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WO2023202706A1 - Salt form and crystal form of selenium heterocyclic compound and application thereof - Google Patents

Salt form and crystal form of selenium heterocyclic compound and application thereof Download PDF

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Publication number
WO2023202706A1
WO2023202706A1 PCT/CN2023/089796 CN2023089796W WO2023202706A1 WO 2023202706 A1 WO2023202706 A1 WO 2023202706A1 CN 2023089796 W CN2023089796 W CN 2023089796W WO 2023202706 A1 WO2023202706 A1 WO 2023202706A1
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Prior art keywords
crystal form
compound
formula
present
xrpd
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French (fr)
Chinese (zh)
Inventor
郭强
郑学建
王伟军
钱文远
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Medshine Discovery Inc
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Medshine Discovery Inc
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

  • the present invention relates to salt forms and crystal forms of selenium heterocyclic compounds and their applications. Specifically, it relates to the crystal form of the compound of formula (I), each salt form and the crystal form of the salt form.
  • IBD Inflammatory bowel disease
  • CD Crohn's disease
  • UC ulcerative colitis
  • Common symptoms include diarrhea, bloody stools, and abdominal pain.
  • the clinical course proceeds by punctuated cycles of exacerbations and remissions, and patients with ulcerative colitis are at increased risk for colorectal cancer (Dennis et al. N Engl J Med, 2011, 365, 1713-1725).
  • the excessive inflammatory response in the gastrointestinal tract is mediated by inflammatory cytokines (such as TNF ⁇ , IFN- ⁇ , IL-1, IL-6, IL-12, IL-21 and IL-23) and is important for congenital and Cells of the adaptive immune system act on T and B lymphocytes, epithelial cells, macrophages, and dendritic cells (Neurath, M.F. Nat. Rev. Immunol. 2014, 14, 329).
  • the Janus kinase (JAK) family: JAK1, JAK2, JAK3 and Tyk2 are non-receptor tyrosine kinases that play a key role in the transduction responses of many of the above-mentioned cytokines.
  • cytokines When cytokines bind to receptors, the associated JAK homo- or heterodimers are phosphorylated and activated, allowing for subsequent recruitment, phosphorylation, and activation of signal transducers and activators of transcription (STAT) family transcription factors .
  • Phosphorylated STATs pSTATs are transported to the nucleus and induce the gene transcription of several chemokines, cytokines and proteases related to the pathogenesis of IBD.
  • ANC absolute neutrophil count
  • Infection Sandborn, WJ et al., N. Engl. J. Med. 2012, 367, 616.
  • Such AEs are consistent with those observed in patients with rheumatoid arthritis taking tovatinib and are consistent with JAK2-dependent inhibition of EPO and TPO.
  • the use of tovatinib 10 mg twice daily will increase the risk of blood clots and death, and the FDA issued a black box warning for tovatinib.
  • JAK1-selective inhibitors such as filgotinib and upadacitinib, which are currently being used in phase 3 clinical trials in CD and UC.
  • the recently approved twice-daily dose of upadacitinib for the treatment of rheumatoid arthritis also carries a boxed warning from the FDA regarding the risk of thrombosis (Upadacitinib Inserts for Use) ).
  • Another approach is to maximize intestinal tissue exposure of JAK inhibitors while avoiding possible systemic exposure.
  • JAK inhibitors Due to the regulatory effects of the JAK/STAT pathway on the immune system, systemic exposure to JAK inhibitors may have adverse systemic immunosuppressive effects. There is therefore a need to provide new JAK inhibitors that have their effects at the site of the lesion without significant systemic effects. Specifically, it has advantages in treating gastrointestinal inflammatory diseases such as UC and CD.
  • the present invention provides the A crystal form of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 9.33 ⁇ 0.20°. , 16.22 ⁇ 0.20° and 22.84 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned A crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.33 ⁇ 0.20°, 14.08 ⁇ 0.20°, 16.22 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.47 ⁇ 0.20°, 20.10 ⁇ 0.20°, 20.10 ⁇ 0.20° and 22.84 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned crystal form A is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.05 ⁇ 0.10°, 9.33 ⁇ 0.10°, 12.95 ⁇ 0.10°, 14.08 ⁇ 0.10°, 16.22 ⁇ 0.10°, 16.74 ⁇ 0.10°, 17.47 ⁇ 0.10°, 19.26 ⁇ 0.10°, 19.81 ⁇ 0.10°, 20.10 ⁇ 0.10°, 21.04 ⁇ 0.10° and 22.84 ⁇ 0.10°.
  • XRPD X-ray powder diffraction
  • the above-mentioned A crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.33 ⁇ 0.10°, 16.22 ⁇ 0.10°, and/or 22.84 ⁇ 0.10°, and/or 9.05 ⁇ 0.10°, and/or 10.57 ⁇ 0.10°, and/or 10.90 ⁇ 0.10°, and/or 11.85 ⁇ 0.10°, and/or 12.48 ⁇ 0.10 °, and/or 12.95 ⁇ 0.10°, and/or 13.24 ⁇ 0.10°, and/or 13.62 ⁇ 0.10°, and/or 14.08 ⁇ 0.10°, and/or 15.34 ⁇ 0.10°, and/or 16.03 ⁇ 0.10°, and/or 16.74 ⁇ 0.10°, and/or 17.47 ⁇ 0.10°, and/or 18.56 ⁇ 0.10°, and/or 19.06 ⁇ 0.10°, and/or 19.26 ⁇ 0.10°, and/
  • the XRPD pattern of the above-mentioned crystal form A is shown in Figure 1.
  • the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak starting point at 216.01 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned crystal form A is shown in Figure 2.
  • the TGA spectrum of the above-mentioned crystal form A is shown in Figure 3.
  • the present invention provides the B crystal form of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 9.47 ⁇ 0.20°. , 16.36 ⁇ 0.20° and 22.95 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned B crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.47 ⁇ 0.20°, 16.36 ⁇ 0.20°, 16.81 ⁇ 0.20°, 19.34 ⁇ 0.20°, 20.08 ⁇ 0.20°, 22.95 ⁇ 0.20°, 25.93 ⁇ 0.20° and 28.10 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned B crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.47 ⁇ 0.20°, 12.60 ⁇ 0.20°, 13.02 ⁇ 0.20°, 16.36 ⁇ 0.20°, 16.81 ⁇ 0.20°, 18.68 ⁇ 0.20°, 19.34 ⁇ 0.20°, 20.08 ⁇ 0.20°, 22.95 ⁇ 0.20°, 25.93 ⁇ 0.20°, 27.51 ⁇ 0.20° and 28.10 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned B crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.47 ⁇ 0.10°, 16.36 ⁇ 0.10°, and/or 22.95 ⁇ 0.10°, and/or 10.61 ⁇ 0.10°, and/or 11.01 ⁇ 0.10°, and/or 11.99 ⁇ 0.10°, and/or 12.60 ⁇ 0.10°, and/or 13.02 ⁇ 0.10 °, and/or 14.13 ⁇ 0.10°, and/or 15.41 ⁇ 0.10°, and/or 16.36 ⁇ 0.10°, and/or 16.81 ⁇ 0.10°, and/or 18.68 ⁇ 0.10°, and/or 19.34 ⁇ 0.10°, and/or 20.08 ⁇ 0.10°, and/or 20.62 ⁇ 0.10°, and/or 20.95 ⁇ 0.10°, and/or 21.23 ⁇ 0.10°, and/or 22.02 ⁇ 0.1
  • the XRPD pattern of the above-mentioned Form B is 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 starting point at 217.39 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned B crystal form is shown in Figure 5.
  • the TGA spectrum of the above-mentioned B crystal form is shown in Figure 6.
  • the present invention provides the C crystal form of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 7.42 ⁇ 0.20° , 16.24 ⁇ 0.20° and 22.84 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned C crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.42 ⁇ 0.20°, 9.37 ⁇ 0.20°, 16.24 ⁇ 0.20°, 16.74 ⁇ 0.20°, 19.15 ⁇ 0.20°, 19.96 ⁇ 0.20°, 22.84 ⁇ 0.20° and 23.55 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned C crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.42 ⁇ 0.20°, 9.37 ⁇ 0.20°, 12.91 ⁇ 0.20°, 13.39 ⁇ 0.20°, 16.24 ⁇ 0.20°, 16.74 ⁇ 0.20°, 18.80 ⁇ 0.20°, 19.15 ⁇ 0.20°, 19.96 ⁇ 0.20°, 22.84 ⁇ 0.20°, 23.55 ⁇ 0.20° and 27.99 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned C crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.42 ⁇ 0.10°, 16.24 ⁇ 0.10° and/or 22.84 ⁇ 0.10°, and/or 9.37 ⁇ 0.10°, and/or 10.89 ⁇ 0.10°, and/or 12.49 ⁇ 0.10°, and/or 12.91 ⁇ 0.10°, and/or 13.39 ⁇ 0.10° , and/or 14.02 ⁇ 0.10°, and/or 14.56 ⁇ 0.10°, and/or 14.74 ⁇ 0.10°, and/or 15.36 ⁇ 0.10°, and/or 16.74 ⁇ 0.10°, and/or 17.75 ⁇ 0.10°, and /or 18.80 ⁇ 0.10°, and/or 19.15 ⁇ 0.10°, and/or 19.96 ⁇ 0.10°, and/or 20.54 ⁇ 0.10°, and/or 22.46 ⁇ 0.10°,
  • the differential scanning calorimetry curve of the above-mentioned crystal form C has an endothermic peak starting point at 52 ⁇ 3°C, 127 ⁇ 3°C, and 212 ⁇ 3°C.
  • the DSC pattern of the above-mentioned C crystal form is shown in Figure 8.
  • thermogravimetric analysis (TGA) curve of the above-mentioned C crystal form has a weight loss of 1.821% between 25 ⁇ 3°C and 65 ⁇ 3°C; and a weight loss of 1.971% between 68 ⁇ 3°C and 115 ⁇ 3°C. %.
  • the present invention provides the D crystal form of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 16.19 ⁇ 0.20°. , 18.04 ⁇ 0.20° and 22.31 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned D crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 16.19 ⁇ 0.20°, 17.60 ⁇ 0.20°, 18.04 ⁇ 0.20°, 18.76 ⁇ 0.20°, 20.21 ⁇ 0.20°, 21.02 ⁇ 0.20°, 22.31 ⁇ 0.20° and 24.36 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned D crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 12.67 ⁇ 0.10°, 15.82 ⁇ 0.10°, 16.19 ⁇ 0.10°, 17.60 ⁇ 0.10°, 18.04 ⁇ 0.10°, 18.76 ⁇ 0.10°, 19.98 ⁇ 0.10°, 20.21 ⁇ 0.10°, 21.02 ⁇ 0.10°, 22.31 ⁇ 0.10°, 23.61 ⁇ 0.10° and 24.36 ⁇ 0.10°.
  • XRPD X-ray powder diffraction
  • the above-mentioned D crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 16.19 ⁇ 0.10°, 18.04 ⁇ 0.10° and/or 22.31 ⁇ 0.10°, and/or 9.26 ⁇ 0.10°, and/or 11.42 ⁇ 0.10°, and/or 12.08 ⁇ 0.10°, and/or 12.67 ⁇ 0.10°, and/or 13.42 ⁇ 0.10°, and/or 14.76 ⁇ 0.10°, and/or 15.82 ⁇ 0.10°, and/or 16.58 ⁇ 0.10°, and/or 17.60 ⁇ 0.10°, and/or 18.76 ⁇ 0.10°, and/or 19.30 ⁇ 0.10°, and/or 19.98 ⁇ 0.10°, and/or 20.21 ⁇ 0.10°, and/or 21.02 ⁇ 0.10° , and/or 21.76 ⁇ 0.10°, and/or 23.21 ⁇ 0.10°
  • the differential scanning calorimetry curve of the above-mentioned crystal form D has an endothermic peak starting point at 143 ⁇ 3°C, 153 ⁇ 3°C, and 211 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned crystal form D is as shown in Figure 11.
  • thermogravimetric analysis (TGA) curve of the above-mentioned D crystal form has a weight loss of 13.345% between 100 ⁇ 3°C and 186 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned D crystal form is shown in Figure 12.
  • the present invention provides the E crystal form of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 7.36 ⁇ 0.20°. , 13.35 ⁇ 0.20° and 22.40 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned E crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.36 ⁇ 0.20°, 9.39 ⁇ 0.20°, 13.35 ⁇ 0.20°, 14.69 ⁇ 0.20°, 18.12 ⁇ 0.20°, 19.09 ⁇ 0.20°, 22.40 ⁇ 0.20° and 23.50 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned E crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.36 ⁇ 0.10°, 9.39 ⁇ 0.10°, 13.35 ⁇ 0.10°, 14.44 ⁇ 0.10°, 14.69 ⁇ 0.10°, 17.68 ⁇ 0.10°, 18.12 ⁇ 0.10°, 18.82 ⁇ 0.10°, 19.09 ⁇ 0.10°, 19.90 ⁇ 0.10°, 22.40 ⁇ 0.10° and 23.50 ⁇ 0.10°.
  • XRPD X-ray powder diffraction
  • the above-mentioned E crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2 ⁇ angles of 7.36 ⁇ 0.10° and 13.35 ⁇ 0.10° and/or 22.40 ⁇ 0.10°, and/or 5.17 ⁇ 0.10°, and/or 8.82 ⁇ 0.10°, and/or 9.39 ⁇ 0.10°, and/or 11.16 ⁇ 0.10°, and/or 11.60 ⁇ 0.10°, and/or 14.44 ⁇ 0.10°, and/or 14.69 ⁇ 0.10°, and/or 15.84 ⁇ 0.10°, and/or 17.68 ⁇ 0.10°, and/or 18.12 ⁇ 0.10°, and/or 18.82 ⁇ 0.10°, and/or or 19.09 ⁇ 0.10°, and/or 19.59 ⁇ 0.10°, and/or 19.90 ⁇ 0.10°, and/or 20.99 ⁇ 0.10°, and/or 21.41 ⁇ 0.10°, and/or
  • the XRPD spectrum analysis data of the above-mentioned E crystal form is shown in Table 5.
  • the differential scanning calorimetry curve of the above-mentioned E crystal form has an endothermic peak starting point at 72 ⁇ 3°C, 98 ⁇ 3°C, and 217 ⁇ 3°C; There is an exothermic peak starting point at each of the three locations °C.
  • thermogravimetric analysis (TGA) curve of the above-mentioned E crystal form loses 7.172% of weight between 66 ⁇ 3°C and 125 ⁇ 3°C.
  • the present invention provides the F crystal form of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 7.35 ⁇ 0.20°. , 7.84 ⁇ 0.20° and 19.09 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned F crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.35 ⁇ 0.20°, 7.84 ⁇ 0.20°, 17.02 ⁇ 0.20°, 17.87 ⁇ 0.20°, 19.09 ⁇ 0.20°, 20.00 ⁇ 0.20°, 22.84 ⁇ 0.20° and 23.57 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the above-mentioned F crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.35 ⁇ 0.10°, 7.84 ⁇ 0.10°, 9.94 ⁇ 0.10°, 13.87 ⁇ 0.10°, 15.86 ⁇ 0.10°, 17.02 ⁇ 0.10°, 17.87 ⁇ 0.10°, 19.09 ⁇ 0.10°, 20.00 ⁇ 0.10°, 22.29 ⁇ 0.10°, 22.84 ⁇ 0.10° and 23.57 ⁇ 0.10°.
  • XRPD X-ray powder diffraction
  • the above-mentioned F crystal form is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.35 ⁇ 0.10°, 7.84 ⁇ 0.10° and/or 19.09 ⁇ 0.10°, and/or 9.45 ⁇ 0.10°, and/or 9.94 ⁇ 0.10°, and/or 13.15 ⁇ 0.10°, and/or 13.70 ⁇ 0.10°, and/or 13.87 ⁇ 0.10° , and/or 14.50 ⁇ 0.10°, and/or 14.75 ⁇ 0.10°, and/or 15.86 ⁇ 0.10°, and/or 17.02 ⁇ 0.10°, and/or 17.87 ⁇ 0.10°, and/or 18.43 ⁇ 0.10°, and /or 20.00 ⁇ 0.10°, and/or 22.29 ⁇ 0.10°, and/or 22.84 ⁇ 0.10°, and/or 23.57 ⁇ 0.10°, and/or 24.54 ⁇ 0.10°
  • thermogravimetric analysis (TGA) curve of the above-mentioned F crystal form has a weight loss of 2.661% between 23 ⁇ 3°C and 55 ⁇ 3°C; a weight loss of 2.629% between 57 ⁇ 3°C and 100 ⁇ 3°C. .
  • the present invention provides salts of compounds of formula (I),
  • the salts are succinate, citrate, maleate, fumarate, L-tartrate, L-malate, oxalate, sulfate, hydrochloride, phosphate and Lactate.
  • the salt of the above-mentioned compound of formula (I) is selected from the group consisting of succinate, hydrochloride and L-tartrate.
  • the salt of the above-mentioned compound of formula (I) is selected from succinate.
  • the molar ratio of the compound of formula (I) to succinic acid is 1:0 to 1.1, and further preferably 1:0.25 to succinic acid. 1.05, more preferably 1:0.50-1.03, most preferably 1:1 or 1:1.02.
  • the salt of the above-mentioned compound of formula (I) is selected from citrate.
  • the molar ratio of the compound of formula (I) to citric acid is 1:0 ⁇ 1, and further preferably is 1:0.25 ⁇ 1, more preferably 1:0.50-1, most preferably 1:1 or 1:0.85.
  • the salt of the above-mentioned compound of formula (I) is selected from maleate, and the molar ratio of the compound of formula (I) to maleic acid is preferably 1:0-2, and further preferably 1: 0.25 ⁇ 2, more preferably 1:0.50 ⁇ 2, most preferably 1:1, 1:1.05, 1:1.98 or 1:2.
  • the salt of the above-mentioned compound of formula (I) is selected from fumarate, and the molar ratio of the compound of formula (I) to fumaric acid is preferably 1:0-1, and further preferably 1: 0.25 ⁇ 1, more preferably 1:0.50 ⁇ 1, most preferably 1:1, 1:0.93 or 1:0.87.
  • the salt of the above-mentioned compound of formula (I) is selected from L-tartrate, and the molar ratio of the compound of formula (I) to L-tartaric acid is preferably 1:0-1, and further preferably 1: 0.25 ⁇ 1, more preferably 1:0.50 ⁇ 1, most preferably 1:1, 1:0.99 or 1:1.07.
  • the salt of the above-mentioned compound of formula (I) is selected from hydrochloride.
  • the molar ratio of the compound of formula (I) to hydrochloric acid is preferably 1:0-1, and further preferably 1:0.25-1 , more preferably 1:0.50-1, most preferably 1:1, 1:0.87 or 1:0.88.
  • the salt of the above-mentioned compound of formula (I) is selected from lactate, and the molar ratio of the compound of formula (I) to lactic acid is preferably 1:0-1, and further preferably 1:0.25-1 , more preferably 1:0.50-1, most preferably 1:1 or 1:0.92.
  • the salt of the above-mentioned compound of formula (I) is selected from L-malate, preferably the molar ratio of the compound of formula (I) to L-tartrate is 1:0-1, and further preferably 1:0.25 ⁇ 1, more preferably 1:0.50 ⁇ 1, most preferably 1:1 or 1:1.02.
  • the present invention provides A crystal form of compound L-tartrate of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 12.79 ⁇ 0.20°, 17.40 ⁇ 0.20° and 19.07 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the A crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 7.82 ⁇ 0.20°, 12.79 ⁇ 0.20°, 17.40 ⁇ 0.20°, 18.19 ⁇ 0.20°, 19.07 ⁇ 0.20°, 19.54 ⁇ 0.20°, 22.58 ⁇ 0.20° and 23.56 ⁇ 0.20°.
  • the A crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 7.82 ⁇ 0.20°, 11.54 ⁇ 0.20°, 12.26 ⁇ 0.20°, 12.79 ⁇ 0.20°, 13.24 ⁇ 0.20°, 17.40 ⁇ 0.20°, 18.19 ⁇ 0.20°, 19.07 ⁇ 0.20°, 19.54 ⁇ 0.20°, 22.58 ⁇ 0.20°, 23.56 ⁇ 0.20° and 24.66 ⁇ 0.20°.
  • the A crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the crystal form
  • the X-ray powder diffraction (XRPD) pattern of the type has characteristic diffraction peaks at the following 2 ⁇ angles: 12.79 ⁇ 0.10°, 17.40 ⁇ 0.10° and 19.07 ⁇ 0.10°, and/or 6.62 ⁇ 0.10°, and/or 7.82 ⁇ 0.10°.
  • the XRPD pattern of the crystal form A of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 18.
  • the differential scanning calorimetry curve of the crystal form A of the L-tartrate salt of the above-mentioned compound of formula (I) has an endothermic peak starting point at 186 ⁇ 3°C.
  • the DSC spectrum of the crystal form A of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 19.
  • the TGA spectrum of crystal form A of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 20.
  • the present invention provides the B crystal form of compound L-tartrate of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 17.53 ⁇ 0.20°, 18.37 ⁇ 0.20° and 19.44 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 6.72 ⁇ 0.20°, 8.10 ⁇ 0.20°, 12.49 ⁇ 0.20°, 12.99 ⁇ 0.20°, 17.53 ⁇ 0.20°, 18.37 ⁇ 0.20°, 19.44 ⁇ 0.20° and 20.02 ⁇ 0.20°.
  • the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 6.72 ⁇ 0.20°, 8.10 ⁇ 0.20°, 12.49 ⁇ 0.20°, 12.99 ⁇ 0.20°, 13.44 ⁇ 0.20°, 17.53 ⁇ 0.20°, 18.37 ⁇ 0.20°, 19.44 ⁇ 0.20°, 20.02 ⁇ 0.20°, 20.97 ⁇ 0.20°, 23.16 ⁇ 0.20° and 28.00 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 6.72 ⁇ 0.10°, 8.10 ⁇ 0.10°, 12.49 ⁇ 0.10°, 12.99 ⁇ 0.10°, 13.44 ⁇ 0.10°, 17.53 ⁇ 0.10°, 18.37 ⁇ 0.10°, 19.44 ⁇ 0.10°, 20.02 ⁇ 0.10°, 20.26 ⁇ 0.10°, 20.97 ⁇ 0.10°, 23.16 ⁇ 0.10°, 23.39 ⁇ 0.10°, 25.25 ⁇ 0.10° and 28.00 ⁇ 0.10°.
  • XRPD X-ray powder diffraction
  • the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 17.53 ⁇ 0.10°, 18.37 ⁇ 0.10° and/or 19.44 ⁇ 0.10°, and/or 3.96 ⁇ 0.10°, and/or 6.72 ⁇ 0.10°, and/or 8.10 ⁇ 0.10°, and/or 9.97 ⁇ 0.10°, and/or 11.21 ⁇ 0.10°, and/or 11.45 ⁇ 0.10°, and/or 11.70 ⁇ 0.10°, and/or 12.49 ⁇ 0.10°, and/or 12.99 ⁇ 0.10°, and/or 13.44 ⁇ 0.10° , and/or 13.70 ⁇ 0.10°, and/or 15.38 ⁇ 0.10°, and/or 16.04 ⁇ 0.10°, and/or 16.24 ⁇ 0.10°, and/or 16.92 ⁇ 0.10
  • the XRPD pattern of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 21.
  • the XRPD spectrum analysis data of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Table 8.
  • the differential scanning calorimetry curve of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) has an endothermic peak starting point at 38 ⁇ 3°C and 199 ⁇ 3°C.
  • the DSC spectrum of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 22.
  • thermogravimetric analysis curve (TGA) of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) loses 4.094% between 25 ⁇ 3°C and 115 ⁇ 3°C.
  • the TGA spectrum of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 23.
  • the present invention provides the C crystal form of compound L-tartrate of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 16.21 ⁇ 0.20°, 16.68 ⁇ 0.20° and 22.84 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle Characteristic diffraction peaks: 9.05 ⁇ 0.10°, 9.32 ⁇ 0.10°, 16.21 ⁇ 0.10°, 16.68 ⁇ 0.10°, 19.99 ⁇ 0.10°, 20.59 ⁇ 0.10°, 22.84 ⁇ 0.10° and 28.05 ⁇ 0.10°.
  • the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle Characteristic diffraction peaks: 16.21 ⁇ 0.10°, 16.68 ⁇ 0.10° and/or 22.84 ⁇ 0.10°, and/or 9.05 ⁇ 0.10°, and/or 9.32 ⁇ 0.10°, and/or 12.44 ⁇ 0.10°, and/or 13.99 ⁇ 0.10°, and/or 17.42 ⁇ 0.10°, and/or 19.99 ⁇ 0.10°, and/or 20.59 ⁇ 0.10°, and/or 28.05 ⁇ 0.10°.
  • XRPD X-ray powder diffraction
  • the XRPD pattern of the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 24.
  • the XRPD spectrum analysis data of the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Table 9.
  • the differential scanning calorimetry curve of the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) has an endothermic peak at 64 ⁇ 3°C and 189 ⁇ 3°C.
  • the DSC spectrum of the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 25.
  • the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) has a thermogravimetric analysis (TGA) weight loss of 3.158% between 25 ⁇ 3°C and 117 ⁇ 3°C; The weight loss is 6.609% between °C and 213 ⁇ 3°C.
  • TGA thermogravimetric analysis
  • the TGA spectrum of the C crystal form of the compound L-tartrate of the above formula (I) is shown in Figure 26.
  • the present invention provides A crystal form of compound L-malate of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles : 16.01 ⁇ 0.20°, 23.61 ⁇ 0.20° and 24.77 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the A crystal form of the L-malate compound of the above formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form is at the following 2 ⁇ angle It has characteristic diffraction peaks: 12.08 ⁇ 0.20°, 13.68 ⁇ 0.20°, 14.82 ⁇ 0.20°, 16.01 ⁇ 0.20°, 18.35 ⁇ 0.20°, 19.01 ⁇ 0.20°, 23.61 ⁇ 0.20° and 24.77 ⁇ 0.20°.
  • the A crystal form of the L-malate compound of the above formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form is at the following 2 ⁇ angle Characteristic diffraction peaks: 12.08 ⁇ 0.20°, 12.41 ⁇ 0.20°, 13.68 ⁇ 0.20°, 14.82 ⁇ 0.20°, 15.08 ⁇ 0.20°, 16.01 ⁇ 0.20°, 18.35 ⁇ 0.20°, 19.01 ⁇ 0.20°, 19.74 ⁇ 0.20°, 23.61 ⁇ 0.20°, 24.29 ⁇ 0.20° and 24.77 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the A crystal form of the L-malate compound of the above formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form is at the following 2 ⁇ angle Has characteristic diffraction peaks: 16.01 ⁇ 0.10°, 23.61 ⁇ 0.10° and/or 24.77 ⁇ 0.10°, and/or 7.38 ⁇ 0.10°, and/or 12.08 ⁇ 0.10°, and/or 12.41 ⁇ 0.10°, and/or 13.68 ⁇ 0.10°, and/or 14.82 ⁇ 0.10°, and/or 15.08 ⁇ 0.10°, and/or 18.35 ⁇ 0.10°, and/or 18.81 ⁇ 0.10°, and/or 19.01 ⁇ 0.10°, and/or 19.74 ⁇ 0.10 °, and/or 21.40 ⁇ 0.10°, and/or 21.92 ⁇ 0.10°, and/or 22.32 ⁇ 0.10°, and/or 24.29 ⁇ 0.10°, and/or 25.73 ⁇ 0.10
  • the XRPD pattern of the crystal form A of the L-malate salt of the above-mentioned compound of formula (I) is shown in Figure 27.
  • the XRPD spectrum analysis data of the crystal form A of the L-malate salt of the above-mentioned compound of formula (I) are shown in Table 10.
  • the differential scanning calorimetry curve of the crystalline form A of the L-malate salt of the above-mentioned compound of formula (I) has an endothermic peak starting point at 185 ⁇ 3°C.
  • the DSC spectrum of the crystal form A of the L-malate salt of the above-mentioned compound of formula (I) is shown in Figure 28.
  • the TGA spectrum of Form A of the compound L-malate of the above formula (I) is shown in Figure 29.
  • the present invention provides the A crystal form of the succinate of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 17.67 ⁇ 0.20°, 18.70 ⁇ 0.20° and 21.32 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the A crystal form of the succinate of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peaks: 12.65 ⁇ 0.20°, 17.00 ⁇ 0.20°, 17.67 ⁇ 0.20°, 18.70 ⁇ 0.20°, 19.31 ⁇ 0.20°, 21.32 ⁇ 0.20°, 25.55 ⁇ 0.20° and 27.61 ⁇ 0.20°.
  • the A crystal form of the succinate of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peaks: 6.84 ⁇ 0.10°, 12.65 ⁇ 0.10°, 12.91 ⁇ 0.10°, 15.95 ⁇ 0.10°, 17.00 ⁇ 0.10°, 17.67 ⁇ 0.10°, 18.70 ⁇ 0.10°, 19.31 ⁇ 0.10°, 21.32 ⁇ 0.10°, 23.58 ⁇ 0.10°, 25.55 ⁇ 0.10° and 27.61 ⁇ 0.10°.
  • XRPD X-ray powder diffraction
  • the A crystal form of the succinate of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peak: 17.67 ⁇ 0.10°, 18.70 ⁇ 0.10° and/or 21.32 ⁇ 0.10°, and/or 6.84 ⁇ 0.10°, and/or 10.95 ⁇ 0.10°, and/or 11.47 ⁇ 0.10°, and/or 11.67 ⁇ 0.10°, and/or 12.17 ⁇ 0.10°, and/or 12.65 ⁇ 0.10°, and/or or 12.91 ⁇ 0.10°, and/or 13.82 ⁇ 0.10°, and/or 15.95 ⁇ 0.10°, and/or 17.00 ⁇ 0.10°, and/or 19.31 ⁇ 0.10°, and/or 19.75 ⁇ 0.10°, and/or 20.21 ⁇ 0.10°, and/or 20.52 ⁇ 0.10°, and/or 22.39 ⁇ 0.10°, and/or 23.
  • XRPD
  • the XRPD pattern of the succinate crystal form A of the compound of formula (I) is shown in Figure 30.
  • the XRPD spectrum analysis data of the crystal form A of the succinate of the compound of formula (I) above is shown in Table 11.
  • the differential scanning calorimetry curve of the crystal form A of the succinate of the above-mentioned compound of formula (I) has an endothermic peak starting point at 103 ⁇ 3°C and 148 ⁇ 3°C.
  • the DSC spectrum of the crystal form A of the succinate of the compound of formula (I) is shown in Figure 31.
  • thermogravimetric analysis (TGA) of the crystal form A of the succinate of the compound of formula (I) above has a weight loss of 3.160% between 65 ⁇ 3°C and 130 ⁇ 3°C.
  • the TGA spectrum of Form A of the succinate of the compound of formula (I) is shown in Figure 32.
  • the present invention provides the A crystal form of the maleate salt of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder of the crystal form
  • the diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 13.13 ⁇ 0.20°, 16.60 ⁇ 0.20° and 23.61 ⁇ 0.20°.
  • the A crystal form of the maleate salt of the compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 10.63 ⁇ 0.20°, 13.13 ⁇ 0.20°, 16.60 ⁇ 0.20°, 18.35 ⁇ 0.20°, 19.47 ⁇ 0.20°, 20.10 ⁇ 0.20°, 23.61 ⁇ 0.20° and 27.14 ⁇ 0.20°.
  • the A crystal form of the maleate salt of the compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 10.63 ⁇ 0.10°, 11.77 ⁇ 0.10°, 13.13 ⁇ 0.10°, 13.57 ⁇ 0.10°, 16.35 ⁇ 0.10°, 16.60 ⁇ 0.10°, 18.35 ⁇ 0.10°, 19.47 ⁇ 0.10°, 20.10 ⁇ 0.10°, 20.50 ⁇ 0.10°, 23.61 ⁇ 0.10° and 27.14 ⁇ 0.10°.
  • XRPD X-ray powder diffraction
  • the A crystal form of the maleate salt of the compound of formula (I) is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2 ⁇ angle: Characteristic diffraction peaks: 13.13 ⁇ 0.10°, 16.60 ⁇ 0.10° and/or 23.61 ⁇ 0.10°, and/or 8.14 ⁇ 0.10°, and/or 9.05 ⁇ 0.10°, and/or 9.79 ⁇ 0.10°, and/or 10.63 ⁇ 0.10°, and/or 10.91 ⁇ 0.10°, and/or 11.77 ⁇ 0.10°, and/or 12.50 ⁇ 0.10°, and/or 13.57 ⁇ 0.10°, and/or 15.33 ⁇ 0.10°, and/or 16.35 ⁇ 0.10° , and/or 17.10 ⁇ 0.10°, and/or 18.10 ⁇ 0.10°, and/or 18.35 ⁇ 0.10°, and/or 19.18 ⁇ 0.10°, and/or 19.47 ⁇ 0.10°, and/or 20.10
  • the XRPD pattern of the maleate salt of the compound of formula (I) is shown in Figure 33.
  • the XRPD spectrum analysis data of the maleate salt of the compound of formula (I) described above is shown in Table 12.
  • the differential scanning calorimetry curves of crystal form A of the maleate salt of the above-mentioned compound of formula (I) are at 69 ⁇ 3°C, 109 ⁇ 3°C, 134 ⁇ 3°C, and 177 ⁇ 3°C. There is an origin of an endothermic peak.
  • the DSC spectrum of the maleate salt of the compound of formula (I) described above is Form A, as shown in Figure 34.
  • thermogravimetric analysis (TGA) of crystal form A of the maleate salt of the above-mentioned compound of formula (I) has a weight loss of 10.278% between 25 ⁇ 3°C and 160 ⁇ 3°C.
  • the TGA spectrum of Form A of the maleate salt of the compound of formula (I) is shown in Figure 35.
  • the present invention provides A crystal form of the hydrochloride of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 15.47 ⁇ 0.20°, 20.70 ⁇ 0.20° and 21.25 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the A crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peaks: 13.50 ⁇ 0.20°, 15.47 ⁇ 0.20°, 17.77 ⁇ 0.20°, 20.70 ⁇ 0.20°, 21.25 ⁇ 0.20°, 23.74 ⁇ 0.20°, 26.28 ⁇ 0.20° and 28.43 ⁇ 0.20°.
  • the A crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peaks: 9.42 ⁇ 0.20°, 11.37 ⁇ 0.20°, 13.50 ⁇ 0.20°, 15.47 ⁇ 0.20°, 17.77 ⁇ 0.20°, 20.70 ⁇ 0.20°, 21.25 ⁇ 0.20°, 23.74 ⁇ 0.20°, 26.28 ⁇ 0.20°, 28.43 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the A crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peak: 15.47 ⁇ 0.10°, 20.70 ⁇ 0.10° and/or 21.25 ⁇ 0.10°, and/or 9.42 ⁇ 0.10°, and/or 10.54 ⁇ 0.10°, and/or 11.37 ⁇ 0.10°, and/or 12.32 ⁇ 0.10 °, and/or 12.86 ⁇ 0.10°, and/or 13.50 ⁇ 0.10°, and/or 14.10 ⁇ 0.10°, and/or 14.97 ⁇ 0.10°, and/or 17.05 ⁇ 0.10°, and/or 17.77 ⁇ 0.10°, and/or 18.32 ⁇ 0.10°, and/or 18.63 ⁇ 0.10°, and/or 19.03 ⁇ 0.10°, and/or 19.91 ⁇ 0.10°, and/or 22.06 ⁇ 0.10°, and/or 23.
  • XRPD
  • the differential scanning calorimetry curve of the crystal form A of the hydrochloride of the compound of formula (I) has an endothermic peak starting point at 202 ⁇ 3°C; and an endothermic peak at 223 ⁇ 3°C. The starting point of the thermal peak.
  • the DSC spectrum of Form A of the hydrochloride of the compound of formula (I) is shown in Figure 37.
  • thermogravimetric analysis (TGA) of the crystal form A of the hydrochloride of the compound of formula (I) above has a weight loss of 1.510% between 21 ⁇ 3°C and 85 ⁇ 3°C.
  • TGA spectrum of Form A of the hydrochloride of the compound of formula (I) is shown in Figure 38.
  • the present invention provides the B crystal form of the hydrochloride of the compound of formula (I), which is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 13.48 ⁇ 0.20°, 20.70 ⁇ 0.20° and 21.18 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the B crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peaks: 9.37 ⁇ 0.20°, 11.34 ⁇ 0.20°, 13.48 ⁇ 0.20°, 18.31 ⁇ 0.20°, 19.93 ⁇ 0.20°, 20.70 ⁇ 0.20°, 21.18 ⁇ 0.20° and 28.40 ⁇ 0.20°.
  • the B crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peaks: 9.37 ⁇ 0.20°, 11.34 ⁇ 0.20°, 13.48 ⁇ 0.20°, 15.83 ⁇ 0.20°, 17.70 ⁇ 0.20°, 18.31 ⁇ 0.20°, 19.93 ⁇ 0.20°, 21.18 ⁇ 0.20°, 22.84 ⁇ 0.20°, 27.28 ⁇ 0.20° and 28.40 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the B crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2 ⁇ angles Diffraction peaks: 13.48 ⁇ 0.10°, 20.70 ⁇ 0.10° and/or 21.18 ⁇ 0.10°, and/or 7.87 ⁇ 0.10°, and/or 9.37 ⁇ 0.10°, and/or 10.58 ⁇ 0.10°, and/or 11.34 ⁇ 0.10 °, and/or 15.83 ⁇ 0.10°, and/or 17.04 ⁇ 0.10°, and/or 17.70 ⁇ 0.10°, and/or 18.31 ⁇ 0.10°, and/or 19.04 ⁇ 0.10°, and/or 19.93 ⁇ 0.10°, and/or 22.84 ⁇ 0.10°, and/or 23.39 ⁇ 0.10°, and/or 23.85 ⁇ 0.10°, and/or 25.45 ⁇ 0.10°, and/or 26.00 ⁇ 0.10°, and
  • the XRPD pattern of the hydrochloride form B of the compound of formula (I) is shown in Figure 39.
  • the differential scanning calorimetry curve of the B crystal form of the hydrochloride of the compound of formula (I) has an endothermic peak starting point at 61 ⁇ 3°C and 188 ⁇ 3°C.
  • the DSC spectrum of the B crystal form of the hydrochloride of the compound of formula (I) is shown in Figure 40.
  • the B crystal form of the hydrochloride of the compound of formula (I) has a thermogravimetric analysis (TGA) weight loss of 4.642% between 20 ⁇ 3°C and 118 ⁇ 3°C; The weight loss is 6.938% between 214 ⁇ 3°C.
  • TGA thermogravimetric analysis
  • TGA spectrum of Form B of the hydrochloride of the compound of formula (I) is shown in Figure 41.
  • the invention provides methods for preparing the above various salts of the compound of formula (I):
  • the invention provides the succinate salt of the compound of formula (I) and its A crystal form, citrate, maleate, fumarate, L-tartrate and its A/B/C crystal form, L- Application of malate and its A crystal form, oxalate, sulfate, hydrochloride and its A/B crystal form, phosphate and lactate in the preparation of drugs for the treatment of JAK related diseases.
  • the present invention provides the use of crystal form A of the compound of formula (I) and crystal form B of the compound of formula (I) in the preparation of drugs for treating JAK-related diseases.
  • the invention provides the succinate salt of the compound of formula (I) and its A crystal form, citrate, maleate, fumarate, L-tartrate and its A/B/C crystal form, L- Application of malate and its A crystal form, oxalate, sulfate, hydrochloride and its A/B crystal form, phosphate and lactate in the preparation of drugs for the treatment of pan-JAK related diseases limited to the intestinal tract .
  • the present invention provides the use of the A/B/C/D/E/F crystal forms of the compound of formula (I) above in the preparation of drugs for treating JAK-related diseases.
  • the present invention provides the use of the A/B/C/D/E/F crystalline forms of the compound of formula (I) in the preparation of drugs for the treatment of pan-JAK related diseases limited to the intestinal tract.
  • the present invention also provides a method for treating pan-JAK-related diseases limited to the intestine in a subject in need, including providing an effective dose of a compound defined in any of the above technical solutions or a pharmaceutically acceptable compound thereof to the subject. salts or pharmaceutical compositions.
  • pan-JAK-related disease limited to the intestine is inflammatory bowel disease.
  • the compound of the present invention exhibits good inhibitory properties in the in vitro activity test of two kinase subtypes, JAK1 and JAK2.
  • the compounds of the present invention showed good inhibitory properties in the in vitro activity test of cell (THP1 and HT29) functional experiments.
  • the compound of the present invention shows good drug exposure levels in the small intestine and colon of rats, and has high small intestine/plasma and colon/plasma ratios, showing good tissue selectivity.
  • the compound of the present invention shows good drug exposure levels in the small intestine and colon of mice, and the compound has high small intestine/plasma and colon/plasma ratios, showing good tissue selectivity.
  • the compound of the present invention can alleviate the weight loss induced by OXA, significantly improve the disease activity index (DAI) score and the colon weight-to-length ratio at the experimental end point, and exhibit good therapeutic effects.
  • DAI disease activity index
  • its salt forms and crystal forms are stable, less affected by light, heat and humidity, have high solubility, and have broad prospects for pharmaceutical preparations.
  • 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 relative intensities of diffraction peaks can change due to preferred orientation due to factors such as crystal morphology. Where there is an influence of preferred orientation, the peak intensity changes, but the diffraction peak position of the crystal form cannot be changed. Furthermore, there may be slight errors in the position of the peaks for any given crystalline form, as is also known in the art of crystallography. For example, due to changes in temperature, movement of the sample, or calibration of the instrument when analyzing the sample, the position of the peak may move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.20°. Therefore, it is well known to those skilled in the art that when determining each crystal This error should be taken into account when constructing.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal.
  • the thermal transition temperature and melting point errors are typically within about 5°C or 3°C.
  • DSC peak or melting point This refers to the DSC peak or melting point ⁇ 5°C or ⁇ 3°C.
  • DSC provides an auxiliary method to distinguish different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary within a wider range. In addition, since the melting process of a substance is accompanied by decomposition, the melting temperature is related to the heating rate.
  • the TGA weight loss temperature may differ due to factors such as measuring instruments, measuring methods/conditions, etc. There may be an error in the weight loss temperature for any particular crystal form, which may be about ⁇ 5°C, and may be about ⁇ 3°C.
  • pharmaceutically acceptable excipients refer to inert substances that are administered together with the active ingredients and are conducive to the administration of the active ingredients, including but not limited to acceptable substances approved by the State Food and Drug Administration for use in humans or animals. (e.g. livestock) any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer agents, isotonic agents, solvents or emulsifiers.
  • acceptable substances approved by the State Food and Drug Administration for use in humans or animals.
  • livestock any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer agents, isotonic agents, solvents or emulsifiers.
  • crystalline composition refers to a mixture of the crystalline form of the compound of formula (I) of the present invention and other crystalline forms or amorphous substances or other impurities of the compound.
  • the crystalline composition of the compound of formula (I) in addition to the crystal of the compound of formula (I), also contains other crystalline forms or amorphous substances of compound 1 or other impurities.
  • composition refers to a mixture of one or more compounds of the present invention or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate the administration to an organism of the compounds of the invention.
  • Therapeutic dosages of the compounds of the present invention may be determined based, for example, on the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportions or concentrations of the compounds of the present invention in pharmaceutical compositions may not be fixed and depend on a variety of factors, including dosage, chemical properties (eg, hydrophobicity), and route of administration.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with said disease, and includes:
  • terapéuticaally effective amount means (i) treating a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying as used herein
  • An amount of a compound of the invention that is associated with the onset of one or more symptoms of a particular disease, condition or disorder An amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • 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.
  • use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, using straight solid line keys and straight dotted keys
  • use represents trans 1,4-disubstituted cyclohexane
  • use represents cis 1,4-disubstituted cyclohexane.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: DCM represents dichloromethane; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; MeOH represents methanol; TFA represents trifluoroacetic acid; TsOH represents p-toluenesulfonic acid; mp represents melting point; EtSO 3 H represents ethanesulfonic acid; MeSO 3 H represents methanesulfonic acid; ATP represents adenosine triphosphate; HEPES represents 4-hydroxyethylpiperazineethanesulfonic acid; EGTA represents ethylene glycol bis(2 -Aminoethyl ether) tetraacetic acid; MgCl 2 represents magnesium dichloride; MnCl 2 represents manganese dichloride; DTT represents dithiothreitol; DCC represents dicyclohexylcarbodiimide;
  • the DSC curve was collected by the DSC 250 model of TA Instruments.
  • the test method of the DSC 250 instrument is: accurately weigh 1-5 mg of the sample into a perforated aluminum crucible, and heat it from 25°C to the final temperature at a heating rate of 10°C/min.
  • the instrument parameters are shown in Table 16.
  • the TGA curve was collected by the TGA 550 of TA Instruments. Put an appropriate amount of sample into an aluminum crucible that has been peeled in advance, and heat it from room temperature to 300°C at a heating rate of 10°C/min.
  • the temperature program and equipment parameters of the TGA 550 instrument are shown in Table 17.
  • Test conditions Take a sample (20 ⁇ 40mg) and place it in the DVS sample tray for testing.
  • RH (%) range: 0%-95%
  • the hygroscopicity evaluation classification is as follows in Table 18:
  • ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Figure 18 XRPD pattern of crystal form A of compound L-tartrate of formula (I);
  • Figure 21 XRPD pattern of crystal form B of compound L-tartrate of formula (I);
  • Figure 30 XRPD pattern of crystal form A of the succinate of the compound of formula (I);
  • Figure 33 XRPD pattern of crystal form A of the maleate salt of the compound of formula (I);
  • Figure 36 XRPD pattern of crystal form A of the hydrochloride of the compound of formula (I);
  • Figure 40 DSC spectrum of crystal form B of the hydrochloride of the compound of formula (I);
  • Step 1 Dissolve compound 1-1 (2g, 11.56mmol) in dimethyl sulfoxide (10mL) at 25°C, add 1-2 (2.88g, 12.72mmol) and N,N-diisopropyl Ethylamine (2.99g, 23.12mmol), stirred at 100°C for 16 hours, added 200mL water to the reaction solution, and extracted with ethyl acetate (500mL ⁇ 3), the combined organic phase was sequentially washed with 0.2M hydrochloric acid aqueous solution ( 100 mL) and washed with saturated brine (200 mL). Finally, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product 1-3. MS ESI calculated value: C 18 H 23 ClN 4 O 2 [M+H] + 363, found value 363.
  • Step 2' Dissolve compound 1-4c (11g, 42.74mmol) in methanol (100mL), add palladium on carbon (0.1g, palladium content 10%) under nitrogen protection, and then replace it with hydrogen three times, at 25°C Stir for 16 hours, filter with diatomaceous earth and concentrate under reduced pressure to obtain crude product 1-4.
  • 1H NMR 400MHz, DMSO-d6) ⁇ -0.05--0.03 (s, 9H), 0.77-0.86 (t, 2H), 1.95 -1.97(s,3H),3.47-3.53(t,2H),5.06-5.08(s,1H),5.08-5.11(s,2H),5.16(s,2H).
  • Step 2 Dissolve compound 1-3 (2.5g, 6.89mmol) in dioxane (30mL), add compound 1-4 (1.64g, 7.23mmol), cesium carbonate (4.49g, 13.78mmol) and [ (2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino -1,1′-biphenyl)]palladium(II) methanesulfonate (312.28 mg, 344.49 ⁇ mol), replaced with nitrogen three times, then heated to 100°C, and stirred under nitrogen protection for 16 hours.
  • Step 3 Add selenium powder (4.39g, 54.17mmol) to ethanol (30mL) at 0-5°C, then slowly add sodium borohydride (2.38g, 62.91mmol) and stir at room temperature until solid particles Completely disappeared, add pyridine (8.57g, 108.35mmol) and compound 1-5 (3g, 5.42mmol) into the reaction solution, raise the temperature to 80°C and stir for half an hour, then slowly add 2M hydrochloric acid aqueous solution (32.50mL,), Continue stirring for half an hour. LC-MS shows that the raw materials are completely consumed.
  • Step 4 Dissolve compound 1-6 (1.4g, 2.21mmol) in ethanol (15mL) at 25°C, add 1-7 (204.07mg, 2.21mmol), and stir at 80°C for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain crude product 1-8.
  • Step 5 Dissolve compound 1-8 (1.4g, 2.08mmol) in ethyl acetate (2mL), add hydrochloric acid ethyl acetate solution (4M, 14mL), and stir at 25°C for 1 hour. The reaction liquid is directly filtered to obtain a crude hydrochloride of compound 1-9 as a filter cake. MS ESI calcd for C 20 H 25 N 7 Se [M+H] + 444, measured value 444.
  • Step 6 Dissolve the crude hydrochloride of 1-9 (0.85g, 1.65mmol) in methanol (10mL), add N,N-diisopropylethylamine (639.52mg, 4.95mmol, 862 ⁇ L), and mix the mixture in Stir at 25°C for 10 minutes, then add compound 1-10 (0.290g, 5.47mmol, 363 ⁇ L), and stir at 25°C for 16 hours.
  • Step 7 Compound 1-9 (128.6g, 290.68mmol) was dissolved in methanol (1040mL) and dimethyl sulfoxide (260mL), and diisopropylethylamine (45.08g, 348.81mmol) and acrylonitrile ( 19.37g, 365.04mmol), reacted at 20°C for 16 hours. Add 3.9L of water to the reaction solution, stir for 2 hours, and filter to obtain a filter cake. Add 145 mL of dimethyl sulfoxide to the filter cake, dissolve it at 100°C, then add 290 mL of ethanol to dilute it, and keep the system at reflux.
  • Example 8 Study on the hygroscopicity of crystal form A of the compound of formula (I)
  • the hygroscopic weight gain of crystal form A of the compound of formula (I) at 25°C and 80% RH is 0.443%, which is slightly hygroscopic.
  • the hygroscopic weight gain of the B crystal form of the compound of formula (I) at 25°C and 80% RH is 0.598%, which is slightly hygroscopic.
  • JAK1, 2, 3 and TYK2 were used method for activity detection.
  • the detection plate mix the enzyme, ULight-labeled peptide substrate, ATP, and detection compound, and incubate the reaction. After the reaction, EDTA was added to terminate the reaction, and Eu-labeled antibodies were added at the same time.
  • Eu-labeled antibodies were added at the same time.
  • kinase assays Europium-labeled anti-phosphorylated matrix antibodies bind to phosphorylated ULight-labeled matrix to bring donor and acceptor molecules closer to each other.
  • the kinase After irradiation with 320nm wavelength light, the kinase reacts, and the energy of the europium donor will be transferred to the ULight acceptor dye and generate light with a wavelength of 665nm.
  • the intensity of light emission is proportional to the phosphorylation level of the ULight matrix.
  • Final test concentration of the compound ranges from 1 ⁇ M to 0.017 nM, 3-fold gradient dilution, 11 concentrations.
  • the content of DMSO in the detection reaction is 1%.
  • Kinase detection preparation of buffer, including: 50mM HEPES (pH 7.5), 0.01% Brij-35, 10mM MgCl 2 , 1mM EDTA, 1mM DTT.
  • test compound of the present invention showed good inhibitory effect on two subtypes of kinases, JAK1 and JAK2, in the in vitro activity test.
  • test compound of the present invention showed good inhibitory properties in the in vitro activity test of cell (THP1 and HT29) functional experiments.
  • Protein precipitation Add 200 ⁇ L of acetonitrile precipitate containing internal standard to 20 ⁇ L of plasma sample, mix and centrifuge at 12,000 g and 4°C. Take 50 ⁇ L of the processed supernatant and add it to a 96-well plate. After centrifugation at 3,220 g and 4°C, the supernatant is directly subjected to LC- MS/MS analysis.
  • the compound of the present invention shows good drug exposure levels in the small intestine and colon of rats, and the compound has high small intestine/plasma and colon/plasma ratios, showing good tissue selectivity.
  • the solvent is 0.5% CMC-Na
  • the body weight and disease activity index (DAI) score of the animals were recorded every day to evaluate the disease incidence of animals in each group and the impact of the test compounds on the disease.
  • the DAI score consists of 3 parts.
  • Table 26 For specific standards, please refer to Table 26 below.
  • the compound of the present invention can alleviate the weight loss induced by OXA in the mouse enteritis model induced by oxazolone (OXA), significantly improve the disease activity index (DAI) score and the experimental endpoint colon weight-to-length ratio, showing good performance treatment effect.
  • OXA oxazolone

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Abstract

The present invention relates to a salt form and a crystal form of a selenium heterocyclic compound and to an application thereof. Specifically, the present invention relates to a crystal form, each salt form and the crystal forms of the salt forms of a compound of formula (I).

Description

硒杂环类化合物的盐型和晶型及其应用Salt forms and crystal forms of selenium heterocyclic compounds and their applications

本发明主张如下优先权申请The present invention claims the following priority application

申请号：CN202210427467.9；申请日：2022年4月21日。Application number: CN202210427467.9; Application date: April 21, 2022.

技术领域Technical field

本发明涉及硒杂环类化合物的盐型和晶型及其应用。具体涉及式(I)化合物的晶型、各盐型以及盐型的晶型。The present invention relates to salt forms and crystal forms of selenium heterocyclic compounds and their applications. Specifically, it relates to the crystal form of the compound of formula (I), each salt form and the crystal form of the salt form.

背景技术Background technique

炎症性肠病(IBD)是一种病因未明的肠道炎症疾病，包括克罗恩病(CD)和溃疡性结肠炎(UC)，其特征是直肠和大肠的粘膜层的发炎和溃疡。常见症状包含腹泻、血便和腹痛。临床过程为间断的、恶化和缓解的交替周期而进行，且患有溃疡性结肠炎的患者罹患结直肠癌的风险增加(丹尼斯等人N Engl J Med,2011,365,1713-1725)。胃肠道的过度炎症反应是由炎性细胞因子(如TNFα、IFN-γ、IL-1、IL-6、IL-12、IL-21和IL-23)介导的，且对先天性和适应性免疫系统的细胞发挥作用，包括对T和B淋巴细胞、上皮细胞、巨噬细胞和树突状细胞(Neurath,M.F.Nat.Rev.Immunol.2014,14,329)。Janus激酶(JAK)家族：JAK1、JAK2、JAK3和Tyk2，是非受体酪氨酸激酶，在许多上述的细胞因子的传导反应中起关键作用。当细胞因子与受体连接后，相关的JAK同源或异二聚体被磷酸化和激活，从而使随后的募集、磷酸化，以及信号转导和转录激活因子(STAT)家族转录因子的激活。磷酸化STATs(pSTATs)转运到细胞核并诱导与IBD发病相关的几种趋化因子、细胞因子和蛋白酶的基因转录。Inflammatory bowel disease (IBD) is an intestinal inflammatory disease of unknown etiology, including Crohn's disease (CD) and ulcerative colitis (UC), characterized by inflammation and ulceration of the mucosal lining of the rectum and large intestine. Common symptoms include diarrhea, bloody stools, and abdominal pain. The clinical course proceeds by punctuated cycles of exacerbations and remissions, and patients with ulcerative colitis are at increased risk for colorectal cancer (Dennis et al. N Engl J Med, 2011, 365, 1713-1725). The excessive inflammatory response in the gastrointestinal tract is mediated by inflammatory cytokines (such as TNFα, IFN-γ, IL-1, IL-6, IL-12, IL-21 and IL-23) and is important for congenital and Cells of the adaptive immune system act on T and B lymphocytes, epithelial cells, macrophages, and dendritic cells (Neurath, M.F. Nat. Rev. Immunol. 2014, 14, 329). The Janus kinase (JAK) family: JAK1, JAK2, JAK3 and Tyk2, are non-receptor tyrosine kinases that play a key role in the transduction responses of many of the above-mentioned cytokines. When cytokines bind to receptors, the associated JAK homo- or heterodimers are phosphorylated and activated, allowing for subsequent recruitment, phosphorylation, and activation of signal transducers and activators of transcription (STAT) family transcription factors . Phosphorylated STATs (pSTATs) are transported to the nucleus and induce the gene transcription of several chemokines, cytokines and proteases related to the pathogenesis of IBD.

IBD患者的遗传学研究发现，与JAK/STAT途径相关的几种蛋白质(如IL-23R、IL-12B、JAK2、Tyk2和STAT3)的多态性是IBD形成的危险因素。它为治疗IBD引起的过度炎症反应提供了一个有吸引力的靶点(Boland,B.S.等人，Gastroenterology clinics of North America 2014,43,603)。目前有几种JAK抑制剂，如托伐替尼(Tofacitinib)和非戈替尼(Filgotinib)正在IBD的临床开发中。托伐替尼在美国被批准用于治疗类风湿关节炎(RA)和UC。托伐替尼也在CD的临床开发中，由于中、重度CD患者在临床二期的4周临床试验中未能取得显著的疗效，该适应症的进一步试验被迫中止，尽管有基于生物标记物分析的靶点参与的确凿证据，但目前尚不清楚托伐替尼的疗效是否与临床研究设计，UC和CD之间的机制差异，或阻止药物充分暴露于肠道组织的剂量限制性全身不良事件(AE)有关。托伐替尼治疗IBD 2期和3期临床试验常见的系统性不良事件(AE)包括血红蛋白下降、中性粒细胞绝对计数(ANC)下降、总胆固醇(低密度和高密度脂)升高和感染(Sandborn,W.J.等人，N.Engl.J.Med.2012,367,616)。此类AE与类风湿关节炎患者服用托伐替尼后观察到的情况一致，并与EPO、TPO的JAK2依赖性抑制一致。根据托伐替尼上市后安全性试验的结果，使用托伐替尼10mg，每日两次给药，会增加血栓和死亡的风险，FDA对托伐替尼提出了黑框警告。 Genetic studies on IBD patients have found that polymorphisms in several proteins related to the JAK/STAT pathway (such as IL-23R, IL-12B, JAK2, Tyk2 and STAT3) are risk factors for the development of IBD. It provides an attractive target for treating the excessive inflammatory response caused by IBD (Boland, BS et al., Gastroenterology clinics of North America 2014, 43, 603). Several JAK inhibitors, such as Tofacitinib and Filgotinib, are currently in clinical development for IBD. Tofacitinib is approved in the United States for the treatment of rheumatoid arthritis (RA) and UC. Tovatinib is also in clinical development for CD. Because patients with moderate and severe CD failed to achieve significant efficacy in the 4-week clinical trial of the second phase of clinical trials, further trials for this indication were forced to be suspended, although there are biomarker-based There is conclusive evidence of target involvement in bioanalyses, but it is unclear whether the efficacy of tovatinib is related to clinical study design, mechanistic differences between UC and CD, or dose-limiting systemic limitations that prevent adequate exposure of the drug to intestinal tissue. related to adverse events (AEs). Common systemic adverse events (AEs) in Phase 2 and Phase 3 clinical trials of tovatinib in the treatment of IBD include decreases in hemoglobin, decreases in absolute neutrophil count (ANC), increases in total cholesterol (low-density and high-density lipids), and Infection (Sandborn, WJ et al., N. Engl. J. Med. 2012, 367, 616). Such AEs are consistent with those observed in patients with rheumatoid arthritis taking tovatinib and are consistent with JAK2-dependent inhibition of EPO and TPO. According to the results of tovatinib's post-marketing safety trial, the use of tovatinib 10 mg twice daily will increase the risk of blood clots and death, and the FDA issued a black box warning for tovatinib.

有几种可能的方法可以克服JAK抑制引起的系统性AE。其中一种方法是开发口服的JAK1选择性抑制剂，如非戈替尼和乌帕达西尼布(Upadacitinib)，目前正在CD和UC的第3阶段临床试验中使用这种方法。尽管JAK1选择性分子具有理论上的安全优势，最近批准的每日两次剂量为15毫克的乌帕达西尼布治疗类风湿关节炎也有来自FDA关于血栓形成风险的黑框警告(Upadacitinib使用说明书)。另一种方法是以最大限度地增加JAK抑制剂的肠道组织暴露，同时避免可能导致全身暴露。由于JAK/STAT通路对免疫系统的调节作用，全身性暴露于JAK抑制剂可能具有不利的全身免疫抑制作用。因而需要提供新的JAK抑制剂，其在病灶部位处具有其作用，同时无显著全身作用。具体来说，对治疗胃肠发炎性疾病，如UC和CD具有优势。There are several possible ways to overcome systemic AEs caused by JAK inhibition. One approach is to develop oral JAK1-selective inhibitors such as filgotinib and upadacitinib, which are currently being used in phase 3 clinical trials in CD and UC. Despite the theoretical safety advantages of the JAK1-selective molecule, the recently approved twice-daily dose of upadacitinib for the treatment of rheumatoid arthritis also carries a boxed warning from the FDA regarding the risk of thrombosis (Upadacitinib Inserts for Use) ). Another approach is to maximize intestinal tissue exposure of JAK inhibitors while avoiding possible systemic exposure. Due to the regulatory effects of the JAK/STAT pathway on the immune system, systemic exposure to JAK inhibitors may have adverse systemic immunosuppressive effects. There is therefore a need to provide new JAK inhibitors that have their effects at the site of the lesion without significant systemic effects. Specifically, it has advantages in treating gastrointestinal inflammatory diseases such as UC and CD.

发明内容Contents of the invention

本发明提供了式(I)化合物的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.33±0.20°，16.22±0.20°和22.84±0.20°。
The present invention provides the A crystal form of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 9.33±0.20°. , 16.22±0.20° and 22.84±0.20°.

本发明的一些方案中，上述A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.33±0.20°，14.08±0.20°，16.22±0.20°，16.74±0.20°，17.47±0.20°，20.10±0.20°，20.10±0.20°和22.84±0.20°。In some aspects of the present invention, the above-mentioned A crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 9.33±0.20°, 14.08 ±0.20°, 16.22±0.20°, 16.74±0.20°, 17.47±0.20°, 20.10±0.20°, 20.10±0.20° and 22.84±0.20°.

本发明的一些方案中，上述A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.05±0.10°，9.33±0.10°，12.95±0.10°，14.08±0.10°，16.22±0.10°，16.74±0.10°，17.47±0.10°，19.26±0.10°，19.81±0.10°，20.10±0.10°，21.04±0.10°和22.84±0.10°。In some aspects of the present invention, the above-mentioned crystal form A is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 9.05±0.10°, 9.33 ±0.10°, 12.95±0.10°, 14.08±0.10°, 16.22±0.10°, 16.74±0.10°, 17.47±0.10°, 19.26±0.10°, 19.81±0.10°, 20.10±0.10°, 21.04±0.10° and 22.84 ±0.10°.

本发明的一些方案中，上述A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.33±0.10°，16.22±0.10°，和/或22.84±0.10°，和/或9.05±0.10°，和/或10.57±0.10°，和/或10.90±0.10°，和/或11.85±0.10°，和/或12.48±0.10°，和/或12.95±0.10°，和/或13.24±0.10°，和/或13.62±0.10°，和/或14.08±0.10°，和/或15.34±0.10°，和/或16.03±0.10°，和/或16.74±0.10°，和/或17.47±0.10°，和/或18.56±0.10°，和/或19.06±0.10°，和/或19.26±0.10°，和/或19.81±0.10°，和/或20.10±0.10°，和/或20.52±0.10°，和/或21.04±0.10°，和/或21.54±0.10°，和/或22.01±0.10°，和/或21.54±0.10°，和/或22.01±0.10°，和/或22.44±0.10°，和/或23.56±0.10°，和/或24.19±0.10°，和/或25.16±0.10°，和/或25.33±0.10°，和/或25.79±0.10°，和/或26.18±0.10°，和/或27.42±0.10°，和/或28.01±0.10°，和/或28.55±0.10°，和/或 29.86±0.10°，和/或37.38±0.10°。In some aspects of the present invention, the above-mentioned A crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 9.33±0.10°, 16.22 ±0.10°, and/or 22.84±0.10°, and/or 9.05±0.10°, and/or 10.57±0.10°, and/or 10.90±0.10°, and/or 11.85±0.10°, and/or 12.48±0.10 °, and/or 12.95±0.10°, and/or 13.24±0.10°, and/or 13.62±0.10°, and/or 14.08±0.10°, and/or 15.34±0.10°, and/or 16.03±0.10°, and/or 16.74±0.10°, and/or 17.47±0.10°, and/or 18.56±0.10°, and/or 19.06±0.10°, and/or 19.26±0.10°, and/or 19.81±0.10°, and/or or 20.10±0.10°, and/or 20.52±0.10°, and/or 21.04±0.10°, and/or 21.54±0.10°, and/or 22.01±0.10°, and/or 21.54±0.10°, and/or 22.01 ±0.10°, and/or 22.44±0.10°, and/or 23.56±0.10°, and/or 24.19±0.10°, and/or 25.16±0.10°, and/or 25.33±0.10°, and/or 25.79±0.10 °, and/or 26.18±0.10°, and/or 27.42±0.10°, and/or 28.01±0.10°, and/or 28.55±0.10°, and/or 29.86±0.10°, and/or 37.38±0.10°.

本发明的一些方案中，上述A晶型，其XRPD图谱如附图1所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned crystal form A is 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)化合物的A晶型XRPD图谱解析数据
Table 1: XRPD spectrum analysis data of crystal form A of compound 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216.01±3℃处有一个吸热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak starting point at 216.01±3°C.

本发明的一些方案中，上述A晶型，其DSC图谱如附图2所示。In some aspects of the present invention, the DSC spectrum of the above-mentioned crystal form A is shown in Figure 2.

本发明的一些方案中，上述A晶型的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.

本发明提供了式(I)化合物的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.47±0.20°，16.36±0.20°和22.95±0.20°。
The present invention provides the B crystal form of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 9.47±0.20°. , 16.36±0.20° and 22.95±0.20°.

本发明的一些方案中，上述B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.47±0.20°，16.36±0.20°，16.81±0.20°，19.34±0.20°，20.08±0.20°，22.95±0.20°，25.93±0.20°和28.10±0.20°。In some aspects of the present invention, the above-mentioned B crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 9.47±0.20°, 16.36 ±0.20°, 16.81±0.20°, 19.34±0.20°, 20.08±0.20°, 22.95±0.20°, 25.93±0.20° and 28.10±0.20°.

本发明的一些方案中，上述B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.47±0.20°，12.60±0.20°，13.02±0.20°，16.36±0.20°，16.81±0.20°，18.68±0.20°，19.34±0.20°，20.08±0.20°，22.95±0.20°，25.93±0.20°，27.51±0.20°和28.10±0.20°。In some aspects of the present invention, the above-mentioned B crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 9.47±0.20°, 12.60 ±0.20°, 13.02±0.20°, 16.36±0.20°, 16.81±0.20°, 18.68±0.20°, 19.34±0.20°, 20.08±0.20°, 22.95±0.20°, 25.93±0.20°, 27.51±0.20° and 28.10 ±0.20°.

本发明的一些方案中，上述B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.47±0.10°，16.36±0.10°，和/或22.95±0.10°，和/或10.61±0.10°，和/或11.01±0.10°，和/或11.99±0.10°，和/或12.60±0.10°，和/或13.02±0.10°，和/或14.13±0.10°，和/或15.41±0.10°，和/或16.36±0.10°，和/或16.81±0.10°，和/或18.68±0.10°，和/或19.34±0.10°，和/或20.08±0.10°，和/或20.62±0.10°，和/或20.95±0.10°，和/或21.23±0.10°，和/或22.02±0.10°，和/或22.95±0.10°，和/或23.58±0.10°，和/或24.00±0.10°，和/或25.22±0.10°，和/或25.51±0.10°，和/或25.93±0.10°，和/或27.15±0.10°，和/或28.10±0.10°，和/或28.60±0.10°，和/或29.04±0.10°，和/或29.93±0.10°，和/或30.40±0.10°，和/或33.04±0.10°，和/或34.46±0.10°，和/或37.35±0.10°。In some aspects of the present invention, the above-mentioned B crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 9.47±0.10°, 16.36 ±0.10°, and/or 22.95±0.10°, and/or 10.61±0.10°, and/or 11.01±0.10°, and/or 11.99±0.10°, and/or 12.60±0.10°, and/or 13.02±0.10 °, and/or 14.13±0.10°, and/or 15.41±0.10°, and/or 16.36±0.10°, and/or 16.81±0.10°, and/or 18.68±0.10°, and/or 19.34±0.10°, and/or 20.08±0.10°, and/or 20.62±0.10°, and/or 20.95±0.10°, and/or 21.23±0.10°, and/or 22.02±0.10°, and/or 22.95±0.10°, and/ or 23.58±0.10°, and/or 24.00±0.10°, and/or 25.22±0.10°, and/or 25.51±0.10°, and/or 25.93±0.10°, and/or 27.15±0.10°, and/or 28.10 ±0.10°, and/or 28.60±0.10°, and/or 29.04±0.10°, and/or 29.93±0.10°, and/or 30.40±0.10°, and/or 33.04±0.10°, and/or 34.46±0.10 °, and/or 37.35±0.10°.

本发明的一些方案中，上述B晶型，其XRPD图谱如附图4所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned Form B is 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(I)化合物的B晶型XRPD图谱解析数据
Table 2: XRPD spectrum analysis data of crystal form B of compound of formula (I)

本发明的一些方案中，上述B晶型，其差示扫描量热曲线在217.39±3℃处有一个吸热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry curve of the above-mentioned B crystal form has an endothermic peak starting point at 217.39±3°C.

本发明的一些方案中，上述B晶型，其DSC图谱如附图5所示。In some aspects of the present invention, the DSC spectrum of the above-mentioned B crystal form is shown in Figure 5.

本发明的一些方案中，上述B晶型的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.

本发明提供了式(I)化合物的C晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.42±0.20°，16.24±0.20°和22.84±0.20°。
The present invention provides the C crystal form of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 7.42±0.20° , 16.24±0.20° and 22.84±0.20°.

本发明的一些方案中，上述C晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.42±0.20°，9.37±0.20°，16.24±0.20°，16.74±0.20°，19.15±0.20°，19.96±0.20°，22.84±0.20°和23.55±0.20°。In some aspects of the present invention, the above-mentioned C crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.42±0.20°, 9.37 ±0.20°, 16.24±0.20°, 16.74±0.20°, 19.15±0.20°, 19.96±0.20°, 22.84±0.20° and 23.55±0.20°.

本发明的一些方案中，上述C晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.42±0.20°，9.37±0.20°，12.91±0.20°，13.39±0.20°，16.24±0.20°，16.74±0.20°，18.80±0.20°，19.15±0.20°，19.96±0.20°，22.84±0.20°，23.55±0.20°和27.99±0.20°。In some aspects of the present invention, the above-mentioned C crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.42±0.20°, 9.37 ±0.20°, 12.91±0.20°, 13.39±0.20°, 16.24±0.20°, 16.74±0.20°, 18.80±0.20°, 19.15±0.20°, 19.96±0.20°, 22.84±0.20°, 23.55±0.20° and 27.99 ±0.20°.

本发明的一些方案中，上述C晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.42±0.10°，16.24±0.10°和/或22.84±0.10°，和/或9.37±0.10°，和/或10.89±0.10°，和/或12.49±0.10°，和/或12.91±0.10°，和/或13.39±0.10°，和/或14.02±0.10°，和/或14.56±0.10°，和/或14.74±0.10°，和/或15.36±0.10°，和/或16.74±0.10°，和/或17.75±0.10°，和/或18.80±0.10°，和/或19.15±0.10°，和/或19.96±0.10°，和/或20.54±0.10°，和/或22.46±0.10°，和/或23.55±0.10°，和/或24.70±0.10°，和/或25.40±0.10°，和/或25.81±0.10°，和/或27.10±0.10°，和/或27.43±0.10°，和/或27.99±0.10°，和/或30.30±0.10°，和/或32.93±0.10°，和/或±0.10°。In some aspects of the present invention, the above-mentioned C crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.42±0.10°, 16.24 ±0.10° and/or 22.84±0.10°, and/or 9.37±0.10°, and/or 10.89±0.10°, and/or 12.49±0.10°, and/or 12.91±0.10°, and/or 13.39±0.10° , and/or 14.02±0.10°, and/or 14.56±0.10°, and/or 14.74±0.10°, and/or 15.36±0.10°, and/or 16.74±0.10°, and/or 17.75±0.10°, and /or 18.80±0.10°, and/or 19.15±0.10°, and/or 19.96±0.10°, and/or 20.54±0.10°, and/or 22.46±0.10°, and/or 23.55±0.10°, and/or 24.70±0.10°, and/or 25.40±0.10°, and/or 25.81±0.10°, and/or 27.10±0.10°, and/or 27.43±0.10°, and/or 27.99±0.10°, and/or 30.30± 0.10°, and/or 32.93±0.10°, and/or ±0.10°.

本发明的一些方案中，上述C晶型，其XRPD图谱如附图7所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned Form C is 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(I)化合物的C晶型XRPD图谱解析数据

Table 3: XRPD spectrum analysis data of the C crystal form of the compound of formula (I)

本发明的一些方案中，上述C晶型，其差示扫描量热曲线在52±3℃、127±3℃、212±3℃三处各有一个吸热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form C has an endothermic peak starting point at 52±3°C, 127±3°C, and 212±3°C.

本发明的一些方案中，上述C晶型，其DSC图谱如附图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晶型的热重分析曲线(TGA)在25±3℃至65±3℃时失重达1.821％；在68±3℃至115±3℃之间又失重1.971％。In some solutions of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned C crystal form has a weight loss of 1.821% between 25±3°C and 65±3°C; and a weight loss of 1.971% between 68±3°C and 115±3°C. %.

本发明的一些方案中，上述C晶型的TGA图谱如图9所示。In some aspects of the present invention, the TGA spectrum of the above crystal form C is shown in Figure 9.

本发明提供了式(I)化合物的D晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：16.19±0.20°，18.04±0.20°和22.31±0.20°。
The present invention provides the D crystal form of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 16.19±0.20°. , 18.04±0.20° and 22.31±0.20°.

本发明的一些方案中，上述D晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：16.19±0.20°，17.60±0.20°，18.04±0.20°，18.76±0.20°，20.21±0.20°，21.02±0.20°，22.31±0.20°和24.36±0.20°。In some aspects of the present invention, the above-mentioned D crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 16.19±0.20°, 17.60 ±0.20°, 18.04±0.20°, 18.76±0.20°, 20.21±0.20°, 21.02±0.20°, 22.31±0.20° and 24.36±0.20°.

本发明的一些方案中，上述D晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.67±0.10°，15.82±0.10°，16.19±0.10°，17.60±0.10°，18.04±0.10°，18.76±0.10°，19.98±0.10°，20.21±0.10°，21.02±0.10°，22.31±0.10°，23.61±0.10°和24.36±0.10°。In some aspects of the present invention, the above-mentioned D crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 12.67±0.10°, 15.82 ±0.10°, 16.19±0.10°, 17.60±0.10°, 18.04±0.10°, 18.76±0.10°, 19.98±0.10°, 20.21±0.10°, 21.02±0.10°, 22.31±0.10°, 23.61±0.10° and 24.36 ±0.10°.

本发明的一些方案中，上述D晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：16.19±0.10°，18.04±0.10°和/或22.31±0.10°，和/或9.26±0.10°，和/或 11.42±0.10°，和/或12.08±0.10°，和/或12.67±0.10°，和/或13.42±0.10°，和/或14.76±0.10°，和/或15.82±0.10°，和/或16.58±0.10°，和/或17.60±0.10°，和/或18.76±0.10°，和/或19.30±0.10°，和/或19.98±0.10°，和/或20.21±0.10°，和/或21.02±0.10°，和/或21.76±0.10°，和/或23.21±0.10°，和/或23.61±0.10°，和/或23.93±0.10°，和/或24.36±0.10°，和/或25.82±0.10°，和/或25.82±0.10°，和/或27.44±0.10°，和/或27.98±0.10°，和/或28.62±0.10°，和/或29.70±0.10°，和/或30.38±0.10°，和/或31.22±0.10°，和/或32.08±0.10°，和/或32.87±0.10°，和/或32.87±0.10°，和/或33.43±0.10°，和/或33.62±0.10°，和/或34.61±0.10°，和/或35.66±0.10°，和/或36.64±0.10°，和/或38.61±0.10°。In some aspects of the present invention, the above-mentioned D crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 16.19±0.10°, 18.04 ±0.10° and/or 22.31±0.10°, and/or 9.26±0.10°, and/or 11.42±0.10°, and/or 12.08±0.10°, and/or 12.67±0.10°, and/or 13.42±0.10°, and/or 14.76±0.10°, and/or 15.82±0.10°, and/or 16.58± 0.10°, and/or 17.60±0.10°, and/or 18.76±0.10°, and/or 19.30±0.10°, and/or 19.98±0.10°, and/or 20.21±0.10°, and/or 21.02±0.10° , and/or 21.76±0.10°, and/or 23.21±0.10°, and/or 23.61±0.10°, and/or 23.93±0.10°, and/or 24.36±0.10°, and/or 25.82±0.10°, and /or 25.82±0.10°, and/or 27.44±0.10°, and/or 27.98±0.10°, and/or 28.62±0.10°, and/or 29.70±0.10°, and/or 30.38±0.10°, and/or 31.22±0.10°, and/or 32.08±0.10°, and/or 32.87±0.10°, and/or 32.87±0.10°, and/or 33.43±0.10°, and/or 33.62±0.10°, and/or 34.61± 0.10°, and/or 35.66±0.10°, and/or 36.64±0.10°, and/or 38.61±0.10°.

本发明的一些方案中，上述D晶型，其XRPD图谱如附图10所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned D crystal form is shown in Figure 10.

本发明的一些方案中，上述D晶型的XRPD图谱解析数据如表4所示。In some solutions of the present invention, the XRPD spectrum analysis data of the above-mentioned D crystal form is shown in Table 4.

表4：式(I)化合物的D晶型XRPD图谱解析数据
Table 4: XRPD spectrum analysis data of the D crystal form of the compound of formula (I)

本发明的一些方案中，上述D晶型，其差示扫描量热曲线在143±3℃、153±3℃、211±3℃三处各有一个吸热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form D has an endothermic peak starting point at 143±3°C, 153±3°C, and 211±3°C.

本发明的一些方案中，上述D晶型，其DSC图谱如附图11所示。In some aspects of the present invention, the DSC spectrum of the above-mentioned crystal form D is as shown in Figure 11.

本发明的一些方案中，上述D晶型的热重分析曲线(TGA)在100±3℃至186±3℃之间失重13.345％。In some aspects of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned D crystal form has a weight loss of 13.345% between 100±3°C and 186±3°C.

本发明的一些方案中，上述D晶型的TGA图谱如图12所示。 In some aspects of the present invention, the TGA spectrum of the above-mentioned D crystal form is shown in Figure 12.

本发明提供了式(I)化合物的E晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.36±0.20°，13.35±0.20°和22.40±0.20°。
The present invention provides the E crystal form of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 7.36±0.20°. , 13.35±0.20° and 22.40±0.20°.

本发明的一些方案中，上述E晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.36±0.20°，9.39±0.20°，13.35±0.20°，14.69±0.20°，18.12±0.20°，19.09±0.20°，22.40±0.20°和23.50±0.20°。In some aspects of the present invention, the above-mentioned E crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.36±0.20°, 9.39 ±0.20°, 13.35±0.20°, 14.69±0.20°, 18.12±0.20°, 19.09±0.20°, 22.40±0.20° and 23.50±0.20°.

本发明的一些方案中，上述E晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.36±0.10°，9.39±0.10°，13.35±0.10°，14.44±0.10°，14.69±0.10°，17.68±0.10°，18.12±0.10°，18.82±0.10°，19.09±0.10°，19.90±0.10°，22.40±0.10°和23.50±0.10°。In some aspects of the present invention, the above-mentioned E crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.36±0.10°, 9.39 ±0.10°, 13.35±0.10°, 14.44±0.10°, 14.69±0.10°, 17.68±0.10°, 18.12±0.10°, 18.82±0.10°, 19.09±0.10°, 19.90±0.10°, 22.40±0.10° and 23.50 ±0.10°.

本发明的一些方案中，上述E晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰7.36±0.10°，13.35±0.10°和/或22.40±0.10°，和/或5.17±0.10°，和/或8.82±0.10°，和/或9.39±0.10°，和/或11.16±0.10°，和/或11.60±0.10°，和/或14.44±0.10°，和/或14.69±0.10°，和/或15.84±0.10°，和/或17.68±0.10°，和/或18.12±0.10°，和/或18.82±0.10°，和/或19.09±0.10°，和/或19.59±0.10°，和/或19.90±0.10°，和/或20.99±0.10°，和/或21.41±0.10°，和/或23.50±0.10°，和/或24.40±0.10°，和/或24.73±0.10°，和/或25.39±0.10°，和/或26.67±0.10°，和/或27.02±0.10°，和/或27.38±0.10°，和/或29.77±0.10°，和/或30.35±0.10°，和/或31.01±0.10°，和/或31.95±0.10°，和/或34.32±0.10°。In some aspects of the present invention, the above-mentioned E crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles of 7.36±0.10° and 13.35± 0.10° and/or 22.40±0.10°, and/or 5.17±0.10°, and/or 8.82±0.10°, and/or 9.39±0.10°, and/or 11.16±0.10°, and/or 11.60±0.10°, and/or 14.44±0.10°, and/or 14.69±0.10°, and/or 15.84±0.10°, and/or 17.68±0.10°, and/or 18.12±0.10°, and/or 18.82±0.10°, and/or or 19.09±0.10°, and/or 19.59±0.10°, and/or 19.90±0.10°, and/or 20.99±0.10°, and/or 21.41±0.10°, and/or 23.50±0.10°, and/or 24.40 ±0.10°, and/or 24.73±0.10°, and/or 25.39±0.10°, and/or 26.67±0.10°, and/or 27.02±0.10°, and/or 27.38±0.10°, and/or 29.77±0.10 °, and/or 30.35±0.10°, and/or 31.01±0.10°, and/or 31.95±0.10°, and/or 34.32±0.10°.

本发明的一些方案中，上述E晶型，其XRPD图谱如附图13所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned E crystal form is shown in Figure 13.

本发明的一些方案中，上述E晶型的XRPD图谱解析数据如表5所示。In some aspects of the present invention, the XRPD spectrum analysis data of the above-mentioned E crystal form is shown in Table 5.

表5：式(I)化合物的E晶型XRPD图谱解析数据

Table 5: XRPD spectrum analysis data of E crystal form of compound of formula (I)

本发明的一些方案中，上述E晶型，其差示扫描量热曲线在72±3℃、98±3℃、217±3℃三处各有一个吸热峰的起始点；在116±3℃三处各有一个放热峰的起始点。In some solutions of the present invention, the differential scanning calorimetry curve of the above-mentioned E crystal form has an endothermic peak starting point at 72±3°C, 98±3°C, and 217±3°C; There is an exothermic peak starting point at each of the three locations ℃.

本发明的一些方案中，上述E晶型，其DSC图谱如附图14所示。In some aspects of the present invention, the DSC spectrum of the above-mentioned E crystal form is shown in Figure 14.

本发明的一些方案中，上述E晶型的热重分析曲线(TGA)在66±3℃至125±3℃之间失重7.172％。In some aspects of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned E crystal form loses 7.172% of weight between 66±3°C and 125±3°C.

本发明的一些方案中，上述E晶型的TGA图谱如图15所示。In some aspects of the present invention, the TGA spectrum of the above-mentioned E crystal form is shown in Figure 15.

本发明提供了式(I)化合物的F晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.35±0.20°，7.84±0.20°和19.09±0.20°。
The present invention provides the F crystal form of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 7.35±0.20°. , 7.84±0.20° and 19.09±0.20°.

本发明的一些方案中，上述F晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.35±0.20°，7.84±0.20°，17.02±0.20°，17.87±0.20°，19.09±0.20°，20.00±0.20°，22.84±0.20°和23.57±0.20°。In some aspects of the present invention, the above-mentioned F crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 7.35±0.20°, 7.84 ±0.20°, 17.02±0.20°, 17.87±0.20°, 19.09±0.20°, 20.00±0.20°, 22.84±0.20° and 23.57±0.20°.

本发明的一些方案中，上述F晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.35±0.10°，7.84±0.10°，9.94±0.10°，13.87±0.10°，15.86±0.10°，17.02±0.10°，17.87±0.10°，19.09±0.10°，20.00±0.10°，22.29±0.10°，22.84±0.10°和23.57±0.10°。In some aspects of the present invention, the above-mentioned F crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 7.35±0.10°, 7.84 ±0.10°, 9.94±0.10°, 13.87±0.10°, 15.86±0.10°, 17.02±0.10°, 17.87±0.10°, 19.09±0.10°, 20.00±0.10°, 22.29±0.10°, 22.84±0.10° and 23.57 ±0.10°.

本发明的一些方案中，上述F晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.35±0.10°，7.84±0.10°和/或19.09±0.10°，和/或9.45±0.10°，和/或9.94±0.10°，和/或13.15±0.10°，和/或13.70±0.10°，和/或13.87±0.10°，和/或14.50±0.10°，和/或14.75±0.10°，和/或15.86±0.10°，和/或17.02±0.10°，和/或17.87±0.10°，和/或18.43±0.10°，和/或20.00±0.10°，和/或 22.29±0.10°，和/或22.84±0.10°，和/或23.57±0.10°，和/或24.54±0.10°，和/或25.14±0.10°，和/或25.82±0.10°，和/或26.97±0.10°，和/或29.40±0.10°。In some aspects of the present invention, the above-mentioned F crystal form is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 7.35±0.10°, 7.84 ±0.10° and/or 19.09±0.10°, and/or 9.45±0.10°, and/or 9.94±0.10°, and/or 13.15±0.10°, and/or 13.70±0.10°, and/or 13.87±0.10° , and/or 14.50±0.10°, and/or 14.75±0.10°, and/or 15.86±0.10°, and/or 17.02±0.10°, and/or 17.87±0.10°, and/or 18.43±0.10°, and /or 20.00±0.10°, and/or 22.29±0.10°, and/or 22.84±0.10°, and/or 23.57±0.10°, and/or 24.54±0.10°, and/or 25.14±0.10°, and/or 25.82±0.10°, and/or 26.97± 0.10°, and/or 29.40±0.10°.

本发明的一些方案中，上述F晶型，其XRPD图谱如附图16所示。In some aspects of the present invention, the XRPD pattern of the above-mentioned F crystal form is shown in Figure 16.

本发明的一些方案中，上述F晶型的XRPD图谱解析数据如表6所示。In some solutions of the present invention, the XRPD spectrum analysis data of the above-mentioned F crystal form is shown in Table 6.

表6：式(I)化合物的F晶型XRPD图谱解析数据
Table 6: XRPD spectrum analysis data of the F crystal form of the compound of formula (I)

本发明的一些方案中，上述F晶型的热重分析曲线(TGA)在23±3℃至55±3℃之间失重2.661％；在57±3℃至100±3℃之间失重2.629％。In some solutions of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned F crystal form has a weight loss of 2.661% between 23±3°C and 55±3°C; a weight loss of 2.629% between 57±3°C and 100±3°C. .

本发明的一些方案中，上述F晶型的TGA图谱如图17所示。In some aspects of the present invention, the TGA spectrum of the above-mentioned F crystal form is shown in Figure 17.

本发明提供式(I)化合物的盐，
The present invention provides salts of compounds of formula (I),

其中，所述的盐为琥珀酸盐、柠檬酸盐、马来酸盐、富马酸盐、L-酒石酸盐、L-苹果酸盐、草酸盐、硫酸盐，盐酸盐、磷酸盐和乳酸盐。Wherein, the salts are succinate, citrate, maleate, fumarate, L-tartrate, L-malate, oxalate, sulfate, hydrochloride, phosphate and Lactate.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自琥珀酸盐、盐酸盐和L-酒石酸盐。In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from the group consisting of succinate, hydrochloride and L-tartrate.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自琥珀酸盐，优选式(I)化合物与琥珀酸的摩尔比为1：0～1.1，进一步优选为1：0.25～1.05，更优选为1：0.50～1.03，最优选为1：1或1：1.02。 In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from succinate. Preferably, the molar ratio of the compound of formula (I) to succinic acid is 1:0 to 1.1, and further preferably 1:0.25 to succinic acid. 1.05, more preferably 1:0.50-1.03, most preferably 1:1 or 1:1.02.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自柠檬酸盐，优选式(I)化合物与柠檬酸的摩尔比为1：0～1，进一步优选为1：0.25～1，更优选为1：0.50～1，最优选为1：1或1：0.85。In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from citrate. Preferably, the molar ratio of the compound of formula (I) to citric acid is 1:0~1, and further preferably is 1:0.25~ 1, more preferably 1:0.50-1, most preferably 1:1 or 1:0.85.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自马来酸盐，优选式(I)化合物与马来酸的摩尔比为1：0～2，进一步优选为1：0.25～2，更优选为1：0.50～2，最优选为1：1，1：1.05，1：1.98或1:2。In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from maleate, and the molar ratio of the compound of formula (I) to maleic acid is preferably 1:0-2, and further preferably 1: 0.25～2, more preferably 1:0.50～2, most preferably 1:1, 1:1.05, 1:1.98 or 1:2.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自富马酸盐，优选式(I)化合物与富马酸的摩尔比为1：0～1，进一步优选为1：0.25～1，更优选为1：0.50～1，最优选为1：1，1：0.93或1：0.87。In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from fumarate, and the molar ratio of the compound of formula (I) to fumaric acid is preferably 1:0-1, and further preferably 1: 0.25～1, more preferably 1:0.50～1, most preferably 1:1, 1:0.93 or 1:0.87.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自L-酒石酸盐，优选式(I)化合物与L-酒石酸的摩尔比为1：0～1，进一步优选为1：0.25～1，更优选为1：0.50～1，最优选为1：1，1：0.99或1：1.07。In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from L-tartrate, and the molar ratio of the compound of formula (I) to L-tartaric acid is preferably 1:0-1, and further preferably 1: 0.25～1, more preferably 1:0.50～1, most preferably 1:1, 1:0.99 or 1:1.07.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自盐酸盐，优选式(I)化合物与盐酸的摩尔比为1：0～1，进一步优选为1：0.25～1，更优选为1：0.50～1，最优选为1：1，1：0.87或1：0.88。In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from hydrochloride. The molar ratio of the compound of formula (I) to hydrochloric acid is preferably 1:0-1, and further preferably 1:0.25-1 , more preferably 1:0.50-1, most preferably 1:1, 1:0.87 or 1:0.88.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自乳酸盐，优选式(I)化合物与乳酸的摩尔比为1：0～1，进一步优选为1：0.25～1，更优选为1：0.50～1，最优选为1：1或1：0.92。In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from lactate, and the molar ratio of the compound of formula (I) to lactic acid is preferably 1:0-1, and further preferably 1:0.25-1 , more preferably 1:0.50-1, most preferably 1:1 or 1:0.92.

在本发明的一些技术方案中，上述的式(I)化合物的盐选自L-苹果酸盐，优选式(I)化合物与L-酒石酸盐的摩尔比为1：0～1，进一步优选为1：0.25～1，更优选为1：0.50～1，最优选为1：1或1：1.02。In some technical solutions of the present invention, the salt of the above-mentioned compound of formula (I) is selected from L-malate, preferably the molar ratio of the compound of formula (I) to L-tartrate is 1:0-1, and further preferably 1:0.25~1, more preferably 1:0.50~1, most preferably 1:1 or 1:1.02.

本发明提供了式(I)化合物L-酒石酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.79±0.20°，17.40±0.20°和19.07±0.20°。
The present invention provides A crystal form of compound L-tartrate of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 12.79±0.20°, 17.40±0.20° and 19.07±0.20°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.82±0.20°，12.79±0.20°，17.40±0.20°，18.19±0.20°，19.07±0.20°，19.54±0.20°，22.58±0.20°和23.56±0.20°。In some aspects of the present invention, the A crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 7.82±0.20°, 12.79±0.20°, 17.40±0.20°, 18.19±0.20°, 19.07±0.20°, 19.54±0.20°, 22.58±0.20° and 23.56±0.20°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：7.82±0.20°，11.54±0.20°，12.26±0.20°，12.79±0.20°，13.24±0.20°，17.40±0.20°，18.19±0.20°，19.07±0.20°，19.54±0.20°，22.58±0.20°，23.56±0.20°和24.66±0.20°。In some aspects of the present invention, the A crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 7.82±0.20°, 11.54±0.20°, 12.26±0.20°, 12.79±0.20°, 13.24±0.20°, 17.40±0.20°, 18.19±0.20°, 19.07±0.20°, 19.54±0.20°, 22.58 ±0.20°, 23.56±0.20° and 24.66±0.20°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶 型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.79±0.10°，17.40±0.10°和19.07±0.10°，和/或6.62±0.10°，和/或7.82±0.10°，和/或11.54±0.10°，和/或12.26±0.10°，和/或13.24±0.10°，和/或15.86±0.10°，和/或16.54±0.10°，和/或18.19±0.10°，和/或19.54±0.10°，和/或20.03±0.10°，和/或20.54±0.10°，和/或21.81±0.10°，和/或22.58±0.10°，和/或23.56±0.10°，和/或24.66±0.10°，和/或25.22±0.10°，和/或26.23±0.10°，和/或27.46±0.10°，和/或28.15±0.10°，和/或29.55±0.10°，和/或30.25±0.10°，和/或31.68±0.10°，和/或32.89±0.10°，和/或33.54±0.10°，和/或35.35±0.10°。In some aspects of the present invention, the A crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the crystal form The X-ray powder diffraction (XRPD) pattern of the type has characteristic diffraction peaks at the following 2θ angles: 12.79±0.10°, 17.40±0.10° and 19.07±0.10°, and/or 6.62±0.10°, and/or 7.82±0.10°. , and/or 11.54±0.10°, and/or 12.26±0.10°, and/or 13.24±0.10°, and/or 15.86±0.10°, and/or 16.54±0.10°, and/or 18.19±0.10°, and /or 19.54±0.10°, and/or 20.03±0.10°, and/or 20.54±0.10°, and/or 21.81±0.10°, and/or 22.58±0.10°, and/or 23.56±0.10°, and/or 24.66±0.10°, and/or 25.22±0.10°, and/or 26.23±0.10°, and/or 27.46±0.10°, and/or 28.15±0.10°, and/or 29.55±0.10°, and/or 30.25± 0.10°, and/or 31.68±0.10°, and/or 32.89±0.10°, and/or 33.54±0.10°, and/or 35.35±0.10°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的A晶型，其XRPD图谱如附图18所示。In some aspects of the present invention, the XRPD pattern of the crystal form A of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 18.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的A晶型的XRPD图谱解析数据如表7所示。In some aspects of the present invention, the XRPD spectrum analysis data of Form A of the compound L-tartrate of the above formula (I) is shown in Table 7.

表7：式(I)化合物L-酒石酸盐的A晶型XRPD图谱解析数据
Table 7: XRPD spectrum analysis data of crystal form A of compound L-tartrate of formula (I)

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的A晶型，其差示扫描量热曲线在186±3℃有一个吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the crystal form A of the L-tartrate salt of the above-mentioned compound of formula (I) has an endothermic peak starting point at 186±3°C.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的A晶型，其DSC图谱如附图19所示。In some aspects of the present invention, the DSC spectrum of the crystal form A of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 19.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的A晶型的TGA图谱如图20所示。In some embodiments of the present invention, the TGA spectrum of crystal form A of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 20.

本发明提供了式(I)化合物L-酒石酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：17.53±0.20°，18.37±0.20°和19.44±0.20°。
The present invention provides the B crystal form of compound L-tartrate of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 17.53±0.20°, 18.37±0.20° and 19.44±0.20°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.72±0.20°，8.10±0.20°，12.49±0.20°，12.99±0.20°，17.53±0.20°，18.37±0.20°，19.44±0.20°和20.02±0.20°。In some aspects of the present invention, the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 6.72±0.20°, 8.10±0.20°, 12.49±0.20°, 12.99±0.20°, 17.53±0.20°, 18.37±0.20°, 19.44±0.20° and 20.02±0.20°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.72±0.20°，8.10±0.20°，12.49±0.20°，12.99±0.20°，13.44±0.20°，17.53±0.20°，18.37±0.20°，19.44±0.20°，20.02±0.20°，20.97±0.20°，23.16±0.20°和28.00±0.20°。In some aspects of the present invention, the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 6.72±0.20°, 8.10±0.20°, 12.49±0.20°, 12.99±0.20°, 13.44±0.20°, 17.53±0.20°, 18.37±0.20°, 19.44±0.20°, 20.02±0.20°, 20.97 ±0.20°, 23.16±0.20° and 28.00±0.20°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.72±0.10°，8.10±0.10°，12.49±0.10°，12.99±0.10°，13.44±0.10°，17.53±0.10°，18.37±0.10°，19.44±0.10°，20.02±0.10°，20.26±0.10°，20.97±0.10°，23.16±0.10°，23.39±0.10°，25.25±0.10°和28.00±0.10°。In some aspects of the present invention, the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 6.72±0.10°, 8.10±0.10°, 12.49±0.10°, 12.99±0.10°, 13.44±0.10°, 17.53±0.10°, 18.37±0.10°, 19.44±0.10°, 20.02±0.10°, 20.26 ±0.10°, 20.97±0.10°, 23.16±0.10°, 23.39±0.10°, 25.25±0.10° and 28.00±0.10°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：17.53±0.10°，18.37±0.10°和/或19.44±0.10°，和/或3.96±0.10°，和/或6.72±0.10°，和/或8.10±0.10°，和/或9.97±0.10°，和/或11.21±0.10°，和/或11.45±0.10°，和/或11.70±0.10°，和/或12.49±0.10°，和/或12.99±0.10°，和/或13.44±0.10°，和/或13.70±0.10°，和/或15.38±0.10°，和/或16.04±0.10°，和/或16.24±0.10°，和/或16.92±0.10°，和/或17.89±0.10°，和/或18.61±0.10°，和/或18.90±0.10°，和/或20.02±0.10°，和/或20.26±0.10°，和/或20.97±0.10°，和/或21.47±0.10°，和/或22.49±0.10°，和/或22.79±0.10°，和/或23.16±0.10°，和/或23.39±0.10°，和/或23.81±0.10°，和/或24.14±0.10°，和/或24.80±0.10°，和/或25.25±0.10°，和/或26.02±0.10°，和/或26.25±0.10°，和/或26.86±0.10°，和/或28.00±0.10°，和/或28.23±0.10°，和/或28.72±0.10°，和/或29.96±0.10°，和/或30.43±0.10°，和/或32.42±0.10°，和/或32.88±0.10°，和/或33.08±0.10°，和/或34.06±0.10°，和/或34.94±0.10°，和/或35.52±0.10°，和/或35.90±0.10°，和/或36.31±0.10°，和/或37.25±0.10°，和/或38.36±0.10°，和/或39.08±0.10°。In some aspects of the present invention, the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 17.53±0.10°, 18.37±0.10° and/or 19.44±0.10°, and/or 3.96±0.10°, and/or 6.72±0.10°, and/or 8.10±0.10°, and/or 9.97± 0.10°, and/or 11.21±0.10°, and/or 11.45±0.10°, and/or 11.70±0.10°, and/or 12.49±0.10°, and/or 12.99±0.10°, and/or 13.44±0.10° , and/or 13.70±0.10°, and/or 15.38±0.10°, and/or 16.04±0.10°, and/or 16.24±0.10°, and/or 16.92±0.10°, and/or 17.89±0.10°, and /or 18.61±0.10°, and/or 18.90±0.10°, and/or 20.02±0.10°, and/or 20.26±0.10°, and/or 20.97±0.10°, and/or 21.47±0.10°, and/or 22.49±0.10°, and/or 22.79±0.10°, and/or 23.16±0.10°, and/or 23.39±0.10°, and/or 23.81±0.10°, and/or 24.14±0.10°, and/or 24.80± 0.10°, and/or 25.25±0.10°, and/or 26.02±0.10°, and/or 26.25±0.10°, and/or 26.86±0.10°, and/or 28.00±0.10°, and/or 28.23±0.10° , and/or 28.72±0.10°, and/or 29.96±0.10°, and/or 30.43±0.10°, and/or 32.42±0.10°, and/or 32.88±0.10°, and/or 33.08±0.10°, and /or 34.06±0.10°, and/or 34.94±0.10°, and/or 35.52±0.10°, and/or 35.90±0.10°, and/or 36.31±0.10°, and/or 37.25±0.10°, and/or 38.36±0.10°, and/or 39.08±0.10°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型，其XRPD图谱如附图21所示。In some aspects of the present invention, the XRPD pattern of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 21.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型的XRPD图谱解析数据如表8所示。In some aspects of the present invention, the XRPD spectrum analysis data of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Table 8.

表8：式(I)化合物L-酒石酸盐的B晶型XRPD图谱解析数据
Table 8: XRPD spectrum analysis data of crystal form B of compound L-tartrate of formula (I)

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型，其差示扫描量热曲线在38±3℃、199±3℃各有一个吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) has an endothermic peak starting point at 38±3°C and 199±3°C.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型，其DSC图谱如附图22所示。In some aspects of the present invention, the DSC spectrum of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 22.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型，其热重分析曲线(TGA)在25±3℃至115±3℃之间失重4.094％。In some aspects of the present invention, the thermogravimetric analysis curve (TGA) of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) loses 4.094% between 25±3°C and 115±3°C.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的B晶型的TGA图谱如图23所示。In some aspects of the present invention, the TGA spectrum of the B crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 23.

本发明提供了式(I)化合物L-酒石酸盐的C晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：16.21±0.20°，16.68±0.20°和22.84±0.20°。
The present invention provides the C crystal form of compound L-tartrate of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 16.21±0.20°, 16.68±0.20° and 22.84±0.20°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的C晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.05±0.10°，9.32±0.10°，16.21±0.10°，16.68±0.10°，19.99±0.10°，20.59±0.10°，22.84±0.10°和28.05±0.10°。In some aspects of the present invention, the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle Characteristic diffraction peaks: 9.05±0.10°, 9.32±0.10°, 16.21±0.10°, 16.68±0.10°, 19.99±0.10°, 20.59±0.10°, 22.84±0.10° and 28.05±0.10°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的C晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：16.21±0.10°，16.68±0.10°和/或22.84±0.10°，和/或9.05±0.10°，和/或9.32±0.10°，和/或12.44±0.10°，和/或13.99±0.10°，和/或17.42±0.10°，和/或19.99±0.10°，和/或20.59±0.10°，和/或28.05±0.10°。In some aspects of the present invention, the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle Characteristic diffraction peaks: 16.21±0.10°, 16.68±0.10° and/or 22.84±0.10°, and/or 9.05±0.10°, and/or 9.32±0.10°, and/or 12.44±0.10°, and/or 13.99± 0.10°, and/or 17.42±0.10°, and/or 19.99±0.10°, and/or 20.59±0.10°, and/or 28.05±0.10°.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的C晶型，其XRPD图谱如附图24所示。In some aspects of the present invention, the XRPD pattern of the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 24.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的C晶型的XRPD图谱解析数据如表9所示。In some aspects of the present invention, the XRPD spectrum analysis data of the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Table 9.

表9：式(I)化合物L-酒石酸盐的C晶型XRPD图谱解析数据
Table 9: XRPD spectrum analysis data of crystal form C of compound L-tartrate of formula (I)

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的C晶型，其差示扫描量热曲线在64±3℃、189±3℃各有一个吸热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) has an endothermic peak at 64±3°C and 189±3°C.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的C晶型，其DSC图谱如附图25所示。In some aspects of the present invention, the DSC spectrum of the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) is shown in Figure 25.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的C晶型，其热重分析曲线(TGA)在25±3℃至117±3℃之间失重3.158％；在118±3℃至213±3℃之间失重6.609％。In some aspects of the present invention, the C crystal form of the L-tartrate salt of the above-mentioned compound of formula (I) has a thermogravimetric analysis (TGA) weight loss of 3.158% between 25±3°C and 117±3°C; The weight loss is 6.609% between ℃ and 213±3℃.

本发明的一些方案中，上述式(I)化合物L-酒石酸盐的C晶型的TGA图谱如图26所示。In some embodiments of the present invention, the TGA spectrum of the C crystal form of the compound L-tartrate of the above formula (I) is shown in Figure 26.

本发明提供了式(I)化合物L-苹果酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：16.01±0.20°，23.61±0.20°和24.77±0.20°。
The present invention provides A crystal form of compound L-malate of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles : 16.01±0.20°, 23.61±0.20° and 24.77±0.20°.

本发明的一些方案中，上述式(I)化合物L-苹果酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.08±0.20°，13.68±0.20°，14.82±0.20°，16.01±0.20°，18.35±0.20°，19.01±0.20°，23.61±0.20°和24.77±0.20°。In some aspects of the present invention, the A crystal form of the L-malate compound of the above formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form is at the following 2θ angle It has characteristic diffraction peaks: 12.08±0.20°, 13.68±0.20°, 14.82±0.20°, 16.01±0.20°, 18.35±0.20°, 19.01±0.20°, 23.61±0.20° and 24.77±0.20°.

本发明的一些方案中，上述式(I)化合物L-苹果酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.08±0.20°，12.41±0.20°，13.68±0.20°，14.82±0.20°，15.08±0.20°，16.01±0.20°，18.35±0.20°，19.01±0.20°，19.74±0.20°，23.61±0.20°，24.29±0.20°和24.77±0.20°。In some aspects of the present invention, the A crystal form of the L-malate compound of the above formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form is at the following 2θ angle Characteristic diffraction peaks: 12.08±0.20°, 12.41±0.20°, 13.68±0.20°, 14.82±0.20°, 15.08±0.20°, 16.01±0.20°, 18.35±0.20°, 19.01±0.20°, 19.74±0.20°, 23.61±0.20°, 24.29±0.20° and 24.77±0.20°.

本发明的一些方案中，上述式(I)化合物L-苹果酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：16.01±0.10°，23.61±0.10°和/或24.77±0.10°，和/或7.38±0.10°，和/或12.08±0.10°，和/或12.41±0.10°，和/或13.68±0.10°，和/或14.82±0.10°，和/或15.08±0.10°，和/或18.35±0.10°，和/或18.81±0.10°，和/或19.01±0.10°，和/或19.74±0.10°，和/或21.40±0.10°，和/或21.92±0.10°，和/或22.32±0.10°，和/或24.29±0.10°，和/或25.73±0.10°，和/或26.20±0.10°，和/或27.61±0.10°，和/或27.98±0.10°，和/或29.34±0.10°，和/或29.81±0.10°，和/或±0.10°，和/或±0.10°，和/或±0.10°，和/或±0.10°，和/或±0.10°，和/或±0.10°，和/或30.19±0.10°，和/或30.48±0.10°，和/或31.64±0.10°，和/或32.14±0.10°，和/或34.53±0.10°，和/或35.21±0.10°，和/或35.87±0.10°，和/或36.30±0.10°，和/或37.71±0.10°，和/或38.25±0.10°，和/或38.76±0.10°。In some aspects of the present invention, the A crystal form of the L-malate compound of the above formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form is at the following 2θ angle Has characteristic diffraction peaks: 16.01±0.10°, 23.61±0.10° and/or 24.77±0.10°, and/or 7.38±0.10°, and/or 12.08±0.10°, and/or 12.41±0.10°, and/or 13.68 ±0.10°, and/or 14.82±0.10°, and/or 15.08±0.10°, and/or 18.35±0.10°, and/or 18.81±0.10°, and/or 19.01±0.10°, and/or 19.74±0.10 °, and/or 21.40±0.10°, and/or 21.92±0.10°, and/or 22.32±0.10°, and/or 24.29±0.10°, and/or 25.73±0.10°, and/or 26.20±0.10°, and/or 27.61±0.10°, and/or 27.98±0.10°, and/or 29.34±0.10°, and/or 29.81±0.10°, and/or ±0.10°, and/or ±0.10°, and/or ± 0.10°, and/or ±0.10°, and/or ±0.10°, and/or ±0.10°, and/or 30.19±0.10°, and/or 30.48±0.10°, and/or 31.64±0.10°, and/ or 32.14±0.10°, and/or 34.53±0.10°, and/or 35.21±0.10°, and/or 35.87±0.10°, and/or 36.30±0.10°, and/or 37.71±0.10°, and/or 38.25 ±0.10°, and/or 38.76±0.10°.

本发明的一些方案中，上述式(I)化合物L-苹果酸盐的A晶型，其XRPD图谱如附图27所示。In some aspects of the present invention, the XRPD pattern of the crystal form A of the L-malate salt of the above-mentioned compound of formula (I) is shown in Figure 27.

本发明的一些方案中，上述式(I)化合物L-苹果酸盐的A晶型，其XRPD图谱解析数据如表10所示。In some aspects of the present invention, the XRPD spectrum analysis data of the crystal form A of the L-malate salt of the above-mentioned compound of formula (I) are shown in Table 10.

表10：式(I)化合物L-苹果酸盐的A晶型XRPD图谱解析数据

Table 10: XRPD spectrum analysis data of Form A of compound L-malate of formula (I)

本发明的一些方案中，上述式(I)化合物L-苹果酸盐的A晶型，其差示扫描量热曲线在185±3℃有一个吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the crystalline form A of the L-malate salt of the above-mentioned compound of formula (I) has an endothermic peak starting point at 185±3°C.

本发明的一些方案中，上述式(I)化合物L-苹果酸盐的A晶型，其DSC图谱如附图28所示。In some aspects of the present invention, the DSC spectrum of the crystal form A of the L-malate salt of the above-mentioned compound of formula (I) is shown in Figure 28.

本发明的一些方案中，上述式(I)化合物L-苹果酸盐的A晶型的TGA图谱如图29所示。In some embodiments of the present invention, the TGA spectrum of Form A of the compound L-malate of the above formula (I) is shown in Figure 29.

本发明提供了式(I)化合物琥珀酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：17.67±0.20°，18.70±0.20°和21.32±0.20°。
The present invention provides the A crystal form of the succinate of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 17.67 ±0.20°, 18.70±0.20° and 21.32±0.20°.

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.65±0.20°，17.00±0.20°，17.67±0.20°，18.70±0.20°，19.31±0.20°，21.32±0.20°，25.55±0.20°和27.61±0.20°。In some aspects of the present invention, the A crystal form of the succinate of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peaks: 12.65±0.20°, 17.00±0.20°, 17.67±0.20°, 18.70±0.20°, 19.31±0.20°, 21.32±0.20°, 25.55±0.20° and 27.61±0.20°.

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.84±0.10°，12.65±0.10°，12.91±0.10°，15.95±0.10°，17.00±0.10°，17.67±0.10°，18.70±0.10°，19.31±0.10°，21.32±0.10°，23.58±0.10°，25.55±0.10°和27.61±0.10°。In some aspects of the present invention, the A crystal form of the succinate of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peaks: 6.84±0.10°, 12.65±0.10°, 12.91±0.10°, 15.95±0.10°, 17.00±0.10°, 17.67±0.10°, 18.70±0.10°, 19.31±0.10°, 21.32±0.10°, 23.58± 0.10°, 25.55±0.10° and 27.61±0.10°.

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：17.67±0.10°，18.70±0.10°和/或21.32±0.10°， 和/或6.84±0.10°，和/或10.95±0.10°，和/或11.47±0.10°，和/或11.67±0.10°，和/或12.17±0.10°，和/或12.65±0.10°，和/或12.91±0.10°，和/或13.82±0.10°，和/或15.95±0.10°，和/或17.00±0.10°，和/或19.31±0.10°，和/或19.75±0.10°，和/或20.21±0.10°，和/或20.52±0.10°，和/或22.39±0.10°，和/或23.58±0.10°，和/或24.58±0.10°，和/或24.84±0.10°，和/或25.55±0.10°，和/或26.11±0.10°，和/或27.61±0.10°，和/或28.30±0.10°，和/或29.08±0.10°，和/或29.54±0.10°，和/或30.51±0.10°，和/或31.52±0.10°，和/或32.24±0.10°，和/或33.01±0.10°，和/或33.93±0.10°，和/或35.07±0.10°，和/或38.05±0.10°。In some aspects of the present invention, the A crystal form of the succinate of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peak: 17.67±0.10°, 18.70±0.10° and/or 21.32±0.10°, and/or 6.84±0.10°, and/or 10.95±0.10°, and/or 11.47±0.10°, and/or 11.67±0.10°, and/or 12.17±0.10°, and/or 12.65±0.10°, and/or or 12.91±0.10°, and/or 13.82±0.10°, and/or 15.95±0.10°, and/or 17.00±0.10°, and/or 19.31±0.10°, and/or 19.75±0.10°, and/or 20.21 ±0.10°, and/or 20.52±0.10°, and/or 22.39±0.10°, and/or 23.58±0.10°, and/or 24.58±0.10°, and/or 24.84±0.10°, and/or 25.55±0.10 °, and/or 26.11±0.10°, and/or 27.61±0.10°, and/or 28.30±0.10°, and/or 29.08±0.10°, and/or 29.54±0.10°, and/or 30.51±0.10°, and/or 31.52±0.10°, and/or 32.24±0.10°, and/or 33.01±0.10°, and/or 33.93±0.10°, and/or 35.07±0.10°, and/or 38.05±0.10°.

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型，其XRPD图谱如附图30所示。In some embodiments of the present invention, the XRPD pattern of the succinate crystal form A of the compound of formula (I) is shown in Figure 30.

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型，其XRPD图谱解析数据如表11所示。In some aspects of the present invention, the XRPD spectrum analysis data of the crystal form A of the succinate of the compound of formula (I) above is shown in Table 11.

表11：式(I)化合物琥珀酸盐的A晶型XRPD图谱解析数据
Table 11: XRPD spectrum analysis data of crystal form A of the succinate of the compound of formula (I)

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型，其差示扫描量热曲线在103±3℃、148±3℃有一个吸热峰的起始点。In some embodiments of the present invention, the differential scanning calorimetry curve of the crystal form A of the succinate of the above-mentioned compound of formula (I) has an endothermic peak starting point at 103±3°C and 148±3°C.

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型，其DSC图谱如附图31所示。In some embodiments of the present invention, the DSC spectrum of the crystal form A of the succinate of the compound of formula (I) is shown in Figure 31.

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型，其热重分析曲线(TGA)在65±3℃至130±3℃之间失重3.160％。In some aspects of the present invention, the thermogravimetric analysis (TGA) of the crystal form A of the succinate of the compound of formula (I) above has a weight loss of 3.160% between 65±3°C and 130±3°C.

本发明的一些方案中，上述式(I)化合物琥珀酸盐的A晶型的TGA图谱如图32所示。In some embodiments of the present invention, the TGA spectrum of Form A of the succinate of the compound of formula (I) is shown in Figure 32.

本发明提供了式(I)化合物马来酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末 衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：13.13±0.20°，16.60±0.20°和23.61±0.20°。
The present invention provides the A crystal form of the maleate salt of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder of the crystal form The diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 13.13±0.20°, 16.60±0.20° and 23.61±0.20°.

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：10.63±0.20°，13.13±0.20°，16.60±0.20°，18.35±0.20°，19.47±0.20°，20.10±0.20°，23.61±0.20°和27.14±0.20°。In some aspects of the present invention, the A crystal form of the maleate salt of the compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 10.63±0.20°, 13.13±0.20°, 16.60±0.20°, 18.35±0.20°, 19.47±0.20°, 20.10±0.20°, 23.61±0.20° and 27.14±0.20°.

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：10.63±0.10°，11.77±0.10°，13.13±0.10°，13.57±0.10°，16.35±0.10°，16.60±0.10°，18.35±0.10°，19.47±0.10°，20.10±0.10°，20.50±0.10°，23.61±0.10°和27.14±0.10°。In some aspects of the present invention, the A crystal form of the maleate salt of the compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 10.63±0.10°, 11.77±0.10°, 13.13±0.10°, 13.57±0.10°, 16.35±0.10°, 16.60±0.10°, 18.35±0.10°, 19.47±0.10°, 20.10±0.10°, 20.50 ±0.10°, 23.61±0.10° and 27.14±0.10°.

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：13.13±0.10°，16.60±0.10°和/或23.61±0.10°，和/或8.14±0.10°，和/或9.05±0.10°，和/或9.79±0.10°，和/或10.63±0.10°，和/或10.91±0.10°，和/或11.77±0.10°，和/或12.50±0.10°，和/或13.57±0.10°，和/或15.33±0.10°，和/或16.35±0.10°，和/或17.10±0.10°，和/或18.10±0.10°，和/或18.35±0.10°，和/或19.18±0.10°，和/或19.47±0.10°，和/或20.10±0.10°，和/或20.50±0.10°，和/或21.04±0.10°，和/或22.14±0.10°，和/或22.81±0.10°，和/或23.28±0.10°，和/或24.71±0.10°，和/或25.22±0.10°，和/或25.85±0.10°，和/或26.62±0.10°，和/或27.14±0.10°，和/或29.27±0.10°，和/或33.28±0.10°。In some aspects of the present invention, the A crystal form of the maleate salt of the compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has the following 2θ angle: Characteristic diffraction peaks: 13.13±0.10°, 16.60±0.10° and/or 23.61±0.10°, and/or 8.14±0.10°, and/or 9.05±0.10°, and/or 9.79±0.10°, and/or 10.63± 0.10°, and/or 10.91±0.10°, and/or 11.77±0.10°, and/or 12.50±0.10°, and/or 13.57±0.10°, and/or 15.33±0.10°, and/or 16.35±0.10° , and/or 17.10±0.10°, and/or 18.10±0.10°, and/or 18.35±0.10°, and/or 19.18±0.10°, and/or 19.47±0.10°, and/or 20.10±0.10°, and /or 20.50±0.10°, and/or 21.04±0.10°, and/or 22.14±0.10°, and/or 22.81±0.10°, and/or 23.28±0.10°, and/or 24.71±0.10°, and/or 25.22±0.10°, and/or 25.85±0.10°, and/or 26.62±0.10°, and/or 27.14±0.10°, and/or 29.27±0.10°, and/or 33.28±0.10°.

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型，其XRPD图谱如附图33所示。In some embodiments of the present invention, the XRPD pattern of the maleate salt of the compound of formula (I) is shown in Figure 33.

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型，其XRPD图谱解析数据如表12所示。In some embodiments of the present invention, the XRPD spectrum analysis data of the maleate salt of the compound of formula (I) described above is shown in Table 12.

表12：式(I)化合物马来酸盐的A晶型XRPD图谱解析数据

Table 12: XRPD spectrum analysis data of crystal form A of the maleate salt of the compound of formula (I)

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型，其差示扫描量热曲线在69±3℃、109±3℃、134±3℃、177±3℃各有一个吸热峰的起始点。In some embodiments of the present invention, the differential scanning calorimetry curves of crystal form A of the maleate salt of the above-mentioned compound of formula (I) are at 69±3°C, 109±3°C, 134±3°C, and 177±3°C. There is an origin of an endothermic peak.

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型，其DSC图谱如附图34所示。In some embodiments of the present invention, the DSC spectrum of the maleate salt of the compound of formula (I) described above is Form A, as shown in Figure 34.

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型，其热重分析曲线(TGA)在25±3℃至160±3℃之间失重10.278％。In some aspects of the present invention, the thermogravimetric analysis (TGA) of crystal form A of the maleate salt of the above-mentioned compound of formula (I) has a weight loss of 10.278% between 25±3°C and 160±3°C.

本发明的一些方案中，上述式(I)化合物马来酸盐的A晶型的TGA图谱如图35所示。In some embodiments of the present invention, the TGA spectrum of Form A of the maleate salt of the compound of formula (I) is shown in Figure 35.

本发明提供了式(I)化合物盐酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：15.47±0.20°，20.70±0.20°和21.25±0.20°。
The present invention provides A crystal form of the hydrochloride of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 15.47 ±0.20°, 20.70±0.20° and 21.25±0.20°.

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：13.50±0.20°，15.47±0.20°，17.77±0.20°，20.70±0.20°，21.25±0.20°，23.74±0.20°，26.28±0.20°和28.43±0.20°。In some aspects of the present invention, the A crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peaks: 13.50±0.20°, 15.47±0.20°, 17.77±0.20°, 20.70±0.20°, 21.25±0.20°, 23.74±0.20°, 26.28±0.20° and 28.43±0.20°.

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.42±0.20°，11.37±0.20°，13.50±0.20°，15.47±0.20°，17.77±0.20°，20.70±0.20°，21.25±0.20°，23.74±0.20°，26.28±0.20°，28.43±0.20°。In some aspects of the present invention, the A crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peaks: 9.42±0.20°, 11.37±0.20°, 13.50±0.20°, 15.47±0.20°, 17.77±0.20°, 20.70±0.20°, 21.25±0.20°, 23.74±0.20°, 26.28±0.20°, 28.43± 0.20°.

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：15.47±0.10°，20.70±0.10°和/或21.25±0.10°，和/或9.42±0.10°，和/或10.54±0.10°，和/或11.37±0.10°，和/或12.32±0.10°，和/或12.86±0.10°，和/或 13.50±0.10°，和/或14.10±0.10°，和/或14.97±0.10°，和/或17.05±0.10°，和/或17.77±0.10°，和/或18.32±0.10°，和/或18.63±0.10°，和/或19.03±0.10°，和/或19.91±0.10°，和/或22.06±0.10°，和/或23.74±0.10°，和/或23.97±0.10°，和/或26.28±0.10°，和/或28.03±0.10°，和/或28.43±0.10°，和/或30.31±0.10°，和/或31.41±0.10°，和/或34.60±0.10°。In some aspects of the present invention, the A crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peak: 15.47±0.10°, 20.70±0.10° and/or 21.25±0.10°, and/or 9.42±0.10°, and/or 10.54±0.10°, and/or 11.37±0.10°, and/or 12.32±0.10 °, and/or 12.86±0.10°, and/or 13.50±0.10°, and/or 14.10±0.10°, and/or 14.97±0.10°, and/or 17.05±0.10°, and/or 17.77±0.10°, and/or 18.32±0.10°, and/or 18.63± 0.10°, and/or 19.03±0.10°, and/or 19.91±0.10°, and/or 22.06±0.10°, and/or 23.74±0.10°, and/or 23.97±0.10°, and/or 26.28±0.10° , and/or 28.03±0.10°, and/or 28.43±0.10°, and/or 30.31±0.10°, and/or 31.41±0.10°, and/or 34.60±0.10°.

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型，其XRPD图谱如附图36所示。In some aspects of the present invention, the XRPD pattern of Form A of the hydrochloride of the compound of formula (I) is shown in Figure 36.

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型，其XRPD图谱解析数据如表13所示。In some aspects of the present invention, the XRPD spectrum analysis data of Form A of the hydrochloride of the compound of formula (I) are shown in Table 13.

表13：式(I)化合物盐酸盐的A晶型XRPD图谱解析数据
Table 13: XRPD spectrum analysis data of Form A of compound hydrochloride of formula (I)

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型，其差示扫描量热曲线在202±3℃有一个吸热峰的起始点；在223±3℃有一个放热峰的起始点。In some embodiments of the present invention, the differential scanning calorimetry curve of the crystal form A of the hydrochloride of the compound of formula (I) has an endothermic peak starting point at 202±3°C; and an endothermic peak at 223±3°C. The starting point of the thermal peak.

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型，其DSC图谱如附图37所示。In some aspects of the present invention, the DSC spectrum of Form A of the hydrochloride of the compound of formula (I) is shown in Figure 37.

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型，其热重分析曲线(TGA)在21±3℃至85±3℃之间失重1.510％。In some aspects of the present invention, the thermogravimetric analysis (TGA) of the crystal form A of the hydrochloride of the compound of formula (I) above has a weight loss of 1.510% between 21±3°C and 85±3°C.

本发明的一些方案中，上述式(I)化合物盐酸盐的A晶型的TGA图谱如图38所示。In some aspects of the present invention, the TGA spectrum of Form A of the hydrochloride of the compound of formula (I) is shown in Figure 38.

本发明提供了式(I)化合物盐酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：13.48±0.20°，20.70±0.20°和21.18±0.20°。
The present invention provides the B crystal form of the hydrochloride of the compound of formula (I), which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 13.48 ±0.20°, 20.70±0.20° and 21.18±0.20°.

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.37±0.20°，11.34±0.20°，13.48±0.20°，18.31±0.20°，19.93±0.20°，20.70±0.20°，21.18±0.20°和28.40±0.20°。In some aspects of the present invention, the B crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peaks: 9.37±0.20°, 11.34±0.20°, 13.48±0.20°, 18.31±0.20°, 19.93±0.20°, 20.70±0.20°, 21.18±0.20° and 28.40±0.20°.

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.37±0.20°，11.34±0.20°，13.48±0.20°，15.83±0.20°，17.70±0.20°，18.31±0.20°，19.93±0.20°，21.18±0.20°，22.84±0.20°，27.28±0.20°和28.40±0.20°。In some aspects of the present invention, the B crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peaks: 9.37±0.20°, 11.34±0.20°, 13.48±0.20°, 15.83±0.20°, 17.70±0.20°, 18.31±0.20°, 19.93±0.20°, 21.18±0.20°, 22.84±0.20°, 27.28± 0.20° and 28.40±0.20°.

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：13.48±0.10°，20.70±0.10°和/或21.18±0.10°，和/或7.87±0.10°，和/或9.37±0.10°，和/或10.58±0.10°，和/或11.34±0.10°，和/或15.83±0.10°，和/或17.04±0.10°，和/或17.70±0.10°，和/或18.31±0.10°，和/或19.04±0.10°，和/或19.93±0.10°，和/或22.84±0.10°，和/或23.39±0.10°，和/或23.85±0.10°，和/或25.45±0.10°，和/或26.00±0.10°，和/或27.01±0.10°，和/或27.28±0.10°，和/或28.40±0.10°，和/或29.51±0.10°，和/或30.59±0.10°，和/或31.42±0.10°，和/或31.82±0.10°，和/或32.28±0.10°，和/或34.04±0.10°，和/或34.62±0.10°，和/或35.93±0.10°，和/或37.31±0.10°，和/或38.76±0.10°。In some aspects of the present invention, the B crystal form of the hydrochloride of the compound of formula (I) above is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristics at the following 2θ angles Diffraction peaks: 13.48±0.10°, 20.70±0.10° and/or 21.18±0.10°, and/or 7.87±0.10°, and/or 9.37±0.10°, and/or 10.58±0.10°, and/or 11.34±0.10 °, and/or 15.83±0.10°, and/or 17.04±0.10°, and/or 17.70±0.10°, and/or 18.31±0.10°, and/or 19.04±0.10°, and/or 19.93±0.10°, and/or 22.84±0.10°, and/or 23.39±0.10°, and/or 23.85±0.10°, and/or 25.45±0.10°, and/or 26.00±0.10°, and/or 27.01±0.10°, and/or or 27.28±0.10°, and/or 28.40±0.10°, and/or 29.51±0.10°, and/or 30.59±0.10°, and/or 31.42±0.10°, and/or 31.82±0.10°, and/or 32.28 ±0.10°, and/or 34.04±0.10°, and/or 34.62±0.10°, and/or 35.93±0.10°, and/or 37.31±0.10°, and/or 38.76±0.10°.

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型，其XRPD图谱如附图39所示。In some aspects of the present invention, the XRPD pattern of the hydrochloride form B of the compound of formula (I) is shown in Figure 39.

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型，其XRPD图谱解析数据如表14所示。In some aspects of the present invention, the XRPD spectrum analysis data of the B crystal form of the hydrochloride of the compound of formula (I) are shown in Table 14.

表14：式(I)化合物盐酸盐的B晶型XRPD图谱解析数据

Table 14: XRPD spectrum analysis data of crystal form B of compound hydrochloride of formula (I)

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型，其差示扫描量热曲线在61±3℃、188±3℃各有一个吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the B crystal form of the hydrochloride of the compound of formula (I) has an endothermic peak starting point at 61±3°C and 188±3°C.

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型，其DSC图谱如附图40所示。In some aspects of the present invention, the DSC spectrum of the B crystal form of the hydrochloride of the compound of formula (I) is shown in Figure 40.

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型，其热重分析曲线(TGA)在20±3℃至118±3℃之间失重4.642％；在118±3℃至214±3℃之间失重6.938％。In some aspects of the present invention, the B crystal form of the hydrochloride of the compound of formula (I) has a thermogravimetric analysis (TGA) weight loss of 4.642% between 20±3°C and 118±3°C; The weight loss is 6.938% between 214±3℃.

本发明的一些方案中，上述式(I)化合物盐酸盐的B晶型的TGA图谱如图41所示。In some aspects of the present invention, the TGA spectrum of Form B of the hydrochloride of the compound of formula (I) is shown in Figure 41.

本发明提供了式(I)化合物上述各种盐的制备方法：The invention provides methods for preparing the above various salts of the compound of formula (I):

1)称取约50mg式(I)化合物的无定形于样品瓶中，将溶剂(1,4-二氧六环或四氢呋喃)加入约50mg的API中，在50℃条件下使其部分溶解。1) Weigh about 50 mg of the amorphous compound of formula (I) into a sample bottle, add the solvent (1,4-dioxane or tetrahydrofuran) to about 50 mg of API, and partially dissolve it at 50°C.

2)在50℃条件下将酸加入到式(I)化合物溶液中，进行成盐反应；搅拌约2小时后放入25℃条件下继续搅拌(搅拌时间约18小时)。2) Add acid to the solution of the compound of formula (I) at 50°C to perform a salt-forming reaction; stir for about 2 hours and then place it at 25°C to continue stirring (stirring time is about 18 hours).

3)对固体过滤，50℃真空烘干(烘约3小时)，对所得固体进行固态表征。3) Filter the solid, dry it under vacuum at 50°C (about 3 hours), and perform solid-state characterization of the obtained solid.

本发明提供了上述式(I)化合物的琥珀酸盐及其A晶型、柠檬酸盐、马来酸盐、富马酸盐、L-酒石酸盐及其A/B/C晶型、L-苹果酸盐及其A晶型、草酸盐、硫酸盐，盐酸盐及其A/B晶型、磷酸盐和乳酸盐在制备治疗JAK相关疾病的药物中的应用。The invention provides the succinate salt of the compound of formula (I) and its A crystal form, citrate, maleate, fumarate, L-tartrate and its A/B/C crystal form, L- Application of malate and its A crystal form, oxalate, sulfate, hydrochloride and its A/B crystal form, phosphate and lactate in the preparation of drugs for the treatment of JAK related diseases.

本发明提供了上述式(I)化合物的A晶型，式(I)化合物的B晶型在制备治疗JAK相关疾病的药物中的应用。The present invention provides the use of crystal form A of the compound of formula (I) and crystal form B of the compound of formula (I) in the preparation of drugs for treating JAK-related diseases.

本发明提供了上述式(I)化合物的琥珀酸盐及其A晶型、柠檬酸盐、马来酸盐、富马酸盐、L-酒石酸盐及其A/B/C晶型、L-苹果酸盐及其A晶型、草酸盐、硫酸盐、盐酸盐及其A/B晶型、磷酸盐和乳酸盐在制备治疗限于肠道的pan-JAK相关疾病的药物中的应用。The invention provides the succinate salt of the compound of formula (I) and its A crystal form, citrate, maleate, fumarate, L-tartrate and its A/B/C crystal form, L- Application of malate and its A crystal form, oxalate, sulfate, hydrochloride and its A/B crystal form, phosphate and lactate in the preparation of drugs for the treatment of pan-JAK related diseases limited to the intestinal tract .

本发明提供了上述式(I)化合物的A/B/C/D/E/F晶型在制备治疗JAK相关疾病的药物中的应用。The present invention provides the use of the A/B/C/D/E/F crystal forms of the compound of formula (I) above in the preparation of drugs for treating JAK-related diseases.

本发明提供了式(I)化合物的A/B/C/D/E/F晶型在制备治疗限于肠道的pan-JAK相关疾病的药物中的应用。The present invention provides the use of the A/B/C/D/E/F crystalline forms of the compound of formula (I) in the preparation of drugs for the treatment of pan-JAK related diseases limited to the intestinal tract.

本发明还提供了一种在需要的受试者中治疗限于肠道的pan-JAK相关疾病的方法，包括向受试者提供有效剂量的上述任意技术方案所限定的化合物或其药学上可接受的盐或药物组合物。The present invention also provides a method for treating pan-JAK-related diseases limited to the intestine in a subject in need, including providing an effective dose of a compound defined in any of the above technical solutions or a pharmaceutically acceptable compound thereof to the subject. salts or pharmaceutical compositions.

在本发明的一些技术方案中，上述限于肠道的pan-JAK相关疾病为炎症性肠病。 In some technical solutions of the present invention, the above-mentioned pan-JAK-related disease limited to the intestine is inflammatory bowel disease.

技术效果Technical effect

本发明的化合物在激酶2个亚型JAK1、JAK2的体外活性测试中展现了良好的抑制性。本发明化合物在细胞(THP1和HT29)功能实验的体外活性测试中展现了对其良好的抑制性。本发明化合物在大鼠小肠和结肠表现出良好的药物暴露水平，并且化合物的小肠/血浆，结肠/血浆的比值较高，表现良好的组织选择性。本发明化合物在小鼠小肠和结肠表现出良好的药物暴露水平，并且化合物的小肠/血浆，结肠/血浆的比值较高，表现良好的组织选择性。本发明化合物在噁唑酮(Oxazolone,OXA)诱导的小鼠肠炎模型中，能够缓解OXA诱导的体重降低，显著改善疾病活动指数(DAI)评分和实验终点结肠重量长度比，展现良好治疗效果。且其各盐型以及各晶型稳定、受光热湿度影响小、溶解性高，成药前景广阔。The compound of the present invention exhibits good inhibitory properties in the in vitro activity test of two kinase subtypes, JAK1 and JAK2. The compounds of the present invention showed good inhibitory properties in the in vitro activity test of cell (THP1 and HT29) functional experiments. The compound of the present invention shows good drug exposure levels in the small intestine and colon of rats, and has high small intestine/plasma and colon/plasma ratios, showing good tissue selectivity. The compound of the present invention shows good drug exposure levels in the small intestine and colon of mice, and the compound has high small intestine/plasma and colon/plasma ratios, showing good tissue selectivity. In the mouse enteritis model induced by oxazolone (OXA), the compound of the present invention can alleviate the weight loss induced by OXA, significantly improve the disease activity index (DAI) score and the colon weight-to-length ratio at the experimental end point, and exhibit good therapeutic effects. Moreover, its salt forms and crystal forms are stable, less affected by light, heat and humidity, have high solubility, and have broad prospects for pharmaceutical preparations.

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.

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.

对于任何给定的结晶形式而言，由于例如结晶形态等因素引起的优选取向，衍射峰的相对强度可以改变，这在结晶学领域中是公知的。存在优选取向影响的地方，峰强度是改变的，但是晶型的衍射峰位置是无法改变的。此外，对任何给定的晶型而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品的移动、或仪器的标定等，峰的位置可以移动，2θ值的测量误差有时约为±0.20°，因此，本领域技术人员公知在确定每种结晶结构时，应该将此误差考虑在内。For any given crystalline form, it is well known in the art of crystallography that the relative intensities of diffraction peaks can change due to preferred orientation due to factors such as crystal morphology. Where there is an influence of preferred orientation, the peak intensity changes, but the diffraction peak position of the crystal form cannot be changed. Furthermore, there may be slight errors in the position of the peaks for any given crystalline form, as is also known in the art of crystallography. For example, due to changes in temperature, movement of the sample, or calibration of the instrument when analyzing the sample, the position of the peak may move, and the measurement error of the 2θ value is sometimes about ±0.20°. Therefore, it is well known to those skilled in the art that when determining each crystal This error should be taken into account when constructing.

DSC测定当结晶由于其结晶结构发生变化或结晶熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃或3℃之内，当我们说一个化合物具有一给定的DSC峰或熔点时，这是指该DSC峰或熔点±5℃或±3℃。DSC提供了一种辨别不同晶型的辅助方法。不同的结晶形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystalline form of the same compound, in successive analyses, the thermal transition temperature and melting point errors are typically within about 5°C or 3°C. When we say that a compound has a given DSC peak or melting point, This refers to the DSC peak or melting point ±5°C or ±3°C. DSC provides an auxiliary method to distinguish different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary within a wider range. In addition, since the melting process of a substance is accompanied by decomposition, the melting temperature is related to the heating rate.

对于同种晶型，TGA失重温度出现可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的晶型，失重温度可能存在误差，误差可以为约±5℃，可以为约±3℃。 For the same crystal form, the TGA weight loss temperature may differ due to factors such as measuring instruments, measuring methods/conditions, etc. There may be an error in the weight loss temperature for any particular crystal form, which may be about ±5°C, and may be about ±3°C.

需要说明的是，在制备药物晶型时，药物分子与溶剂分子在接触的过程中，外部条件与内部因素造成溶剂分子与化合物分子形成共晶而残留在固体物质中的情况很难避免，从而形成溶剂合物，具体包括化学计量类溶剂合物和非化学计量类溶剂合物。所述的溶剂合物均包括在本发明的范围内。It should be noted that when preparing drug crystal forms, during the contact process between drug molecules and solvent molecules, external conditions and internal factors cause the solvent molecules and compound molecules to form a eutectic and remain in the solid material. Therefore, it is difficult to avoid the situation. Solvates are formed, specifically including stoichiometric solvates and non-stoichiometric solvates. The solvates described are all included in the scope of the present invention.

所述“药学上可接受的辅料”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。The "pharmaceutically acceptable excipients" refer to inert substances that are administered together with the active ingredients and are conducive to the administration of the active ingredients, including but not limited to acceptable substances approved by the State Food and Drug Administration for use in humans or animals. (e.g. livestock) any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer agents, isotonic agents, solvents or emulsifiers.

术语“结晶组合物”是指本发明的式(I)化合物的晶型与该化合物的其他晶型或无定形物或其他杂质组成的混合物。例如，式(I)化合物的结晶组合物除了式(I)化合物的结晶之外，还包含化合物1的其他晶型或无定形物或者其他杂质。The term "crystalline composition" refers to a mixture of the crystalline form of the compound of formula (I) of the present invention and other crystalline forms or amorphous substances or other impurities of the compound. For example, the crystalline composition of the compound of formula (I), in addition to the crystal of the compound of formula (I), also contains other crystalline forms or amorphous substances of compound 1 or other impurities.

术语“药物组合物”是指一种或多种本发明的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本发明的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or salts thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate the administration to an organism of the compounds of the invention.

本发明化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本发明化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。Therapeutic dosages of the compounds of the present invention may be determined based, for example, on the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportions or concentrations of the compounds of the present invention in pharmaceutical compositions may not be fixed and depend on a variety of factors, including dosage, chemical properties (eg, hydrophobicity), and route of administration.

术语“治疗”意为将本发明所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with said disease, and includes:

(i)抑制疾病或疾病状态，即遏制其发展；(i) To inhibit a disease or disease state, that is, to arrest its progression;

(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) Alleviation of a disease or condition, i.e. resolution of the disease or condition.

术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本发明化合物的用量。构成“治疗有效量”的本发明化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means (i) treating a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying as used herein An amount of a compound of the invention that is associated with the onset of one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.

除非本发明中另外要求，在整个说明书和其后的权利要求书中，词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义，即“包括但不限于”。Unless the invention requires otherwise, throughout this specification and the claims that follow, the word "comprise" and its English variations such as "comprises" and "comprising" are to be interpreted as open-ended The inclusive meaning is "including but not limited to".

在整个本说明书中提到的“一些实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一些实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。 Reference throughout this specification to "some embodiments" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that at least one embodiment includes Relevant specific reference elements, structures or characteristics described above. Thus, appearances of the phrases "in some embodiments" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, specific elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

应当理解，在本发明说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包括“催化剂”的反应包括一种催化剂，或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。It will be understood that, as used in this specification and the appended claims, the singular form "a" (corresponding to "a", "an" and "the") includes plural referents unless the context clearly dictates otherwise. local regulations. Thus, for example, reference to a reaction involving a "catalyst" includes one catalyst, or two or more catalysts. It will also be understood that the term "or" is generally used in its sense including "and/or" unless the context clearly dictates otherwise.

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.

除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示相对构型，例如，例如，用表示反式1、4-二取代的环己烷，用表示顺式1、4-二取代的环己烷。Unless otherwise stated, use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, using straight solid line keys and straight dotted keys To express the relative configuration, for example, use represents trans 1,4-disubstituted cyclohexane, use Represents cis 1,4-disubstituted cyclohexane.

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.

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。本发明采用下述缩略词：DCM代表二氯甲烷；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOH代表乙醇；MeOH代表甲醇；TFA代表三氟乙酸；TsOH代表对甲苯磺酸；mp代表熔点；EtSO3H代表乙磺酸；MeSO3H代表甲磺酸；ATP代表三磷酸腺苷；HEPES代表4-羟乙基哌嗪乙磺酸；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；MgCl2代表二氯化镁；MnCl2代表二氯化锰；DTT代表二硫苏糖醇；DCC代表二环己基碳二亚胺；DMAP代表4-二甲氨基吡啶；EA代表乙酸乙酯；LiHMDS代表六甲基二硅基胺基锂；Pd(dppf)Cl2.CH2Cl2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯的二氯甲烷络合物；EDCI代表碳化二亚胺；HOBt代表1-羟基苯并三唑。The solvent used in the present invention is commercially available. The present invention uses the following abbreviations: DCM represents dichloromethane; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; MeOH represents methanol; TFA represents trifluoroacetic acid; TsOH represents p-toluenesulfonic acid; mp represents melting point; EtSO 3 H represents ethanesulfonic acid; MeSO 3 H represents methanesulfonic acid; ATP represents adenosine triphosphate; HEPES represents 4-hydroxyethylpiperazineethanesulfonic acid; EGTA represents ethylene glycol bis(2 -Aminoethyl ether) tetraacetic acid; MgCl 2 represents magnesium dichloride; MnCl 2 represents manganese dichloride; DTT represents dithiothreitol; DCC represents dicyclohexylcarbodiimide; DMAP represents 4-dimethylaminopyridine; EA represents ethyl acetate; LiHMDS represents lithium hexamethyldisilazide; Pd(dppf)Cl 2 .CH 2 Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloride dichloromethane complex of palladium; EDCI represents carbodiimide; HOBt represents 1-hydroxybenzotriazole.

XRPD、DSC、TGA、DVS的具体方法(包括设备型号以及各参数)Specific methods of XRPD, DSC, TGA, and DVS (including equipment models and parameters)

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

XRPD衍射图由Bruker D2 Phaser型采集获得。将待测样品放置于光滑无背景的硅片上进行测样。仪器测量参数如表15。XRPD diffraction patterns were collected using a Bruker D2 Phaser. Place the sample to be tested on a smooth, background-free silicon wafer for testing. The instrument measurement parameters are shown in Table 15.

表15.XRPD方法参数
Table 15. XRPD method parameters

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

DSC曲线由TA仪器的DSC 250型采集获得。DSC 250型仪器测试方法为：精密称取1-5mg的样品至扎孔的铝坩埚中，以10℃/min的升温速率从25℃升温至最终温度。仪器参数如表16所示。The DSC curve was collected by the DSC 250 model of TA Instruments. The test method of the DSC 250 instrument is: accurately weigh 1-5 mg of the sample into a perforated aluminum crucible, and heat it from 25°C to the final temperature at a heating rate of 10°C/min. The instrument parameters are shown in Table 16.

表16.DSC分析参数
Table 16.DSC analysis parameters

热重分析(TGA)Thermogravimetric Analysis (TGA)

TGA曲线由TA仪器的TGA 550采集获得。取适量的样品放入提前去皮的铝坩埚内，以10℃/min的升温速率从室温升温至300℃。TGA 550型仪器的温度程序与设备参数如表17所示。The TGA curve was collected by the TGA 550 of TA Instruments. Put an appropriate amount of sample into an aluminum crucible that has been peeled in advance, and heat it from room temperature to 300°C at a heating rate of 10°C/min. The temperature program and equipment parameters of the TGA 550 instrument are shown in Table 17.

表17.TGA分析参数
Table 17. TGA analysis parameters

动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)Dynamic Vapor Sorption (DVS)

仪器型号：SMS(Surface Measurement Systems)的DVS Intrinsic Plus动态蒸汽吸附仪Instrument model: DVS Intrinsic Plus dynamic vapor adsorption instrument from SMS (Surface Measurement Systems)

测试条件：取样品(20～40mg)置于DVS样品盘内进行测试。Test conditions: Take a sample (20~40mg) and place it in the DVS sample tray for testing.

详细的DVS参数如下：The detailed DVS parameters are as follows:

保护气体及流量：N2，200mL/minProtective gas and flow rate: N2, 200mL/min

温度：25℃Temperature: 25℃

初始平衡：dm/dt≤0.002％Initial balance: dm/dt≤0.002%

每步平衡：60minBalance per step: 60min

干燥：0％RH下干燥120minDrying: 120min at 0%RH

RH(％)范围：0％-95％RH (%) range: 0%-95%

RH(％)梯度：10％(0％RH-90％RH，90％RH-0％RH)；5％(90％RH-95％RH，95％RH-90％RH)RH (%) gradient: 10% (0%RH-90%RH, 90%RH-0%RH); 5% (90%RH-95%RH, 95%RH-90%RH)

引湿性评价分类如下表18：The hygroscopicity evaluation classification is as follows in Table 18:

表18.引湿性评价
Table 18. Hygroscopicity evaluation

注：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重。Note: ΔW% represents the moisture absorption weight gain of the test product at 25±1℃ and 80±2%RH.

附图说明Description of the drawings

图1：式(I)化合物A晶型的XRPD图谱；Figure 1: XRPD pattern of crystal form A of compound of formula (I);

图2：式(I)化合物A晶型的DSC图谱；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图谱；Figure 3: TGA spectrum of crystal form A of compound of formula (I);

图4：式(I)化合物B晶型的XRPD图谱；Figure 4: XRPD pattern of crystal form B of compound of formula (I);

图5：式(I)化合物B晶型的DSC图谱；Figure 5: DSC spectrum of crystal form B of compound of formula (I);

图6：式(I)化合物B晶型的TGA图谱；Figure 6: TGA spectrum of crystal form B of compound of formula (I);

图7：式(I)化合物C晶型的XRPD图谱； Figure 7: XRPD pattern of crystal form C of compound of formula (I);

图8：式(I)化合物C晶型的DSC图谱；Figure 8: DSC spectrum of crystal form C of compound of formula (I);

图9：式(I)化合物C晶型的TGA图谱；Figure 9: TGA spectrum of crystal form C of compound of formula (I);

图10：式(I)化合物D晶型的XRPD图谱；Figure 10: XRPD pattern of crystal form D of compound of formula (I);

图11：式(I)化合物D晶型的DSC图谱；Figure 11: DSC spectrum of crystal form D of compound of formula (I);

图12：式(I)化合物D晶型的TGA图谱；Figure 12: TGA spectrum of crystal form D of compound of formula (I);

图13：式(I)化合物E晶型的XRPD图谱；Figure 13: XRPD pattern of crystal form E of compound of formula (I);

图14：式(I)化合物E晶型的DSC图谱；Figure 14: DSC spectrum of crystal form E of compound of formula (I);

图15：式(I)化合物E晶型的TGA图谱；Figure 15: TGA spectrum of crystal form E of compound of formula (I);

图16：式(I)化合物F晶型的XRPD图谱；Figure 16: XRPD pattern of crystal form F of compound of formula (I);

图17：式(I)化合物F晶型的TGA图谱；Figure 17: TGA spectrum of crystal form F of compound of formula (I);

图18：式(I)化合物L-酒石酸盐的A晶型的XRPD图谱；Figure 18: XRPD pattern of crystal form A of compound L-tartrate of formula (I);

图19：式(I)化合物L-酒石酸盐的A晶型的DSC图谱；Figure 19: DSC spectrum of crystal form A of compound L-tartrate of formula (I);

图20：式(I)化合物L-酒石酸盐的A晶型的TGA图谱；Figure 20: TGA spectrum of crystal form A of compound L-tartrate of formula (I);

图21：式(I)化合物L-酒石酸盐的B晶型的XRPD图谱；Figure 21: XRPD pattern of crystal form B of compound L-tartrate of formula (I);

图22：式(I)化合物L-酒石酸盐的B晶型的DSC图谱；Figure 22: DSC spectrum of crystal form B of compound L-tartrate of formula (I);

图23：式(I)化合物L-酒石酸盐的B晶型的TGA图谱；Figure 23: TGA spectrum of crystal form B of compound L-tartrate of formula (I);

图24：式(I)化合物L-酒石酸盐的C晶型的XRPD图谱；Figure 24: XRPD pattern of the C crystal form of compound L-tartrate of formula (I);

图25：式(I)化合物L-酒石酸盐的C晶型的DSC图谱；Figure 25: DSC spectrum of the C crystal form of compound L-tartrate of formula (I);

图26：式(I)化合物L-酒石酸盐的C晶型的TGA图谱；Figure 26: TGA spectrum of the C crystal form of compound L-tartrate of formula (I);

图27：式(I)化合物L-苹果酸盐的A晶型的XRPD图谱；Figure 27: XRPD pattern of crystal form A of compound L-malate of formula (I);

图28：式(I)化合物L-苹果酸盐的A晶型的DSC图谱；Figure 28: DSC spectrum of crystal form A of compound L-malate of formula (I);

图29：式(I)化合物L-苹果酸盐的A晶型的TGA图谱；Figure 29: TGA spectrum of crystal form A of compound L-malate of formula (I);

图30：式(I)化合物琥珀酸盐的A晶型的XRPD图谱；Figure 30: XRPD pattern of crystal form A of the succinate of the compound of formula (I);

图31：式(I)化合物琥珀酸盐的A晶型的DSC图谱；Figure 31: DSC spectrum of crystal form A of the succinate of the compound of formula (I);

图32：式(I)化合物琥珀酸盐的A晶型的TGA图谱；Figure 32: TGA spectrum of crystal form A of the succinate of the compound of formula (I);

图33：式(I)化合物马来酸盐的A晶型的XRPD图谱；Figure 33: XRPD pattern of crystal form A of the maleate salt of the compound of formula (I);

图34：式(I)化合物马来酸盐的A晶型的DSC图谱；Figure 34: DSC spectrum of crystal form A of the maleate salt of the compound of formula (I);

图35：式(I)化合物马来酸盐的A晶型的TGA图谱；Figure 35: TGA spectrum of crystal form A of the maleate salt of the compound of formula (I);

图36：式(I)化合物盐酸盐的A晶型的XRPD图谱；Figure 36: XRPD pattern of crystal form A of the hydrochloride of the compound of formula (I);

图37：式(I)化合物盐酸盐的A晶型的DSC图谱；Figure 37: DSC spectrum of crystal form A of the hydrochloride of the compound of formula (I);

图38：式(I)化合物盐酸盐的A晶型的TGA图谱； Figure 38: TGA spectrum of crystal form A of the hydrochloride of the compound of formula (I);

图39：式(I)化合物盐酸盐的B晶型的XRPD图谱；Figure 39: XRPD pattern of the B crystal form of the hydrochloride of the compound of formula (I);

图40：式(I)化合物盐酸盐的B晶型的DSC图谱；Figure 40: DSC spectrum of crystal form B of the hydrochloride of the compound of formula (I);

图41：式(I)化合物盐酸盐的B晶型的TGA图谱；Figure 41: TGA spectrum of the B crystal form of the hydrochloride of the compound of formula (I);

图42：式(I)化合物的A晶型的DVS图谱；Figure 42: DVS spectrum of crystal form A of compound of formula (I);

图43：式(I)化合物的B晶型的DVS图谱。Figure 43: DVS spectrum of crystal form B of compound of formula (I).

具体实施方式Detailed ways

为了更好的理解本申请的内容，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申请的内容所做的限制。In order to better understand the content of the present application, further description will be given below in conjunction with specific embodiments, but the specific implementations do not limit the content of the present application.

实施例1
Example 1

步骤1：在25℃下将化合物1-1(2g,11.56mmol)溶于二甲基亚砜(10mL)中，加入1-2(2.88g,12.72mmol)和N,N-二异丙基乙胺(2.99g,23.12mmol)，在100℃下搅拌16小时，向反应液中加入200mL水，并用乙酸乙酯萃取(500mL×3)，合并的有机相再依次用0.2M的盐酸水溶液(100mL)和饱和食盐水(200mL)洗涤，最后有机相用无水硫酸钠干燥，过滤并减压浓缩，得到粗品1-3。MS ESI计算值:C18H23ClN4O2[M+H]+363，实测值363。 Step 1: Dissolve compound 1-1 (2g, 11.56mmol) in dimethyl sulfoxide (10mL) at 25°C, add 1-2 (2.88g, 12.72mmol) and N,N-diisopropyl Ethylamine (2.99g, 23.12mmol), stirred at 100°C for 16 hours, added 200mL water to the reaction solution, and extracted with ethyl acetate (500mL×3), the combined organic phase was sequentially washed with 0.2M hydrochloric acid aqueous solution ( 100 mL) and washed with saturated brine (200 mL). Finally, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product 1-3. MS ESI calculated value: C 18 H 23 ClN 4 O 2 [M+H] + 363, found value 363.

步骤1’：在0℃下，将化合物1-4a(10g,78.68mmol)溶于二氯甲烷(100mL)中，加入N,N-二异丙基乙胺(12.20g,94.41mmol,16.45mL)和1-4b((15.74g,94.41mmol,16.71mL)，25℃下搅拌16小时，向反应液中加入200mL水，并用乙酸乙酯萃取(500mL×3)，合并的有机相用饱和食盐水(200mL)洗涤，最后有机相用无水硫酸钠干燥，过滤并减压浓缩，得到粗品，粗品经过柱层析(SiO2,石油醚：乙酸乙酯＝1/0～30/1)纯化得到化合物1-4c。Step 1': Dissolve compound 1-4a (10g, 78.68mmol) in dichloromethane (100mL) at 0°C, add N,N-diisopropylethylamine (12.20g, 94.41mmol, 16.45mL ) and 1-4b ((15.74g, 94.41mmol, 16.71mL), stir at 25°C for 16 hours, add 200mL water to the reaction solution, and extract with ethyl acetate (500mL×3), the combined organic phase is washed with saturated salt Wash with water (200 mL), and finally the organic phase is dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which is purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 1/0 ~ 30/1) Compound 1-4c was obtained.

步骤2’：将化合物1-4c(11g,42.74mmol)溶于甲醇(100mL)中，氮气保护下，加入钯碳(0.1g,钯含量10％)，然后用氢气置换三次后，25℃下搅拌16小时，用硅藻土过滤并减压浓缩得到粗品1-4。1H NMR(400MHz,DMSO-d6)δ-0.05--0.03(s,9H),0.77-0.86(t,2H),1.95-1.97(s,3H),3.47-3.53(t,2H),5.06-5.08(s,1H),5.08-5.11(s,2H),5.16(s,2H)。Step 2': Dissolve compound 1-4c (11g, 42.74mmol) in methanol (100mL), add palladium on carbon (0.1g, palladium content 10%) under nitrogen protection, and then replace it with hydrogen three times, at 25°C Stir for 16 hours, filter with diatomaceous earth and concentrate under reduced pressure to obtain crude product 1-4. 1H NMR (400MHz, DMSO-d6) δ-0.05--0.03 (s, 9H), 0.77-0.86 (t, 2H), 1.95 -1.97(s,3H),3.47-3.53(t,2H),5.06-5.08(s,1H),5.08-5.11(s,2H),5.16(s,2H).

步骤2：将化合物1-3(2.5g,6.89mmol)溶于二氧六环(30mL)中，加入化合物1-4(1.64g,7.23mmol)，碳酸铯(4.49g,13.78mmol)和[(2-二-环己基膦基-3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯基)-2-(2′-氨基-1,1′-联苯基)]甲磺酸钯(II)甲磺酸酯(312.28mg,344.49μmol)，氮气置换三次后升温至100℃，氮气保护下搅拌16小时。向反应液中加入50mL氯化铵水溶液，并用乙酸乙酯萃取(100mL×3)，合并的有机相再用饱和食盐水(100mL)洗涤，最后有机相用无水硫酸钠干燥，过滤并减压浓缩，得到粗品，粗品经过柱层析(SiO2,石油醚：乙酸乙酯＝1/0～5/1)纯化得到化合物1-5。MS ESI计算值:C28H43N7O3Si[M+H]+554,实测值554。1H NMR(400MHz,CD3OD)δ-0.09--0.06(s,9H),0.81-0.88(t,2H),1.45-1.52(m,11H),1.76-1.85(m,2H),1.87-2.01(m,4H),2.21-2.25(s,3H),3.49-3.55(t,2H),4.16-4.23(m,2H),4.33-4.48(m,1H),5.34(s,2H),6.04-6.09(m,1H),6.09-6.13(m,1H),6.22-6.30(s,1H)。Step 2: Dissolve compound 1-3 (2.5g, 6.89mmol) in dioxane (30mL), add compound 1-4 (1.64g, 7.23mmol), cesium carbonate (4.49g, 13.78mmol) and [ (2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino -1,1′-biphenyl)]palladium(II) methanesulfonate (312.28 mg, 344.49 μmol), replaced with nitrogen three times, then heated to 100°C, and stirred under nitrogen protection for 16 hours. Add 50 mL of ammonium chloride aqueous solution to the reaction solution, and extract with ethyl acetate (100 mL × 3). The combined organic phase is washed with saturated brine (100 mL). Finally, the organic phase is dried over anhydrous sodium sulfate, filtered and reduced pressure. Concentrate to obtain a crude product, which is purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 1/0 to 5/1) to obtain compound 1-5. MS ESI calculated value: C 28 H 43 N 7 O 3 Si[M+H] + 554, measured value 554. 1 H NMR (400MHz, CD 3 OD) δ-0.09--0.06(s,9H),0.81-0.88(t,2H),1.45-1.52(m,11H),1.76-1.85(m,2H),1.87 -2.01(m,4H),2.21-2.25(s,3H),3.49-3.55(t,2H),4.16-4.23(m,2H),4.33-4.48(m,1H),5.34(s,2H) ,6.04-6.09(m,1H),6.09-6.13(m,1H),6.22-6.30(s,1H).

步骤3：在0-5℃下，将硒粉(4.39g,54.17mmol)加入到乙醇(30mL)中，然后将硼氢化钠(2.38g,62.91mmol)慢慢加入，室温搅拌，直到固体颗粒完全消失，将吡啶(8.57g,108.35mmol)和化合物1-5(3g,5.42mmol)加入反应液中，并升温至80℃搅拌半个小时，然后缓慢加入2M盐酸水溶液(32.50mL,)，继续搅拌半个小时，LC-MS显示原料被消耗完全，向反应液中加入50mL氯化铵水溶液，并用乙酸乙酯萃取(50mL×3)，合并的有机相再用饱和食盐水(50mL)洗涤，最后有机相用无水硫酸钠干燥，过滤并减压浓缩，得到粗品，粗品经过柱层析(SiO2,石油醚：乙酸乙酯＝1/0～1/1)纯化得到化合物1-6。MS ESI计算值:C28H45N7O3SeSi[M+H]+636,实测值636。1H NMR(400MHz,CD3OD)δ-0.02-0.01(s,9H),0.90-0.96(t,2H),1.52-1.55(m,11H),1.85-1.93(m,2H),1.96-2.08(m,4H),2.24-2.30(s,3H),3.58-3.64(t,2H),4.22-4.31(m,2H),4.37-4.53(m,1H),5.36-5.43(s,2H),6.22-6.25(m,1H),6.32-6.35(s,1H),6.36-6.39(m,1H)。Step 3: Add selenium powder (4.39g, 54.17mmol) to ethanol (30mL) at 0-5°C, then slowly add sodium borohydride (2.38g, 62.91mmol) and stir at room temperature until solid particles Completely disappeared, add pyridine (8.57g, 108.35mmol) and compound 1-5 (3g, 5.42mmol) into the reaction solution, raise the temperature to 80°C and stir for half an hour, then slowly add 2M hydrochloric acid aqueous solution (32.50mL,), Continue stirring for half an hour. LC-MS shows that the raw materials are completely consumed. Add 50 mL of ammonium chloride aqueous solution to the reaction solution and extract with ethyl acetate (50 mL × 3). The combined organic phases are washed with saturated brine (50 mL). , finally the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 1/0 ~ 1/1) to obtain compound 1-6 . MS ESI calculated value: C 28 H 45 N 7 O 3 SeSi[M+H] + 636, measured value 636. 1 H NMR (400MHz, CD 3 OD) δ-0.02-0.01(s,9H),0.90-0.96(t,2H),1.52-1.55(m,11H),1.85-1.93(m,2H),1.96- 2.08(m,4H),2.24-2.30(s,3H),3.58-3.64(t,2H),4.22-4.31(m,2H),4.37-4.53(m,1H),5.36-5.43(s,2H ),6.22-6.25(m,1H),6.32-6.35(s,1H),6.36-6.39(m,1H).

步骤4：在25℃下将化合物1-6(1.4g,2.21mmol)溶于乙醇(15mL)中，加入1-7(204.07mg,2.21mmol),80℃下搅拌1小时。反应液直接减压浓缩得到粗品1-8。Step 4: Dissolve compound 1-6 (1.4g, 2.21mmol) in ethanol (15mL) at 25°C, add 1-7 (204.07mg, 2.21mmol), and stir at 80°C for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain crude product 1-8.

步骤5：将化合物1-8(1.4g,2.08mmol)溶于乙酸乙酯中(2mL)，加入盐酸乙酸乙酯溶液(4M,14mL)，在25℃下搅拌1小时。反应液直接过滤得到滤饼为化合物1-9的盐酸盐粗品。MS ESI计算值C20H25N7Se [M+H]+444，实测值444。1H NMR(400MHz,CD3OD)δ1.93-2.05(m,2H),2.20-2.42(m,9H),2.56-2.62(s,3H),4.13-4.26(m,3H),5.98(s,1H),6.67(s,1H),6.79(s,1H),8.06-8.16(s,1H)。Step 5: Dissolve compound 1-8 (1.4g, 2.08mmol) in ethyl acetate (2mL), add hydrochloric acid ethyl acetate solution (4M, 14mL), and stir at 25°C for 1 hour. The reaction liquid is directly filtered to obtain a crude hydrochloride of compound 1-9 as a filter cake. MS ESI calcd for C 20 H 25 N 7 Se [M+H] + 444, measured value 444. 1 H NMR (400MHz, CD 3 OD) δ1.93-2.05(m,2H),2.20-2.42(m,9H),2.56-2.62(s,3H),4.13-4.26(m,3H),5.98( s,1H),6.67(s,1H),6.79(s,1H),8.06-8.16(s,1H).

步骤6：将1-9的盐酸盐粗品(0.85g,1.65mmol)溶于甲醇(10mL)中，加入N,N-二异丙基乙胺(639.52mg,4.95mmol,862μL)，混合物在25℃搅拌10分钟，然后加入化合物1-10(0.290g,5.47mmol,363μL)，在25℃下搅拌16小时。向反应液中加入50mL氯化铵水溶液，并用乙酸乙酯萃取(50mL×3)，合并的有机相再用饱和食盐水(50mL)洗涤，最后有机相用无水硫酸钠干燥，过滤并减压浓缩得到粗品，粗品经过高效液相色谱法制备分离(柱子:Phenomenex Luna C18 150*40mm*15μm；流动相:[水(0.1％TFA)-ACN]；B(ACN)％:8％-38％,11分钟)得到式(I)化合物的三氟乙酸盐。MS ESI计算值C23H28N8Se[M+H]+497，实测值497,1H NMR(400MHz,CD3OD)δ2.10-2.20(m,2H),2.31-2.50(m,9H),2.51-2.56(s,3H),3.10-3.17(t,2H),3.48-3.59(t,2H),4.17-4.31(m,3H),5.90-5.95(s,1H),6.68-6.74(m,2H),7.96(m,1H)。Step 6: Dissolve the crude hydrochloride of 1-9 (0.85g, 1.65mmol) in methanol (10mL), add N,N-diisopropylethylamine (639.52mg, 4.95mmol, 862μL), and mix the mixture in Stir at 25°C for 10 minutes, then add compound 1-10 (0.290g, 5.47mmol, 363 μL), and stir at 25°C for 16 hours. Add 50 mL of ammonium chloride aqueous solution to the reaction solution and extract with ethyl acetate (50 mL Concentrate to obtain a crude product, which is prepared and separated by high performance liquid chromatography (column: Phenomenex Luna C18 150*40mm*15μm; mobile phase: [water (0.1% TFA)-ACN]; B (ACN)%: 8%-38% , 11 minutes) to obtain the trifluoroacetate salt of the compound of formula (I). MS ESI calculated value for C 23 H 28 N 8 Se[M+H] + 497, found value 497, 1 H NMR (400MHz, CD 3 OD) δ2.10-2.20(m,2H),2.31-2.50(m, 9H),2.51-2.56(s,3H),3.10-3.17(t,2H),3.48-3.59(t,2H),4.17-4.31(m,3H),5.90-5.95(s,1H),6.68- 6.74(m,2H),7.96(m,1H).

步骤7：化合物1-9(128.6g,290.68mmol)溶于甲醇(1040mL)和二甲基亚砜(260mL)中，加入二异丙基乙基胺(45.08g,348.81mmol)和丙烯腈(19.37g,365.04mmol)，在20℃反应16小时。反应液加入3.9L水，搅拌2小时，过滤得到滤饼。滤饼加入145mL二甲基亚砜，100℃下溶解，再加入290mL乙醇稀释，保持体系回流。配好乙醇：水＝1:1(共580mL)溶液，回流条件下缓慢滴加入上述溶清体系，滴完后，体系缓慢降温至2-5℃，保温4小时。过滤，滤饼用乙醇：水＝1:1(共400mL)洗涤，滤饼真空干燥后得到式(I)化合物。MS ESI计算值:C23H28N8Se[M+H]+497，实测值497。1H NMR(400MHz,CDCl3)δ1.56(m,2H),1.80-1.86(m,2H),1.96-2.07(m,4H),2.29(s,3H),2.47-2.53(m,2H),2.62(s,1H),2.65-2.71(m,2H),2.79(s,3H),3.31(s,2H),3.97-4.17(m,1H),4.38(d,J＝8.4Hz,1H),5.71-6.18(m,1H),6.37(d,J＝0.8Hz,1H),6.59(s,1H),7.05(s,1H),8.04(s,1H)Step 7: Compound 1-9 (128.6g, 290.68mmol) was dissolved in methanol (1040mL) and dimethyl sulfoxide (260mL), and diisopropylethylamine (45.08g, 348.81mmol) and acrylonitrile ( 19.37g, 365.04mmol), reacted at 20°C for 16 hours. Add 3.9L of water to the reaction solution, stir for 2 hours, and filter to obtain a filter cake. Add 145 mL of dimethyl sulfoxide to the filter cake, dissolve it at 100°C, then add 290 mL of ethanol to dilute it, and keep the system at reflux. Prepare a solution of ethanol: water = 1:1 (580 mL in total), and slowly add the above solution system dropwise under reflux conditions. After the drops are completed, slowly cool the system to 2-5°C and keep it warm for 4 hours. Filter, wash the filter cake with ethanol: water = 1:1 (400 mL in total), and dry the filter cake under vacuum to obtain the compound of formula (I). MS ESI calculated value: C 23 H 28 N 8 Se[M+H]+497, measured value 497. 1 H NMR (400MHz, CDCl 3 ) δ1.56(m,2H),1.80-1.86(m,2H),1.96-2.07(m,4H),2.29(s,3H),2.47-2.53(m,2H ),2.62(s,1H),2.65-2.71(m,2H),2.79(s,3H),3.31(s,2H),3.97-4.17(m,1H),4.38(d,J＝8.4Hz, 1H),5.71-6.18(m,1H),6.37(d,J＝0.8Hz,1H),6.59(s,1H),7.05(s,1H),8.04(s,1H)

实施例2：式(I)化合物的A晶型的制备方法Example 2: Preparation method of crystal form A of the compound of formula (I)

化合物1-9(110g,213.45mmol)溶于甲醇(1000mL)，加入二异丙基乙基胺(110.35g,853.80mmol,)在15℃搅拌十分钟，然后加入丙烯腈(27.34g,515.24mmol)，在35℃反应16小时。反应完毕后，向反应液中加入2.0L饱和氯化铵溶液，用2.0L乙酸乙酯萃取三次，合并的有机相用2.0L饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩得到粗品，向粗品中加入1.6L的乙醇：二氯甲烷＝1：1的混合溶剂，在30℃搅拌三十分钟，然后将溶剂浓缩到1.2L，然后将体系在80℃搅拌一个小时，冷却到15℃，搅拌十六个小时，过滤得到滤饼。滤饼真空干燥后得到式(I)化合物的A晶型，如图1、图2和图3所示。MS ESI计算值:C23H28N8Se[M+H]+497，实测值497。1H NMR(400MHz,DMSO-d6)δ1.45-1.56(m,2H),1.70-1.95(m,6H),2.08-2.25(m,3H),2.56-2.65(m,4H),2.68-2.76(m,3H),3.27-3.33(m,3H),5.42-6.11(m,1H),6.22-6.32(m,1H),6.36-6.50(m,1H),6.52-6.71(m,1H),8.22(br s,1H),8.65(br s,1H),11.63(br s,1H)。Compound 1-9 (110g, 213.45mmol) was dissolved in methanol (1000mL), diisopropylethylamine (110.35g, 853.80mmol,) was added and stirred at 15°C for ten minutes, then acrylonitrile (27.34g, 515.24mmol) was added ), react at 35°C for 16 hours. After the reaction is completed, add 2.0L saturated ammonium chloride solution to the reaction solution, extract three times with 2.0L ethyl acetate, wash the combined organic phase once with 2.0L saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. Add 1.6L of ethanol: dichloromethane = 1:1 mixed solvent to the crude product, stir at 30°C for 30 minutes, then concentrate the solvent to 1.2L, then stir the system at 80°C for one hour, and cool to 15°C. Stir for sixteen hours and filter to obtain a filter cake. After vacuum drying the filter cake, crystal form A of the compound of formula (I) is obtained, as shown in Figure 1, Figure 2 and Figure 3. MS ESI calculated value: C 23 H 28 N 8 Se[M+H]+497, measured value 497. 1 H NMR (400MHz, DMSO-d 6 ) δ1.45-1.56(m,2H),1.70-1.95(m,6H),2.08-2.25(m,3H),2.56-2.65(m,4H),2.68 -2.76(m,3H),3.27-3.33(m,3H),5.42-6.11(m,1H),6.22-6.32(m,1H),6.36-6.50(m,1H),6.52-6.71(m, 1H),8.22(br s,1H),8.65(br s,1H),11.63(br s,1H).

实施例3：式(I)化合物各晶型的制备方法 Example 3: Preparation method of each crystal form of the compound of formula (I)

称取约500mg的式(I)化合物的A晶型于15mL的乙酸乙酯中，将混悬液于25℃搅拌16天，过滤烘干，将滤饼于50℃真空干燥7h后，得到式(I)化合物的B晶型。Weigh about 500 mg of Form A of the compound of formula (I) into 15 mL of ethyl acetate, stir the suspension at 25°C for 16 days, filter and dry it, and vacuum dry the filter cake at 50°C for 7 hours to obtain the formula (I) Form B of the compound.

称取约30mg式(I)化合物的A晶型于样品瓶中，分别加入0.9mL水和四氢呋喃(v/v＝2:1)的混合溶液，将所得混悬液于25℃搅拌3天过滤，在50℃烘箱烘干，得到式(I)化合物的C晶型。Weigh about 30 mg of crystal form A of the compound of formula (I) into a sample bottle, add 0.9 mL of a mixed solution of water and tetrahydrofuran (v/v=2:1), and stir the resulting suspension at 25°C for 3 days and filter. , dried in an oven at 50°C to obtain the C crystal form of the compound of formula (I).

称取约40mg式(I)化合物的A晶型于样品瓶中，于20℃下加入0.4mL二甲亚砜溶解，随后在20℃条件下将0.3mL水缓慢加入到溶液中直至析出固体，继续搅拌1天后过滤、在50℃烘箱烘干，烘了约三个小时，得到式(I)化合物的D晶型。Weigh about 40 mg of Form A of the compound of formula (I) into a sample bottle, add 0.4 mL of dimethyl sulfoxide at 20° C. to dissolve, and then slowly add 0.3 mL of water to the solution at 20° C. until solid precipitates. Continue stirring for 1 day, filter, and dry in an oven at 50°C for about three hours to obtain the D crystal form of the compound of formula (I).

称取约40mg式(I)化合物的A晶型于样品瓶中，于50℃下加入2mL 1,4-二氧六环溶解，随后在20℃条件下将4mL水缓慢加入到溶液中直至析出固体，继续搅拌1天后过滤、在50℃烘箱烘干，烘了约三个小时，得到式(I)化合物的E晶型。Weigh about 40 mg of crystal form A of the compound of formula (I) into a sample bottle, add 2 mL of 1,4-dioxane at 50°C to dissolve, and then slowly add 4 mL of water to the solution at 20°C until it precipitates. The solid was continuously stirred for 1 day, filtered, and dried in an oven at 50°C for about three hours to obtain the E crystal form of the compound of formula (I).

称取约适量式(I)化合物的A晶型和式(I)化合物的B晶型在乙醇：水(v/v＝1：1)饱和溶液中打浆得到，得到式(I)化合物的F晶型。Weigh about an appropriate amount of the A crystal form of the compound of formula (I) and the B crystal form of the compound of formula (I) and beat them in a saturated solution of ethanol:water (v/v=1:1) to obtain F of the compound of formula (I). Crystal form.

实施例4：式(I)化合物各种盐型及其晶型的制备方法Example 4: Preparation methods of various salt forms and crystal forms of the compound of formula (I)

1)称取约50mg式(I)化合物于样品瓶中，将溶剂(1,4-二氧六环或四氢呋喃)加入装有约50mg式(I)化合物的样品瓶中，在50℃条件下使其部分溶解形成式(I)化合物溶液。1) Weigh about 50 mg of the compound of formula (I) into a sample bottle, add the solvent (1,4-dioxane or tetrahydrofuran) into the sample bottle containing about 50 mg of the compound of formula (I), and place it at 50°C It is partially dissolved to form a solution of the compound of formula (I).

2)在50℃条件下将酸加入到式(I)化合物溶液中，进行成盐反应；搅拌约2小时后放入25℃条件下继续搅拌(搅拌时间约18小时)。2) Add acid to the solution of the compound of formula (I) at 50°C to perform a salt-forming reaction; stir for about 2 hours and then place it at 25°C to continue stirring (stirring time is about 18 hours).

3)对固体过滤，50℃真空烘干(烘约3小时)，对所得固体进行固态表征，得到结果如下表19：3) Filter the solid, dry it under vacuum at 50°C (about 3 hours), and conduct solid-state characterization of the obtained solid. The results are as follows in Table 19:

表19.盐型制备实验及结果
Table 19. Salt preparation experiments and results

实施例5：式(I)化合物盐酸盐及其晶型的制备方法Example 5: Preparation method of hydrochloride of compound of formula (I) and crystal form thereof

1)配置药液：将5.0mL的四氢呋喃溶剂加入约500mg的式(I)化合物中，在50℃条件下使其部分溶解； 1) Preparing the medicinal solution: Add 5.0 mL of tetrahydrofuran solvent to approximately 500 mg of the compound of formula (I), and partially dissolve it at 50°C;

2)配置酸液：将5.0mL的四氢呋喃溶剂加入85μL的浓盐酸(12mol/L)中，使酸稀释；2) Prepare acid solution: Add 5.0 mL of tetrahydrofuran solvent to 85 μL of concentrated hydrochloric acid (12 mol/L) to dilute the acid;

3)在50℃条件下将酸液慢慢滴加到药液中，进行成盐反应；搅拌约2小时后放入25℃条件下继续搅拌(搅拌时间约18小时)；3) Slowly drop the acid solution into the medicinal solution at 50°C to perform a salt-forming reaction; stir for about 2 hours and then place it at 25°C to continue stirring (stirring time is about 18 hours);

4)对固体过滤，烘干(50℃真空烘6小时)，对所得固体进行固态表征，得到式(I)化合物盐酸盐的B晶型。4) Filter the solid, dry it (vacuum drying at 50°C for 6 hours), conduct solid-state characterization of the obtained solid, and obtain the B crystal form of the hydrochloride of the compound of formula (I).

实施例6：式(I)化合物L-酒石酸盐及其晶型的制备方法Example 6: Preparation method of L-tartrate salt of compound of formula (I) and its crystal form

称取约50mg的式(I)化合物和16.36mg的L-酒石酸于样品瓶中；将1.0mL的甲醇加入于样品瓶中；在50℃条件下进行成盐反应，搅拌约2小时后放入25℃条件下继续搅拌约18小时；对固体过滤，50℃下真空烘24小时，对所得固体进行表征，得到式(I)化合物L-酒石酸盐的B晶型。Weigh about 50 mg of the compound of formula (I) and 16.36 mg of L-tartaric acid into the sample bottle; add 1.0 mL of methanol into the sample bottle; perform a salt-forming reaction at 50°C, stir for about 2 hours, and then put Continue stirring at 25°C for about 18 hours; filter the solid, vacuum dry it at 50°C for 24 hours, characterize the solid obtained, and obtain the B crystal form of compound L-tartrate of formula (I).

称取约50mg的式(I)化合物和16.28mg的L-酒石酸于样品瓶中溶解；将1.0mL的乙酸乙酯加入上述样品瓶中；在50℃条件下进行成盐反应，搅拌约2小时后放入25℃条件下继续搅拌约18小时；对固体过滤，50℃下真空烘24小时，对所得固体进行表征，得到式(I)化合物L-酒石酸盐的C晶型。Weigh about 50 mg of the compound of formula (I) and 16.28 mg of L-tartaric acid and dissolve it in the sample bottle; add 1.0 mL of ethyl acetate to the above sample bottle; perform a salt-forming reaction at 50°C and stir for about 2 hours. Afterwards, the mixture was placed at 25°C and continued to stir for about 18 hours; the solid was filtered, and dried under vacuum at 50°C for 24 hours. The obtained solid was characterized to obtain the C crystal form of compound L-tartrate of formula (I).

实施例7：式(I)化合物L-苹果酸盐及其晶型的制备方法Example 7: Preparation method of L-malate salt of compound of formula (I) and its crystal form

称取约500mg的式(I)化合物和143.52mg的L-苹果酸于样品瓶中；将10.0mL的甲醇溶剂加入于样品瓶中；在50℃条件下进行成盐反应；搅拌约2小时后放入25℃条件下继续搅拌18小时；对固体过滤，在50℃真空烘27小时，对所得固体进行固态表征，得到式(I)化合物L-苹果酸盐的A晶型。Weigh about 500 mg of the compound of formula (I) and 143.52 mg of L-malic acid into the sample bottle; add 10.0 mL of methanol solvent into the sample bottle; perform a salt-forming reaction at 50°C; stir for about 2 hours. Place the solid at 25°C and continue stirring for 18 hours; filter the solid and dry it under vacuum at 50°C for 27 hours. Perform solid-state characterization of the obtained solid to obtain the A crystal form of compound L-malate of formula (I).

实施例8：式(I)化合物的A晶型吸湿性研究Example 8: Study on the hygroscopicity of crystal form A of the compound of formula (I)

实验材料：Experimental Materials:

动态水分吸附仪Dynamic moisture adsorption instrument

实验方法：experimental method:

取式(I)化合物的A晶型20～40mg置于DVS样品盘内进行测试。Take 20 to 40 mg of crystal form A of the compound of formula (I) and place it in the DVS sample tray for testing.

实验结果：Experimental results:

式(I)化合物的A晶型的DVS谱图如图42所示，当湿度升至80％时，△W＝0.443％。The DVS spectrum of crystal form A of the compound of formula (I) is shown in Figure 42. When the humidity rises to 80%, ΔW=0.443%.

实验结论：Experimental results:

式(I)化合物的A晶型在25℃和80％RH下的吸湿增重为0.443％，略有吸湿性。The hygroscopic weight gain of crystal form A of the compound of formula (I) at 25°C and 80% RH is 0.443%, which is slightly hygroscopic.

实施例9：式(I)化合物的B晶型吸湿性研究Example 9: Study on the hygroscopicity of crystal form B of the compound of formula (I)

实验材料：Experimental Materials:

动态水分吸附仪Dynamic moisture adsorption instrument

实验方法：experimental method:

取式(I)化合物的B晶型20～40mg置于DVS样品盘内进行测试。Take 20-40 mg of the B crystal form of the compound of formula (I) and place it in the DVS sample tray for testing.

实验结果： Experimental results:

式(I)化合物的B晶型的DVS谱图如图43所示，当湿度升至80％时，△W＝0.598％。The DVS spectrum of the B crystal form of the compound of formula (I) is shown in Figure 43. When the humidity rises to 80%, ΔW=0.598%.

实验结论：Experimental results:

式(I)化合物的B晶型在25℃和80％RH下的吸湿增重为0.598％，略有吸湿性。The hygroscopic weight gain of the B crystal form of the compound of formula (I) at 25°C and 80% RH is 0.598%, which is slightly hygroscopic.

生物测试biological testing

实验例1Experimental example 1

主要试剂和耗材如表20所示：The main reagents and consumables are shown in Table 20:

表20.主要试剂和耗材参数
Table 20. Main reagent and consumable parameters

实验方法experimental method

本次试验中JAK1,2,3和TYK2使用方法进行活性检测。在检测板中，将酶、ULight标记的多肽底物、ATP以及检测化合物混合，孵育反应。反应后，加入EDTA终止反应，并同时加入Eu标记的抗体。在激酶检测中，铕标记的抗磷酸化基质抗体与磷酸化的ULight标记的基质结合可使供体和受体分子相互趋近。经过320nm波长光的照射后，激酶发生反应，铕供体的能量将转移到ULight受体染料中，并生成波长665nm的光。光的发射强度与ULight基质的磷酸化水平成比例。In this experiment, JAK1, 2, 3 and TYK2 were used method for activity detection. In the detection plate, mix the enzyme, ULight-labeled peptide substrate, ATP, and detection compound, and incubate the reaction. After the reaction, EDTA was added to terminate the reaction, and Eu-labeled antibodies were added at the same time. exist In kinase assays, Europium-labeled anti-phosphorylated matrix antibodies bind to phosphorylated ULight-labeled matrix to bring donor and acceptor molecules closer to each other. After irradiation with 320nm wavelength light, the kinase reacts, and the energy of the europium donor will be transferred to the ULight acceptor dye and generate light with a wavelength of 665nm. The intensity of light emission is proportional to the phosphorylation level of the ULight matrix.

化合物最终测试浓度：受试化合物最终测试浓度从1μM到0.017nM，3倍梯度稀释，11个浓度。DMSO在检测反应中的含量为1％。Final test concentration of the compound: The final test concentration of the test compound ranges from 1 μM to 0.017 nM, 3-fold gradient dilution, 11 concentrations. The content of DMSO in the detection reaction is 1%.

激酶检测：缓冲液的配制，缓冲液包括:50mM HEPES(pH 7.5),0.01％Brij-35,10mM MgCl2,1mM EDTA,1mM DTT。Kinase detection: preparation of buffer, including: 50mM HEPES (pH 7.5), 0.01% Brij-35, 10mM MgCl 2 , 1mM EDTA, 1mM DTT.

JAK1酶反应：JAK1 enzyme reaction:

在缓冲液中，将2nM JAK1和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加38μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。 Pre-incubate 2 nM JAK1 and 50 nM substrate with different concentrations of pre-diluted compounds in buffer for 15 minutes. Start the reaction by adding 38 μM ATP and incubate at room temperature for 90 minutes. After the reaction is completed, add antibody detection, incubate at room temperature for 60 minutes, and then detect using Evnvision to collect data.

JAK2酶反应：JAK2 enzyme reaction:

在缓冲液中，将0.03nM JAK2和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加12μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。In buffer, 0.03 nM JAK2 and 50 nM substrate were mixed with pre-diluted compounds of varying concentrations and pre-incubated for 15 minutes. Start the reaction by adding 12 μM ATP and incubate at room temperature for 90 minutes. After the reaction is completed, add antibody detection, incubate at room temperature for 60 minutes, and then detect using Evnvision to collect data.

数据分析：data analysis:

根据％抑制vs.log[化合物浓度]，使用XLfit5软件mode205进行数据分析及拟图得到IC50数据，结果总结见表21。According to % inhibition vs. log [compound concentration], use XLfit5 software mode205 for data analysis and plotting to obtain IC 50 data. The results are summarized in Table 21.

表21.受试化合物激酶活性总结
Table 21. Summary of kinase activities of test compounds

结论：本发明的受试化合物在激酶2个亚型JAK1、JAK2的体外活性测试中展现了对其良好的抑制作用。Conclusion: The test compound of the present invention showed good inhibitory effect on two subtypes of kinases, JAK1 and JAK2, in the in vitro activity test.

实验例2Experimental example 2

主要试剂及仪器Main reagents and instruments

主要试剂耗材如表22所示：The main reagent consumables are shown in Table 22:

表22.主要试剂和耗材参数
Table 22. Main reagent and consumable parameters

仪器instrument

流式细胞仪；品牌：BD；型号：FortessaFlow cytometer; Brand: BD; Model: Fortessa

试剂配置： Reagent configuration:

完全培养液：1640培养液+10％胎牛血清+1％青/链霉素(百分比皆为体积比)Complete culture medium: 1640 culture medium + 10% fetal bovine serum + 1% penicillin/streptomycin (all percentages are volume ratios)

实验步骤Experimental steps

a)药物处理及诱导a) Drug treatment and induction

(1)倒掉HT29细胞培养液，加入10mM乙二胺四乙酸，37℃孵育5min将细胞消化下来。(1) Pour away the HT29 cell culture medium, add 10mM ethylenediaminetetraacetic acid, and incubate at 37°C for 5 minutes to digest the cells.

(2)将HT29细胞和THP1细胞一起320g离心3min。(2) Centrifuge HT29 cells and THP1 cells together at 320g for 3 minutes.

(3)细胞计数，然后用完全培养液将细胞浓度调整至7.5×105/mL；200μL/孔接种至96孔圆底板。(3) Count the cells, then use complete culture medium to adjust the cell concentration to 7.5×10 5 /mL; inoculate 200 μL/well into a 96-well round bottom plate.

(4)在细胞中加入药物，终浓度为5000.00nM、1000.00nM、200.00nM、40.00nM、8.00nM、1.60nM、0.32nM、0.06nM。37℃孵育30min(阴性及阳性对照组不加药物，加入相同浓度二甲基亚砜)。(4) Add drugs to the cells at final concentrations of 5000.00nM, 1000.00nM, 200.00nM, 40.00nM, 8.00nM, 1.60nM, 0.32nM, and 0.06nM. Incubate at 37°C for 30 minutes (no drugs are added to the negative and positive control groups, and the same concentration of dimethyl sulfoxide is added).

(5)在HT29细胞中加入IL-13(终浓度6ng/mL)，37℃孵育30min；在THP1细胞中加入IL-6(终浓度30ng/mL)，37℃孵育15min(阴性对照组不加细胞因子刺激，阳性对照组加入同样浓度细胞因子)。(5) Add IL-13 (final concentration 6ng/mL) to HT29 cells and incubate at 37°C for 30 minutes; add IL-6 (final concentration 30ng/mL) to THP1 cells and incubate at 37°C for 15 minutes (the negative control group does not add Cytokine stimulation, the same concentration of cytokines was added to the positive control group).

b)细胞染色及流式细胞术检测b) Cell staining and flow cytometry detection

(1)将上面的HT29和THP1细胞320g离心3min。(1) Centrifuge the above HT29 and THP1 cells at 320g for 3 minutes.

(2)用染色缓冲液洗涤细胞两次。(2) Wash cells twice with staining buffer.

(3)每孔加入100μL细胞固定液，4℃固定15min。(3) Add 100 μL cell fixative to each well and fix at 4°C for 15 minutes.

(4)用染色缓冲液洗涤细胞两次。(4) Wash the cells twice with staining buffer.

(5)每孔加入100μL细胞破膜液，4℃破膜30min。(5) Add 100 μL of cell membrane rupture solution to each well and rupture the membrane at 4°C for 30 minutes.

(6)以2:48的比例将pSTAT3抗体或pSTAT6抗体加入到染色缓冲液中，50μL/孔分别加入到THP1或HT29细胞里，4℃染色30min。(6) Add pSTAT3 antibody or pSTAT6 antibody to the staining buffer at a ratio of 2:48, and add 50 μL/well to THP1 or HT29 cells respectively, and stain for 30 minutes at 4°C.

(7)用染色缓冲液洗涤细胞两次。(7) Wash the cells twice with staining buffer.

(8)用150μL染色缓冲液重悬细胞，用流式细胞仪检测PE通道(pSTAT)平均荧光强度(MFI)。(8) Resuspend the cells in 150 μL of staining buffer, and use a flow cytometer to detect the mean fluorescence intensity (MFI) of the PE channel (pSTAT).

c)数据处理c)Data processing

(1)流式细胞仪检测得到样品对应的MFI。(1) Flow cytometry detects the MFI corresponding to the sample.

(2)响应率(Response％)＝100×(样品MFI–阴性对照组MFI)/(阳性对照组MFI–阴性对照组MFI)(2) Response rate (Response%) = 100 × (sample MFI – negative control MFI) / (positive control MFI – negative control MFI)

(3)将响应率带入graphpad prism8软件用log(inhibitor)vs.response--Variable slope(four parameters)方法拟合曲线并得到半数抑制浓度(IC50)。(3) Bring the response rate into the graphpad prism8 software and use the log(inhibitor) vs. response--Variable slope (four parameters) method to fit the curve and obtain the half inhibitory concentration (IC 50 ).

THP1和HT29细胞JAK抑制活性测试的结果见表23。The results of the JAK inhibitory activity test of THP1 and HT29 cells are shown in Table 23.

表23.受试化合物细胞活性总结

Table 23. Summary of cell activities of test compounds

结论：本发明的受试化合物在细胞(THP1和HT29)功能实验的体外活性测试中展现了对其良好的抑制性。Conclusion: The test compound of the present invention showed good inhibitory properties in the in vitro activity test of cell (THP1 and HT29) functional experiments.

实验例3Experimental example 3

试验动物：Test animals:

SD大鼠，每组2只，雄性，北京维通利华实验动物技术有限公司。SD rats, 2 in each group, male, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

给药：Administration:

雄性SD大鼠每个时间点2只，4个时间点，共8只；禁食一夜后分别p.o给药，剂量为5mg/kg，给药体积5mL/kg。There were 2 male SD rats at each time point, 4 time points, a total of 8 rats; they were administered p.o. after fasting overnight, the dose was 5 mg/kg, and the administration volume was 5 mL/kg.

样品采集：Sample Collection:

大鼠给药后，在1、3、6、12小时，采用CO2处死，采用颈静脉采血约200μL，置于EDTA-K2试管中，4℃,3,200g离心10min分离获得血浆，于-70±10℃保存；在每个时间点取小肠和结肠，结肠和小肠挤去内容物之后用生理盐水冲洗后称重匀浆(匀浆液为甲醇:15mM PBS＝1:2)，匀浆比例为1：4(1g组织4ml匀浆液)，于-70±10℃保存。After administration, the rats were sacrificed with CO2 at 1, 3, 6, and 12 hours. About 200 μL of blood was collected from the jugular vein, placed in an EDTA-K2 test tube, and centrifuged at 3,200 g for 10 min at 4°C to separate the plasma. Store at ±10°C; take the small intestine and colon at each time point. After squeezing out the contents, rinse the colon and small intestine with physiological saline and weigh the homogenate (the homogenate is methanol:15mM PBS=1:2). The homogenate ratio is: 1:4 (1g tissue 4ml homogenate), stored at -70±10℃.

样品处理:Sample processing:

血浆样品处理：Plasma sample processing:

蛋白沉淀：20μL血浆样品中加入200μL含内标乙腈沉淀，混合后12,000g,4℃离心，取处理后上清液50μL加入96孔板，3,220g,4℃离心后，上清直接进行LC-MS/MS分析。Protein precipitation: Add 200 μL of acetonitrile precipitate containing internal standard to 20 μL of plasma sample, mix and centrifuge at 12,000 g and 4°C. Take 50 μL of the processed supernatant and add it to a 96-well plate. After centrifugation at 3,220 g and 4°C, the supernatant is directly subjected to LC- MS/MS analysis.

小肠匀浆样品处理：Small intestine homogenate sample processing:

40μL小肠匀浆样品中加入400μL含内标乙腈沉淀，混合后12,000g,4℃离心，取处理后上清液50μL加入96孔板，3220g,4℃离心后，上清直接进行LC-MS/MS分析。Add 400 μL of acetonitrile precipitate containing internal standard to 40 μL of small intestinal homogenate sample, mix and centrifuge at 12,000 g at 4°C. Add 50 μL of the processed supernatant to a 96-well plate, centrifuge at 3220 g at 4°C, and then perform LC-MS/MS directly on the supernatant. MS analysis.

结肠匀浆样品处理：Colon homogenate sample processing:

40μL结肠匀浆样品中加入400μL含内标乙腈沉淀，混合后12,000g,4℃离心，取处理后上清液50μL加入96孔板，3,220g,4℃离心后，上清直接进行LC-MS/MS分析。Add 400 μL of acetonitrile precipitate containing internal standard to 40 μL of colon homogenate sample, mix and centrifuge at 12,000 g and 4°C. Take 50 μL of the processed supernatant and add it to a 96-well plate. After centrifugation at 3,220 g and 4°C, the supernatant is directly subjected to LC-MS. /MS analysis.

实验结果如下表24：The experimental results are as follows in Table 24:

表24.大鼠小肠、结肠和血浆实验结果

Table 24. Rat small intestine, colon and plasma experimental results

结论：本发明化合物在大鼠小肠和结肠表现出良好的药物暴露水平，并且化合物的小肠/血浆，结肠/血浆的比值较高，表现良好的组织选择性。Conclusion: The compound of the present invention shows good drug exposure levels in the small intestine and colon of rats, and the compound has high small intestine/plasma and colon/plasma ratios, showing good tissue selectivity.

实验例4Experimental example 4

噁唑酮(Oxazolone,OXA)诱导的小鼠肠炎模型Oxazolone (OXA)-induced enteritis model in mice

试验动物：Test animals:

Balb/c小鼠45只，8-10周龄，18-20g，雌性。45 Balb/c mice, 8-10 weeks old, 18-20g, female.

实验步骤：Experimental steps:

随机分成9组，空白对照组，5只小鼠，100微升丙酮+橄榄油(4:1)背部致敏5天，于Day 0天开始直肠灌注50％的乙醇；其余8组模型组，每组5只小鼠，100微升2％的Oxazolone(丙酮+橄榄油稀释)致敏5天，于Day 0天开始直肠灌注150微升1％的Oxazolone溶液。待测试化合物于Day-1天开始给药至Day3结束，Day4为实验终点具体分组见表25。Randomly divided into 9 groups, blank control group, 5 mice, 100 μl acetone + olive oil (4:1) back sensitization for 5 days, rectal infusion of 50% ethanol starting on Day 0; the remaining 8 model groups, Five mice in each group were sensitized with 100 μl of 2% Oxazolone (diluted in acetone + olive oil) for 5 days, and rectal infusion of 150 μl of 1% Oxazolone solution began on Day 0. The compounds to be tested were administered from Day-1 to the end of Day 3. Day 4 is the end point of the experiment. The specific groupings are shown in Table 25.

表25.动物分组及给药方案
Table 25. Animal grouping and dosage regimen

注：溶媒为0.5％CMC-NaNote: The solvent is 0.5% CMC-Na

数据处理data processing

实验期间(In-life)During the experiment (In-life)

每天记录动物的体重及疾病活动指数(DAI)评分，用于评价各组动物发病情况及测试化合物对疾病的影响。DAI评分由3部分组成，具体标准参考下表26。The body weight and disease activity index (DAI) score of the animals were recorded every day to evaluate the disease incidence of animals in each group and the impact of the test compounds on the disease. The DAI score consists of 3 parts. For specific standards, please refer to Table 26 below.

表26.DAI评分标准
Table 26. DAI scoring criteria

粪便隐血测定的方法描述 Description of methods for fecal occult blood determination

见到粪便或肛门处有新鲜血液，不再测定隐血。其余将未见明显血便小鼠的粪便收集起来，进行隐血的测定。若粪便在1-2分钟内，颜色越来越深，给2分。若粪便在1-2分钟内内未见明显的颜色或颜色很弱，后面有颜色出现，但颜色深度明显低于2分小鼠粪便的颜色，给1分。If fresh blood is seen in the feces or anus, occult blood will not be measured. The feces of the remaining mice without obvious bloody stools were collected and occult blood was measured. If the color of the stool becomes darker and darker within 1-2 minutes, give 2 points. If there is no obvious color in the feces within 1-2 minutes or the color is very weak, and then color appears later, but the color depth is significantly lower than the color of mouse feces, which is 2 points, give 1 point.

实验结果Experimental results

所得数据采用平均数±标准误表示，并分析统计学差异，结果见表27、表28和表29。 The obtained data are expressed as mean ± standard error, and statistical differences are analyzed. The results are shown in Table 27, Table 28 and Table 29.

表27.体重变化
Table 27. Weight changes

表28.DAI评分变化
Table 28. DAI score changes

表29.结肠长度和重量变化
Table 29. Colon length and weight changes

结论：本发明的化合物在噁唑酮(Oxazolone,OXA)诱导的小鼠肠炎模型中，能够缓解OXA诱导的体重降低，显著改善疾病活动指数(DAI)评分和实验终点结肠重量长度比，展现良好治疗效果。 Conclusion: The compound of the present invention can alleviate the weight loss induced by OXA in the mouse enteritis model induced by oxazolone (OXA), significantly improve the disease activity index (DAI) score and the experimental endpoint colon weight-to-length ratio, showing good performance treatment effect.

Claims (11)

式(I)化合物的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.33±0.20°，16.22±0.20°和22.84±0.20°，
The A crystal form of the compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 9.33±0.20°, 16.22±0.20 ° and 22.84±0.20°,
根据权利要求1所述的式(I)化合物的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.33±0.20°，14.08±0.20°，16.22±0.20°，16.74±0.20°，17.47±0.20°，20.10±0.20°，20.10±0.20°和22.84±0.20°。The A crystal form of the compound of formula (I) according to claim 1, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 9.33 ±0.20°, 14.08±0.20°, 16.22±0.20°, 16.74±0.20°, 17.47±0.20°, 20.10±0.20°, 20.10±0.20° and 22.84±0.20°. 根据权利要求2所述的式(I)化合物的A晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.05±0.10°，9.33±0.10°，12.95±0.10°，14.08±0.10°，16.22±0.10°，16.74±0.10°，17.47±0.10°，19.26±0.10°，19.81±0.10°，20.10±0.10°，21.04±0.10°和22.84±0.10°。The A crystal form of the compound of formula (I) according to claim 2, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 9.05 ±0.10°, 9.33±0.10°, 12.95±0.10°, 14.08±0.10°, 16.22±0.10°, 16.74±0.10°, 17.47±0.10°, 19.26±0.10°, 19.81±0.10°, 20.10±0.10°, 21.04 ±0.10° and 22.84±0.10°. 式(I)化合物的A晶型，
Form A of the compound of formula (I),
其XRPD图谱如附图1所示。Its XRPD pattern is shown in Figure 1. 根据权利要求1～4任意一项所述的式(I)化合物的A晶型差示扫描量热曲线在216.01±3℃处有一个吸热峰的起始点。The differential scanning calorimetry curve of crystal form A of the compound of formula (I) according to any one of claims 1 to 4 has an endothermic peak starting point at 216.01±3°C. 式(I)化合物的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.47±0.20°，16.36±0.20°和22.95±0.20°，
The B crystal form of the compound of formula (I) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 9.47±0.20°, 16.36±0.20 ° and 22.95±0.20°,
根据权利要求5所述的式(I)化合物的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.47±0.20°，16.36±0.20°，16.81±0.20°，19.34±0.20°，20.08±0.20°，22.95±0.20°，25.93±0.20°和28.10±0.20°。The B crystal form of the compound of formula (I) according to claim 5, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 9.47 ±0.20°, 16.36±0.20°, 16.81±0.20°, 19.34±0.20°, 20.08±0.20°, 22.95±0.20°, 25.93±0.20° and 28.10±0.20°. 根据权利要求6所述的式(I)化合物的B晶型，其特征在于，使用Cu-Kα辐射，该晶型的X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：9.47±0.20°，12.60±0.20°，13.02±0.20°，16.36±0.20°，16.81±0.20°，18.68±0.20°，19.34±0.20°，20.08±0.20°，22.95±0.20°，25.93±0.20°，27.51±0.20°和28.10±0.20°。The B crystal form of the compound of formula (I) according to claim 6, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has a characteristic diffraction peak at the following 2θ angle: 9.47 ±0.20°, 12.60±0.20°, 13.02±0.20°, 16.36±0.20°, 16.81±0.20°, 18.68±0.20°, 19.34±0.20°, 20.08±0.20°, 22.95±0.20°, 25.93±0.20°, 27.51 ±0.20° and 28.10±0.20°. 式(I)化合物的B晶型，
Form B of the compound of formula (I),
其XRPD图谱如附图4所示。Its XRPD pattern is shown in Figure 4. 根据权利要求6～9任意一项所述的式(I)化合物的B晶型，其差示扫描量热曲线在217.39±3℃处有一个吸热峰的起始点。According to the B crystal form of the compound of formula (I) according to any one of claims 6 to 9, the differential scanning calorimetry curve has an endothermic peak starting point at 217.39±3°C. 根据权利要求1～5任意一项所述式(I)化合物的A晶型，权利要求6～10任意一项所述式(I)化合物的B晶型在制备治疗JAK相关疾病的药物中的应用。 According to the A crystal form of the compound of formula (I) according to any one of claims 1 to 5, and the B crystal form of the compound of formula (I) according to any one of claims 6 to 10 in the preparation of drugs for treating JAK related diseases. application.
PCT/CN2023/089796 2022-04-21 2023-04-21 Salt form and crystal form of selenium heterocyclic compound and application thereof Ceased WO2023202706A1 (en)

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