.10°, and/or 25.55±0.10°, and/or 26.08±0.10°, and/or 26.49±0.10°, and/or 26.89±0.10°, and/or 27.12 ±0.10°, and/or 27.92±0.10°, and/or 28.62±0.10°, and/or 29.03±0.10°, and/or 29.75±0.10°, and/or 30.10±0.10°, and/or 31.21±0.10 °, and/or 32.10±0.10°, and/or 32.89±0.10°, and/or 33.26±0.10°, and/or 34.45±0.10°, and/or 35.64±0.10°, and/or 36.06±0.10°, and/or 37.24±0.10°, and/or 38.84±0.10°.
本发明的一些方案中，上述A晶型的XRPD图谱基本如图1所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned crystal form A is basically as shown in Figure 1.
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示。In some solutions of the present invention, the XRPD spectrum analysis data of the above-mentioned crystal form A is shown in Table 1.
表1式(I)化合物A晶型的XRPD图谱解析数据

Table 1 XRPD spectrum analysis data of compound A crystal form of formula (I)

本发明的一些方案中，上述A晶型，其差示扫描量热曲线在164.0±5℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak starting point at 164.0±5°C.
本发明的一些方案中，上述A晶型，其DSC图谱如图2所示。In some aspects of the present invention, the DSC pattern of the above-mentioned crystal form A is shown in Figure 2.
本发明的一些方案中，上述A晶型，其热重分析曲线在150.0±3℃时失重达1.25％。In some solutions of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 1.25% at 150.0±3°C.
本发明的一些方案中，上述A晶型，其TGA图谱如图3所示。In some aspects of the present invention, the TGA spectrum of the above-mentioned crystal form A is shown in Figure 3.
本发明还提供式(Ⅱ)化合物，其结构式如下：
The present invention also provides compounds of formula (II), whose structural formula is as follows:
本发明还提供式(Ⅱ)化合物的B晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：6.22±0.20°、8.11±0.20°、14.59±0.20°、19.11±0.20°和21.75±0.20°；
The present invention also provides the B crystal form of the compound of formula (II), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 8.11±0.20°, 14.59±0.20°, 19.11 ±0.20° and 21.75±0.20°;
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.20°、8.11±0.20°、13.89±0.20°、14.59±0.20°、15.31±0.20°、19.11±0.20°、21.75±0.20°、24.94±0.20°和25.73±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 8.11±0.20°, 13.89±0.20°, 14.59±0.20°, 15.31± 0.20°, 19.11±0.20°, 21.75±0.20°, 24.94±0.20° and 25.73±0.20°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.20°、8.11±0.20°、13.89±0.20°、14.59±0.20°、15.31±0.20°、16.62±0.20°、19.11±0.20°、21.75±0.20°、22.23±0.20°、24.94±0.20°、25.73±0.20°、26.22±0.20°、27.88±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 8.11±0.20°, 13.89±0.20°, 14.59±0.20°, 15.31± 0.20°, 16.62±0.20°, 19.11±0.20°, 21.75±0.20°, 22.23±0.20°, 24.94±0.20°, 25.73±0.20°, 26.22±0.20°, 27.88±0.20°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.20°、7.66±0.20°、8.11±0.20°、13.89±0.20°、14.59±0.20°、15.31±0.20°、16.62±0.20°、17.65±0.20°、18.35±0.20°、19.11±0.20°、21.75±0.20°、22.23±0.20°、24.94±0.20°、25.73±0.20°、26.22±0.20°、27.88±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 7.66±0.20°, 8.11±0.20°, 13.89±0.20°, 14.59± 0.20°、15.31±0.20°、16.62±0.20°、17.65±0.20°、18.35±0.20°、19.11±0.20°、21.75±0.20°、22.23±0.20°、24.94±0.20°、25.73±0.20°、26.22± 0.20°, 27.88±0.20°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.20°、7.66±0.20°、8.11±0.20°、11.34±0.20°、12.21±0.20°、13.89±0.20°、14.59±0.20°、14.84±0.20°、15.31±0.20°、16.20±0.20°、16.62±0.20°、17.44±0.20°、17.65±0.20°、18.35±0.20°、19.11±0.20°、19.84±0.20°、20.43±0.20°、21.75±0.20°、22.23±0.20°、22.46±0.20°、23.50±0.20°、24.36±0.20°、24.94±0.20°、25.73±0.20°、26.22±0.20°、27.43±0.20°、27.88±0.20°、28.72±0.20°、29.14±0.20°、30.11±0.20°、30.64±0.20°、32.04±0.20°、32.87±0.20°、33.46±0.20°、35.89±0.20°、38.78±0.20°和39.28±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 7.66±0.20°, 8.11±0.20°, 11.34±0.20°, 12.21± 0.20°、13.89±0.20°、14.59±0.20°、14.84±0.20°、15.31±0.20°、16.20±0.20°、16.62±0.20°、17.44±0.20°、17.65±0.20°、18.35±0.20°、19.11± 0.20°、19.84±0.20°、20.43±0.20°、21.75±0.20°、22.23±0.20°、22.46±0.20°、23.50±0.20°、24.36±0.20°、24.94±0.20°、25.73±0.20°、26.22± 0.20°、27.43±0.20°、27.88±0.20°、28.72±0.20°、29.14±0.20°、30.11±0.20°、30.64±0.20°、32.04±0.20°、32.87±0.20°、33.46±0.20°、35.89± 0.20°, 38.78±0.20° and 39.28±0.20°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.10°、7.66±0.10°、8.11±0.10°、11.34±0.10°、12.21±0.10°、13.89±0.10°、14.59±0.10°、14.84±0.10°、15.31±0.10°、16.20±0.10°、16.62±0.10°、17.44±0.10°、17.65±0.10°、18.35±0.10°、19.11±0.10°、19.84±0.10°、20.43±0.10°、21.75±0.10°、22.23±0.10°、22.46±0.10°、23.50±0.10°、24.36±0.10°、24.94±0.10°、25.73±0.10°、26.22±0.10°、 27.43±0.10°、27.88±0.10°、28.72±0.10°、29.14±0.10°、30.11±0.10°、30.64±0.10°、32.04±0.10°、32.87±0.10°、33.46±0.10°、35.89±0.10°、38.78±0.10°和39.28±0.10°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.22±0.10°, 7.66±0.10°, 8.11±0.10°, 11.34±0.10°, 12.21± 0.10°、13.89±0.10°、14.59±0.10°、14.84±0.10°、15.31±0.10°、16.20±0.10°、16.62±0.10°、17.44±0.10°、17.65±0.10°、18.35±0.10°、19.11± 0.10°、19.84±0.10°、20.43±0.10°、21.75±0.10°、22.23±0.10°、22.46±0.10°、23.50±0.10°、24.36±0.10°、24.94±0.10°、25.73±0.10°、26.22± 0.10°, 27.43±0.10°, 27.88±0.10°, 28.72±0.10°, 29.14±0.10°, 30.11±0.10°, 30.64±0.10°, 32.04±0.10°, 32.87±0.10°, 33.46±0.10°, 35.89±0.10°, 38.78±0.10° and 39.28±0.10°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22、7.66、8.11、11.34、12.21、13.89、14.59、14.84、15.31、16.20、16.62、17.44、17.65、18.35、19.11、19.84、20.43、21.75、22.23、22.46、23.50、24.36、24.94、25.73、26.22、27.43、27.88、28.72、29.14、30.11、30.64、32.04、32.87、33.46、35.89、38.78和39.28。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.22, 7.66, 8.11, 11.34, 12.21, 13.89, 14.59, 14.84, 15.31, 16.20, 16.62, 17.44, 17.65, 18.35, 19.11, 19.84, 20.43, 21.75, 22.23, 22.46, 23.50, 24.36, 24.94, 25.73, 26.22, 27.43, 27.88, 28.72, 29.14, 30.11, 30.64, 32. 04, 32.87, 33.46, 35.89, 38.78 and 39.28.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.20°、8.11±0.20°、和/或7.66±0.20°、和/或11.34±0.20°、和/或12.21±0.20°、和/或13.89±0.20°、和/或14.59±0.20°、和/或14.84±0.20°、和/或15.31±0.20°、和/或16.20±0.20°、和/或16.62±0.20°、和/或17.44±0.20°、和/或17.65±0.20°、和/或18.35±0.20°、和/或19.11±0.20°、和/或19.84±0.20°、和/或20.43±0.20°、和/或21.75±0.20°、和/或22.23±0.20°、和/或22.46±0.20°、和/或23.50±0.20°、和/或24.36±0.20°、和/或24.94±0.20°、和/或25.73±0.20°、和/或26.22±0.20°、和/或27.43±0.20°、和/或27.88±0.20°、和/或28.72±0.20°、和/或29.14±0.20°、和/或30.11±0.20°、和/或30.64±0.20°、和/或32.04±0.20°、和/或32.87±0.20°、和/或33.46±0.20°、和/或35.89±0.20°、和/或38.78±0.20°、和/或39.28±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 8.11±0.20°, and/or 7.66±0.20°, and/or 11.34 ±0.20°, and/or 12.21±0.20°, and/or 13.89±0.20°, and/or 14.59±0.20°, and/or 14.84±0.20°, and/or 15.31±0.20°, and/or 16.20±0.20 °, and/or 16.62±0.20°, and/or 17.44±0.20°, and/or 17.65±0.20°, and/or 18.35±0.20°, and/or 19.11±0.20°, and/or 19.84±0.20°, and/or 20.43±0.20°, and/or 21.75±0.20°, and/or 22.23±0.20°, and/or 22.46±0.20°, and/or 23.50±0.20°, and/or 24.36±0.20°, and/ or 24.94±0.20°, and/or 25.73±0.20°, and/or 26.22±0.20°, and/or 27.43±0.20°, and/or 27.88±0.20°, and/or 28.72±0.20°, and/or 29.14 ±0.20°, and/or 30.11±0.20°, and/or 30.64±0.20°, and/or 32.04±0.20°, and/or 32.87±0.20°, and/or 33.46±0.20°, and/or 35.89±0.20 °, and/or 38.78±0.20°, and/or 39.28±0.20°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.10°、8.11±0.10°、和/或7.66±0.10°、和/或11.34±0.10°、和/或12.21±0.10°、和/或13.89±0.10°、和/或14.59±0.10°、和/或14.84±0.10°、和/或15.31±0.10°、和/或16.20±0.10°、和/或16.62±0.10°、和/或17.44±0.10°、和/或17.65±0.10°、和/或18.35±0.10°、和/或19.11±0.10°、和/或19.84±0.10°、和/或20.43±0.10°、和/或21.75±0.10°、和/或22.23±0.10°、和/或22.46±0.10°、和/或23.50±0.10°、和/或24.36±0.10°、和/或24.94±0.10°、和/或25.73±0.10°、和/或26.22±0.10°、和/或27.43±0.10°、和/或27.88±0.10°、和/或28.72±0.10°、和/或29.14±0.10°、和/或30.11±0.10°、和/或30.64±0.10°、和/或32.04±0.10°、和/或32.87±0.10°、和/或33.46±0.10°、和/或35.89±0.10°、和/或38.78±0.10°、和/或39.28±0.10°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.22±0.10°, 8.11±0.10°, and/or 7.66±0.10°, and/or 11.34 ±0.10°, and/or 12.21±0.10°, and/or 13.89±0.10°, and/or 14.59±0.10°, and/or 14.84±0.10°, and/or 15.31±0.10°, and/or 16.20±0.10 °, and/or 16.62±0.10°, and/or 17.44±0.10°, and/or 17.65±0.10°, and/or 18.35±0.10°, and/or 19.11±0.10°, and/or 19.84±0.10°, and/or 20.43±0.10°, and/or 21.75±0.10°, and/or 22.23±0.10°, and/or 22.46±0.10°, and/or 23.50±0.10°, and/or 24.36±0.10°, and/or or 24.94±0.10°, and/or 25.73±0.10°, and/or 26.22±0.10°, and/or 27.43±0.10°, and/or 27.88±0.10°, and/or 28.72±0.10°, and/or 29.14 ±0.10°, and/or 30.11±0.10°, and/or 30.64±0.10°, and/or 32.04±0.10°, and/or 32.87±0.10°, and/or 33.46±0.10°, and/or 35.89±0.10 °, and/or 38.78±0.10°, and/or 39.28±0.10°.
本发明的一些方案中，上述B晶型的XRPD图谱基本如图4所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned crystal form B is basically as shown in Figure 4.
本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表2所示。In some aspects of the present invention, the XRPD spectrum analysis data of the above-mentioned Form B is shown in Table 2.
表2式(Ⅱ)化合物B晶型的XRPD图谱解析数据

Table 2 XRPD spectrum analysis data of compound B crystal form of formula (II)

本发明的一些方案中，上述B晶型，其差示扫描量热曲线在153.7±3℃处具有吸热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned B crystal form has an endothermic peak at 153.7±3°C.
本发明的一些方案中，上述B晶型，其DSC图谱如图5所示。In some aspects of the present invention, the DSC pattern of the above-mentioned B crystal form is shown in Figure 5.
本发明的一些方案中，上述B晶型，其热重分析曲线在150.0±3℃时失重达2.88％。In some solutions of the present invention, the thermogravimetric analysis curve of the above-mentioned B crystal form has a weight loss of 2.88% at 150.0±3°C.
本发明的一些方案中，上述B晶型，其TGA图谱如图6所示。In some aspects of the present invention, the TGA spectrum of the above-mentioned B crystal form is shown in Figure 6.
本发明还提供式(Ⅲ)化合物，其结构式如下：
The present invention also provides a compound of formula (III), whose structural formula is as follows:
本发明还提供式(Ⅲ)化合物的C晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：5.46±0.20°、13.19±0.20°、15.22±0.20°和20.59±0.20°；
The present invention also provides the C crystal form of the compound of formula (III), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2θ angles: 5.46±0.20°, 13.19±0.20°, 15.22±0.20° and 20.59 ±0.20°;
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.46±0.20°、13.19±0.20°、15.22±0.20°、15.80±0.20°、16.25±0.20°、18.12±0.20°、20.59±0.20°、21.63±0.20°和26.50±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 5.46±0.20°, 13.19±0.20°, 15.22±0.20°, 15.80±0.20°, 16.25± 0.20°, 18.12±0.20°, 20.59±0.20°, 21.63±0.20° and 26.50±0.20°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.46±0.20°、13.19±0.20°、15.22±0.20°、15.80±0.20°、16.25±0.20°、18.12±0.20°、20.59±0.20°、21.63±0.20°、24.11±0.20°、26.50±0.20°、27.75±0.20°和28.15±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 5.46±0.20°, 13.19±0.20°, 15.22±0.20°, 15.80±0.20°, 16.25± 0.20°, 18.12±0.20°, 20.59±0.20°, 21.63±0.20°, 24.11±0.20°, 26.50±0.20°, 27.75±0.20° and 28.15±0.20°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.46±0.20°、9.30±0.20°、13.19±0.20°、15.22±0.20°、15.80±0.20°、16.25±0.20°、18.12±0.20°、20.59±0.20°、21.63±0.20°、24.11±0.20°、24.91±0.20°、25.87±0.20°、26.50±0.20°、27.75±0.20°、28.15±0.20°、30.73±0.20°和31.74±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 5.46±0.20°, 9.30±0.20°, 13.19±0.20°, 15.22±0.20°, 15.80± 0.20°、16.25±0.20°、18.12±0.20°、20.59±0.20°、21.63±0.20°、24.11±0.20°、24.91±0.20°、25.87±0.20°、26.50±0.20°、27.75±0.20°、28.15± 0.20°, 30.73±0.20° and 31.74±0.20°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.46、9.30、13.19、15.22、15.80、16.25、18.12、20.59、21.63、24.11、24.91、25.87、26.50、27.75、28.15、30.73和 31.74。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 5.46, 9.30, 13.19, 15.22, 15.80, 16.25, 18.12, 20.59, 21.63, 24.11, 24.91, 25.87, 26.50, 27.75, 28.15, 30.73 and 31.74.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.46±0.20°、15.22±0.20°、和/或9.30±0.20°、和/或13.19±0.20°、和/或15.80±0.20°、和/或16.25±0.20°、和/或18.12±0.20°、和/或20.59±0.20°、和/或21.63±0.20°、和/或24.11±0.20°、和/或24.91±0.20°、和/或25.87±0.20°、和/或26.50±0.20°、和/或27.75±0.20°、和/或28.15±0.20°、和/或30.73±0.20°、和/或31.74±0.20°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 5.46±0.20°, 15.22±0.20°, and/or 9.30±0.20°, and/or 13.19 ±0.20°, and/or 15.80±0.20°, and/or 16.25±0.20°, and/or 18.12±0.20°, and/or 20.59±0.20°, and/or 21.63±0.20°, and/or 24.11±0.20 °, and/or 24.91±0.20°, and/or 25.87±0.20°, and/or 26.50±0.20°, and/or 27.75±0.20°, and/or 28.15±0.20°, and/or 30.73±0.20°, and/or 31.74±0.20°.
本发明的一些方案中，上述C晶型的XRPD图谱基本如图7所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned crystal form C is basically as shown in Figure 7.
本发明的一些方案中，上述C晶型的XRPD图谱解析数据如表3所示。In some solutions of the present invention, the XRPD spectrum analysis data of the above-mentioned C crystal form is shown in Table 3.
表3式(Ⅲ)化合物C晶型的XRPD图谱解析数据
Table 3 XRPD spectrum analysis data of compound C crystal form of formula (III)
本发明的一些方案中，上述C晶型，其差示扫描量热曲线在105.1±3℃和216.0±3℃处具有吸热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form C has endothermic peaks at 105.1±3°C and 216.0±3°C.
本发明的一些方案中，上述C晶型，其DSC图谱如图8所示。In some aspects of the present invention, the DSC pattern of the above-mentioned C crystal form is shown in Figure 8.
本发明的一些方案中，上述C晶型，其热重分析曲线在150.0±3℃时失重达8.22％。In some solutions of the present invention, the weight loss of the above-mentioned C crystal form in the thermogravimetric analysis curve reaches 8.22% at 150.0±3°C.
本发明的一些方案中，上述C晶型，其TGA图谱如图9所示。In some aspects of the present invention, the TGA spectrum of the above-mentioned crystal form C is shown in Figure 9.
本发明还提供了一种药物组合物，其中含有治疗有效剂量的式(I)化合物或其药学上可接受的盐或溶剂化物作为活性成份和药学上可接受的辅料；
The present invention also provides a pharmaceutical composition, which contains a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and pharmaceutically acceptable excipients;
本发明的一些方案中，上述药物组合物的剂型选自胶囊剂、颗粒剂、注射剂、丸剂、糖浆剂、散剂、膏剂、乳液、溶液、悬浮液或酊剂，其他变量如本发明所定义。In some aspects of the present invention, the dosage form of the above-mentioned pharmaceutical composition is selected from capsules, granules, injections, pills, syrups, powders, ointments, emulsions, solutions, suspensions or tinctures, and other variables are as defined in the present invention.
本发明的一些方案中，上述辅料选自赋形剂、填料、粘合剂、保湿剂、崩解剂、缓溶剂、吸收加速剂、吸附剂、稀释剂、增溶剂、乳化剂、润滑剂、润湿剂、助流剂、悬浮剂、矫味剂、香料或其混合物，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned auxiliary materials are selected from excipients, fillers, binders, humectants, disintegrants, slow solvents, absorption accelerators, adsorbents, diluents, solubilizers, emulsifiers, lubricants, Wetting agents, glidants, suspending agents, flavoring agents, perfumes or mixtures thereof, other variables are as defined in the present invention.
本发明还提供式(Ⅰ)化合物的制备方法，其制备如下：
The present invention also provides a preparation method of the compound of formula (I), which is prepared as follows:
其中，R1选自H、CH3、Boc、Cbz、Bn和PMB；Among them, R 1 is selected from H, CH 3 , Boc, Cbz, Bn and PMB;
1)当R1选自H时，式(Ⅰ)化合物的制备方法选自：
1) When R 1 is selected from H, the preparation method of the compound of formula (I) is selected from:
2)当R1选自CH3时，式(Ⅱ-3)化合物即为式(Ⅰ)化合物；2) When R 1 is selected from CH 3 , the compound of formula (II-3) is the compound of formula (I);
3)当R1选自Boc、Cbz、Bn和PMB时，式(Ⅰ)化合物的制备方法选自：
3) When R 1 is selected from Boc, Cbz, Bn and PMB, the preparation method of the compound of formula (I) is selected from:
其中，所述式(Ⅱ-3)化合物的制备方法选自：Wherein, the preparation method of the compound of formula (II-3) is selected from:
方法一包含：
Method one includes:
方法二包含：
Method two includes:
方法三包含：
Method three includes:
其中，in,
R1选自H、CH3、Boc、Cbz、Bn和PMB； R 1 is selected from H, CH 3 , Boc, Cbz, Bn and PMB;
R2选自Bn，PMB，PNB和MOM；R 2 is selected from Bn, PMB, PNB and MOM;
R4选自CH3、MOM、Bn、SEM和Ac；R 4 is selected from CH 3 , MOM, Bn, SEM and Ac;
R5选自F、Cl、Br、I、OTf和OCH2CF3；R 5 is selected from F, Cl, Br, I, OTf and OCH 2 CF 3 ;
R31选自B(OH)2；、和BF3K；R 31 is selected from B(OH) 2 ;, and BF 3K ;
R6选自F、Cl、Br和I。R 6 is selected from F, Cl, Br and I.
R7选自Cl、Br、OTf、OCH2CF3和OTs。R 7 is selected from Cl, Br, OTf, OCH 2 CF 3 and OTs.
本发明还提供式(Ⅰ)化合物的制备方法，
The present invention also provides a method for preparing the compound of formula (I),
其包括如下步骤：It includes the following steps:
步骤一：使化合物EE-3反应以获得化合物EE-4，
Step 1: React compound EE-3 to obtain compound EE-4,
步骤二：使化合物EE-4反应以获得化合物EE-5，
Step 2: react compound EE-4 to obtain compound EE-5,
步骤三：使化合物EE-5和化合物AA反应以获得化合物H-1，
Step 3: React compound EE-5 and compound AA to obtain compound H-1,
步骤四：使化合物H-1反应以获得式(Ⅰ)化合物，
Step 4: react compound H-1 to obtain the compound of formula (I),
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法，其包含如下步骤：步骤一：使化合物EE-3和试剂A、B反应以获得化合物EE-4，
In some aspects of the present invention, the preparation method of the compound of formula (I) above includes the following steps: Step 1: react compound EE-3 with reagents A and B to obtain compound EE-4,
其中，in,
试剂A选自氯甲醚、溴甲醚、碘甲醚和甲氧基甲基甲磺酸酯，优选氯甲醚； Reagent A is selected from the group consisting of methyl chloride, methyl bromide, methyl iodide and methoxymethyl methanesulfonate, with methyl chloride being preferred;
试剂B选自碳酸钾、碳酸铯、碳酸钠、碳酸锂、钠氢、六甲基二硅基胺锂、六甲基二硅基胺钠、六甲基二硅基胺钾、叔丁醇钾、叔丁醇钠、氢氧化钠、氢氧化锂和氢氧化钾，优选碳酸钾；Reagent B is selected from potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen, lithium hexamethyldisilazide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium tert-butoxide , sodium tert-butoxide, sodium hydroxide, lithium hydroxide and potassium hydroxide, preferably potassium carbonate;
溶剂C选自DMF、DCM、THF、2-MeTHF、EtOAc、i-PrOAc、NMP和二氧六环，优选DMF。Solvent C is selected from DMF, DCM, THF, 2-MeTHF, EtOAc, i-PrOAc, NMP and dioxane, with DMF being preferred.
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法，其包含如下步骤：In some aspects of the present invention, the preparation method of the compound of formula (I) above includes the following steps:
步骤二：使化合物EE-4和试剂D、E、F、G反应以获得化合物EE-5，
Step 2: React compound EE-4 with reagents D, E, F, and G to obtain compound EE-5,
其中，in,
试剂D选自双联嚬哪醇硼酸酯和嚬哪醇硼烷，优选嚬哪醇硼烷；Reagent D is selected from the group consisting of zonacol borane and zonacol borane, preferably zonacol borane;
试剂E选自Pd(dppf)Cl2、Pd(dppf)Cl2.CH2Cl2、双(乙腈)二氯化钯(II)、Pd(OAc)2和Pd2(dba)3，优选Pd(OAc)2；Reagent E is selected from Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , bis(acetonitrile)palladium(II) dichloride, Pd(OAc) 2 and Pd 2 (dba) 3 , preferably Pd (OAc) 2 ;
试剂F选自Sphos、Xphos、XantPhos和2-(二环己基磷)联苯，优选2-(二环己基磷)联苯；Reagent F is selected from Sphos, Xphos, XantPhos and 2-(dicyclohexylphosphonium)biphenyl, preferably 2-(dicyclohexylphosphonium)biphenyl;
试剂G选自醋酸钾、醋酸钠、TEA、DIPEA和2-乙基己酸钾，优选TEA；Reagent G is selected from potassium acetate, sodium acetate, TEA, DIPEA and potassium 2-ethylhexanoate, with TEA being preferred;
溶剂H选自二氧六环、DMSO、DMF、NMP、DCM、THF、2-MeTHF和水，优选二氧六环。Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, with dioxane being preferred.
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法，其包含如下步骤：In some aspects of the present invention, the preparation method of the compound of formula (I) above includes the following steps:
步骤三：使化合物EE-5和化合物AA与试剂I和J反应以获得化合物H-1，
Step 3: React compound EE-5 and compound AA with reagents I and J to obtain compound H-1,
其中，in,
溶剂H选自二氧六环、DMSO、DMF、NMP、DCM、THF、2-MeTHF和水，优选二氧六环；Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, preferably dioxane;
试剂I选自Pd(OAc)2-BINAP、Pd2(dba)3-Xphos、Brettphos-Pd-G3、Pd(PPh3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2CH2Cl2和Pd(OAc)2-Sphos，优选Pd(dppf)Cl2CH2Cl2；Reagent I is selected from Pd(OAc) 2 -BINAP, Pd 2 (dba) 3 -Xphos, Brettphos-Pd-G3, Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 CH 2 Cl 2 and Pd(OAc) 2 -Sphos, preferably Pd(dppf)Cl 2 CH 2 Cl 2 ;
试剂J选自Cs2CO3、K2CO3、Na2CO3、K3PO4、KOAc、KF和TEA，优选K2CO3。Reagent J is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , KOAc, KF and TEA, preferably K 2 CO 3 .
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法，其包含如下步骤：In some aspects of the present invention, the preparation method of the compound of formula (I) above includes the following steps:
步骤四：使化合物H-1和试剂K反应以获得式(Ⅰ)化合物，
Step 4: React compound H-1 and reagent K to obtain the compound of formula (I),
其中，in,
试剂K选自盐酸、氢溴酸、三氟乙酸、硫酸、甲酸、甲磺酸、苯磺酸和对甲苯磺酸，优选盐酸。Reagent K is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably hydrochloric acid.
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法，其包含如下步骤：In some aspects of the present invention, the preparation method of the compound of formula (I) above includes the following steps:
步骤一：使化合物EE-3和试剂A、B反应以获得化合物EE-4，
Step 1: React compound EE-3 with reagents A and B to obtain compound EE-4,
步骤二：使化合物EE-4和试剂D、E、F、G反应以获得化合物EE-5，
Step 2: React compound EE-4 with reagents D, E, F, and G to obtain compound EE-5,
步骤三：使化合物EE-5和化合物AA与试剂I和J反应以获得化合物H-1，
Step 3: React compound EE-5 and compound AA with reagents I and J to obtain compound H-1,
步骤四：使化合物H-1和试剂K反应以获得式(Ⅰ)化合物，
Step 4: React compound H-1 and reagent K to obtain the compound of formula (I),
其中，in,
试剂A选自氯甲醚、溴甲醚、碘甲醚和甲氧基甲基甲磺酸酯，优选氯甲醚；Reagent A is selected from the group consisting of methyl chloride, methyl bromide, methyl iodide and methoxymethyl methanesulfonate, with methyl chloride being preferred;
试剂B选自碳酸钾、碳酸铯、碳酸钠、碳酸锂、钠氢、六甲基二硅基胺锂、六甲基二硅基胺钠、六甲基二硅基胺钾、叔丁醇钾、叔丁醇钠、氢氧化钠、氢氧化锂和氢氧化钾，优选碳酸钾；Reagent B is selected from potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen, lithium hexamethyldisilazide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium tert-butoxide , sodium tert-butoxide, sodium hydroxide, lithium hydroxide and potassium hydroxide, preferably potassium carbonate;
溶剂C选自DMF、DCM、THF、2-MeTHF、EtOAc、i-PrOAc、NMP和二氧六环，优选DMF；Solvent C is selected from DMF, DCM, THF, 2-MeTHF, EtOAc, i-PrOAc, NMP and dioxane, preferably DMF;
试剂D选自双联嚬哪醇硼酸酯和嚬哪醇硼烷，优选嚬哪醇硼烷；Reagent D is selected from the group consisting of zonacol borane and zonacol borane, preferably zonacol borane;
试剂E选自Pd(dppf)Cl2、Pd(dppf)Cl2.CH2Cl2、双(乙腈)二氯化钯(II)、Pd(OAc)2和Pd2(dba)3，优选Pd(OAc)2；Reagent E is selected from Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , bis(acetonitrile)palladium(II) dichloride, Pd(OAc) 2 and Pd 2 (dba) 3 , preferably Pd (OAc) 2 ;
试剂F选自Sphos、Xphos、XantPhos和2-(二环己基磷)联苯，优选2-(二环己基磷)联苯；Reagent F is selected from Sphos, Xphos, XantPhos and 2-(dicyclohexylphosphonium)biphenyl, preferably 2-(dicyclohexylphosphonium)biphenyl;
试剂G选自醋酸钾、醋酸钠、TEA、DIPEA和2-乙基己酸钾，优选TEA；Reagent G is selected from potassium acetate, sodium acetate, TEA, DIPEA and potassium 2-ethylhexanoate, with TEA being preferred;
溶剂H选自二氧六环、DMSO、DMF、NMP、DCM、THF、2-MeTHF和水，优选二氧六环；Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, preferably dioxane;
试剂I选自Pd(OAc)2-BINAP、Pd2(dba)3-Xphos、Brettphos-Pd-G3、Pd(PPh3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2CH2Cl2和Pd(OAc)2-Sphos，优选Pd(dppf)Cl2CH2Cl2；Reagent I is selected from Pd(OAc) 2 -BINAP, Pd 2 (dba) 3 -Xphos, Brettphos-Pd-G3, Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 CH 2 Cl 2 and Pd(OAc) 2 -Sphos, preferably Pd(dppf)Cl 2 CH 2 Cl 2 ;
试剂J选自Cs2CO3、K2CO3、Na2CO3、K3PO4、KOAc、KF和TEA，优选K2CO3；Reagent J is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , KOAc, KF and TEA, preferably K 2 CO 3 ;
试剂K选自盐酸、氢溴酸、三氟乙酸、硫酸、甲酸、甲磺酸、苯磺酸和对甲苯磺酸，优选盐酸。Reagent K is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably hydrochloric acid.
本发明还提供了一种式(AA)中间体化合物的制备方法：
The invention also provides a method for preparing the intermediate compound of formula (AA):
其中，in,
R51选自F、Cl、Br和I；R 51 is selected from F, Cl, Br and I;
R11选自CH3、Boc、Cbz、Bn和PMB。R 11 is selected from CH 3 , Boc, Cbz, Bn and PMB.
本发明的一些方案中，上述式(AA)中间体化合物的制备方法，其中，R51选自Cl，R11选自Boc，其他如本发明所定义。In some aspects of the present invention, there is a method for preparing the intermediate compound of the above formula (AA), wherein R 51 is selected from Cl, R 11 is selected from Boc, and the others are as defined in the present invention.
本发明还提供了一种式(AA)中间体化合物的制备方法：
The invention also provides a method for preparing the intermediate compound of formula (AA):
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法选自：In some aspects of the present invention, the preparation method of the compound of formula (I) above is selected from:
方法一包含：
Method one includes:
方法二包含：
Method two includes:
方法三包含：
Method three includes:
方法四包含：
Method four includes:
方法五包含：
Method five includes:
方法六包含：
Method six includes:
方法七包含：
Method seven includes:
方法八包含：
Method eight includes:
方法九包含：
Method nine includes:
方法十包含：
Method ten includes:
方法十一包含：
Method 11 includes:
方法十二包含：
Method twelve includes:
方法十三包含：
Method thirteen includes:
方法十四包含：
Method fourteen includes:
本发明还提供了上述式(I)化合物A晶型、上述的式(Ⅱ)化合物、上述的式(Ⅱ)化合物B晶型、上述的药物组合物以及上述的制备方法在制备治疗与NLRP3炎性小体相关疾病的药物中的应用。The present invention also provides the above-mentioned compound A crystal form of the formula (I), the above-mentioned compound formula (II), the above-mentioned compound B crystal form of the formula (II), the above-mentioned pharmaceutical composition and the above-mentioned preparation method for the preparation and treatment of NLRP3 inflammation. Application in medicines for sex body-related diseases.
本发明的一些方案中，上述与NLRP3炎性小体相关疾病，选自NLRP3炎性小体相关神经炎症性疾病(如脑部炎症、脑损伤)和神经退行性疾病(如帕金森疾病、阿尔兹海默病、多发性硬化)。In some solutions of the present invention, the above-mentioned NLRP3 inflammasome-related diseases are selected from NLRP3 inflammasome-related neuroinflammatory diseases (such as brain inflammation, brain injury) and neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease). Alzheimer's disease, multiple sclerosis).
本发明的一些方案中，上述与NLRP3炎性小体相关疾病，选自NLRP3炎性小体相关神经炎症性疾病和神经退行性疾病。In some aspects of the present invention, the above-mentioned NLRP3 inflammasome-related diseases are selected from the group consisting of NLRP3 inflammasome-related neuroinflammatory diseases and neurodegenerative diseases.
本发明的一些方案中，上述NLRP3炎性小体相关神经炎症性疾病选自脑部炎症和脑损伤。In some aspects of the present invention, the above-mentioned NLRP3 inflammasome-related neuroinflammatory disease is selected from brain inflammation and brain injury.
本发明的一些方案中，上述神经退行性疾病选自帕金森疾病、阿尔兹海默病和多发性硬化。In some aspects of the invention, the above-mentioned neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease and multiple sclerosis.
本发明的一些方案中，上述神经退行性疾病选自帕金森疾病和阿尔兹海默病。In some aspects of the present invention, the above-mentioned neurodegenerative disease is selected from Parkinson's disease and Alzheimer's disease.
技术效果Technical effect
本发明式(I)化合物的A晶型和式(Ⅱ)化合物的B晶型易于获得、物理稳定性和化学稳定性均较 好，具有很高的工业应用价值和经济价值。The A crystal form of the compound of formula (I) and the B crystal form of the compound of formula (II) of the present invention are easy to obtain, and have relatively high physical and chemical stability. Well, it has high industrial application value and economic value.
本发明给出的合成式(I)化合物及其中间体的工艺，有益效果为：原料价格便宜易得，克服分离纯化困难以及不易工业化等缺点。The process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the following beneficial effects: the raw materials are cheap and easy to obtain, and overcome the shortcomings of difficulty in separation and purification and difficulty in industrialization.
本发明提供的NLRP3抑制剂可以有效抑制NLRP3炎性小体的活性，以及下游caspase-1的活化，从而抑制IL-1β的成熟和分泌，并且具有良好的药代动力学性质，可用于NLRP3炎性小体异常活化的相关疾病的治疗，如帕金森疾病、阿尔兹海默病。The NLRP3 inhibitor provided by the invention can effectively inhibit the activity of NLRP3 inflammasome and the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1β, and has good pharmacokinetic properties and can be used for NLRP3 inflammation. Treatment of diseases related to abnormal activation of sex bodies, such as Parkinson's disease and Alzheimer's disease.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
必须注意的是，除非上下文另有明确说明或与本文明显相悖，否则如本文和所附权利要求所用的本发明的内容(尤其随附权利要求书的内容)中使用的单数形式“一”、“一个”、“所述”及类似术语应解释为包括单数和复数两者。因此，例如，提及“所述化合物”包括提及一种或多种化合物；等等。It must be noted that, as used herein and in the appended claims, the singular forms "a", "a", "A", "the" and similar terms shall be construed to include both the singular and the plural. Thus, for example, reference to "the compound" includes reference to one or more compounds; and so on.
术语“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。The term "pharmaceutical composition" means a mixture containing one or more compounds described herein, or physiologically acceptable salts or prodrugs thereof, and other chemical components, as well as other components such as physiologically acceptable carriers. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
本申请所述的“式(I)化合物或其可药用盐”，可以是“包含式(I)化合物或其可药用盐的药物组合物”，进一步的，可以是“包含式(II)化合物的药物组合物”，也可以是“包含式(Ⅲ)化合物的药物组合物”。例如上述“向有需要的个体给予式(I)化合物或其可药用盐”可以是“向有需要的个体给予包含式(I)化合物或其可药用盐的药物组合物”，进一步的，可以是“向有需要的个体给予包含式(II)化合物的药物组合物”或可以是“向有需要的个体给予包含式(Ⅲ)化合物的药物组合物”。The "compound of formula (I) or a pharmaceutically acceptable salt thereof" described in this application can be a "pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof", and further, it can be "a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof". ) compound” may also be “a pharmaceutical composition containing a compound of formula (III)”. For example, the above "administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need" may be "administering a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need", and further , may be "administering a pharmaceutical composition containing a compound of formula (II) to an individual in need" or may be "administering a pharmaceutical composition containing a compound of formula (III) to an individual in need".
术语“治疗有效剂量”意指化合物被施用于人用于治疗疾病时，足以实现对该疾病的治疗的量。The term "therapeutically effective dose" means an amount of a compound sufficient to effect treatment of a disease when administered to a human for the treatment of the disease.
术语“溶剂化物”指本发明化合物或其盐与分子间非共价力结合的化学计量或非化学计量的溶剂形成的物质。当溶剂为水时，则为水合物。The term "solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.
术语“治疗”包括抑制、减缓、停止或逆转现有症状或病患的进展或严重程度。The term "treatment" includes inhibiting, slowing, stopping or reversing existing symptoms or the progression or severity of a disease.
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那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients. For example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。 The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, dragees, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, those skilled in the art sometimes need to modify or select the synthesis steps or reaction procedures based on the existing embodiments.
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。An important consideration in planning any synthetic route in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this invention).
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。The present invention will be described in detail through examples below. These examples do not mean any limitation to the present invention.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and used without further purification.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：Boc代表叔丁氧基羰基；Cbz代表苄氧羰基；Bn代表苄基；PMB代表对甲氧基苄基、DCM代表二氯甲烷；DMF代表N，N-二甲基甲酰胺；THF代表四氢呋喃；DMSO代表二甲亚砜；EtOH代表乙醇；MeOH代表甲醇；ACN(MeCN)代表乙腈；EtOAc代表乙酸乙酯；H2O代表水；i-PrOH代表异丙醇；Acetone代表丙酮；IPAc代表乙酸异丙酯；2-MeTHF代表2-甲基四氢呋喃；1,4-Dioxane代表1,4-二氧六环；CHCl3代表三氯甲烷；Toluene代表甲苯；n-Heptane代表正庚烷；DMAc代表N,N-二甲基乙酰胺；NMP代表N-甲基吡咯烷酮；PNB代表对硝基苯基；MOM代表甲氧基甲基；SEM代表2-(三甲基硅)乙氧基甲基；Ac代表乙酰基；OTf代表三氟甲磺酸酯基；OTs代表对甲苯磺酸酯基；i-PrOAc代表醋酸异丙酯；Pd(dppf)Cl2.CH2Cl2代表[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷；Pd(dppf)Cl2代表[1,1-双(二苯基膦)二茂铁]二氯化钯；Pd2(dba)3代表三(二苯亚甲基丙酮)二钯；Sphos代表2-双环己基膦-2,6-二甲氧基联苯；Xphos代表2-二叔丁基膦-2′,4′,6′-三异丙基联苯；TEA代表三乙胺；DIPEA代表二异丙基乙胺；BINAP代表2,2-双(二苯膦基)-11-联萘；Pd(PPh3)2Cl2代表二(三苯基膦)二氯化钯；Pd(PPh3)4代表四(三苯基膦)钯；Brettphos-Pd-G3代表甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-氨基-1,1-联苯-2-基)钯；BID代表每天两次；QD代表每天一次；p.o.或者P.O.代表口服。The following abbreviations are used in the present invention: Boc represents tert-butoxycarbonyl; Cbz represents benzyloxycarbonyl; Bn represents benzyl; PMB represents p-methoxybenzyl, DCM represents dichloromethane; DMF represents N, N-bis Methylformamide; THF represents tetrahydrofuran; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; MeOH represents methanol; ACN (MeCN) represents acetonitrile; EtOAc represents ethyl acetate; H 2 O represents water; i-PrOH represents isopropyl alcohol ; Acetone represents acetone; IPAc represents isopropyl acetate; 2-MeTHF represents 2-methyltetrahydrofuran; 1,4-Dioxane represents 1,4-dioxane; CHCl 3 represents chloroform; Toluene represents toluene; n- Heptane represents n-heptane; DMAc represents N,N-dimethylacetamide; NMP represents N-methylpyrrolidone; PNB represents p-nitrophenyl; MOM represents methoxymethyl; SEM represents 2-(trimethyl Silicon) ethoxymethyl; Ac represents acetyl group; OTf represents triflate group; OTs represents p-toluenesulfonate group; i-PrOAc represents isopropyl acetate; Pd(dppf)Cl 2 .CH 2 Cl 2 represents [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane; Pd(dppf)Cl 2 represents [1,1-bis(diphenylphosphine)ferrocene] Palladium dichloride; Pd 2 (dba) 3 represents tris(diphenylmethylacetone)dipalladium; Sphos represents 2-bicyclohexylphosphine-2,6-dimethoxybiphenyl; Xphos represents 2-di-tert-butyl Phosphine-2′,4′,6′-triisopropylbiphenyl; TEA represents triethylamine; DIPEA represents diisopropylethylamine; BINAP represents 2,2-bis(diphenylphosphino)-11- Binaphthyl; Pd(PPh 3 ) 2 Cl 2 represents bis(triphenylphosphine) palladium dichloride; Pd(PPh 3 ) 4 represents tetrakis (triphenylphosphine) palladium; Brettphos-Pd-G3 represents methane sulfonic acid ( 2-Dicyclohexylphosphine)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl ) Palladium; BID stands for twice daily; QD stands for once daily; po or PO stands for oral administration.
化合物经手工或者软件命名，市售化合物采用供应商目录名称。Compounds are prepared manually or For software naming, commercially available compounds adopt supplier catalog names.
本发明仪器测试参数及分析方法Instrument test parameters and analysis method of the present invention
本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法，测试参数见表4。The test parameters of the X-ray powder diffraction (X-ray powder diffractometer, XRPD) method of the present invention are shown in Table 4.
表4 XRPD测试参数
Table 4 XRPD test parameters
本发明差热分析(Differential Scanning Calorimeter,DSC)方法，测试参数见表5。The test parameters of the differential scanning calorimeter (DSC) method of the present invention are shown in Table 5.
表5 DSC测试参数
Table 5 DSC test parameters
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法，测试参数见表6。The test parameters of the thermogravimetric analyzer (TGA) method of the present invention are shown in Table 6.
表6 TGA测试参数
Table 6 TGA test parameters
本发明动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)方法，测试参数见表7。The test parameters of the dynamic vapor adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention are shown in Table 7.
表7 DVS测试参数
Table 7 DVS test parameters
附图说明Description of drawings
图1：式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图；Figure 1: XRPD spectrum of Cu-Kα radiation of crystal form A of compound of formula (I);
图2：式(I)化合物A晶型的DSC谱图；Figure 2: DSC spectrum of crystal form A of compound of formula (I);
图3：式(I)化合物A晶型的TGA谱图；Figure 3: TGA spectrum of crystal form A of compound of formula (I);
图4：式(Ⅱ)化合物B晶型的Cu-Kα辐射的XRPD谱图；Figure 4: XRPD spectrum of Cu-Kα radiation of compound B crystal form of formula (II);
图5：式(Ⅱ)化合物B晶型的DSC谱图；Figure 5: DSC spectrum of crystal form B of compound of formula (II);
图6：式(Ⅱ)化合物B晶型的TGA谱图；Figure 6: TGA spectrum of crystal form B of compound of formula (II);
图7：式(Ⅲ)化合物C晶型的Cu-Kα辐射的XRPD谱图；Figure 7: XRPD spectrum of Cu-Kα radiation of crystal form C of compound (III);
图8：式(Ⅲ)化合物C晶型的DSC谱图；Figure 8: DSC spectrum of crystal form C of compound of formula (III);
图9：式(Ⅲ)化合物C晶型的TGA谱图；Figure 9: TGA spectrum of crystal form C of compound of formula (III);
图10：式(I)化合物A晶型的DVS谱图；Figure 10: DVS spectrum of crystal form A of compound of formula (I);
图11：式(Ⅱ)化合物B晶型的DVS谱图；Figure 11: DVS spectrum of crystal form B of compound of formula (II);
图12：式(Ⅲ)化合物C晶型的DVS谱图；Figure 12: DVS spectrum of crystal form C of compound (III);
图13：式(I)化合物A晶型的PSD谱图；Figure 13: PSD spectrum of crystal form A of compound of formula (I);
图14：式(I)化合物的单晶X射线衍射(SC-XRD)立体结构椭球图。Figure 14: Single crystal X-ray diffraction (SC-XRD) three-dimensional structure ellipsoid diagram of the compound of formula (I).
具体实施方式Detailed ways
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。In order to better understand the content of the present invention, further description is given below with reference to specific embodiments, but the specific implementations do not limit the content of the present invention.
实施例1：中间体AA的制备Example 1: Preparation of intermediate AA
合成路线：
synthetic route:
第一步first step
将化合物AA-1(100g,691.76mmol)和吡啶(109.98g,1.39mol)溶于无水二氯甲烷(1000mL)中,0℃下向反应液中滴加三氟甲磺酸酐(255.68g,906.21mmol)。反应液在25℃下搅拌12小时。向反应液中加入水(1000mL),用二氯甲烷(500mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用硅胶柱层析法(洗脱剂：石油醚/乙酸乙酯＝100％到90％)纯化得到化合物AA-2。1H NMR(400MHz,CDCl3)δ7.34(s,1H),2.53(s,3H)。MS-ESI计算值[M+H]+277,实测值277。Compound AA-1 (100g, 691.76mmol) and pyridine (109.98g, 1.39mol) were dissolved in anhydrous dichloromethane (1000mL), and trifluoromethanesulfonic anhydride (255.68g) was added dropwise to the reaction solution at 0°C. 906.21mmol). The reaction solution was stirred at 25°C for 12 hours. Add water (1000mL) to the reaction solution, extract with dichloromethane (500mL Compound AA-2 was obtained through purification using solvent: petroleum ether/ethyl acetate = 100% to 90%). 1 H NMR (400MHz, CDCl 3 ) δ7.34 (s, 1H), 2.53 (s, 3H). MS-ESI calculated value [M+H] + 277, measured value 277.
第二步Step 2
将化合物AA-3(117.29g,585.64mmol)和化合物AA-2(90g,325.36mmol)溶于无水DMF(90mL),反应液在90℃下搅拌1小时。向反应液中加入乙酸乙酯(1000mL),过滤,滤液用氢氧化钠(1％水溶液,1000mL)和水(500mL×3)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用硅胶柱层析法(洗脱剂：石油醚/乙酸乙酯,10/1)纯化得到化合物AA-4。MS-ESI计算值[M+H]+327,实测值327。Compound AA-3 (117.29g, 585.64mmol) and compound AA-2 (90g, 325.36mmol) were dissolved in anhydrous DMF (90mL), and the reaction solution was stirred at 90°C for 1 hour. Add ethyl acetate (1000mL) to the reaction solution, filter, wash the filtrate with sodium hydroxide (1% aqueous solution, 1000mL) and water (500mL×3), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate, 10/1) to obtain compound AA-4. MS-ESI calculated value [M+H] + 327, measured value 327.
第三步third step
将化合物AA-4(53g,162.17mmol)溶解在乙酸乙酯(500mL)中,向反应液中加入盐酸乙酸乙酯(4mol/L,162.17mL)。反应液在25℃下搅拌12小时。过滤,滤饼用乙酸乙酯(300mL)洗涤,收集滤饼真空干燥后得到化合物AA-5的盐酸盐。1H NMR(400MHz,CD3OD)δ7.53(s,1H),4.20-4.18(m,1H),3.60-3.57(m,1H),3.34-3.31(m,1H),3.13-3.10(m,2H),2.48(s,3H),2.31-2.21(m,1H),2.15-2.05(m,1H),2,01-1.95(m,1H),1.79-1.77(m,1H)。MS-ESI计算值[M+H]+227,实测值227。Compound AA-4 (53g, 162.17mmol) was dissolved in ethyl acetate (500mL), and ethyl acetate hydrochloride (4mol/L, 162.17mL) was added to the reaction solution. The reaction solution was stirred at 25°C for 12 hours. Filter, wash the filter cake with ethyl acetate (300 mL), collect the filter cake and dry it under vacuum to obtain the hydrochloride of compound AA-5. 1 H NMR (400MHz, CD 3 OD) δ7.53(s,1H),4.20-4.18(m,1H),3.60-3.57(m,1H),3.34-3.31(m,1H),3.13-3.10( m,2H),2.48(s,3H),2.31-2.21(m,1H),2.15-2.05(m,1H),2,01-1.95(m,1H),1.79-1.77(m,1H). MS-ESI calculated value [M+H] + 227, measured value 227.
第四步the fourth step
氮气保护下将化合物AA-5的盐酸盐(85.0g,283.69mmol)溶于无水甲醇(850mL)中,向反应液中加入37％的甲醛水溶液(69.06g,851mmol),反应液在20℃下搅拌反应0.5小时,20℃下向反应液中分批加入醋酸硼氢化钠(123.97g,567mmol),反应液在20℃下搅拌反11.5小时。向反应液中加入饱和氯化铵水溶液(300mL),将反应液减压浓缩除去甲醇,将剩余的水相用NaOH(3mol/L)水溶液调节pH到8,大量固体析出,过滤,滤饼用正庚烷(200mL×2)洗涤,滤饼真空干燥得到粗品。将粗品加入到正庚烷:乙酸异丙酯:NaOH水溶液(3mol/L)(700mL:70mL:70mL)的混合溶剂中,在25℃下悬浮搅拌1小时,过滤,滤饼用(100mL×2)正庚烷洗涤,真空干燥得到化合物AA。1H NMR(400MHz,CD3OD)δ6.78(s,1H),4.10-3.97(m,1H),2.99(br d,J＝8.0Hz,1H),2.66(br d,J＝9.6Hz,1H),2.27(s,3H),2.26(s,3H),2.16-2.07(m,1H),2.05-1.91(m,2H),1.82-1.74(m,1H),1.72-1.60(m,1H),1.44-1.20(m,1H)。MS-ESI计算值[M+H]+241,实测值241。Under nitrogen protection, the hydrochloride of compound AA-5 (85.0g, 283.69mmol) was dissolved in anhydrous methanol (850mL), and 37% formaldehyde aqueous solution (69.06g, 851mmol) was added to the reaction solution. The reaction solution was heated at 20 The reaction was stirred at 20°C for 0.5 hours. Sodium acetate borohydride (123.97g, 567mmol) was added in batches to the reaction solution at 20°C, and the reaction solution was stirred at 20°C for 11.5 hours. Add saturated aqueous ammonium chloride solution (300 mL) to the reaction solution, concentrate the reaction solution under reduced pressure to remove methanol, and adjust the pH of the remaining aqueous phase to 8 with NaOH (3 mol/L) aqueous solution. A large amount of solid will precipitate, filter, and use the filter cake to Wash with n-heptane (200mL×2), and dry the filter cake under vacuum to obtain crude product. Add the crude product to a mixed solvent of n-heptane:isopropyl acetate:NaOH aqueous solution (3mol/L) (700mL:70mL:70mL), suspend and stir at 25°C for 1 hour, filter, and filter the filter cake with (100mL×2 ) n-heptane washing, vacuum drying to obtain compound AA. 1 H NMR (400MHz, CD 3 OD) δ6.78 (s, 1H), 4.10-3.97 (m, 1H), 2.99 (br d, J = 8.0Hz, 1H), 2.66 (br d, J = 9.6Hz ,1H),2.27(s,3H),2.26(s,3H),2.16-2.07(m,1H),2.05-1.91(m,2H),1.82-1.74(m,1H),1.72-1.60(m ,1H),1.44-1.20(m,1H). MS-ESI calculated value [M+H] + 241, measured value 241.
实施例2：中间体EE-5的制备Example 2: Preparation of intermediate EE-5
合成路线：
synthetic route:
第一步first step
将溴化铜(733.69g,3.28mol)和乙酸乙酯(1200mL)混合物在80℃下搅拌10分钟,将化合物EE-1(125g,821.22mmol)溶于氯仿(1200mL)后加入到上述反应液中,反应液在80℃下加热搅拌12小时。反应液冷却后经中性氧化铝和硅藻土过滤,滤饼用二氯甲烷(1000mL)洗涤,滤液减压浓缩得到粗产物。粗产物用乙酸乙酯(500mL)打浆纯化得到化合物EE-2。1H NMR(400MHz,CDCl3)δ7.48(d,J＝5.2Hz,1H),7.18(d,J＝5.2Hz,1H),3.20-3.15(m,4H)。MS-ESI计算值[M+H]+311,实测值311。The mixture of copper bromide (733.69g, 3.28mol) and ethyl acetate (1200mL) was stirred at 80°C for 10 minutes. Compound EE-1 (125g, 821.22mmol) was dissolved in chloroform (1200mL) and added to the above reaction solution. , the reaction solution was heated and stirred at 80°C for 12 hours. After cooling, the reaction solution was filtered through neutral alumina and diatomaceous earth, the filter cake was washed with dichloromethane (1000 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified with ethyl acetate (500 mL) to obtain compound EE-2. 1 H NMR (400MHz, CDCl 3 ) δ7.48 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 3.20-3.15 (m, 4H). MS-ESI calculated value [M+H] + 311, measured value 311.
第二步Step 2
将化合物EE-2(215g,693.54mmol)溶解在DMF(1000mL)中,向反应液中加入碳酸锂(307.47g,4.16mol)。反应液在100℃下搅拌6小时。将反应液过滤,滤饼用DMF(1000mL)洗涤,滤液减压浓缩至(600mL)。剩余物加入到水(6000mL)中,用稀盐酸(1mol/L)条件pH到1,有大量固体析出,室温下搅拌30分钟,过滤干燥得到化合物EE-3。1H NMR(400MHz,CDCl3)δ7.51(d,J＝5.6Hz,1H),7.45-7.37(m,2H),7.34(d,J＝8.8Hz,1H),5.87(s,1H)。Compound EE-2 (215g, 693.54mmol) was dissolved in DMF (1000mL), and lithium carbonate (307.47g, 4.16mol) was added to the reaction solution. The reaction solution was stirred at 100°C for 6 hours. The reaction solution was filtered, the filter cake was washed with DMF (1000 mL), and the filtrate was concentrated under reduced pressure to (600 mL). The residue was added to water (6000 mL), and the pH was adjusted to 1 with dilute hydrochloric acid (1 mol/L). A large amount of solid precipitated. Stir at room temperature for 30 minutes, filter and dry to obtain compound EE-3. 1 H NMR (400MHz, CDCl 3 ) δ7.51 (d, J = 5.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.34 (d, J = 8.8 Hz, 1H), 5.87 (s, 1H) .
第三步third step
将化合物EE-3(200g,873.01mmol)和碳酸钾(301.65g,2.18mol)溶于DMF(1000mL)中,反应液冷却至0℃,向反应液中缓慢滴加氯甲醚(153.070g,1.90mol),反应液在25℃下反应12小时。搅拌下将反应液加入到冰水(5000mL)中,用饱和碳酸钾调节pH至10,用乙酸乙酯(1000mL×3)萃取,有机像用无水硫酸钠干燥,过滤,滤液减压浓缩。浓缩物经过硅胶柱层析法(石油醚/乙酸乙酯＝200/1到100/1)分离得到化合物EE-4。1H NMR(400MHz,CD3OD)δ7.61-7.56(m,2H),7.53-7.46(m,2H),5.24(s,2H),3.66(s,3H)。Compound EE-3 (200g, 873.01mmol) and potassium carbonate (301.65g, 2.18mol) were dissolved in DMF (1000mL). The reaction solution was cooled to 0°C, and chloromethyl ether (153.070g) was slowly added dropwise to the reaction solution. 1.90mol), the reaction solution was reacted at 25°C for 12 hours. Add the reaction solution to ice water (5000 mL) under stirring, adjust the pH to 10 with saturated potassium carbonate, extract with ethyl acetate (1000 mL × 3), dry the organic image with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The concentrate was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 200/1 to 100/1) to obtain compound EE-4. 1 H NMR (400 MHz, CD 3 OD) δ7.61-7.56 (m, 2H), 7.53-7.46 (m, 2H), 5.24 (s, 2H), 3.66 (s, 3H).
第四步the fourth step
将化合物EE-4(100g,366.10mmol,1eq),化合物4,4,5,5-四甲基-1,3,2-二氧杂环硼烷(70.28g,549.16mmol),三乙胺(111.14g,1.10mol),醋酸钯(6.58g,29.29mmol)和2-(二环己基磷)联苯(20.53g,58.58mmol,0.16eq)溶于二氧六环(1000mL)中,混合物在氮气保护下100℃下搅拌反应12小时。将反应液减压浓缩除去溶剂,剩余物用乙酸乙酯(500mL)溶解,经硅胶垫过滤,滤液减压浓缩。浓缩物经过硅胶柱层析法(石油醚/乙酸乙酯＝200/1到100/1)分离得到化合物EE-5。1H NMR(400MHz,CD3OD)δ7.69-7.65(m,2H),7.57-7.52(m,2H),5.24(s,2H),3.59(s,3H),1.39(s,12H)。Combine compound EE-4 (100g, 366.10mmol, 1eq), compound 4,4,5,5-tetramethyl-1,3,2-dioxaborane (70.28g, 549.16mmol), triethylamine (111.14g, 1.10mol), palladium acetate (6.58g, 29.29mmol) and 2-(dicyclohexylphosphorus)biphenyl (20.53g, 58.58mmol, 0.16eq) were dissolved in dioxane (1000mL), the mixture The reaction was stirred at 100°C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to remove the solvent, the residue was dissolved in ethyl acetate (500 mL), filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 200/1 to 100/1) to obtain compound EE-5. 1 H NMR (400MHz, CD 3 OD) δ7.69-7.65(m,2H),7.57-7.52(m,2H),5.24(s,2H),3.59(s,3H),1.39(s,12H) .
实施例3：式(I)化合物的制备Example 3: Preparation of compounds of formula (I)
合成路线：
synthetic route:
第一步first step
氮气保护下将化合物AA(64.0g,265.86mmol),化合物EE-5(102.16g,319mmol)溶于二氧六环(378mL)中,再缓慢加入碳酸钾(73.49g,531.71mmol)的水(252mL)溶液,向反应液中加入1,1-双(二苯基磷)二茂铁二氯化钯二氯甲烷(4.34g,5.32mmol),反应液在85℃下搅拌反应3小时,反应液用硅藻土过滤,2-甲基四氢呋喃(200mL×3)洗涤滤饼,滤液减压浓缩除去二氧六环和2-甲基四氢呋喃。剩余的水相用盐酸水溶液(1mol/L)调节pH到4,用2-甲基四氢呋喃(1000mL×2)萃取,水相用氢氧化钠水溶液(1mol/L)调节pH到10,用2-甲基四氢呋喃(1000mL×1,700mL×2)萃取,合并有机相,浓缩,有机相用1400毫升的二甲基四氢呋喃溶解，加入除钯用改性硅胶(LI-511,50g),45℃搅拌6小时,过滤,滤液继续加入除钯用改性硅胶(LI-511,50g),50℃搅拌12小时,过滤,滤液加入除钯用改性硅胶(LI-511,50g),50℃搅拌6小时,过滤,滤液继续加入除钯用改性硅胶(iMoLboX-LMat-NH01x,50g),50℃搅拌12小时,过滤,滤液减压浓缩得到粗品。将粗品加入到正庚烷:醋乙酸异丙酯(700mL:70mL)的混合溶剂中,在25℃下悬浮搅拌30分钟,悬浊液过滤后滤饼用正庚烷洗涤(100mL×3),滤饼真空干燥得到化合物I-1。1H NMR(400MHz,CD3OD)δ7.79(d,J＝8.4Hz,1H),7.64(d,J＝5.6Hz,1H),7.54(d,J＝5.6Hz,1H),7.27(d,J＝8.4Hz,1H),6.80(s,1H),4.94(s,2H),4.24-4.03(m,1H),3.15(s,3H),3.09(br d,J＝5.2Hz,1H),2.71(br d,J＝6.0Hz,1H),2.30(s,3H),2.19-2.01(m,6H),1.87-1.64(m,2H),1.39-1.36(m,1H)。MS-ESI计算值[M+H]+399,实测值399。Dissolve compound AA (64.0g, 265.86mmol) and compound EE-5 (102.16g, 319mmol) in dioxane (378mL) under nitrogen protection, and then slowly add potassium carbonate (73.49g, 531.71mmol) in water ( 252mL) solution, add 1,1-bis(diphenylphosphorus)ferrocene dichloride palladium dichloromethane (4.34g, 5.32mmol) to the reaction solution, stir the reaction solution at 85°C for 3 hours, and react The liquid was filtered through diatomaceous earth, and the filter cake was washed with 2-methyltetrahydrofuran (200mL×3). The filtrate was concentrated under reduced pressure to remove dioxane and 2-methyltetrahydrofuran. The remaining aqueous phase was adjusted to pH 4 with hydrochloric acid aqueous solution (1mol/L), extracted with 2-methyltetrahydrofuran (1000mL×2), and the aqueous phase was adjusted to pH 10 with sodium hydroxide aqueous solution (1mol/L), and 2- Extract with methyltetrahydrofuran (1000mL×1,700mL×2), combine the organic phases, concentrate, dissolve the organic phase with 1400ml of dimethyltetrahydrofuran, add modified silica gel (LI-511, 50g) for palladium removal, and stir at 45°C for 6 hours, filter, continue adding modified silica gel (LI-511, 50g) for palladium removal to the filtrate, stir at 50°C for 12 hours, filter, add modified silica gel (LI-511, 50g) for palladium removal to the filtrate, stir at 50°C for 6 hours , filter, continue adding modified silica gel for palladium removal (iMoLboX-LMat-NH01x, 50g) to the filtrate, stir at 50°C for 12 hours, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Add the crude product to a mixed solvent of n-heptane:isopropyl acetate (700mL:70mL), suspend and stir at 25°C for 30 minutes, filter the suspension and wash the filter cake with n-heptane (100mL×3). The filter cake was vacuum dried to obtain compound I-1. 1 H NMR (400MHz, CD 3 OD) δ7.79(d,J＝8.4Hz,1H),7.64(d,J＝5.6Hz,1H),7.54(d,J＝5.6Hz,1H),7.27( d,J＝8.4Hz,1H),6.80(s,1H),4.94(s,2H),4.24-4.03(m,1H),3.15(s,3H),3.09(br d,J＝5.2Hz, 1H), 2.71 (br d, J = 6.0Hz, 1H), 2.30 (s, 3H), 2.19-2.01 (m, 6H), 1.87-1.64 (m, 2H), 1.39-1.36 (m, 1H). MS-ESI calculated value [M+H] + 399, measured value 399.
第二步Step 2
将化合物I-1(73.0g,183.18mmol)在10℃下分批加入到盐酸(2mol/L,730.0mL)中,反应液在25℃下搅拌6小时。向反应液加入水365mL和二氯甲烷292mL稀释。在10℃下,加入氨水调节pH至8到9后分液,水相用二氯甲烷萃取(146mL×2),有机相干燥,过滤,减压浓缩得到式(I)化合物的无定形。1H NMR(400MHz,CD3OD)δ7.58(d,J＝5.2Hz,1H),7.48-7.46(m,2H),7.23(d,J＝8.4Hz,1H),6.79(s,1H),4.19-3.99(m,1H),3.04(br d,J＝6.0Hz,1H),2.68(br d,J＝7.2Hz,1H),2.30(s,3H),2.22-2.12(m,4H),2.10-1.95(m,2H),1.91-1.77(m,1H),1.76-1.62(m,1H),1.39-1.36(m,1H)。MS-ESI计算值[M+H]+355,实测值355。Compound I-1 (73.0g, 183.18mmol) was added to hydrochloric acid (2mol/L, 730.0mL) in batches at 10°C, and the reaction solution was stirred at 25°C for 6 hours. To the reaction solution, 365 mL of water and 292 mL of methylene chloride were added to dilute. At 10°C, add ammonia water to adjust the pH to 8 to 9 and then separate the liquids. The aqueous phase is extracted with dichloromethane (146 mL × 2). The organic phase is dried, filtered, and concentrated under reduced pressure to obtain the amorphous form of the compound of formula (I). 1 H NMR (400MHz, CD 3 OD) δ7.58 (d, J = 5.2 Hz, 1H), 7.48-7.46 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 6.79 (s, 1H ),4.19-3.99(m,1H),3.04(br d,J＝6.0Hz,1H),2.68(br d,J＝7.2Hz,1H),2.30(s,3H),2.22-2.12(m, 4H),2.10-1.95(m,2H),1.91-1.77(m,1H),1.76-1.62(m,1H),1.39-1.36(m,1H). MS-ESI calculated value [M+H] + 355, measured value 355.
实施例4：式(I)化合物A晶型的制备Example 4: Preparation of crystal form A of compound of formula (I)
将式(I)化合物的无定形(150mg,423.17μmol)加入到乙腈(1.5mL)中,在50℃下悬浮搅拌24小时,冷却至室温过滤,滤饼用乙腈(1mL)洗涤,滤饼真空干燥得到式(I)化合物的A晶型。XRPD,DSC,TGA,DVS,PSD检测结果依次如图1、2、3、10、13所示。Add the amorphous form of the compound of formula (I) (150 mg, 423.17 μmol) to acetonitrile (1.5 mL), suspend and stir at 50°C for 24 hours, cool to room temperature and filter, wash the filter cake with acetonitrile (1 mL), and vacuum the filter cake Drying gives the crystal form A of the compound of formula (I). The XRPD, DSC, TGA, DVS, and PSD detection results are shown in Figures 1, 2, 3, 10, and 13 in sequence.
将上述溶剂乙腈替换为水、异丙醇、乙腈、丙酮、乙酸乙酯、醋酸异丙酯、2-甲基四氢呋喃、四氢呋喃、甲基异丁酮、乙腈/水(1:1)、乙腈/水(1:4)、丙酮/水(1:1)、丙酮/水(1:4)，均得到式(I)化合物的A晶型。实验结果如表8所示。Replace the above solvent acetonitrile with water, isopropyl alcohol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methylisobutylketone, acetonitrile/water (1:1), acetonitrile/ Water (1:4), acetone/water (1:1), acetone/water (1:4), all obtained the A crystal form of the compound of formula (I). The experimental results are shown in Table 8.
表8 50℃悬浮搅拌试验

Table 8 50℃ suspension stirring test

实施例5：式(Ⅱ)化合物的B晶型的制备Example 5: Preparation of Form B of the Compound of Formula (II)
将式(I)化合物的无定形(1.0g,2.82mmol)加入到丙酮(10mL)中搅拌溶解,向上述溶液中加入D-苹果酸(378.28mg,2.82mmol)丙酮溶液,继续向反应液中加入丙酮(20mL),反应液在50℃下悬浮搅拌24小时,冷却至室温过滤,滤饼真空干燥得到式(Ⅱ)化合物的B晶型。1H NMR(400MHz,CD3OD)δ7.62(d,J＝5.6Hz,1H),7.55-7.51(m,2H),7.24(d,J＝8.0Hz,1H),6.92(s,1H),4.47-4.39(m,1H),4.34(dd,J＝7.6,5.2Hz,1H),3.74-3.60(m,1H),3.22-3.19(m,1H),3.08-2.87(m,2H),2.85-2.80(m,1H),2.79(s,3H),2.61-2.54(m,1H),2.21(s,3H),2.16-2.06(m,2H),2.00-1.88(m,1H),1.75-1.69(m,1H)。XRPD,DSC,TGA,DVS检测结果依次如图4、5、6、11所示。Add the amorphous form of the compound of formula (I) (1.0g, 2.82mmol) to acetone (10mL) and stir to dissolve. Add D-malic acid (378.28mg, 2.82mmol) acetone solution to the above solution, and continue to add it to the reaction solution. Acetone (20 mL) was added, the reaction solution was suspended and stirred at 50°C for 24 hours, cooled to room temperature, filtered, and the filter cake was vacuum dried to obtain the B crystal form of the compound of formula (II). 1 H NMR (400MHz, CD3OD) δ7.62 (d, J = 5.6 Hz, 1H), 7.55-7.51 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 4.47-4.39(m,1H),4.34(dd,J＝7.6,5.2Hz,1H),3.74-3.60(m,1H),3.22-3.19(m,1H),3.08-2.87(m,2H), 2.85-2.80(m,1H),2.79(s,3H),2.61-2.54(m,1H),2.21(s,3H),2.16-2.06(m,2H),2.00-1.88(m,1H), 1.75-1.69(m,1H). The XRPD, DSC, TGA, and DVS detection results are shown in Figures 4, 5, 6, and 11 in sequence.
实施例6：式(Ⅲ)化合物的C晶型的制备Example 6: Preparation of Form C of the Compound of Formula (III)
将式(I)化合物的无定形用高效液相色谱法(色谱柱:Phenomenex C18 150×40mm×5μm；流动相:[水(盐酸)-乙腈]；B％:1％-30％,10分钟)制备得到式(Ⅲ)化合物的无定形。向式(Ⅲ)化合物的无定形(50.2mg)中加入丙酮(0.5mL),所得悬浊液在室温下搅拌3天得到式(Ⅲ)化合物的C晶型。XRPD,DSC,TGA,DVS检测结果依次如图7、8、9、12所示。The amorphous form of the compound of formula (I) was analyzed by high performance liquid chromatography (chromatographic column: Phenomenex C18 150×40mm×5μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 1%-30%, 10 minutes ) to prepare the amorphous form of the compound of formula (III). Acetone (0.5 mL) was added to the amorphous form (50.2 mg) of the compound of formula (III), and the resulting suspension was stirred at room temperature for 3 days to obtain the C crystal form of the compound of formula (III). The XRPD, DSC, TGA, and DVS detection results are shown in Figures 7, 8, 9, and 12 in sequence.
实施例7：式(I)化合物A晶型和式(Ⅱ)化合物B晶型的固体预稳定性试验Example 7: Solid pre-stability test of crystal form A of compound of formula (I) and crystal form of compound B of formula (II)
依据《原料药与制剂稳定性试验指导原则》(中国药典2020版四部通则9001)，考察式(I)化合物A晶型和式(Ⅱ)化合物B晶型在高温(60℃，敞口)，高湿(25℃/相对湿度92.5％，敞口)，强光照(5000lx与紫外强度90μw/cm2，敞口)以及高温高湿条件下(40℃/相对湿度75％以及60℃/相对湿度75％或30℃/相对湿度65％，敞口)的预稳定性。According to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" (Chinese Pharmacopoeia 2020 Edition Four General Chapters 9001), the crystal form of compound A of formula (I) and the crystal form of compound B of formula (II) were investigated at high temperature (60°C, exposed), High humidity (25℃/relative humidity 92.5%, open), strong light (5000lx and UV intensity 90μw/cm 2 , open) and high temperature and high humidity conditions (40℃/relative humidity 75% and 60℃/relative humidity 75% or 30℃/65% relative humidity, open) pre-stability.
称取式(I)化合物A晶型和式(Ⅱ)化合物B晶型每份约30mg，置于干燥洁净的玻璃瓶中，摊成薄薄一层，作为供试样品，放置于影响因素条件下和加速条件下，其样品为完全暴露放样。高温、高湿在5天、10天取样分析，加速条件在1个月、2个月和3个月取样分析。光照条件下放置的样品为室温完全暴露放样。不同条件下放置的样品检测XRPD，检测结果与0天的初始检测结果进行比较，晶型结果见下表9和表10，结果表明式(I)化合物A晶型和式(Ⅱ)化合物B晶型为稳定晶型。Weigh about 30 mg each of the crystal form of compound A of formula (I) and the crystal form of compound of formula (II) B, place it in a dry and clean glass bottle, spread it into a thin layer, use it as a test sample, and place it under the influence of factors. Under low and accelerated conditions, the samples are fully exposed and set out. High temperature and high humidity were sampled and analyzed at 5 and 10 days, and accelerated conditions were sampled and analyzed at 1 month, 2 months and 3 months. Samples placed under light conditions are fully exposed to room temperature. Samples placed under different conditions were tested by The form is a stable crystalline form.
表9式(I)化合物A晶型预稳定性晶型结果

Table 9 Pre-stabilized crystal form results of compound A crystal form of formula (I)

表10式(Ⅱ)化合物B晶型预稳定性晶型结果
Table 10 Pre-stabilized crystal form results of compound B crystal form of formula (II)
实施例8式(I)化合物A晶型、式(Ⅱ)化合物B晶型和式(Ⅲ)化合物C晶型的吸湿性研究Example 8 Study on hygroscopicity of crystal form of compound A of formula (I), crystal form of compound B of formula (II) and crystal form of compound C of formula (III)
实验材料：Experimental Materials:
动态蒸汽吸附仪Dynamic vapor adsorption instrument
实验方法：experimental method:
称取约10mg的化合物置于DVS样品盘内进行测试。Weigh approximately 10 mg of the compound and place it in the DVS sample pan for testing.
引湿性评价分类如表11所示：The classification of hygroscopicity evaluation is shown in Table 11:
表11引湿性评价分类表


注：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重。Table 11 Hygroscopicity evaluation classification table


Note: ΔW% represents the moisture absorption weight gain of the test product at 25±1℃ and 80±2%RH.
实验结果：Experimental results:
式(I)化合物A晶型的DVS谱图如图10所示。DVS结果显示，样品在25℃/80％RH条件下吸湿增重0.1665％，样品无或几乎无吸湿性。完成DVS测试(0-95-0％RH)后，取出样品暴露在空气中测试XRPD，结果显示DVS测试前、后晶型未变。The DVS spectrum of the crystal form A of compound of formula (I) is shown in Figure 10. The DVS results show that the sample absorbs moisture and gains weight by 0.1665% under the conditions of 25°C/80% RH, and the sample has no or almost no hygroscopicity. After completing the DVS test (0-95-0% RH), take out the sample and expose it to the air for XRPD testing. The results show that the crystal form has not changed before and after the DVS test.
式(Ⅱ)化合物B晶型的DVS谱图如图11所示。DVS结果显示，样品在25℃/80％RH条件下与25℃/0％RH条件下相比吸湿增重7.15％，样品有吸湿性。The DVS spectrum of the crystalline form B of compound (II) is shown in Figure 11. The DVS results showed that the sample gained 7.15% moisture and weight under the condition of 25°C/80%RH compared with the condition of 25°C/0%RH, and the sample was hygroscopic.
式(Ⅲ)化合物C晶型的DVS谱图如图12所示。DVS结果显示，样品在25℃/80％RH条件下与25℃/0％RH条件下相比吸湿增重21.09％，样品极具吸湿性。The DVS spectrum of the crystalline form C of compound (III) is shown in Figure 12. The DVS results show that the sample has a hygroscopic weight gain of 21.09% under the condition of 25°C/80%RH compared with the condition of 25°C/0%RH. The sample is extremely hygroscopic.
实验结论：Experimental results:
式(I)化合物A晶型在25±1℃和80±2％RH下无或几乎无吸湿性，且晶型前后不变；式(Ⅱ)化合物B晶型在25±1℃和80±2％RH下有吸湿性；式(Ⅲ)化合物C晶型在25±1℃和80±2％RH下极具吸湿性。The crystal form of compound A of formula (I) has no or almost no hygroscopicity at 25±1℃ and 80±2%RH, and the crystal form remains unchanged; the crystal form of compound B of formula (II) has no or almost no hygroscopicity at 25±1℃ and 80±2% RH. It is hygroscopic at 2% RH; the crystal form C of the compound of formula (III) is extremely hygroscopic at 25±1°C and 80±2% RH.
实施例9粒径分布和形态研究试验Example 9 Particle size distribution and morphology research test
粒径分布测试参数设置见表12，实验结果见表13。The particle size distribution test parameter settings are shown in Table 12, and the experimental results are shown in Table 13.
表12粒径分布的测试参数

*：流速60％为65mL/s的60％。Table 12 Test parameters of particle size distribution

*: 60% of the flow rate is 60% of 65mL/s.
表13式(I)化合物A晶型的PSD结果
Table 13 PSD results of crystal form A of compound of formula (I)
MV：按照体积计算的平均粒径；MV: average particle size calculated by volume;
SD：表示标准偏差；SD: represents standard deviation;
D10：表示粒径分布中(体积分布)占10％所对应的粒径；D10: Indicates the particle size corresponding to 10% of the particle size distribution (volume distribution);
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径； D50: Indicates the particle size corresponding to 50% of the particle size distribution (volume distribution), also known as the median diameter;
D90：表示粒径分布中(体积分布)占90％所对应的粒径；D90: Indicates the particle size corresponding to 90% of the particle size distribution (volume distribution);
实验结论：Experimental results:
式(I)化合物A晶型的PSD结果图13所示，式(I)化合物A晶型体积平均粒径为12.05微米。且粒径分布较窄，几乎呈现一个正态分布，粒径分布均匀。The PSD results of the crystal form of compound A of formula (I) are shown in Figure 13. The volume average particle size of the crystal form of compound A of formula (I) is 12.05 microns. And the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform.
实施例10：式(I)化合物的单晶X射线衍射检测分析Example 10: Single crystal X-ray diffraction detection and analysis of the compound of formula (I)
1.单晶X射线衍射仪的生产厂家和仪器参数1. Manufacturer and instrument parameters of single crystal X-ray diffractometer
生产厂家：布鲁克公司；Manufacturer: Bruker Company;
仪器型号：D8 VENTUREInstrument model: D8 VENTURE
X-射线光源：采用高强度微聚焦旋转阳极光源，Cu靶；X-ray light source: high-intensity micro-focus rotating anode light source, Cu target;
功率2.5KW；Power 2.5KW;
管电压50kV；Tube voltage 50kV;
管电流50mA；Tube current 50mA;
测角仪：四轴(Kappa，ω，2θ，)测角仪；Goniometer: four axes (Kappa, ω, 2θ, ) goniometer;
探测器：大面积photon II探测器，探测器有效面积14cm×10cm，探测器到样品的距离马达自动可调。Detector: Large area photon II detector, the effective area of the detector is 14cm × 10cm, the distance between the detector and the sample is automatically adjustable by the motor.
2.晶体培养2.Crystal culture
称取式(I)化合物(15mg)样品在室温条件下溶解于甲苯(0.6mL)，再加入石油醚(0.05mL)，用滤头过滤，将样品溶液置于2mL样品瓶中，室温下静置2周培养得到单晶。Weigh a sample of the compound of formula (I) (15 mg) and dissolve it in toluene (0.6 mL) at room temperature, then add petroleum ether (0.05 mL), filter with a filter head, place the sample solution in a 2 mL sample bottle, and let stand at room temperature. Single crystals were obtained after culturing for 2 weeks.
3.结论3.Conclusion
式(I)化合物的单晶SC-XRD立体结构椭球图如图14所示。其结果显示，图中C15和C34为R构型。The single crystal SC-XRD three-dimensional structure ellipsoid diagram of the compound of formula (I) is shown in Figure 14. The results show that C15 and C34 in the figure are R configurations.
生物测试数据：Biological test data:
实验例1：LPS刺激大鼠原代小胶质细胞IL-1β释放实验Experimental Example 1: LPS-stimulated IL-1β release experiment in rat primary microglia
一.实验目的：1. Experimental purpose:
本实验利用大鼠原代小胶质细胞来研究NLRP3抑制剂对大鼠原代小胶质细胞IL-1β分泌的抑制活性。This experiment used rat primary microglia to study the inhibitory activity of NLRP3 inhibitors on IL-1β secretion in rat primary microglia.
二.实验试剂：实验试剂明细表见表14。2. Experimental reagents: See Table 14 for the detailed list of experimental reagents.
表14实验试剂明细表

Table 14 Experimental reagent details

三.实验操作3. Experimental operation
新生SD大鼠，取大脑皮层，消化分离获得混合胶质细胞，接种到培养瓶中进行培养。每3-4天换液，培养10天左右，至细胞完全汇合后，37℃震荡，离心收集小胶质细胞，接种到96孔细胞培养板中培养过夜。细胞换无血清培养基，加50ng/mL LPS作用3h，然后加入不同浓度的化合物作用0.5h，再加入0.3μg/mL Nigericin作用1h。收集上清放入-80℃保存或直接通过ELISA的方法检测IL-1β的释放情况，按试剂盒说明书进行操作。数据处理以10μM的阳性化合物组为低值(L)，以DMSO组为高值(H)，通过以下公式计算化合物的抑制率(Inhibition％＝(Ave_H-Sample)/(Ave_H-Ave_L)*100)，并通过非线性回归方程Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))计算化合物的IC50。From newborn SD rats, the cerebral cortex was removed, digested and separated to obtain mixed glial cells, which were inoculated into culture bottles for culture. Change the medium every 3-4 days and culture for about 10 days. After the cells are completely confluent, shake at 37°C, collect microglia by centrifugation, inoculate them into a 96-well cell culture plate and culture them overnight. The cells were replaced with serum-free medium, 50ng/mL LPS was added for 3h, then different concentrations of compounds were added for 0.5h, and then 0.3μg/mL Nigericin was added for 1h. Collect the supernatant and store it at -80°C or directly detect the release of IL-1β by ELISA and follow the instructions of the kit. Data processing uses the 10 μM positive compound group as the low value (L) and the DMSO group as the high value (H). The inhibition rate of the compound is calculated by the following formula (Inhibition%=(Ave_H-Sample)/(Ave_H-Ave_L)*100 ), and calculate the IC 50 of the compound through the nonlinear regression equation Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope)).
四.实验结果见表154. The experimental results are shown in Table 15
表15大鼠原代小胶质细胞检测NLRP3抑制剂的IC50实验的测试结果
Table 15 Test results of rat primary microglia testing IC 50 experiment for NLRP3 inhibitors
结论：本发明化合物对大鼠原代小胶质细胞IL-1β的成熟和分泌有显著的抑制活性。Conclusion: The compound of the present invention has significant inhibitory activity on the maturation and secretion of IL-1β in rat primary microglia.
实验例2：LPS诱导大鼠中枢炎症模型的药效研究Experimental Example 2: Study on the efficacy of LPS-induced central inflammation model in rats
一、实验目的：1. Experimental purpose:
通过大鼠侧脑室注射LPS建立中枢炎症模型，运用ELISA评价脑脊液IL-1β水平，以此评估受试化合物的体内药效。A central inflammation model was established by injecting LPS into the lateral ventricle of rats, and ELISA was used to evaluate the IL-1β levels in cerebrospinal fluid to evaluate the in vivo efficacy of the test compounds.
二.实验方法2. Experimental methods
SD雄性大鼠10-14周龄，采用异氟烷呼吸麻醉；确保动物头部不会出现移动，并调节脑表面平整；大鼠头部剃毛，沿矢状缝作一皮肤切口，暴露前囟点；使玻璃电极定位到前囟，将坐标显示器各轴归零，根据坐标定位；缓慢进针定位至侧脑室后，注射12.5μg LPS，2小时后给予5mg/kg式(I)化合物，3小时后给予ATP，3.5小时后收集脑脊液，通过ELISA评价IL-1β抑制水平。SD male rats aged 10-14 weeks were anesthetized using isoflurane breathing; ensure that the animal's head does not move and adjust the brain surface to be flat; the rat's head is shaved, and a skin incision is made along the sagittal suture. fontanelle; position the glass electrode to the anterior fontanelle, reset each axis of the coordinate display to zero, and position according to the coordinates; slowly insert the needle to locate the lateral ventricle, inject 12.5 μg LPS, and give 5 mg/kg compound of formula (I) 2 hours later. ATP was administered 3 hours later, cerebrospinal fluid was collected 3.5 hours later, and IL-1β inhibition level was evaluated by ELISA.
三.实验结果见表163. The experimental results are shown in Table 16
表16大鼠脑脊液IL-1β抑制活性实验结果

注：Mean±SEM，n＝3；与溶媒组比较：*p<0.05，***p<0.001。Table 16 Rat cerebrospinal fluid IL-1β inhibitory activity experimental results

Note: Mean±SEM, n=3; compared with vehicle group: *p<0.05, ***p<0.001.
结果表明：5mg/kg单次给予式(I)化合物对中枢IL-1β有抑制活性，展示出更优的体内药效。The results show that a single administration of 5 mg/kg of the compound of formula (I) has inhibitory activity on central IL-1β and exhibits better in vivo efficacy.
实验例3：6-羟基多巴胺诱导大鼠帕金森模型的药效研究Experimental Example 3: Study on the efficacy of 6-hydroxydopamine in inducing rat Parkinson’s model
一、实验目的：1. Experimental purpose:
选用SD大鼠，通过脑立体定位的方式注射6-羟基多巴胺(6-OHDA)建立帕金森疾病(Parkinson’s disease，PD)模型，给予化合物进行处理5天后收集纹状体，通过ELISA评价IL-1β抑制水平。SD rats were selected and a Parkinson's disease (PD) model was established by injecting 6-hydroxydopamine (6-OHDA) through brain stereotaxy. The striatum was collected after treatment with the compound for 5 days, and IL-1β was evaluated by ELISA. Inhibition level.
二、实验对象、分组给药方案明细表见表172. The detailed list of experimental subjects and grouped dosing regimens is shown in Table 17.
表17实验对象、分组和给药方案明细表
Table 17 Detailed list of experimental subjects, groups and dosage regimens
三、实验方法：3. Experimental methods:
8周龄SD雄性大鼠，采用异氟烷呼吸麻醉，确保动物头部不会出现移动，并调节脑表面平整。大鼠头部剃毛，沿矢状缝作一皮肤切口，暴露前囟点。使玻璃电极定位到前囟，将坐标显示器各轴归零，根据坐标定位黑质(SN)、纹状体(Str)两脑区；缓慢进针定位至SN、Str后，等待10min再以0.4μL/min的速率注射6-OHDA，给完药后再次停留10min后缓慢拔针。受试物(式(I)化合物，5、10mg/kg)及溶媒对照(溶剂原液)在造模前一天开始给药，每天灌胃给药(BID或QD)至实验取材结束。药物处理6天后，给药2h后进行取材，取材部位为造模侧纹状体的一半。使用ELISA试剂盒测定大鼠纹状体中IL-1β的水平。Eight-week-old SD male rats were anesthetized using isoflurane breathing to ensure that the animal's head would not move and the brain surface should be adjusted to be flat. The head of the rat was shaved, and a skin incision was made along the sagittal suture to expose the bregma. Position the glass electrode to the bregma, reset each axis of the coordinate display to zero, and locate the substantia nigra (SN) and striatum (Str) brain areas according to the coordinates; slowly insert the needle to locate SN and Str, wait for 10 minutes, and then use 0.4 Inject 6-OHDA at a rate of μL/min. After the drug is administered, stay for another 10 minutes and then slowly withdraw the needle. The test substance (compound of formula (I), 5, 10 mg/kg) and the vehicle control (solvent stock solution) were administered one day before modeling, and were administered by intragastric administration (BID or QD) every day until the end of the experiment. After drug treatment for 6 days, the samples were collected 2 hours after drug administration. The sample site was half of the striatum on the modeling side. The level of IL-1β in rat striatum was measured using ELISA kit.
四.实验结果见表184. The experimental results are shown in Table 18
表18大鼠纹状体IL-1β抑制活性实验结果


注：Mean±SEM，n＝4；与6-OHDA造模组比较：***p<0.001。Table 18 Experimental results of IL-1β inhibitory activity in rat striatum


Note: Mean±SEM, n=4; compared with 6-OHDA modeling group: ***p<0.001.
结果表明：受试化合物对6-羟基多巴胺诱导大鼠帕金森模型中，纹状体IL-1β水平具有显著的抑制作用。The results showed that the test compound had a significant inhibitory effect on striatal IL-1β levels in the 6-hydroxydopamine-induced rat Parkinson model.
实验例4：6-羟基多巴胺诱导大鼠帕金森模型的行为学及组织学检测Experimental Example 4: Behavioral and histological examination of 6-hydroxydopamine-induced rat Parkinson’s model
一、实验目的：1. Experimental purpose:
选用SD大鼠，通过脑立体定位的方式注射6-羟基多巴胺(6-OHDA)建立帕金森疾病(Parkinson’s disease，PD)模型，给予化合物进行处理21天后开展相关的行为学(平衡木测试、转棒测试)及组织学检测【酪氨酸羟化酶(Tyrosine hydroxylase，TH)、小胶质细胞标记物(Iba1)免疫荧光染色】以评估待测化合物药效。SD rats were selected to establish a Parkinson's disease (PD) model by injecting 6-hydroxydopamine (6-OHDA) through brain stereotaxy. The compound was administered for 21 days and then related behavioral tests (balance beam test, rotarod test) were conducted. Test) and histological testing [tyrosine hydroxylase (TH), microglia marker (Iba1) immunofluorescence staining] to evaluate the efficacy of the compound to be tested.
二、实验对象及分组：2. Experimental objects and groups:
SD雄性大鼠(180～220g)，具体给药方案如表19所示。SD male rats (180~220g), the specific dosage regimen is shown in Table 19.
表19实验对象给药方案明细表
Table 19 Detailed list of dosing regimen for experimental subjects
三、实验方法：3. Experimental methods:
SD大鼠采用异氟烷呼吸麻醉，确保动物头部不会出现移动，并调节脑表面平整。大鼠头部剃毛，沿矢状缝作一皮肤切口，暴露前囟点。使玻璃电极定位到前囟，将坐标显示器各轴归零，根据坐标定位黑质(SN)、纹状体(Str)脑区；缓慢进针定位至SN、Str后，等待10min再以0.4μL/min的速率注射6-OHDA，给完药后再次停留10min后缓慢拔针。SD rats were anesthetized with isoflurane breathing to ensure that the animal's head would not move and the brain surface should be adjusted to be flat. The head of the rat was shaved, and a skin incision was made along the sagittal suture to expose the bregma. Position the glass electrode to the bregma, reset each axis of the coordinate display to zero, and locate the substantia nigra (SN) and striatum (Str) brain areas according to the coordinates; slowly insert the needle to locate SN and Str, wait 10 minutes, and then inject 0.4 μL Inject 6-OHDA at a rate of /min. After the drug is administered, stay for another 10 minutes and then slowly withdraw the needle.
平衡木测试训练期：将动物放在平衡木上每天适应10分钟，每次训练穿过平衡木2次，共2天；正式试验适应环境30-60min，将动物放在平衡木上，记录动物2次通过平衡木的脚滑次数。评价标准：两次成功通过平衡木的脚滑次数(脚离开平衡木上表面)。Balance beam test training period: put the animal on the balance beam to adapt for 10 minutes every day, and cross the balance beam twice for each training, for a total of 2 days; the formal test adapts to the environment for 30-60 minutes, place the animal on the balance beam, and record the animal passing the balance beam twice. number of foot slips. Evaluation criteria: The number of foot slides (feet leaving the upper surface of the balance beam) that successfully pass the balance beam twice.
转棒测试(肌力测试)：动物测试前放置于测试房间适应环境30-60min；适应训练将每只实验动物放置于转棒疲劳仪上适应性训练5min。正式检测：转棒疲劳仪参数设置为转速20rpm/min，测试时间5min，将大鼠分批放置于转棒上进行测试。结果分析：统计各动物在棒时间。Rotarod test (muscle strength test): Before testing, animals are placed in the test room to adapt to the environment for 30-60 minutes; adaptation training: Each experimental animal is placed on the rotarod fatigue instrument for adaptive training for 5 minutes. Formal testing: The parameters of the rotary rod fatigue meter are set to a rotation speed of 20 rpm/min and a test time of 5 minutes. Rats are placed on the rotary rod in batches for testing. Result analysis: count the time each animal spent on the bar.
行为学测试结束次日取材进行酪氨酸羟化酶(Tyrosine hydroxylase，TH)、小胶质细胞标记物(Iba1)的免疫荧光染色。On the day after the behavioral test, samples were collected for immunofluorescence staining of tyrosine hydroxylase (TH) and microglia marker (Iba1).
数据汇总统计后，使用SPSS数据统计软件进行分析(单因素方差分析)，根据SPSS分析结果使用Graph Pad软件绘制图像。免疫组化使用Adobe Photoshop和Adobe illustrator软件作图。After data summary statistics, use SPSS data statistics software for analysis (one-way analysis of variance), and use Graph Pad software to draw images based on the SPSS analysis results. Immunohistochemistry was performed using Adobe Photoshop and Adobe illustrator software.
四、实验结果见表20、表21、表22、表23和表24。 4. The experimental results are shown in Table 20, Table 21, Table 22, Table 23 and Table 24.
表20脑立体定位注射6-OHDA 21天后大鼠在平衡木测试中脚滑次数的统计分析结果

注：Mean±SEM，n＝12～15；*：与6-OHDA造模组比较，*p＜0.05，***p＜0.001Table 20 Statistical analysis results of the number of foot slips in rats in the balance beam test 21 days after stereotaxic injection of 6-OHDA into the brain

Note: Mean±SEM, n=12～15; *: Compared with 6-OHDA modeling set, *p＜0.05, ***p＜0.001
结果表明：平衡木测试式(I)化合物组与6-OHDA造模组比较，式(I)化合物组大鼠滑脚次数少于6-OHDA造模组，二者差异具有显著性(p<0.05)。The results showed that in the balance beam test, compared with the compound group of formula (I) and the 6-OHDA model group, the number of rats in the compound group of formula (I) slipped less than that of the 6-OHDA model group, and the difference between the two was significant (p<0.05 ).
表21脑立体定位注射6-OHDA 21天后大鼠在转棒测试中在棒时间的统计分析结果

注：Mean±SEM，n＝12～15；*：与6-OHDA造模组比较，*p＜0.05，***p＜0.001Table 21 Statistical analysis results of rod time in rats in rotarod test 21 days after brain stereotaxic injection of 6-OHDA

Note: Mean±SEM, n=12～15; *: compared with 6-OHDA modeling set, *p<0.05, ***p<0.001
结果表明：式(I)化合物组与6-OHDA造模组比较，式(I)化合物组大鼠在棒时间长于6-OHDA造模组大鼠，二者差异有显著性(p<0.05)。The results show that: compared with the compound group of formula (I) and the 6-OHDA modeling group, the rats in the compound group of formula (I) stay on the rod longer than the rats in the 6-OHDA modeling group, and the difference between the two is significant (p<0.05) .
表22 TH染色中给予化合物21天对大鼠SN脑区信号个数的影响

注：Mean±SEM，n＝12～15；*：与6-OHDA造模组比较，***p＜0.001Table 22 Effect of compound administration for 21 days on the number of signals in the SN brain area of rats in TH staining

Note: Mean±SEM, n=12～15; *: Compared with 6-OHDA modeling group, ***p<0.001
结果表明：大鼠进行大脑纹状体、黑质区域立体定位微量注射6-OHDA(20μg/8μL)21天后进行酪氨酸羟化酶(TH)染色，在SN脑区，空白组，式(I)化合物组与6-OHDA造模组比较，TH阳性细胞数差异有极显著性(p<0.001)。The results show that rats were subjected to stereotaxic microinjection of 6-OHDA (20 μg/8 μL) in the striatum and substantia nigra area of the brain for 21 days and then stained with tyrosine hydroxylase (TH). In the SN brain area, the blank group, the formula ( I) Compared with the 6-OHDA modeling group, the difference in the number of TH-positive cells is extremely significant (p<0.001).
表23 Iba-1染色中给予化合物21天对大鼠SN脑区信号个数的影响

注：Mean±SEM，n＝12～15；*：与6-OHDA造模组比较，***p＜0.001 Table 23 Effect of compound administration for 21 days on the number of signals in the SN brain area of rats in Iba-1 staining

Note: Mean±SEM, n=12～15; *: Compared with 6-OHDA modeling group, ***p<0.001
表24 Iba-1染色中给予化合物21天对大鼠Str脑区信号个数的影响

注：Mean±SEM，n＝12～15；*：与6-OHDA造模组比较，***p＜0.001Table 24 Effect of compound administration for 21 days on the number of signals in rat Str brain area in Iba-1 staining

Note: Mean±SEM, n=12～15; *: Compared with 6-OHDA modeling group, ***p<0.001
结果表明：在Str脑区及SN脑区，6-OHDA造模组与空白组比较，Iba1阳性细胞数明显增多，且差异有极显著性(p<0.001)，表明PD建模后SN,Str脑区被诱导明显的炎症反应成功；药物处理后，式(I)化合物组与6-OHDA造模组差异有极显著性(p<0.001)。The results showed that in the Str brain area and SN brain area, compared with the blank group, the number of Iba1-positive cells in the 6-OHDA modeling group increased significantly, and the difference was extremely significant (p<0.001), indicating that after PD modeling, SN, Str An obvious inflammatory response was successfully induced in the brain area; after drug treatment, the difference between the compound group of formula (I) and the 6-OHDA model group was extremely significant (p<0.001).
实验例5：基于人源化寡聚态Aβ1-42(oAβ1-42)诱导的阿尔茨海默小鼠模型及测试受试品药效实验Experimental Example 5: Alzheimer's mouse model induced by humanized oligomeric Aβ1-42 (oAβ1-42) and test drug efficacy experiment
一、实验目的：1. Experimental purpose:
选用C57BL/6小鼠，通过脑室定位注射人源化寡聚肽Aβ1-42(oAβ1-42)诱导建立阿尔茨海默(Alzheimer’s Disease，AD)小鼠模型，并完成受试化合物的体内相关药效。C57BL/6 mice were selected, and the Alzheimer's Disease (AD) mouse model was established through localized intracerebroventricular injection of humanized oligomeric peptide Aβ1-42 (oAβ1-42), and in vivo related drug studies of the test compounds were completed. effect.
二、实验对象、分组给药方案见表25。2. Experimental subjects and group dosing regimen are shown in Table 25.
表25：实验动物分组，模型诱导和给药治疗
Table 25: Grouping of experimental animals, model induction and drug administration and treatment
三、实验方法：小鼠脑室定位注射：各组动物使用水合氯醛轻微麻醉后固定头部，颅骨表面皮肤用3％H2O2擦拭，参考小鼠脑图谱，定位侧脑室，利用脑立体定位(M/L＝-0.9mm,A/P＝-0.2mm,D/V＝-2.35mm)垂直颅骨表面刺入无菌微量注射器，第二、三组缓慢注射oAβ1-42溶液(100μM/5μL/只)，速度0.8uL/min，注射完留针5min，而后缓慢移出针约5min，第一组对照组注射等体积的空白溶媒。动物造模当日定位为第0天。3. Experimental method: Mouse ventricular positioning injection: The animals in each group were lightly anesthetized with chloral hydrate and then their heads were fixed. The skin on the skull surface was wiped with 3% H 2 O 2. Refer to the mouse brain atlas to locate the lateral ventricles and use brain stereo. Position (M/L=-0.9mm, A/P=-0.2mm, D/V=-2.35mm) vertically on the skull surface and insert a sterile microsyringe. The second and third groups slowly inject oAβ1-42 solution (100μM/ 5 μL/animal), speed 0.8 μL/min, leave the needle for 5 minutes after injection, and then slowly remove the needle for about 5 minutes. The first control group is injected with an equal volume of blank solvent. The day of animal modeling is positioned as day 0.
给药治疗：动物从第一天开始给药或溶媒，溶媒组和oAβ1-42造模组口服给予溶媒，第三组口服受试化合物溶液，两次/天，间隔8小时。第八天和第十天进行为学实验，行为学实验结束后进行第二次给药。第十三天首次给药2小时后小鼠取组织样本。Administration and treatment: Animals were administered orally administered with vehicle or vehicle from the first day. The vehicle group and oAβ1-42 modeling group were orally administered vehicle, and the third group was orally administered test compound solution twice a day with an interval of 8 hours. Behavioral experiments were conducted on the eighth and tenth days, and the second dose was administered after the behavioral experiment. On the thirteenth day, tissue samples were taken from the mice 2 hours after the first administration.
Y迷宫试验：将小鼠放在Y迷宫任意一臂末端，任其自由探索8min，摄像记录动物的运动轨迹及行为变化，记录以下各项指标：①总进臂次数(the total number of entries)：动物进入迷宫臂的次数(以小鼠四只脚均进入臂为进臂一次标准)；②轮流(交替)一次(an alternation)：依次连续进入Y迷宫全部三个臂一次；③*轮流次数(The number of maximum alternations)：总进臂次数-2。最终得到检测指标即自发轮流行为得分＝总轮流次数/*轮流次数*100％。利用EthosVision-XT8.0视频分析系统对小鼠行为进行分析。Y maze test: Place the mouse at the end of any arm of the Y maze and let it explore freely for 8 minutes. The animal's movement trajectory and behavioral changes are recorded with video, and the following indicators are recorded: ① The total number of entries (the total number of entries) : The number of times an animal enters the arms of the maze (taking all four legs of the mouse into the arms is considered as one arm entry); ② One turn (an alternation): Enter all three arms of the Y maze consecutively once; ③*Number of turns (The number of maximum alternations): The total number of arm advances -2. Finally, the detection index is obtained, that is, the spontaneous turn behavior score = total number of turns/*number of turns*100%. Mouse behavior was analyzed using the EthosVision-XT8.0 video analysis system.
行为学测试结束后继续给药，第十三天取材进行海马脑区和皮层脑区通过ELISA进行炎症因子水平 检测；对海马和皮层微管磷酸化Tau蛋白(AT8)和小胶质细胞标志物(Iba-1)进行免疫荧光染色。After the behavioral test, drug administration was continued. On the 13th day, samples were collected to measure the levels of inflammatory factors in the hippocampus and cortex areas through ELISA. Detection; Immunofluorescence staining for hippocampal and cortical microtubule phosphorylated Tau protein (AT8) and microglial marker (Iba-1).
四、数据分析方法4. Data analysis methods
全部免疫荧光实验图片采用Image J图像处理分析软件进行阳性细胞个数分析。所有实验结果均以Mean±S.E.M.表示，实验数据采用SPSS 20.0软件进行分析。组间比较采用独立样本T检验(Independent-Sample Test)来判断总体显著性差异。采用Levene’s检验来判断方差齐性，当p>0.05时，方差齐；再根据均值方程的t检验来判断组间的显著性差异，当p<0.05时，组间有显著性差异。All immunofluorescence experiment pictures were analyzed using Image J image processing and analysis software to analyze the number of positive cells. All experimental results are expressed as Mean±S.E.M., and the experimental data were analyzed using SPSS 20.0 software. The independent sample T test (Independent-Sample Test) was used to determine the overall significant difference between groups. Levene’s test was used to determine the homogeneity of variances. When p>0.05, the variances were homogeneous. The t-test of the mean equation was then used to determine the significant difference between the groups. When p<0.05, there was a significant difference between the groups.
五、实验结果见表26、表27、表28、表29和表30。5. The experimental results are shown in Table 26, Table 27, Table 28, Table 29 and Table 30.
表26脑室注射oAβ1-42 10天后小鼠Y迷宫自发交替行为得分的统计分析结果

注：数据以Mean±S.E.M.表示；n＝14；*：与溶媒组比较，**p<0.01；#：与oAβ1-42造模组比较，#p<
0.05。Table 26 Statistical analysis results of spontaneous alternation behavior scores in the Y maze of mice 10 days after intracerebroventricular injection of oAβ1-42

Note: Data are expressed as Mean±SEM; n=14; *: compared with vehicle group, **p<0.01;# : compared with oAβ1-42 modeling group, # p<
0.05.
结果表明：Y迷宫测试式(I)化合物组与oAβ1-42造模组比较自发交替行为得分显著提高，提示式(I)化合物对oAβ造成的小鼠空间学习记忆损伤具有显著的改善作用。The results showed that the spontaneous alternation behavior score of the compound group of formula (I) in the Y maze test was significantly improved compared with the oAβ1-42 model group, suggesting that the compound of formula (I) has a significant improvement effect on the spatial learning and memory impairment of mice caused by oAβ.
表27脑室注射oAβ1-42 13天后海马脑区炎症因子水平检测结果

注：数据以Mean±S.E.M.表示；*：与溶媒组比较，***p<0.001，****P<0.0001；#：与oAβ1-42造
模组比较，##p<0.01，###p<0.001。Table 27 Detection results of inflammatory factor levels in the hippocampus 13 days after intracerebroventricular injection of oAβ1-42

Note: Data are expressed as Mean±SEM; *: compared with vehicle group, ***p<0.001, ****P<0.0001;# : compared with oAβ1-42 modeling group, ## p<0.01, ## #p <0.001.
结果表明：式(I)化合物组与oAβ1-42造模组比较海马区IL-6和IL-1β的水平显著降低，提示式(I)化合物对oAβ造成的小鼠海马区炎症损伤具有显著的改善作用。The results show that compared with the oAβ1-42 model group, the levels of IL-6 and IL-1β in the hippocampus of the compound group of formula (I) are significantly reduced, suggesting that the compound of formula (I) has a significant effect on the inflammatory damage in the hippocampus of mice caused by oAβ. Improvement effect.
表28脑室注射oAβ1-42 13天后皮层脑区炎症因子水平检测结果

注：数据以Mean±S.E.M.表示；*：与溶媒组比较，**p<0.01，****p<0.0001；#：与oAβ1-42造模组
比较，###p<0.001。 Table 28 Detection results of inflammatory factor levels in cortical brain areas 13 days after intracerebroventricular injection of oAβ1-42

Note: Data are expressed as Mean±SEM; *: compared with vehicle group, **p<0.01, ****p<0.0001;# : compared with oAβ1-42 modeling group, ### p<0.001.
结果表明：式(I)化合物组与oAβ1-42造模组比较皮层区IL-6水平显著降低，IL-1β的水平有所降低，提示式(I)化合物对oAβ造成的小鼠海马区炎症损伤具有显著的改善作用。The results showed that: compared with the oAβ1-42 model group, the level of IL-6 in the cortical area of the compound group of formula (I) was significantly reduced, and the level of IL-1β was also reduced, suggesting that the compound of formula (I) affects the inflammation in the hippocampus of mice caused by oAβ. Damage has a significant improvement effect.
表29脑室注射oAβ1-42 13天后海马脑区Tau蛋白磷酸化水平和小胶质细胞活化情况分析结果

注：数据以Mean±S.E.M.表示；*：与溶媒组比较，****p<0.0001；#：与oAβ1-42造模组比较，####p
<0.0001。Table 29 Analysis results of Tau protein phosphorylation level and microglia activation in the hippocampus 13 days after intracerebroventricular injection of oAβ1-42

Note: Data are expressed as Mean±SEM; *: compared with vehicle group, ****p<0.0001;# : compared with oAβ1-42 modeling group, #### p
<0.0001.
结果表明：式(I)化合物组与oAβ1-42造模组比较海马脑区AT8表达水平和Iba-1活化态小胶质细胞比例都显著下降，提示式(I)化合物对oAβ引起的海马Tau蛋白过度磷酸化和小胶质细胞过度活化有显著的抑制作用。The results show that: compared with the oAβ1-42 model group, the AT8 expression level and the proportion of Iba-1 activated microglia in the hippocampus were significantly reduced in the compound group of formula (I), suggesting that the compound of formula (I) has an effect on hippocampal Tau caused by oAβ. Protein hyperphosphorylation and microglial hyperactivation have significant inhibitory effects.
表30脑室注射oAβ1-42 13天后皮层脑区Tau蛋白磷酸化水平和小胶质细胞活化情况分析结果

注：数据以Mean±S.E.M.表示；*：与溶媒组比较，****p<0.0001；#：与oAβ1-42造模组比较，####p
<0.0001。Table 30 Analysis results of Tau protein phosphorylation levels and microglia activation in cortical brain areas 13 days after intracerebroventricular injection of oAβ1-42

Note: Data are expressed as Mean±SEM; *: compared with vehicle group, ****p<0.0001;# : compared with oAβ1-42 modeling group, #### p
<0.0001.
结果表明：式(I)化合物组与oAβ1-42造模组比较皮层脑区AT8表达水平和Iba-1活化态小胶质细胞比例都显著下降，提示式(I)化合物对oAβ引起的皮层区Tau蛋白过度磷酸化和小胶质细胞过度活化有显著的抑制作用。 The results show that compared with the oAβ1-42 model group, the AT8 expression level and the proportion of Iba-1 activated microglia in the cortical brain area of the compound group of formula (I) were significantly reduced, suggesting that the compound of formula (I) has an effect on the cortical areas caused by oAβ. Hyperphosphorylation of Tau protein and excessive activation of microglia have significant inhibitory effects.

Claims (32)

  1. 式(I)化合物的A晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：8.41±0.20°、16.53±0.20°和18.12±0.20°；
    The X-ray powder diffraction pattern (XRPD) of the A crystal form of the compound of formula (I) has characteristic diffraction peaks at the following 2θ angles: 8.41±0.20°, 16.53±0.20° and 18.12±0.20°;
  2. 根据权利要求1所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.41±0.20°、13.48±0.20°、16.53±0.20°、18.12±0.20°、21.44±0.20°和24.06±0.20°。According to the A crystal form of claim 1, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.41±0.20°, 13.48±0.20°, 16.53±0.20°, 18.12±0.20°, 21.44± 0.20° and 24.06±0.20°.
  3. 根据权利要求2所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.41±0.20°、12.72±0.20°、13.48±0.20°、16.53±0.20°、18.12±0.20°、21.44±0.20°、24.06±0.20°和25.55±0.20°。According to the A crystal form of claim 2, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.41±0.20°, 12.72±0.20°, 13.48±0.20°, 16.53±0.20°, 18.12± 0.20°, 21.44±0.20°, 24.06±0.20° and 25.55±0.20°.
  4. 根据权利要求3所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80±0.20°、8.41±0.20°、12.16±0.20°、12.72±0.20°、13.48±0.20°、14.72±0.20°、15.92±0.20°、16.53±0.20°、16.89±0.20°、17.37±0.20°、18.12±0.20°、21.44±0.20°、24.06±0.20°、24.84±0.20°、25.55±0.20°、27.12±0.20°和29.03±0.20°。According to the A crystal form of claim 3, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.80±0.20°, 8.41±0.20°, 12.16±0.20°, 12.72±0.20°, 13.48± 0.20°、14.72±0.20°、15.92±0.20°、16.53±0.20°、16.89±0.20°、17.37±0.20°、18.12±0.20°、21.44±0.20°、24.06±0.20°、24.84±0.20°、25.55± 0.20°, 27.12±0.20° and 29.03±0.20°.
  5. 根据权利要求4所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.80、8.41、11.58、12.16、12.72、13.07、13.48、14.72、15.92、16.53、16.89、17.37、18.12、18.43、19.11、21.24、21.44、22.41、23.02、23.23、23.52、24.06、24.84、25.34、25.55、26.08、26.49、26.89、27.12、27.92、28.62、29.03、29.75、30.10、31.21、32.10、32.89、33.26、34.45、35.64、36.06、37.24、38.84。According to the A crystal form of claim 4, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.80, 8.41, 11.58, 12.16, 12.72, 13.07, 13.48, 14.72, 15.92, 16.53, 16.89, 17.37, 18.12, 18.43, 19.11, 21.24, 21.44, 22.41, 23.02, 23.23, 23.52, 24.06, 24.84, 25.34, 25.55, 26.08, 26.49, 26.89, 27.12, 27.92, 28.62, 29. 03, 29.75, 30.10, 31.21, 32.10, 32.89, 33.26, 34.45, 35.64, 36.06, 37.24, 38.84.
  6. 根据权利要求5所述的A晶型，其XRPD图谱基本如图1所示。According to the A crystal form of claim 5, its XRPD pattern is basically as shown in Figure 1.
  7. 根据权利要求1～6任意一项所述的A晶型，其差示扫描量热(DSC)曲线164.0±5℃处具有吸热峰的起始点。According to the A crystal form according to any one of claims 1 to 6, its differential scanning calorimetry (DSC) curve has the starting point of the endothermic peak at 164.0±5°C.
  8. 根据权利要求7所述的A晶型，其DSC图谱如图2所示。According to the A crystal form of claim 7, its DSC pattern is shown in Figure 2.
  9. 根据权利要求1～6任意一项所述的A晶型，其热重分析(TGA)曲线在150.0±3℃时失重达1.25％。According to the A crystal form according to any one of claims 1 to 6, its thermogravimetric analysis (TGA) curve has a weight loss of 1.25% at 150.0±3°C.
  10. 根据权利要求9所述的A晶型，其TGA图谱如图3所示。According to the A crystal form of claim 9, its TGA spectrum is shown in Figure 3.
  11. 式(Ⅱ)化合物，其结构式如下：
    The compound of formula (II) has the following structural formula:
  12. 式(Ⅱ)化合物B晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：6.22±0.20°、8.11±0.20°、14.59±0.20°、19.11±0.20°和21.75±0.20°；
    The X-ray powder diffraction pattern (XRPD) of compound B of formula (II) has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 8.11±0.20°, 14.59±0.20°, 19.11±0.20° and 21.75 ±0.20°;
  13. 根据权利要求12所述的B晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.20°、8.11±0.20°、13.89±0.20°、14.59±0.20°、15.31±0.20°、19.11±0.20°、21.75±0.20°、24.94±0.20°和25.73±0.20°。According to the B crystal form of claim 12, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 8.11±0.20°, 13.89±0.20°, 14.59±0.20°, 15.31± 0.20°, 19.11±0.20°, 21.75±0.20°, 24.94±0.20° and 25.73±0.20°.
  14. 根据权利要求13所述的B晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.20°、8.11±0.20°、13.89±0.20°、14.59±0.20°、15.31±0.20°、16.62±0.20°、19.11±0.20°、21.75±0.20°、22.23±0.20°、24.94±0.20°、25.73±0.20°、26.22±0.20°、27.88±0.20°。According to the B crystal form of claim 13, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 8.11±0.20°, 13.89±0.20°, 14.59±0.20°, 15.31± 0.20°, 16.62±0.20°, 19.11±0.20°, 21.75±0.20°, 22.23±0.20°, 24.94±0.20°, 25.73±0.20°, 26.22±0.20°, 27.88±0.20°.
  15. 根据权利要求14所述的B晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22±0.20°、7.66±0.20°、8.11±0.20°、13.89±0.20°、14.59±0.20°、15.31±0.20°、16.62±0.20°、17.65±0.20°、18.35±0.20°、19.11±0.20°、21.75±0.20°、22.23±0.20°、24.94±0.20°、25.73±0.20°、26.22±0.20°、27.88±0.20°。According to the B crystal form of claim 14, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.22±0.20°, 7.66±0.20°, 8.11±0.20°, 13.89±0.20°, 14.59± 0.20°、15.31±0.20°、16.62±0.20°、17.65±0.20°、18.35±0.20°、19.11±0.20°、21.75±0.20°、22.23±0.20°、24.94±0.20°、25.73±0.20°、26.22± 0.20°, 27.88±0.20°.
  16. 根据权利要求15所述的B晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.22、7.66、8.11、11.34、12.21、13.89、14.59、14.84、15.31、16.20、16.62、17.44、17.65、18.35、19.11、19.84、20.43、21.75、22.23、22.46、23.50、24.36、24.94、25.73、26.22、27.43、27.88、28.72、29.14、30.11、30.64、32.04、32.87、33.46、35.89、38.78和39.28。According to the B crystal form of claim 15, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.22, 7.66, 8.11, 11.34, 12.21, 13.89, 14.59, 14.84, 15.31, 16.20, 16.62, 17.44, 17.65, 18.35, 19.11, 19.84, 20.43, 21.75, 22.23, 22.46, 23.50, 24.36, 24.94, 25.73, 26.22, 27.43, 27.88, 28.72, 29.14, 30.11, 30.64, 32. 04, 32.87, 33.46, 35.89, 38.78 and 39.28.
  17. 根据权利要求16所述的B晶型，其XRPD图谱基本如图4所示。According to the B crystal form of claim 16, its XRPD pattern is basically as shown in Figure 4.
  18. 根据权利要求12～17任意一项所述的B晶型，其差示扫描量热(DSC)曲线在153.7±3℃处具有吸热峰的峰值。According to the B crystal form according to any one of claims 12 to 17, its differential scanning calorimetry (DSC) curve has an endothermic peak at 153.7±3°C.
  19. 根据权利要求18所述的B晶型，其DSC图谱如图5所示。According to the B crystal form of claim 18, its DSC pattern is shown in Figure 5.
  20. 根据权利要求12～17任意一项所述的B晶型，其热重分析(TGA)曲线在150.0±3℃时失重达2.88％。According to the B crystal form according to any one of claims 12 to 17, its thermogravimetric analysis (TGA) curve has a weight loss of 2.88% at 150.0±3°C.
  21. 根据权利要求20所述的B晶型，其TGA图谱如图6所示。According to the B crystal form of claim 20, its TGA pattern is shown in Figure 6.
  22. 一种药物组合物，其中含有治疗有效剂量的式(I)化合物或其药学上可接受的盐或溶剂化物作为活性成份和药学上可接受的辅料；
    A pharmaceutical composition containing a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and pharmaceutically acceptable excipients;
  23. 根据权利要求22所述的药物组合物，其中所述药物组合物的剂型选自胶囊剂、颗粒剂、注射剂、丸剂、糖浆剂、散剂、膏剂、乳液、溶液、悬浮液或酊剂。The pharmaceutical composition according to claim 22, wherein the dosage form of the pharmaceutical composition is selected from the group consisting of capsules, granules, injections, pills, syrups, powders, ointments, emulsions, solutions, suspensions or tinctures.
  24. 根据权利要求22所述的药物组合物，其中所述辅料选自赋形剂、填料、粘合剂、保湿剂、崩解剂、缓溶剂、吸收加速剂、吸附剂、稀释剂、增溶剂、乳化剂、润滑剂、润湿剂、助流剂、悬浮剂、矫味剂、香料或其混合物。The pharmaceutical composition according to claim 22, wherein the auxiliary materials are selected from the group consisting of excipients, fillers, binders, humectants, disintegrants, slow solvents, absorption accelerators, adsorbents, diluents, solubilizers, Emulsifiers, lubricants, wetting agents, glidants, suspending agents, flavoring agents, fragrances or mixtures thereof.
  25. 式(Ⅰ)化合物的制备方法，其制备方法如下：
    The preparation method of the compound of formula (I) is as follows:
    其中，R1选自H、CH3、Boc、Cbz、Bn和PMB；Among them, R1 is selected from H, CH 3 , Boc, Cbz, Bn and PMB;
    1)当R1选自H时，式(Ⅰ)化合物的制备方法选自：
    1) When R 1 is selected from H, the preparation method of the compound of formula (I) is selected from:
    2)当R1选自CH3时，式(Ⅱ-3)化合物即为式(Ⅰ)化合物；2) When R 1 is selected from CH 3 , the compound of formula (II-3) is the compound of formula (I);
    3)当R1选自Boc、Cbz、Bn和PMB时，式(Ⅰ)化合物的制备方法选自：
    3) When R 1 is selected from Boc, Cbz, Bn and PMB, the preparation method of the compound of formula (I) is selected from:
    其中，所述式(Ⅱ-3)化合物的制备方法选自：Wherein, the preparation method of the compound of formula (II-3) is selected from:
    方法一包含：
    Method one includes:
    方法二包含：
    Method two includes:
    方法三包含：
    Method three includes:
    其中，in,
    R1选自H、CH3、Boc、Cbz、Bn和PMB；R 1 is selected from H, CH 3 , Boc, Cbz, Bn and PMB;
    R2选自Bn，PMB，PNB和MOM；R 2 is selected from Bn, PMB, PNB and MOM;
    R4选自CH3、MOM、Bn、SEM和Ac；R 4 is selected from CH 3 , MOM, Bn, SEM and Ac;
    R5选自F、Cl、Br、I、OTf和OCH2CF3；R 5 is selected from F, Cl, Br, I, OTf and OCH 2 CF 3 ;
    R31选自B(OH)2；、和BF3K； R 31 is selected from B(OH) 2 ;, and BF 3K ;
    R6选自F、Cl、Br和I；R 6 is selected from F, Cl, Br and I;
    R7选自Cl、Br、OTf、OCH2CF3和OTs。R 7 is selected from Cl, Br, OTf, OCH 2 CF 3 and OTs.
  26. 式(Ⅰ)化合物的制备方法，
    Preparation method of compound of formula (I),
    其包括如下步骤：It includes the following steps:
    步骤一：使化合物EE-3反应以获得化合物EE-4，
    Step 1: React compound EE-3 to obtain compound EE-4,
    步骤二：使化合物EE-4反应以获得化合物EE-5，
    Step 2: react compound EE-4 to obtain compound EE-5,
    步骤三：使化合物EE-5和化合物AA反应以获得化合物H-1，
    Step 3: React compound EE-5 and compound AA to obtain compound H-1,
    步骤四：使化合物H-1反应以获得式(Ⅰ)化合物，
    Step 4: react compound H-1 to obtain the compound of formula (I),
  27. 根据权利要求26所述式(Ⅰ)化合物的制备方法，其包含如下步骤：The preparation method of the compound of formula (I) according to claim 26, which comprises the following steps:
    步骤一：使化合物EE-3和试剂A、B反应以获得化合物EE-4，
    Step 1: React compound EE-3 with reagents A and B to obtain compound EE-4,
    步骤二：使化合物EE-4和试剂D、E、F、G反应以获得化合物EE-5，
    Step 2: React compound EE-4 with reagents D, E, F, and G to obtain compound EE-5,
    步骤三：使化合物EE-5和化合物AA与试剂I和J反应以获得化合物H-1，
    Step 3: React compound EE-5 and compound AA with reagents I and J to obtain compound H-1,
    步骤四：使化合物H-1和试剂K反应以获得式(Ⅰ)化合物，
    Step 4: React compound H-1 and reagent K to obtain the compound of formula (I),
    其中，in,
    试剂A选自氯甲醚、溴甲醚、碘甲醚和甲氧基甲基甲磺酸酯，优选氯甲醚；Reagent A is selected from the group consisting of methyl chloride, methyl bromide, methyl iodide and methoxymethyl methanesulfonate, with methyl chloride being preferred;
    试剂B选自碳酸钾、碳酸铯、碳酸钠、碳酸锂、钠氢、六甲基二硅基胺锂、六甲基二硅基胺钠、六甲基二硅基胺钾、叔丁醇钾、叔丁醇钠、氢氧化钠、氢氧化锂和氢氧化钾，优选碳酸钾；Reagent B is selected from potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen, lithium hexamethyldisilazide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium tert-butoxide , sodium tert-butoxide, sodium hydroxide, lithium hydroxide and potassium hydroxide, preferably potassium carbonate;
    溶剂C选自DMF、DCM、THF、2-MeTHF、EtOAc、i-PrOAc、NMP和二氧六环，优选DMF；Solvent C is selected from DMF, DCM, THF, 2-MeTHF, EtOAc, i-PrOAc, NMP and dioxane, preferably DMF;
    试剂D选自双联嚬哪醇硼酸酯和嚬哪醇硼烷，优选嚬哪醇硼烷；Reagent D is selected from the group consisting of zonacol borane and zonacol borane, preferably zonacol borane;
    试剂E选自Pd(dppf)Cl2、Pd(dppf)Cl2.CH2Cl2、双(乙腈)二氯化钯(II)、Pd(OAc)2和Pd2(dba)3，优选Pd(OAc)2；Reagent E is selected from Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , bis(acetonitrile)palladium(II) dichloride, Pd(OAc) 2 and Pd 2 (dba) 3 , preferably Pd (OAc) 2 ;
    试剂F选自Sphos、Xphos、XantPhos和2-(二环己基磷)联苯，优选2-(二环己基磷)联苯；Reagent F is selected from Sphos, Xphos, XantPhos and 2-(dicyclohexylphosphonium)biphenyl, preferably 2-(dicyclohexylphosphonium)biphenyl;
    试剂G选自醋酸钾、醋酸钠、TEA、DIPEA和2-乙基己酸钾，优选TEA；Reagent G is selected from potassium acetate, sodium acetate, TEA, DIPEA and potassium 2-ethylhexanoate, with TEA being preferred;
    溶剂H选自二氧六环、DMSO、DMF、NMP、DCM、THF、2-MeTHF和水，优选二氧六环；Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, preferably dioxane;
    试剂I选自Pd(OAc)2-BINAP、Pd2(dba)3-Xphos、Brettphos-Pd-G3、Pd(PPh3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2CH2Cl2和Pd(OAc)2-Sphos，优选Pd(dppf)Cl2CH2Cl2；Reagent I is selected from Pd(OAc) 2 -BINAP, Pd 2 (dba) 3 -Xphos, Brettphos-Pd-G3, Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 CH 2 Cl 2 and Pd(OAc) 2 -Sphos, preferably Pd(dppf)Cl 2 CH 2 Cl 2 ;
    试剂J选自Cs2CO3、K2CO3、Na2CO3、K3PO4、KOAc、KF和TEA，优选K2CO3；Reagent J is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , KOAc, KF and TEA, preferably K 2 CO 3 ;
    试剂K选自盐酸、氢溴酸、三氟乙酸、硫酸、甲酸、甲磺酸、苯磺酸和对甲苯磺酸，优选盐酸。Reagent K is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably hydrochloric acid.
  28. 一种式(AA)所示中间体化合物的制备方法：
    Preparation method of an intermediate compound represented by formula (AA):
    其中，in,
    R51选自F、Cl、Br和I；R 51 is selected from F, Cl, Br and I;
    R11选自CH3、Boc、Cbz、Bn和PMB。R 11 is selected from CH 3 , Boc, Cbz, Bn and PMB.
  29. 根据权利要求28所述式(AA)中间体化合物的制备方法，其中，R51选自Cl，R11选自Boc。The preparation method of the intermediate compound of formula (AA) according to claim 28, wherein R 51 is selected from Cl and R 11 is selected from Boc.
  30. 式(Ⅰ)化合物的制备方法，其制备方法选自：The preparation method of the compound of formula (I) is selected from:
    方法一包含：
    Method one includes:
    方法二包含：
    Method two includes:
    方法三包含：
    Method three includes:
    方法四包含：
    Method four includes:
    方法五包含：
    Method five includes:
    方法六包含：
    Method six includes:
    方法七包含：
    Method seven includes:
    方法八包含：
    Method eight includes:
    方法九包含：
    Method nine includes:
    方法十包含：
    Method ten includes:
    方法十一包含：
    Method 11 includes:
    方法十二包含：
    Method twelve includes:
    方法十三包含：
    Method thirteen includes:
    方法十四包含：
    Method fourteen includes:
  31. 根据权利要求1～10任意一项所述的式(I)化合物A晶型、权利要求11所述的式(Ⅱ)化合物、权利要求12～21任意一项所述的式(Ⅱ)化合物B晶型、权利要求22～24任意一项所述的药物组合物或权利要求25～30任意一项所述的制备方法在制备治疗与NLRP3炎性小体相关疾病的药物中的应用。The crystal form of compound A of formula (I) according to any one of claims 1 to 10, the compound of formula (II) according to claim 11, and the compound B of formula (II) according to any one of claims 12 to 21 The application of the crystal form, the pharmaceutical composition according to any one of claims 22 to 24, or the preparation method according to any one of claims 25 to 30 in the preparation of drugs for the treatment of diseases related to NLRP3 inflammasome.
  32. 根据权利要求31所述的应用，其中所述与NLRP3炎性小体相关疾病，选自NLRP3炎性小体相关神经炎症性疾病(如脑部炎症、脑损伤)和神经退行性疾病(如帕金森疾病、阿尔兹海默病、多发性硬化)。 The application according to claim 31, wherein the NLRP3 inflammasome-related diseases are selected from the group consisting of NLRP3 inflammasome-related neuroinflammatory diseases (such as brain inflammation, brain injury) and neurodegenerative diseases (such as Parkinson's disease). Alzheimer's disease, multiple sclerosis).
PCT/CN2023/110617 2022-08-01 2023-08-01 Crystal form, salt type and composition of pyridazine compound and preparation method therefor WO2024027723A1 (en)

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WO2022135567A1 (en) * 2020-12-25 2022-06-30 上海拓界生物医药科技有限公司 Pyridazine-containing compound and medicinal use thereof
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