WO2023202706A1 - Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application - Google Patents

Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
compound
formula
present
xrpd
Prior art date
Application number
PCT/CN2023/089796
Other languages
English (en)
Chinese (zh)
Inventor
郭强
郑学建
王伟军
钱文远
Original Assignee
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Publication of WO2023202706A1 publication Critical patent/WO2023202706A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme saline et une forme cristalline d'un composé hétérocyclique de sélénium et une application de celles-ci. Spécifiquement, la présente invention concerne une forme cristalline, chaque forme saline et les formes cristallines des formes salines d'un composé de formule (I).
PCT/CN2023/089796 2022-04-21 2023-04-21 Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application WO2023202706A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210427467 2022-04-21
CN202210427467.9 2022-04-21

Publications (1)

Publication Number Publication Date
WO2023202706A1 true WO2023202706A1 (fr) 2023-10-26

Family

ID=88419304

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/089796 WO2023202706A1 (fr) 2022-04-21 2023-04-21 Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application

Country Status (1)

Country Link
WO (1) WO2023202706A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103153300A (zh) * 2010-08-11 2013-06-12 米伦纽姆医药公司 杂芳基化合物和其用途
CN103848798A (zh) * 2012-11-30 2014-06-11 镇江新元素医药科技有限公司 2-芳基硒唑化合物及其药物组合物
CN107667108A (zh) * 2015-05-28 2018-02-06 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的萘啶化合物
CN109071529A (zh) * 2016-04-28 2018-12-21 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的嘧啶化合物
WO2020108516A1 (fr) * 2018-11-27 2020-06-04 江苏豪森药业集团有限公司 Régulateur de dérivé d'hétéroaryle contenant un nitrogène, son procédé de préparation et ses applications
WO2020219640A1 (fr) * 2019-04-24 2020-10-29 Theravance Biopharma R&D Ip, Llc Inhibiteurs de jak à base de pyrimidine pour le traitement de maladies de la peau
WO2022083687A1 (fr) * 2020-10-21 2022-04-28 南京明德新药研发有限公司 Composés hétérocycliques de sélénium et leur application

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103153300A (zh) * 2010-08-11 2013-06-12 米伦纽姆医药公司 杂芳基化合物和其用途
CN103848798A (zh) * 2012-11-30 2014-06-11 镇江新元素医药科技有限公司 2-芳基硒唑化合物及其药物组合物
CN107667108A (zh) * 2015-05-28 2018-02-06 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的萘啶化合物
CN109071529A (zh) * 2016-04-28 2018-12-21 施万生物制药研发Ip有限责任公司 作为jak激酶抑制剂的嘧啶化合物
WO2020108516A1 (fr) * 2018-11-27 2020-06-04 江苏豪森药业集团有限公司 Régulateur de dérivé d'hétéroaryle contenant un nitrogène, son procédé de préparation et ses applications
WO2020219640A1 (fr) * 2019-04-24 2020-10-29 Theravance Biopharma R&D Ip, Llc Inhibiteurs de jak à base de pyrimidine pour le traitement de maladies de la peau
WO2022083687A1 (fr) * 2020-10-21 2022-04-28 南京明德新药研发有限公司 Composés hétérocycliques de sélénium et leur application

Similar Documents

Publication Publication Date Title
JP6476253B2 (ja) Ｎ−（５Ｓ，６Ｓ，９Ｒ）−５−アミノ−６−（２，３−ジフルオロフェニル）−６，７，８，９−テトラヒドロ−５Ｈ−シクロヘプタ［ｂ］ピリジン−９−イル−４−（２−オキソ−２，３−ジヒドロ−１Ｈ−イミダゾ［４，５−ｂ］ピリジン−１−イル）ピペリジン−１−カルボキシレート塩
US10457680B2 (en) Process for preparing a PARP inhibitor, crystalline forms, and uses thereof
CN104936953B (zh) 化合物
CN109689641B (zh) 一种取代的2-氢-吡唑衍生物的晶型、盐型及其制备方法
US20190330215A1 (en) Pyrrolopyrimidine crystal for preparing jak inhibitor
TWI836822B (zh) p38 MAPK/MK2通路調節劑及其組合物、製備方法和用途
EA023103B1 (ru) Замещенный натрий-1н-пиразол-5-олат
CN116768861A (zh) Sos1蛋白降解靶向嵌合体及其组合物、制剂和用途
EP3896063A1 (fr) Sel d&#39;inhibiteur de syk et forme cristalline correspondante
WO2023202706A1 (fr) Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application
WO2022257965A1 (fr) Inhibiteur de kinase 9 dépendante de la cycline sous forme solide et son utilisation
TW202311252A (zh) 作為tyk2/jak1假激酶結構域抑制劑的化合物及合成和使用方法
AU2007221194A1 (en) CCR5 antagonists useful for treating HIV
WO2023093861A1 (fr) Mono-p-toluènesulfonate d&#39;inhibiteur de kinase axl et forme cristalline de celui-ci
WO2023246858A1 (fr) Sel pharmaceutique de dérivé de borate, et forme de cristallisation de celui-ci et utilisation associée
CN115397827B (zh) Fgfr4抑制剂的盐型、晶型及其用途
TWI835909B (zh) 週期素依賴性激酶7(cdk7)之抑制劑
WO2023246854A1 (fr) Cristal de dérivé de borate, son procédé de préparation et son utilisation
WO2024027825A1 (fr) Inhibiteur de cdk et polymorphe de phosphate de celui-ci
WO2023020600A1 (fr) Forme saline et forme cristalline d&#39;un inhibiteur de l&#39;egfr, et composition et utilisation associées
CN117247382A (zh) 吡啶并嘧啶酮化合物的晶型
CN115504980A (zh) 嘧啶并含氮六元芳香杂环类化合物及其用途
TW202100513A (zh) 氘原子取代的吲哚甲酰胺類衍生物的晶型及其製備方法
CN112209934A (zh) 含有氮杂螺庚烷的btk抑制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23791358

Country of ref document: EP

Kind code of ref document: A1