WO2023207933A1 - 一种作为免疫调节剂的联苯类化合物的晶型及其制备方法 - Google Patents

一种作为免疫调节剂的联苯类化合物的晶型及其制备方法 Download PDF

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WO2023207933A1
WO2023207933A1 PCT/CN2023/090466 CN2023090466W WO2023207933A1 WO 2023207933 A1 WO2023207933 A1 WO 2023207933A1 CN 2023090466 W CN2023090466 W CN 2023090466W WO 2023207933 A1 WO2023207933 A1 WO 2023207933A1
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crystal form
crystal
angles
ray powder
following
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PCT/CN2023/090466
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French (fr)
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杨千姣
余金迪
山松
王晓亮
张钰
刘霞
潘德思
李志斌
鲁先平
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深圳微芯生物科技股份有限公司
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Publication of WO2023207933A1 publication Critical patent/WO2023207933A1/zh

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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a crystal form of a biphenyl compound as an immunomodulator and a preparation method thereof. It also includes the application of the crystal form in preparing drugs for treating diseases related to immune modulation.
  • Tumor immunotherapy is a new treatment method that stimulates the body's immune system and enhances its own anti-tumor immunity, thereby inhibiting or killing tumor cells. This method has achieved breakthrough progress after more than a hundred years of efforts. In 2013, Science magazine ranked tumor immunotherapy among the top ten scientific breakthroughs of the year (Couzin-Frankel J., 2013, Science, 342:1432-1433), and it has become one of the most promising fields of anti-tumor treatment. .
  • T cell anti-tumor immunity Compared with normal cells, tumor cells have a variety of genetic and epigenetic changes.
  • the immune system can use the surface antigens produced by tumor cells to distinguish the two, thereby triggering an anti-tumor immune response.
  • T cell anti-tumor immunity after being activated by the antigen recognition signal mediated by T cell receptor (TCR), it comprehensively regulates T cell effects through costimulation and costinhibitory signals, including cytotoxic T lymphocytes.
  • Cytotoxic T-lymphocyte associated antigen 4 CTL4
  • programmed death protein 1 PD-1
  • T cell activation immunoglobulin inhibitory V-domain V-domain immunoglobulin suppressor of T-cell activation
  • TIM3 T cell immunoglobulin and mucin domain-containing-3
  • LAG3 lymphocyte activation gene 3
  • Inhibitory receptors such as inhibitory signals, and activating receptors for stimulatory signals such as CD28, CD134 (OX40), Glucocorticoid-induced TNFR-related protein (GITR), CD137, CD27, HVEM, etc.
  • immune checkpoints are involved in maintaining immune tolerance to self-antigens and avoiding autoimmune diseases; on the other hand, they are involved in preventing tissue damage caused by excessive activation of immune responses.
  • tumor cells they can evade immune killing by inhibiting T cell activation through immune checkpoints. Therefore, it is necessary to reactivate T cells to attack tumor cells by activating co-stimulatory signals (stepping on the "gas pedal") and inhibiting co-inhibitory signals (loosening the "brakes”) to achieve tumor immunotherapy.
  • PD-1 is expressed in activated T cells, B cells and bone marrow cells. It belongs to the CD28 family. It is a type 1 transmembrane glycoprotein on T cells and consists of 288 amino acids.
  • the molecular structure of PD-1 consists of an immunoglobulin IgV-like (amino acid 35-145) extracellular region, a transmembrane region, and a cytoplasmic tail region with the function of connecting a signal peptide. The extracellular region binds to the ligand. Play important functions (Cheng X., Veverka V., Radhakrishnan A., et al. 2013, J. Biol. Chem., 288: 11771-11785).
  • Programmed death protein ligand 1 is one of the ligands of PD-1 and belongs to the B7 family. It is continuously expressed in a variety of tumor cells, T cells, and antigen-presenting cells (APC). And in a variety of non-hematopoietic cells, it is also a type1 transmembrane glycoprotein, which consists of 290 amino acids. The interaction between PD-1 and PD-L1 inhibits T cell activation, which is crucial for maintaining immune tolerance of the normal body. PD-1 on T cells is inducibly expressed in tumor cells and during viral infection.
  • the expression of PD-L1 is up-regulated, resulting in continuous activation of the PD-1 signaling pathway and inhibition of T cell proliferation, resulting in immune evasion of tumor cells and pathogens (Fuller MJ, Callendret B., Zhu B., et al. 2013, Proc. Natl .Acad.Sci.USA.,110:15001-15006;Dolan DE,Gupta S.,2014,Cancer Control,21:231-237;Chen L.,Han X.,2015,J.Clin.Invest.,125 :3384-3391; Postow MA, Callahan MK, Wolchok JD, 2015, J. Clin. Oncol., 33:1974-1982).
  • Multiple antibody drugs for PD-1 and PD-L1 that have been launched in recent years have fully proved that blocking the PD-1/PD-L1 interaction is a very effective treatment in tumor immunotherapy and various other immune-related diseases. means.
  • PD-L1 can interact with CD80 and inhibit the binding of PD-L1 and PD-1, as well as inhibit the ability of T cells to activate. Therefore, blocking immune activation caused by CD80/PD-L1 interaction may also promote the enhancement of T cell activity, thereby providing new treatment opportunities for immune-related diseases (Sugiura D., Maruhashi T., Okazaki ll-mi, et al. 2019, Science, 364:558-566).
  • small-molecule immunomodulators have certain advantages, including being orally available, more tissue-penetrating, and able to minimize side effects through pharmacological adjustment.
  • small molecule inhibitors will have a lower price advantage.
  • nivolumab T 1/2 is administered for 25.2 days, and the dosing frequency is once every two weeks; pembrolizumab T 1/2 is administered for 25 days, and the dosing frequency is once every two weeks. The frequency is once every three weeks; atezolizumab T 1/2 is 27 days and the frequency of dosing is once every three weeks.
  • the administration frequency of the above-mentioned drugs is shorter than the drug half-life, indicating that the continuous exposure of such target drugs in the body is the key to obtaining ideal clinical efficacy.
  • the exposure of disclosed small molecule immunomodulators in vivo is low and the continuous exposure time is short, which will affect the clinical efficacy.
  • the invention provides a crystal form of the compound represented by formula (I) or a solvate thereof.
  • the crystal form is selected from the group consisting of Form A crystal form, Form B crystal form, Form C crystal form, Form D crystal form, and Form E crystal form.
  • Form F and Form G crystal form are selected from the group consisting of Form A crystal form, Form B crystal form, Form C crystal form, Form D crystal form, and Form E crystal form.
  • the X-ray powder diffraction pattern of the Form A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.39 ⁇ 0.2°, 13.85 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.70 ⁇ 0.2°, 9.54 ⁇ 0.2°, 13.90 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.10 ⁇ 0.2°, 12.30 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.45 ⁇ 0.2°, 12.95 ⁇ 0.2°, 13.65 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.81 ⁇ 0.2°, 13.73 ⁇ 0.2°, 15.89 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.73 ⁇ 0.2°, 9.07 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the Form G crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 14.75 ⁇ 0.2°, 17.72 ⁇ 0.2°.
  • the compound represented by formula (I) is described in patent CN202180004723.7, the entire content of which is incorporated into the present invention.
  • the invention provides the Form A crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.39 ⁇ 0.2°, 13.85 ⁇ 0.2°.
  • the Form A crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.39 ⁇ 0.2°, 13.85 ⁇ 0.2°, 17.25 ⁇ 0.2° .
  • the Form A crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.39 ⁇ 0.2°, 12.70 ⁇ 0.2°, 13.85 ⁇ 0.2° , 15.30 ⁇ 0.2°, 17.25 ⁇ 0.2°, 25.06 ⁇ 0.2°.
  • the compound represented by formula (I), Form A crystal form has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.39 ⁇ 0.2°, 9.28 ⁇ 0.2°, 10.75 ⁇ 0.2° , 11.46 ⁇ 0.2°, 12.70 ⁇ 0.2°, 12.93 ⁇ 0.2°, 13.85 ⁇ 0.2°, 14.55 ⁇ 0.2°, 15.30 ⁇ 0.2°, 16.30 ⁇ 0.2°, 16.83 ⁇ 0.2°, 17.25 ⁇ 0.2°, 18.52 ⁇ 0.2° , 18.94 ⁇ 0.2°, 20.37 ⁇ 0.2°, 20.83 ⁇ 0.2°, 21.65 ⁇ 0.2°, 22.97 ⁇ 0.2°, 24.18 ⁇ 0.2°, 25.06 ⁇ 0.2°, 25.94 ⁇ 0.2°, 27.40 ⁇ 0.2°, 28.96 ⁇ 0.2° , 29.88 ⁇ 0.2°, 30.78 ⁇ 0.2°, 32.50 ⁇ 0.2°, 33.16 ⁇ 0.2°.
  • the compound shown in Formula (I) is in Form A crystal form, and its XPRD spectrum is as shown in Figure 1.
  • the XPRD spectrum analysis data of the Form A crystal form of the compound represented by formula (I) is shown in Table 1.
  • the differential scanning calorimetry curve of the Form A crystal form of the compound represented by formula (I) has an endothermic signal at 40°C.
  • the differential scanning calorimetry curve of the Form A crystal form of the compound represented by formula (I) has a melting endotherm peak at 162°C.
  • the compound represented by formula (I) is in Form A crystal form, and its DSC spectrum is as shown in Figure 2.
  • thermogravimetric analysis curve of the Form A crystal form of the compound represented by formula (I) has a weight loss of 0.9% during heating to 100°C.
  • the compound shown in Formula (I) is in Form A crystal form, and its TGA spectrum is as shown in Figure 3.
  • the present invention also provides the Form B crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.70 ⁇ 0.2°.
  • the Form B crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 5.70 ⁇ 0.2°, 9.54 ⁇ 0.2°, 13.90 ⁇ 0.2° .
  • the Form B crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 5.70 ⁇ 0.2°, 9.54 ⁇ 0.2°, 13.90 ⁇ 0.2° , 17.48 ⁇ 0.2°.
  • the Form B crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 5.70 ⁇ 0.2°, 9.54 ⁇ 0.2°, 13.90 ⁇ 0.2° , 16.93 ⁇ 0.2°, 17.48 ⁇ 0.2°, 17.72 ⁇ 0.2°.
  • the Form B crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 4.40 ⁇ 0.2°, 5.70 ⁇ 0.2°, 6.52 ⁇ 0.2° , 7.78 ⁇ 0.2°, 8.11 ⁇ 0.2°, 8.74 ⁇ 0.2°, 9.54 ⁇ 0.2°, 11.46 ⁇ 0.2°, 12.66 ⁇ 0.2°, 12.94 ⁇ 0.2°, 13.35 ⁇ 0.2°, 13.90 ⁇ 0.2°, 14.83 ⁇ 0.2° , 15.33 ⁇ 0.2°, 15.80 ⁇ 0.2°, 16.93 ⁇ 0.2°, 17.48 ⁇ 0.2°, 17.72 ⁇ 0.2°, 18.47 ⁇ 0.2°, 18.66 ⁇ 0.2°, 19.11 ⁇ 0.2°, 19.61 ⁇ 0.2°, 20.24 ⁇ 0.2° , 20.77 ⁇ 0.2°, 21.45 ⁇ 0.2°, 22.07 ⁇ 0.2°, 22.91 ⁇ 0.2°, 23.55 ⁇ 0.2°, 24.28 ⁇ 0.2°, 25.09 ⁇ 0.2°, 25.41 ⁇ 0.2°, 25.91 ⁇ 0.2°, 26
  • Form B crystal form of the compound represented by formula (I) has an XPRD spectrum as shown in Figure 4.
  • the XPRD spectrum analysis data of the Form B crystal form of the compound represented by formula (I) is shown in Table 2.
  • the differential scanning calorimetry curve of the Form B crystal form of the compound represented by formula (I) has an endothermic signal at 31°C.
  • the differential scanning calorimetry curve of the Form B crystal form of the compound represented by formula (I) has a melting endotherm peak at 188°C.
  • the compound shown in formula (I) is in Form B crystal form, and its DSC spectrum is as shown in Figure 5.
  • thermogravimetric analysis curve of the Form B crystal form of the compound represented by formula (I) has a weight loss of 1.0% during heating to 150°C.
  • the Form B crystal form of the compound represented by formula (I) has a TGA spectrum as shown in Figure 6.
  • the invention also provides the Form C crystal form of the compound represented by formula (I), and its X-ray powder diffraction pattern It has characteristic diffraction peaks at the following 2 ⁇ angles: 6.10 ⁇ 0.2°.
  • the Form C crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.10 ⁇ 0.2° and 12.30 ⁇ 0.2°.
  • the Form C crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.10 ⁇ 0.2°, 12.30 ⁇ 0.2°, 13.22 ⁇ 0.2° , 15.00 ⁇ 0.2°.
  • the Form C crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.10 ⁇ 0.2°, 9.89 ⁇ 0.2°, 10.68 ⁇ 0.2° , 12.30 ⁇ 0.2°, 13.22 ⁇ 0.2°, 13.90 ⁇ 0.2°, 15.00 ⁇ 0.2°, 15.82 ⁇ 0.2°, 16.63 ⁇ 0.2°, 17.86 ⁇ 0.2°, 18.13 ⁇ 0.2°, 18.68 ⁇ 0.2°, 19.98 ⁇ 0.2° , 20.41 ⁇ 0.2°, 21.84 ⁇ 0.2°, 22.77 ⁇ 0.2°, 23.79 ⁇ 0.2°, 24.14 ⁇ 0.2°, 24.53 ⁇ 0.2°, 26.10 ⁇ 0.2°, 26.52 ⁇ 0.2°, 26.91 ⁇ 0.2°, 27.50 ⁇ 0.2° , 28.21 ⁇ 0.2°, 30.06 ⁇ 0.2°, 31.18 ⁇ 0.2°, 32.28 ⁇ 0.2°, 33.12 ⁇ 0.2°.
  • the compound shown in formula (I) is in Form C crystal form, and its XPRD spectrum is as shown in Figure 7.
  • the XPRD spectrum analysis data of the Form C crystal form of the compound represented by formula (I) is shown in Table 3.
  • the differential scanning calorimetry curve of the Form C crystal form of the compound represented by formula (I) The line has endothermic signals at 33°C, 158°C, and 213°C.
  • the compound shown in formula (I) is in Form C crystal form, and its DSC spectrum is as shown in Figure 8.
  • thermogravimetric analysis curve of the Form C crystal form of the compound represented by formula (I) has a weight loss of 9.8% during heating to 250°C.
  • the compound shown in formula (I) is in Form C crystal form, and its TGA spectrum is as shown in Figure 9.
  • the present invention also provides the Form D crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ angle: 6.45 ⁇ 0.2°.
  • the Form D crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.45 ⁇ 0.2°, 12.95 ⁇ 0.2°, 13.65 ⁇ 0.2° .
  • the Form D crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.45 ⁇ 0.2°, 10.98 ⁇ 0.2°, 12.95 ⁇ 0.2° , 13.41 ⁇ 0.2°, 13.65 ⁇ 0.2°, 16.30 ⁇ 0.2°.
  • the Form D crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.45 ⁇ 0.2°, 9.41 ⁇ 0.2°, 10.13 ⁇ 0.2° , 10.98 ⁇ 0.2°, 11.59 ⁇ 0.2°, 12.95 ⁇ 0.2°, 13.41 ⁇ 0.2°, 13.65 ⁇ 0.2°, 14.42 ⁇ 0.2°, 15.55 ⁇ 0.2°, 15.79 ⁇ 0.2°, 16.30 ⁇ 0.2°, 16.89 ⁇ 0.2° , 17.50 ⁇ 0.2°, 17.97 ⁇ 0.2°, 18.26 ⁇ 0.2°, 18.81 ⁇ 0.2°, 19.49 ⁇ 0.2°, 19.73 ⁇ 0.2°, 20.02 ⁇ 0.2°, 20.35 ⁇ 0.2°, 20.66 ⁇ 0.2°, 21.38 ⁇ 0.2° , 21.67 ⁇ 0.2°, 22.07 ⁇ 0.2°, 22.75 ⁇ 0.2°, 23.82 ⁇ 0.2°, 24.66 ⁇ 0.2°, 25.87 ⁇ 0.2°, 26.52 ⁇ 0.2°, 26.84 ⁇ 0.2°, 27.50 ⁇ 0.2
  • Form D crystal form of the compound represented by formula (I) has an XPRD spectrum as shown in Figure 10.
  • the XPRD spectrum analysis data of the Form D crystal form of the compound represented by formula (I) is shown in Table 4.
  • the differential scanning calorimetry curve of the Form D crystal form of the compound represented by formula (I) has endothermic signals at 70°C and 199°C.
  • the compound shown in formula (I) is in Form D crystal form, and its DSC spectrum is as shown in Figure 11.
  • thermogravimetric analysis curve of the Form D crystalline form of the compound represented by formula (I) has a weight loss of 2.5% during heating to 150°C.
  • Form D crystal form of the compound represented by formula (I) has a TGA spectrum as shown in Figure 12.
  • the present invention also provides the Form E crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ angle: 13.73 ⁇ 0.2°.
  • the Form E crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.81 ⁇ 0.2°, 13.73 ⁇ 0.2°, 15.89 ⁇ 0.2° .
  • the Form E crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.81 ⁇ 0.2°, 13.11 ⁇ 0.2°, 13.73 ⁇ 0.2° , 15.49 ⁇ 0.2°, 15.89 ⁇ 0.2°, 19.37 ⁇ 0.2°.
  • the Form E crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.81 ⁇ 0.2°, 9.93 ⁇ 0.2°, 10.59 ⁇ 0.2° , 11.59 ⁇ 0.2°, 13.11 ⁇ 0.2°, 13.73 ⁇ 0.2°, 15.49 ⁇ 0.2°, 15.89 ⁇ 0.2°, 16.58 ⁇ 0.2°, 17.15 ⁇ 0.2°, 17.69 ⁇ 0.2°, 18.19 ⁇ 0.2°, 19.12 ⁇ 0.2° , 19.37 ⁇ 0.2°, 20.91 ⁇ 0.2°, 21.40 ⁇ 0.2°, 22.16 ⁇ 0.2°, 23.97 ⁇ 0.2°, 25.32 ⁇ 0.2°, 25.94 ⁇ 0.2°, 26.67 ⁇ 0.2°, 27.50 ⁇ 0.2°, 29.00 ⁇ 0.2° , 30.13 ⁇ 0.2°, 31.07 ⁇ 0.2°, 32.57 ⁇ 0.2°, 33.65 ⁇ 0.2°, 35.92 ⁇ 0.2°, 37.48 ⁇ 0.2°, 39.50 ⁇ 0.2°, 42.10 ⁇ 0.2°.
  • Form E crystal form of the compound represented by formula (I) has an XPRD spectrum as shown in Figure 13.
  • the XPRD spectrum analysis data of the Form E crystal form of the compound represented by formula (I) is shown in Table 5.
  • the differential scanning calorimetry curve of the Form E crystal form of the compound represented by formula (I) has endothermic signals at 40°C, 151°C, 174°C, and 191°C.
  • the compound shown in Formula (I) is in Form E crystal form, and its DSC spectrum is as shown in Figure 14.
  • thermogravimetric analysis curve of the Form E crystal form of the compound represented by formula (I) is at There is a weight loss of 2.7% during heating to 150°C.
  • Form E crystal form of the compound represented by formula (I) has a TGA spectrum as shown in Figure 15.
  • the present invention also provides the Form F crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.73 ⁇ 0.2°, 9.07 ⁇ 0.2°.
  • the Form F crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.73 ⁇ 0.2°, 9.07 ⁇ 0.2°, 13.33 ⁇ 0.2° , 18.17 ⁇ 0.2°, 19.20 ⁇ 0.2°.
  • the Form F crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 6.32 ⁇ 0.2°, 6.73 ⁇ 0.2°, 9.07 ⁇ 0.2° , 13.33 ⁇ 0.2°, 17.04 ⁇ 0.2°, 17.81 ⁇ 0.2°, 18.17 ⁇ 0.2°, 19.20 ⁇ 0.2°, 21.08 ⁇ 0.2°, 21.30 ⁇ 0.2°.
  • the Form F crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 4.56 ⁇ 0.2°, 6.32 ⁇ 0.2°, 6.73 ⁇ 0.2° , 7.82 ⁇ 0.2°, 9.07 ⁇ 0.2°, 10.41 ⁇ 0.2°, 11.65 ⁇ 0.2°, 12.66 ⁇ 0.2°, 13.33 ⁇ 0.2°, 13.62 ⁇ 0.2°, 14.63 ⁇ 0.2°, 15.00 ⁇ 0.2°, 15.24 ⁇ 0.2° , 15.58 ⁇ 0.2°, 16.08 ⁇ 0.2°, 16.47 ⁇ 0.2°, 17.04 ⁇ 0.2°, 17.81 ⁇ 0.2°, 18.17 ⁇ 0.2°, 18.68 ⁇ 0.2°, 19.20 ⁇ 0.2°, 19.98 ⁇ 0.2°, 20.45 ⁇ 0.2° , 21.08 ⁇ 0.2°, 21.30 ⁇ 0.2°, 21.97 ⁇ 0.2°, 22.62 ⁇ 0.2°, 22.80 ⁇ 0.2°, 23.50 ⁇ 0.2°, 23.85 ⁇ 0.2°, 24.09 ⁇ 0.2°, 24.39 ⁇ 0.2°, 24
  • the compound shown in Formula (I) is in Form F crystal form, and its XPRD spectrum is as shown in Figure 16.
  • the XPRD spectrum analysis data of the Form F crystal form of the compound represented by formula (I) is shown in Table 6.
  • the differential scanning calorimetry curve of the Form F crystal form of the compound represented by formula (I) has endothermic signals at 102°C, 151°C, and 174°C.
  • the compound shown in Formula (I) is in Form F crystal form, and its DSC spectrum is as shown in Figure 17.
  • thermogravimetric analysis curve of the Form F crystal form of the compound represented by formula (I) has a weight loss of 7.8% during heating to 100°C.
  • the compound shown in formula (I) is in Form F crystal form, and its TGA spectrum is as shown in Figure 18.
  • the present invention also provides the Form G crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 14.75 ⁇ 0.2°, 17.72 ⁇ 0.2°.
  • the Form G crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 14.75 ⁇ 0.2°, 17.72 ⁇ 0.2°, 18.47 ⁇ 0.2° , 19.22 ⁇ 0.2°.
  • the Form G crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.2°, 14.10 ⁇ 0.2°, 14.75 ⁇ 0.2° , 15.49 ⁇ 0.2°, 17.06 ⁇ 0.2°, 17.72 ⁇ 0.2°, 18.47 ⁇ 0.2°, 19.22 ⁇ 0.2°, 24.61 ⁇ 0.2°.
  • the Form F crystal form of the compound represented by formula (I), its X-ray powder diffraction The radiation pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.2°, 8.02 ⁇ 0.2°, 8.21 ⁇ 0.2°, 8.50 ⁇ 0.2°, 8.97 ⁇ 0.2°, 9.49 ⁇ 0.2°, 9.99 ⁇ 0.2°, 10.67 ⁇ 0.2 °, 11.04 ⁇ 0.2°, 11.69 ⁇ 0.2°, 12.78 ⁇ 0.2°, 13.64 ⁇ 0.2°, 14.10 ⁇ 0.2°, 14.75 ⁇ 0.2°, 15.49 ⁇ 0.2°, 16.08 ⁇ 0.2°, 16.50 ⁇ 0.2°, 17.06 ⁇ 0.2 °, 17.72 ⁇ 0.2°, 18.47 ⁇ 0.2°, 18.86 ⁇ 0.2°, 19.22 ⁇ 0.2°, 19.73 ⁇ 0.2°, 20.20 ⁇ 0.2°, 20.94 ⁇ 0.2°, 21.29 ⁇ 0.2°, 21.53 ⁇ 0.2°, 22.83 ⁇ 0.2 °, 23.46 ⁇ 0.2°, 24.24 ⁇ 0.2°, 24.61 ⁇ 0.2°, 24.99 ⁇ 0.2°, 25.
  • the Form G crystal form of the compound represented by formula (I) has an XPRD spectrum as shown in Figure 19.
  • the XPRD spectrum analysis data of the Form G crystal form of the compound represented by formula (I) is shown in Table 7.
  • the differential scanning calorimetry curve of the Form G crystal form of the compound represented by formula (I) has endothermic signals at 152°C and 175°C.
  • the differential scanning calorimetry curve of the Form G crystal form of the compound represented by formula (I) has a melting endothermic peak at 210°C.
  • the compound shown in formula (I) is in Form G crystal form, and its DSC spectrum is as shown in Figure 20.
  • thermogravimetric analysis curve of the Form G crystal form of the compound represented by formula (I) has a weight loss of 0.6% during heating to 150°C.
  • the compound shown in formula (I) is in Form G crystal form, and its TGA spectrum is as shown in Figure 21.
  • the present invention also provides the use of the pharmaceutically acceptable crystal form of the compound represented by the above formula (I) in related drugs of small molecule immunomodulators.
  • the present invention also provides different crystal forms of the compound represented by formula (I) prepared by solvent evaporation method, suspension method, solution crystallization method, cooling method, gas phase diffusion method, and thermal conversion crystallization method, which are further described as follows:
  • Solvent evaporation method Weigh an appropriate amount of sample, dissolve it in the selected single solvent or binary solvent, and let the resulting clear solution stand in the open at room temperature until the solvent completely evaporates to obtain a solid;
  • Suspension method 1) Suspension at room temperature, that is, weigh an appropriate amount of samples of different crystal forms, add a certain amount of sample to the selected single solvent or binary solvent until a suspension is formed, suspend and stir at room temperature for a certain period of time, and then centrifuge the suspension Separate and dry the solid under vacuum at room temperature. 2) Suspension at 50°C, that is, weigh an appropriate amount of samples of different crystal forms, add a certain amount of sample to the selected solvent until a suspension is formed, suspend and stir at 50°C for 24 hours, centrifuge the suspension, and vacuum the solid at room temperature dry;
  • Dissolution crystallization method 1) Binary solvent forward dropping method, that is, weigh a certain amount of sample, add an appropriate amount of good solvent at room temperature to completely dissolve the sample; take a certain amount of solution, and add the solution dropwise to 10 times or 20 times the volume. in poor solvents. After stirring for 1 hour, the system with solid precipitation was centrifuged, and the solid was vacuum dried at room temperature; the clarified solution was continued to stir for 24 hours. The system that still had no solid precipitation was placed in a 4°C refrigerator for 3 days, and the system with solid precipitation was centrifuged. , and dry the solid under vacuum at room temperature. If there is still no solid precipitated, let the solution stand in the open at room temperature until the solvent completely evaporates and a solid is obtained.
  • Cooling method 1) Single solvent cooling method, that is, weigh an appropriate amount of sample and add the preheated selected solvent dropwise at 50°C until the solid is completely dissolved. The solution was quickly transferred to room temperature to cool. Let the solution stand for more than 2 hours at room temperature. If there is no sufficient solid to precipitate, stir the solution at room temperature for 1 day. If there is still no solid to precipitate, cool the solution at 4°C for 1 day. After a sufficient amount of solid has precipitated, the system is centrifuged and the solid is vacuum dried at room temperature. 2) Binary solvent cooling method, that is, weigh an appropriate amount of sample and mix it with a certain amount of poor solvent at 50°C to form a suspension.
  • Vapor phase diffusion method Weigh a certain amount of sample, drop an appropriate amount of good solvent at room temperature to completely dissolve the sample; take a certain amount of solution respectively, place the clear solution in a poor solvent atmosphere and let it stand at room temperature until solid precipitates. Use a syringe to remove the solution from the system with solid precipitation, and perform XRPD testing on the wet sample;
  • Thermal crystallization method Use Instec HCS424GXY hot stage (Instec Inc., US). Place 6-8mg sample on the glass piece on the hot stage, heat to 120°C at a rate of 20°C/min, and keep the temperature constant for 20min. Then naturally cool to room temperature to obtain a solid;
  • the solvent of the aforementioned method is selected from methanol, ethanol, n-propanol, isopropyl alcohol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, ethyl formate, butyl formate, n-butyl formate, Heptane, cyclohexane, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, water, acetonitrile, toluene, N,N'-bis Methylformamide, dimethyl sulfoxide, methylene chloride, chloroform, tetrahydrofuran, N-methylpyrrolidone, trifluoroethanol, or a mixed solvent of two or more of these solvents.
  • the peaks calculated by different software may be different, which are all within the scope of the present invention.
  • the temperature is allowed to have a certain error.
  • ⁇ 5°C is preferred, ⁇ 3°C is more preferred, ⁇ 2°C is more preferred, and ⁇ 1°C is most preferred.
  • ⁇ 3°C is more preferred, ⁇ 2°C is more preferred, and ⁇ 1°C is most preferred.
  • ⁇ 5°C is preferred, ⁇ 3°C is more preferred, ⁇ 2°C is more preferred, and ⁇ 1°C is most preferred.
  • "The differential scanning calorimetry curve of the Form A crystal form has an endothermic signal at 40°C” means that "the differential scanning calorimetry curve of the Form A crystal form has an endothermic signal at 40 ⁇ 5°C" is more preferred.
  • the differential scanning calorimetry curve of the Form A crystal form has an endothermic signal at 40 ⁇ 3°C
  • the differential scanning calorimetry curve of the Form A crystalline form has an endothermic signal at 40 ⁇ 2°C
  • the differential scanning calorimetry curve of Form A crystal form has an endothermic signal at 40 ⁇ 1°C
  • Figure 1 is the XPRD spectrum of the Form A crystal form of the compound represented by formula (I).
  • Figure 2 is the DSC spectrum of the Form A crystal form of the compound represented by formula (I).
  • Figure 3 is the TGA spectrum of the Form A crystal form of the compound represented by formula (I).
  • Figure 4 is the XPRD spectrum of the Form B crystal form of the compound represented by formula (I).
  • Figure 5 is a DSC spectrum of the Form B crystal form of the compound represented by formula (I).
  • Figure 6 is a TGA spectrum of the Form B crystal form of the compound represented by formula (I).
  • Figure 7 is the XPRD spectrum of the Form C crystal form of the compound represented by formula (I).
  • Figure 8 is the DSC spectrum of the Form C crystal form of the compound represented by formula (I).
  • Figure 9 is the TGA spectrum of the Form C crystal form of the compound represented by formula (I).
  • Figure 10 is the XPRD spectrum of the Form D crystal form of the compound represented by formula (I).
  • Figure 11 is the DSC spectrum of the Form D crystal form of the compound represented by formula (I).
  • Figure 12 is the TGA spectrum of the Form D crystalline form of the compound represented by formula (I).
  • Figure 13 is the XPRD spectrum of the Form E crystal form of the compound represented by formula (I).
  • Figure 14 is the DSC spectrum of the Form E crystal form of the compound represented by formula (I).
  • Figure 15 is the TGA spectrum of the Form E crystal form of the compound represented by formula (I).
  • Figure 16 is the XPRD spectrum of the Form F crystal form of the compound represented by formula (I).
  • Figure 17 is the DSC spectrum of the Form F crystalline form of the compound represented by formula (I).
  • Figure 18 is the TGA spectrum of the Form F crystal form of the compound represented by formula (I).
  • Figure 19 is the XPRD spectrum of the Form G crystal form of the compound represented by formula (I).
  • Figure 20 is a DSC spectrum of the Form G crystal form of the compound represented by formula (I).
  • Figure 21 is the TGA spectrum of the Form G crystal form of the compound represented by formula (I).
  • Figure 22 is the DVS spectrum of the Form B crystal form of the compound represented by formula (I).
  • Figure 23 is a superimposed spectrum of XPRD data before and after DVS testing of the Form B crystal form of the compound represented by formula (I).
  • Figure 24 is the XRPD data superimposed spectrum of the stability study of the Form B crystal form of the compound represented by formula (I).
  • All compounds and all intermediates involved in the present invention can be purified by common separation methods, such as extraction, recrystallization, silica gel column chromatography, preparative TLC separation, etc.
  • the 200-300 mesh silica gel and thin layer chromatography silica gel plates used were produced by Qingdao Ocean Chemical Factory.
  • the solvents and chemical reagents used were analytically pure or chemically pure commercially available general reagents and were used without further purification.
  • XRPD X-ray powder diffraction
  • the solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Empyrean (Panalytical, NL).
  • the 2 ⁇ scanning angle ranges from 3° to 45°, the scanning step is 0.013°, and the total test time is 4 minutes.
  • the light tube voltage and current are 45kV and 40mA respectively, and the sample disk is a zero-background sample disk.
  • DSC Differential scanning calorimetry
  • the model of differential scanning calorimetry analyzer is TA Discovery 2500 (TA, US).
  • the 1-2mg sample was accurately weighed and placed in a perforated DSC Tzero sample pan, heated to the final temperature at a rate of 10°C/min, and the nitrogen purge rate in the furnace was 50mL/min.
  • thermogravimetric analysis (TGA) method of the present invention is thermogravimetric analysis (TGA) method of the present invention.
  • thermogravimetric analyzer is TA Discovery 550 (TA, US). Place 2-5 mg of sample into a balanced open aluminum sample pan and automatically weigh it in a TGA heating furnace. The sample was heated to the final temperature at a rate of 10°C/min, the nitrogen purge rate at the sample was 60 mL/min, and the nitrogen purge rate at the balance was 40 mL/min.
  • Dynamic water vapor adsorption and desorption analysis was measured using DVS Intrinsic (SMS, UK).
  • the test adopts gradient mode, the humidity change is 50%-95%-0%-50%, the humidity change amount of each gradient in the range of 0% to 90% is 10%, the gradient end point is judged by dm/dt method, with The gradient endpoint is when dm/dt is less than 0.002% and maintained for 10 minutes.
  • XRPD analysis is performed on the sample to confirm whether the solid form has changed.
  • Hygroscopicity classification evaluation is as follows: Attached: ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH
  • 1 H-NMR uses a BRUKER AVANCE-400MHz nuclear magnetic resonance spectrometer at room temperature in deuterated dimethyl sulfoxide (DMSO-d 6 ) or deuterated chloroform (CDCl 3 ), etc., with tetramethylsilane (TMS) as the inner
  • TMS tetramethylsilane
  • the signal peaks are expressed as s (single peak), d (double peak), t (triplet peak), q (quartet peak), m (multiple peak), dd (double doublet peak).
  • the unit of coupling constant (J) is Hertz (Hz).
  • Dissolve 1a (530.00 mg, 1.13 mmol, 1.0 eq, synthesis reference CN202111092852.4) in 1,4-dioxane (10 mL), add trifluoroacetic acid (5 mL), and stir at ambient temperature for 1 h.
  • the present invention evaluates the hygroscopicity of Form B crystal form based on the aforementioned dynamic water vapor adsorption and desorption analysis (DVS) method. After the test is completed, XRPD analysis is performed on the sample to confirm whether the solid form has changed. The results are shown in Table 22.

Abstract

一种作为免疫调节剂的联苯类化合物(I)的晶型及其制备方法，还包括所述晶型在制备免疫调节剂的相关药物中的应用。

Description

一种作为免疫调节剂的联苯类化合物的晶型及其制备方法 技术领域
本发明属于药物化学领域，具体涉及一种作为免疫调节剂的联苯类化合物的晶型及其制备方法，还包括所述晶型在制备用于治疗免疫调节相关疾病药物中的应用。
背景技术
肿瘤免疫治疗是一种通过激发人体的免疫系统，增强自身的抗肿瘤免疫力，从而抑制或杀死肿瘤细胞的新治疗方法。该方法经过百余年的努力取得了突破性进展。2013年，《Science》杂志将肿瘤免疫治疗列为年度十大科学突破之首(Couzin-Frankel J.,2013,Science,342:1432-1433)，已成为最具前景的抗肿瘤治疗领域之一。
肿瘤细胞相比正常细胞，具有多种遗传学和表观遗传学的改变，免疫系统可利用肿瘤细胞产生的表面抗原将二者区分，进而引发抗肿瘤免疫反应。在T细胞抗肿瘤免疫过程中，其被T细胞受体(T cell receptor，TCR)介导的抗原识别信号激活后，通过共刺激和共抑制信号综合调节T细胞效应，包括细胞毒性T淋巴细胞相关抗原4(Cytotoxic T-lymphocyte associated antigen 4,CTLA4)、程序性死亡受体1(Programmed death protein 1,PD-1)、T细胞活化的免疫球蛋白抑制V型结构域(V-domain immunoglobulin suppressor of T-cell activation,VISTA)、T细胞免疫球蛋白及黏蛋白结构域的分子3(T cell immunoglobulin and mucin domain–containing-3,TIM3)、淋巴细胞活化基因3(Lymphocyte activation gene 3,LAG3)等抑制信号的抑制性受体，及CD28、CD134(OX40)、糖皮质激素诱导的TNFR相关蛋白(Glucocorticoid-induced TNFR-related protein,GITR)、CD137、CD27、HVEM等刺激信号的活化性受体(Mellman I.,Coukos G.,Dranoff G.,2011,Nature,480:480-489)。在正常生理条件下，免疫检查点一方面参与维持自身抗原的免疫耐受，避免自身免疫性疾病；另一方面避免免疫反应过度激活导致组织损伤。然而，在肿瘤细胞中，其可通过免疫检查点抑制T细胞激活而逃避免疫杀伤。因此，需要通过激活共刺激信号(踩“油门”)并抑制共抑制信号(松“刹车”)而重新激活T细胞攻击肿瘤细胞，进而实现肿瘤免疫治疗。
PD-1表达于激活的T细胞、B细胞及骨髓细胞中，属于CD28家族，是T细胞上的一种type1跨膜糖蛋白，由288个氨基酸组成。PD-1的分子结构由具有免疫球蛋白IgV样(氨基酸35-145)的胞外区、跨膜区、具有连接信号肽功能的胞质尾区构成，其上的胞外区与配体结合发挥重要功能(Cheng X.,Veverka V., Radhakrishnan A.,et al.2013,J.Biol.Chem.,288:11771-11785)。程序性死亡配体1(Programmed death protein ligand 1,PD-L1)是PD-1的配体之一，属于B7家族，可持续性表达于多种肿瘤细胞、T细胞、抗原呈递细胞(APC)及多种非造血细胞中，也为type1跨膜糖蛋白，它由290个氨基酸组成。PD-1与PD-L1相互作用会抑制T细胞激活，这对于维持正常机体的免疫耐受至关重要，而在肿瘤细胞中和病毒感染时，T细胞上的PD-1被诱导性高表达，PD-L1的表达上调，导致PD-1信号通路持续激活而抑制T细胞增殖，造成肿瘤细胞和病原体的免疫逃逸(Fuller M.J.,Callendret B.,Zhu B.,et al.2013,Proc.Natl.Acad.Sci.USA.,110:15001-15006；Dolan D.E.,Gupta S.,2014,Cancer Control,21:231-237；Chen L.,Han X.,2015,J.Clin.Invest.,125:3384-3391；Postow M.A.,Callahan M.K.,Wolchok J.D.,2015,J.Clin.Oncol.,33:1974-1982)。近年上市的PD-1和PD-L1的多个抗体药物充分证明了阻断PD-1/PD-L1相互作用在肿瘤的免疫治疗和免疫相关的其他多种疾病中是一种非常有效的治疗手段。
研究发现，PD-L1能够与CD80发生相互作用并抑制PD-L1和PD-1结合，以及抑制T细胞激活的能力。因此，阻断CD80/PD-L1相互作用引起的免疫激活，也可能促进T细胞活性增强，进而为免疫相关的疾病提供了新的治疗机会(Sugiura D.,Maruhashi T.,Okazaki ll-mi,et al.2019,Science,364:558-566)。
至目前，靶向PD-1/PD-L1抗体药物取得了重要进展。然而，所有的抗体药物均须注射给药、具有多种ADMET问题、免疫系统相关的严重副作用等。与抗体药物相比，小分子的免疫调节剂具有一定优势，包括可口服、更具组织渗透性、可通过药理学特性调整最大限度降低副作用等。另外，小分子抑制剂将具有更低的价格优势。
PD-1/PD-L1抗体药物的临床研究表明，纳武利尤单抗T1/2为25.2天，给药频率为二周一次；帕博利珠单抗T1/2为25天，给药频率为三周一次；阿替利珠单抗T1/2为27天，给药频率为三周一次。上述药物的给药频率均短于药物半衰期，说明这类靶点药物在体内的持续暴露是获得理想临床疗效的关键。然而，已公开的小分子免疫调节剂在体内暴露量偏低，持续暴露时间偏短，将影响临床疗效。
发明内容
本发明提供了式(I)所示化合物的晶型或其溶剂化物，所述晶型选自Form A晶型、Form B晶型、Form C晶型、Form D晶型、Form E晶型、Form F晶型 和Form G晶型，
所述Form A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、13.85±0.2°；
所述Form B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.70±0.2°、9.54±0.2°、13.90±0.2°；
所述Form C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.10±0.2°、12.30±0.2°；
所述Form D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.45±0.2°、12.95±0.2°、13.65±0.2°；
所述Form E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.81±0.2°、13.73±0.2°、15.89±0.2°；
所述Form F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.73±0.2°、9.07±0.2°；
所述Form G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.75±0.2°、17.72±0.2°。式(I)所示化合物记载于专利CN202180004723.7中，其全部内容被引入本发明。
本发明提供了式(I)所示化合物Form A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、13.85±0.2°。
在本发明的一些方案中，式(I)所示化合物Form A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、13.85±0.2°、17.25±0.2°。
在本发明的一些方案中，式(I)所示化合物Form A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、12.70±0.2°、13.85±0.2°、 15.30±0.2°、17.25±0.2°、25.06±0.2°。
在本发明的一些方案中，式(I)所示化合物Form A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、9.28±0.2°、10.75±0.2°、11.46±0.2°、12.70±0.2°、12.93±0.2°、13.85±0.2°、14.55±0.2°、15.30±0.2°、16.30±0.2°、16.83±0.2°、17.25±0.2°、18.52±0.2°、18.94±0.2°、20.37±0.2°、20.83±0.2°、21.65±0.2°、22.97±0.2°、24.18±0.2°、25.06±0.2°、25.94±0.2°、27.40±0.2°、28.96±0.2°、29.88±0.2°、30.78±0.2°、32.50±0.2°、33.16±0.2°。
在本发明的一些方案中，式(I)所示化合物Form A晶型，其XPRD谱图如图1所示。
在本发明的一些方案中，式(I)所示化合物Form A晶型的XPRD图谱解析数据如表1所示。
表1式(I)所示化合物Form A晶型的XPRD图谱解析
在本发明的一些方案中，式(I)所示化合物Form A晶型的差示扫描量热曲线在40℃有吸热信号。
在本发明的一些方案中，式(I)所示化合物Form A晶型的差示扫描量热曲线在162℃具有熔融吸热峰。
在本发明的一些方案中，式(I)所示化合物Form A晶型，其DSC谱图如图2所示。
在本发明的一些方案中，式(I)所示化合物Form A晶型的热重分析曲线在加热至100℃过程中有0.9％的失重。
在本发明的一些方案中，式(I)所示化合物Form A晶型，其TGA谱图如图3所示。
本发明还提供了式(I)所示化合物Form B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.70±0.2°。
在本发明的一些方案中，式(I)所示化合物Form B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.70±0.2°、9.54±0.2°、13.90±0.2°。
在本发明的一些方案中，式(I)所示化合物Form B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.70±0.2°、9.54±0.2°、13.90±0.2°、17.48±0.2°。
在本发明的一些方案中，式(I)所示化合物Form B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.70±0.2°、9.54±0.2°、13.90±0.2°、16.93±0.2°、17.48±0.2°、17.72±0.2°。
在本发明的一些方案中，式(I)所示化合物Form B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.40±0.2°、5.70±0.2°、6.52±0.2°、7.78±0.2°、8.11±0.2°、8.74±0.2°、9.54±0.2°、11.46±0.2°、12.66±0.2°、12.94±0.2°、13.35±0.2°、13.90±0.2°、14.83±0.2°、15.33±0.2°、15.80±0.2°、16.93±0.2°、17.48±0.2°、17.72±0.2°、18.47±0.2°、18.66±0.2°、19.11±0.2°、19.61±0.2°、20.24±0.2°、20.77±0.2°、21.45±0.2°、22.07±0.2°、22.91±0.2°、23.55±0.2°、24.28±0.2°、25.09±0.2°、25.41±0.2°、25.91±0.2°、26.16±0.2°、27.19±0.2°、27.99±0.2°、28.58±0.2°、29.38±0.2°、29.97±0.2°、31.30±0.2°、32.04±0.2°、32.95±0.2°、33.23±0.2°、33.91±0.2°、34.25±0.2°、34.88±0.2°、35.35±0.2°、36.06±0.2°、37.34±0.2°、38.19±0.2°、39.46±0.2°、42.23±0.2°、44.02±0.2°。
在本发明的一些方案中，式(I)所示化合物Form B晶型，其XPRD谱图如图4所示。
在本发明的一些方案中，式(I)所示化合物Form B晶型的XPRD图谱解析数据如表2所示。
表2式(I)所示化合物Form B晶型的XPRD图谱解析

在本发明的一些方案中，式(I)所示化合物Form B晶型的差示扫描量热曲线在31℃有吸热信号。
在本发明的一些方案中，式(I)所示化合物Form B晶型的差示扫描量热曲线在188℃具有熔融吸热峰。
在本发明的一些方案中，式(I)所示化合物Form B晶型，其DSC谱图如图5所示。
在本发明的一些方案中，式(I)所示化合物Form B晶型的热重分析曲线在加热至150℃过程中有1.0％的失重。
在本发明的一些方案中，式(I)所示化合物Form B晶型，其TGA谱图如图6所示。
本发明还提供了式(I)所示化合物Form C晶型，其X射线粉末衍射图谱 在下列2θ角处具有特征衍射峰：6.10±0.2°。
在本发明的一些方案中，式(I)所示化合物Form C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.10±0.2°、12.30±0.2°。
在本发明的一些方案中，式(I)所示化合物Form C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.10±0.2°、12.30±0.2°、13.22±0.2°、15.00±0.2°。
在本发明的一些方案中，式(I)所示化合物Form C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.10±0.2°、9.89±0.2°、10.68±0.2°、12.30±0.2°、13.22±0.2°、13.90±0.2°、15.00±0.2°、15.82±0.2°、16.63±0.2°、17.86±0.2°、18.13±0.2°、18.68±0.2°、19.98±0.2°、20.41±0.2°、21.84±0.2°、22.77±0.2°、23.79±0.2°、24.14±0.2°、24.53±0.2°、26.10±0.2°、26.52±0.2°、26.91±0.2°、27.50±0.2°、28.21±0.2°、30.06±0.2°、31.18±0.2°、32.28±0.2°、33.12±0.2°。
在本发明的一些方案中，式(I)所示化合物Form C晶型，其XPRD谱图如图7所示。
在本发明的一些方案中，式(I)所示化合物Form C晶型的XPRD图谱解析数据如表3所示。
表3式(I)所示化合物Form C晶型的XPRD图谱解析
在本发明的一些方案中，式(I)所示化合物Form C晶型的差示扫描量热曲 线在33℃、158℃、213℃有吸热信号。
在本发明的一些方案中，式(I)所示化合物Form C晶型，其DSC谱图如图8所示。
在本发明的一些方案中，式(I)所示化合物Form C晶型的热重分析曲线在加热至250℃过程中有9.8％的失重。
在本发明的一些方案中，式(I)所示化合物Form C晶型，其TGA谱图如图9所示。
本发明还提供了式(I)所示化合物Form D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.45±0.2°。
在本发明的一些方案中，式(I)所示化合物Form D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.45±0.2°、12.95±0.2°、13.65±0.2°。
在本发明的一些方案中，式(I)所示化合物Form D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.45±0.2°、10.98±0.2°、12.95±0.2°、13.41±0.2°、13.65±0.2°、16.30±0.2°。
在本发明的一些方案中，式(I)所示化合物Form D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.45±0.2°、9.41±0.2°、10.13±0.2°、10.98±0.2°、11.59±0.2°、12.95±0.2°、13.41±0.2°、13.65±0.2°、14.42±0.2°、15.55±0.2°、15.79±0.2°、16.30±0.2°、16.89±0.2°、17.50±0.2°、17.97±0.2°、18.26±0.2°、18.81±0.2°、19.49±0.2°、19.73±0.2°、20.02±0.2°、20.35±0.2°、20.66±0.2°、21.38±0.2°、21.67±0.2°、22.07±0.2°、22.75±0.2°、23.82±0.2°、24.66±0.2°、25.87±0.2°、26.52±0.2°、26.84±0.2°、27.50±0.2°、28.76±0.2°、29.35±0.2°、29.71±0.2°、31.40±0.2°、31.95±0.2°、32.81±0.2°、33.29±0.2°、34.17±0.2°、36.99±0.2°、38.16±0.2°、39.46±0.2°。
在本发明的一些方案中，式(I)所示化合物Form D晶型，其XPRD谱图如图10所示。
在本发明的一些方案中，式(I)所示化合物Form D晶型的XPRD图谱解析数据如表4所示。
表4式(I)所示化合物Form D晶型的XPRD图谱解析

在本发明的一些方案中，式(I)所示化合物Form D晶型的差示扫描量热曲线在70℃、199℃有吸热信号。
在本发明的一些方案中，式(I)所示化合物Form D晶型，其DSC谱图如图11所示。
在本发明的一些方案中，式(I)所示化合物Form D晶型的热重分析曲线在加热至150℃过程中有2.5％的失重。
在本发明的一些方案中，式(I)所示化合物Form D晶型，其TGA谱图如图12所示。
本发明还提供了式(I)所示化合物Form E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.73±0.2°。
在本发明的一些方案中，式(I)所示化合物Form E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.81±0.2°、13.73±0.2°、15.89±0.2°。
在本发明的一些方案中，式(I)所示化合物Form E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.81±0.2°、13.11±0.2°、13.73±0.2°、15.49±0.2°、15.89±0.2°、19.37±0.2°。
在本发明的一些方案中，式(I)所示化合物Form E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.81±0.2°、9.93±0.2°、10.59±0.2°、11.59±0.2°、13.11±0.2°、13.73±0.2°、15.49±0.2°、15.89±0.2°、16.58±0.2°、17.15±0.2°、17.69±0.2°、18.19±0.2°、19.12±0.2°、19.37±0.2°、20.91±0.2°、21.40±0.2°、22.16±0.2°、23.97±0.2°、25.32±0.2°、25.94±0.2°、26.67±0.2°、27.50±0.2°、29.00±0.2°、30.13±0.2°、31.07±0.2°、32.57±0.2°、33.65±0.2°、35.92±0.2°、37.48±0.2°、39.50±0.2°、42.10±0.2°。
在本发明的一些方案中，式(I)所示化合物Form E晶型，其XPRD谱图如图13所示。
在本发明的一些方案中，式(I)所示化合物Form E晶型的XPRD图谱解析数据如表5所示。
表5式(I)所示化合物Form E晶型的XPRD图谱解析
在本发明的一些方案中，式(I)所示化合物Form E晶型的差示扫描量热曲线在40℃、151℃、174℃、191℃有吸热信号。
在本发明的一些方案中，式(I)所示化合物Form E晶型，其DSC谱图如图14所示。
在本发明的一些方案中，式(I)所示化合物Form E晶型的热重分析曲线在 加热至150℃过程中有2.7％的失重。
在本发明的一些方案中，式(I)所示化合物Form E晶型，其TGA谱图如图15所示。
本发明还提供了式(I)所示化合物Form F晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.73±0.2°、9.07±0.2°。
在本发明的一些方案中，式(I)所示化合物Form F晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.73±0.2°、9.07±0.2°、13.33±0.2°、18.17±0.2°、19.20±0.2°。
在本发明的一些方案中，式(I)所示化合物Form F晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.32±0.2°、6.73±0.2°、9.07±0.2°、13.33±0.2°、17.04±0.2°、17.81±0.2°、18.17±0.2°、19.20±0.2°、21.08±0.2°、21.30±0.2°。
在本发明的一些方案中，式(I)所示化合物Form F晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.56±0.2°、6.32±0.2°、6.73±0.2°、7.82±0.2°、9.07±0.2°、10.41±0.2°、11.65±0.2°、12.66±0.2°、13.33±0.2°、13.62±0.2°、14.63±0.2°、15.00±0.2°、15.24±0.2°、15.58±0.2°、16.08±0.2°、16.47±0.2°、17.04±0.2°、17.81±0.2°、18.17±0.2°、18.68±0.2°、19.20±0.2°、19.98±0.2°、20.45±0.2°、21.08±0.2°、21.30±0.2°、21.97±0.2°、22.62±0.2°、22.80±0.2°、23.50±0.2°、23.85±0.2°、24.09±0.2°、24.39±0.2°、24.77±0.2°、25.72±0.2°、26.29±0.2°、26.83±0.2°、27.44±0.2°、28.12±0.2°、28.89±0.2°、29.16±0.2°、29.51±0.2°、30.46±0.2°、31.47±0.2°、32.06±0.2°、32.81±0.2°。
在本发明的一些方案中，式(I)所示化合物Form F晶型，其XPRD谱图如图16所示。
在本发明的一些方案中，式(I)所示化合物Form F晶型的XPRD图谱解析数据如表6所示。
表6式(I)所示化合物Form F晶型的XPRD图谱解析

在本发明的一些方案中，式(I)所示化合物Form F晶型的差示扫描量热曲线在102℃、151℃、174℃有吸热信号。
在本发明的一些方案中，式(I)所示化合物Form F晶型，其DSC谱图如图17所示。
在本发明的一些方案中，式(I)所示化合物Form F晶型的热重分析曲线在加热至100℃过程中有7.8％的失重。
在本发明的一些方案中，式(I)所示化合物Form F晶型，其TGA谱图如图18所示。
本发明还提供了式(I)所示化合物Form G晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.75±0.2°、17.72±0.2°。
在本发明的一些方案中，式(I)所示化合物Form G晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.75±0.2°、17.72±0.2°、18.47±0.2°、19.22±0.2°。
在本发明的一些方案中，式(I)所示化合物Form G晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.2°、14.10±0.2°、14.75±0.2°、15.49±0.2°、17.06±0.2°、17.72±0.2°、18.47±0.2°、19.22±0.2°、24.61±0.2°。
在本发明的一些方案中，式(I)所示化合物Form F晶型，其X射线粉末衍 射图谱在下列2θ角处具有特征衍射峰：7.03±0.2°、8.02±0.2°、8.21±0.2°、8.50±0.2°、8.97±0.2°、9.49±0.2°、9.99±0.2°、10.67±0.2°、11.04±0.2°、11.69±0.2°、12.78±0.2°、13.64±0.2°、14.10±0.2°、14.75±0.2°、15.49±0.2°、16.08±0.2°、16.50±0.2°、17.06±0.2°、17.72±0.2°、18.47±0.2°、18.86±0.2°、19.22±0.2°、19.73±0.2°、20.20±0.2°、20.94±0.2°、21.29±0.2°、21.53±0.2°、22.83±0.2°、23.46±0.2°、24.24±0.2°、24.61±0.2°、24.99±0.2°、25.73±0.2°、26.58±0.2°、27.50±0.2°、28.54±0.2°、29.13±0.2°、29.77±0.2°、30.43±0.2°、31.14±0.2°、31.95±0.2°、32.57±0.2°、33.55±0.2°、35.05±0.2°、36.42±0.2°、36.80±0.2°、38.82±0.2°、40.87±0.2°。
在本发明的一些方案中，式(I)所示化合物Form G晶型，其XPRD谱图如图19所示。
在本发明的一些方案中，式(I)所示化合物Form G晶型的XPRD图谱解析数据如表7所示。
表7式(I)所示化合物Form G晶型的XPRD图谱解析

在本发明的一些方案中，式(I)所示化合物Form G晶型的差示扫描量热曲线在152℃、175℃有吸热信号。
在本发明的一些方案中，式(I)所示化合物Form G晶型的差示扫描量热曲线在210℃有熔融吸热峰。
在本发明的一些方案中，式(I)所示化合物Form G晶型，其DSC谱图如图20所示。
在本发明的一些方案中，式(I)所示化合物Form G晶型的热重分析曲线在加热至150℃过程中有0.6％的失重。
在本发明的一些方案中，式(I)所示化合物Form G晶型，其TGA谱图如图21所示。
本发明还提供上述式(I)所示化合物的可药用晶型在小分子免疫调节剂的相关药物中的应用。
本发明还提供了通过溶剂挥发法、悬浮法、溶析结晶法、降温法、气相扩散法、热转晶法制备式(I)所示化合物的不同晶型，进一步描述如下：
溶剂挥发法：称取适量样品，溶于所选的单一溶剂或二元溶剂中，将所得澄清溶液在室温敞口静置，直至溶剂完全挥发得到固体；
悬浮法：1)室温悬浮，即称取适量不同晶型的样品，在所选单一溶剂或二元溶剂中加入一定量样品，直至形成悬浮液，在室温悬浮搅拌一定时间后，将悬浮液离心分离，并将固体室温真空干燥。2)50℃悬浮，即称取适量不同晶型的样品，在所选溶剂中加入一定量样品，直至形成悬浮液，在50℃悬浮搅拌24h后，将悬浮液离心分离，并将固体室温真空干燥；
溶析结晶法：1)二元溶剂正滴法，即称取一定量样品，室温下滴加适量良溶剂使样品完全溶解；分别取一定量溶液，将溶液滴加至10倍或20倍体积的不良溶剂中。搅拌1h后将有固体析出的体系离心分离后，并将固体室温真空干燥；澄清溶液则继续搅拌24h，仍无固体析出的体系放置于4℃冰箱3天，将有固体析出的体系离心分离后，并将固体室温真空干燥。若仍无固体析出将溶液在室温敞口静置，直至溶剂完全挥发得到固体。2)二元溶剂反滴法，即称取一定量样 品，室温下滴加适量良溶剂使样品完全溶解；分别取一定量溶液，滴加不良溶剂至有固体析出。室温搅拌1h后将有固体析出的体系离心分离后，并将固体室温真空干燥；澄清溶液则继续搅拌24h，仍无固体析出的体系放置于4℃冰箱3天，将有固体析出的体系离心分离后，并将固体室温真空干燥。若仍无固体析出将溶液在室温敞口静置，直至溶剂完全挥发得到固体；
降温法：1)单一溶剂降温法，即称取适量样品，在50℃滴加已预热的所选溶剂，直至固体刚好完全溶解。将溶液迅速转移至室温冷却。室温静置2h以上，，如无足量固体析出，则将溶液置于室温搅拌1天，仍无固体析出的体系置于4℃冷却1天。对于足量固体析出的体系离心分离后，并将固体室温真空干燥。2)二元溶剂降温法，即称取适量左右样品，在50℃与一定量的不良溶剂混合，形成悬浊液。逐渐滴加已经预热的良溶剂，直至固体刚好完全溶解，将溶液转移至室温冷却。室温静置2h以上，如无足量固体析出，则将溶液置于4℃进一步冷却1天。对于足量固体析出的体系离心分离后，并将固体室温真空干燥；
气相扩散法：称取一定量样品，室温下滴加适量良溶剂使样品完全溶解；分别取一定量溶液，将澄清溶液置于不良溶剂气氛中室温静置，直至有固体析出。用注射器将有固体析出的体系中的溶液移除，对湿样进行XRPD测试；
热转晶法：采用Instec HCS424GXY热台(Instec Inc.，US)进行，将6-8mg样品置于玻璃片放在热台上，以20℃/min的速率加热至120℃，并恒温20min，然后自然降温冷却至室温得固体；
所述前述方法的溶剂选自甲醇、乙醇、正丙醇、异丙醇、丙酮、4-甲基-2-戊酮、乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸丁酯、正庚烷、环己烷、1,4-二氧六环、乙醚、甲基叔丁基醚、乙二醇甲醚、乙二醇二甲醚、水、乙腈、甲苯、N,N′-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、四氢呋喃、N-甲基吡咯烷酮、三氟乙醇，或者为所述这些溶剂的二种或者多种溶剂的混合溶剂。优选包括但并不限于甲醇，乙醇、正丙醇、异丙醇、丙酮、四氢呋喃、乙酸乙酯、甲基叔丁基醚、N,N′-二甲基甲酰胺、二氯甲烷、氯仿、4-甲基-2-戊酮、乙酸异丙酯、甲酸乙酯、环己烷、乙醚、乙二醇甲醚、乙二醇二甲醚、水、乙腈、甲苯、二甲基亚砜、二氯甲烷和氯仿、二氯甲烷和四氢呋喃、二氯甲烷和甲醇、二氯甲烷和丙酮、二氯甲烷和丙酮、二氯甲烷和乙酸乙酯、二氯甲烷和环己烷、二氯甲烷和正庚烷、二氯甲烷和甲基叔丁基醚、二氯甲烷和甲苯、二氯甲烷和甲酸丁酯、氯仿和甲酸丁酯、氯仿和乙醇、氯仿和四氢呋喃、氯仿和丙酮、氯仿和4-甲基-2-戊酮、氯仿和乙酸异丙酯、氯仿和正庚烷、氯仿和乙腈、氯仿和1,4-二氧六环、氯仿和甲苯、四氢呋喃和异丙醇、四氢呋喃和4-甲基-2-戊酮、四氢呋喃和乙酸乙酯、四氢呋喃和甲苯、四氢呋喃和甲酸丁酯、四氢呋喃和正庚烷、四氢呋喃和环己烷、四氢呋 喃和乙二醇二甲醚、四氢呋喃和甲基叔丁基醚、四氢呋喃和水、甲醇和丙酮、乙醇和乙酸乙酯、正丙醇和正庚烷、异丙醇和环已烷、甲醇和1,4-二氧六环、正丙醇和甲基叔丁基醚、乙醇和水、异丙醇和甲苯、丙酮和乙酸乙酯、丙酮和环己烷、丙酮和乙醚、4-甲基-2-戊酮和正庚烷、4-甲基-2-戊酮和甲醇、4-甲基-2-戊酮和甲基叔丁基醚、4-甲基-2-戊酮和乙腈、乙酸乙酯和环已烷、乙酸异丙酯和乙二醇甲醚、乙酸异丙酯和甲苯、甲酸丁酯和乙腈、甲基叔丁基醚和乙腈、乙二醇二甲醚和甲苯、水和乙腈、乙腈和甲苯、N,N′-二甲基甲酰胺和乙二醇甲醚、N,N′-二甲基甲酰胺和甲酸丁酯、N,N′-二甲基甲酰胺和4-甲基-2-戊酮、N,N′-二甲基甲酰胺和甲苯、N,N′-二甲基甲酰胺和甲醇、N,N′-二甲基甲酰胺和正丙醇、N,N′-二甲基甲酰胺和异丙醇、N,N′-二甲基甲酰胺和水、N,N′-二甲基甲酰胺和乙腈、二甲基亚砜和甲基叔丁基醚、二甲基亚砜和水、二二甲基亚砜和甲苯、甲基亚砜和乙腈、二甲基亚砜和甲醇、二甲基亚砜和乙醇、二甲基亚砜和正丙醇、二甲基亚砜和丙酮、乙醇和乙酸异丙酯、乙醇和乙腈、乙二醇二甲醚和乙腈、醇和水、正丙醇和环己烷、1,4-二氧六环和水。
除非另有说明，本发明所有的下列术语和短语旨在含有下列含义。一个特定的短语或者术语没有特别定义的情况下不应该被认为是不确定的或者不清楚的，而应该按照普通的含义去理解。
当本发明所述化合物的结构式与中文名称不符时，以化学结构式为准。
当XPRD谱图中的峰形不是很尖锐的衍射峰时，因不同软件计算得到的峰值可能会有差异，均在本发明范围内。
本发明中，所述温度均允许有一定的误差，若无特殊说明，优选±5℃，更优选±3℃，还要优选±2℃，最优选±1℃。例如，“Form A晶型的差示扫描量热曲线在40℃有吸热信号”，表示优选“Form A晶型的差示扫描量热曲线在40±5℃有吸热信号”，更优选“Form A晶型的差示扫描量热曲线在40±3℃有吸热信号”，还要优选“Form A晶型的差示扫描量热曲线在40±2℃有吸热信号”，最优选“Form A晶型的差示扫描量热曲线在40±1℃有吸热信号”。
附图说明
图1为式(I)所示化合物Form A晶型的XPRD谱图。
图2为式(I)所示化合物Form A晶型的DSC谱图。
图3为式(I)所示化合物Form A晶型的TGA谱图。
图4为式(I)所示化合物Form B晶型的XPRD谱图。
图5为式(I)所示化合物Form B晶型的DSC谱图。图6为式(I)所示化合物Form B晶型的TGA谱图。
图7为式(I)所示化合物Form C晶型的XPRD谱图。
图8为式(I)所示化合物Form C晶型的DSC谱图。
图9为式(I)所示化合物Form C晶型的TGA谱图。
图10为式(I)所示化合物Form D晶型的XPRD谱图。
图11为式(I)所示化合物Form D晶型的DSC谱图。
图12为式(I)所示化合物Form D晶型的TGA谱图。
图13为式(I)所示化合物Form E晶型的XPRD谱图。
图14为式(I)所示化合物Form E晶型的DSC谱图。
图15为式(I)所示化合物Form E晶型的TGA谱图。
图16为式(I)所示化合物Form F晶型的XPRD谱图。
图17为式(I)所示化合物Form F晶型的DSC谱图。
图18为式(I)所示化合物Form F晶型的TGA谱图。
图19为式(I)所示化合物Form G晶型的XPRD谱图。
图20为式(I)所示化合物Form G晶型的DSC谱图。
图21为式(I)所示化合物Form G晶型的TGA谱图。
图22为式(I)所示化合物Form B晶型的DVS谱图。
图23为式(I)所示化合物Form B晶型的DVS测试前后XPRD数据叠合谱图。
图24为式(I)所示化合物Form B晶型的稳定性研究的XRPD数据叠合谱图。
具体实施方式
下面结合实例进一步阐明本发明的内容，但本发明的保护范围并不仅仅局限于这些实例。本发明所述的百分比除特别注明外，均为重量百分比。说明书中所描述的数值范围，如计量单位、反应条件、化合物物理状态或百分比，均是为了提供明白无误的书面参考。本领域技术人员在实践本专利时，使用在此范围之外或有别于单个数值的温度、浓度、数量、碳原子数等，仍然可以得到预期的结果。
本发明涉及的所有化合物和所有中间体均可通过常见的分离方法进行纯化，如萃取、重结晶及硅胶柱层析、制备TLC分离等。所用200-300目的硅胶和薄层层析硅胶板均由青岛海洋化工厂生产。所用溶剂和化学试剂为一般试剂的分析纯或化学纯市售商品，使用时未经进一步纯化。
本发明X射线粉末衍射(XRPD)分析方法：
实验所得固体样品用X射线粉末衍射仪Empyrean(Panalytical，NL)进行分析。2θ扫描角度从3°到45°，扫描步长为0.013°，测试总时间为4min。测试样品时光管电压和电流分别为45kV和40mA，样品盘为零背景样品盘。
在线变温XRPD测试使用X射线粉末衍射仪Malvern PANalytical Aeris (Malvern Panalytical，UK)进行，2θ扫描角度从8°到40°，扫描步长为0.02°，测试时间为15min。测试样品时光管电压和电流分别为40kV和7.5mA，样品盘为零背景样品盘。样品置于BTS500热台(Anton Paar，AT)，室温下进行XRPD测试，随后以20℃/min加热至120℃或150℃，恒温20min后在相同温度进行XRPD测试。
本发明差式扫描量热分析(DSC)方法：
差示扫描量热分析仪的型号为TA Discovery 2500(TA，US)。1-2mg样品经精确称重后置于扎孔的DSC Tzero样品盘中，以10℃/min的速率加热至最终温度，炉内氮气吹扫速度为50mL/min。
本发明热重分析(TGA)方法：
热重分析仪的型号为TA Discovery 550(TA，US)。将2-5mg样品置于已平衡的开口铝制样品盘中，在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。
本发明动态水蒸汽吸脱附分析(DVS)方法：
动态水蒸汽吸脱附分析采用DVS Intrinsic(SMS，UK)进行测定。测试采用梯度模式，湿度变化为50％-95％-0％-50％，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。测试完成后，对样品进行XRPD分析确认固体形态是否发生变化。
吸湿性分类评价如下：

附：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重
本发明核磁(1H-NMR)分析方法：
1H-NMR在室温下采用BRUKER AVANCE-400MHz型核磁共振波谱仪在氘代二甲亚砜(DMSO-d6)或氘代氯仿(CDCl3)等中以四甲基硅烷(TMS)为内标物测定，信号峰表示为s(单峰)，d(双峰)，t(三重峰)，q(四重峰)，m(多重峰)，dd(双二重峰)。耦合常数(J)的单位为赫兹(Hz)。
实施例1式(I)化合物的制备
第一步
将1a(530.00mg,1.13mmol,1.0eq，合成参考文献CN202111092852.4)溶于1,4-二氧六环(10mL)中，加入三氟乙酸(5mL)，在环境温度下搅拌1h。浓缩反应液，将残余物溶解在1,4-二氧六环(10mL)中，加入1b(583.08mg,1.13mmol,1.0eq，合成参考文献CN202111092852.4)，1,1'-双(二环己基膦基)二茂铁二氯化钯(83.05mg,0.11mmol,0.1eq)，无水碳酸钠(359.34mg,3.39mmol,3.0eq)和水(5mL)，所得混合液用微波加热到110℃并反应1h，冷却至环境温度。浓缩反应液，粗品经硅胶柱柱层析(二氯甲烷/甲醇(v/v)＝40/1～20/1)分离后，得到固体1c。(363.00mg，收率47.3％)。LC-MS MS-ESI(m/z)679.6[M+H]+。
第二步
将中间体1c(363.00mg,0.53mmol,1.0eq)溶于二氯甲烷(10mL)中，加入三乙胺(1mL)和1d(143.78mg,0.79mmol,1.5eq，合成参考文献CN202111092852.4)，所得混合液在环境温度下搅拌1h后，加入醋酸硼氢化钠(674.16mg,3.18mmol,6.0eq)并继续搅拌16h。反应液用饱和碳酸氢钠溶液淬灭，用二氯甲烷/甲醇(10/1,100mL)萃取3次。合并有机相，用无水硫酸钠干燥，浓缩。粗品经制备TLC(二氯甲烷/甲醇(v/v)＝8/1)分离后，得到固体1e。(363.00mg，收率47.3％)。LC-MS MS-ESI(m/z)845.9[M+H]+。
第三步
将中间体1e(338.00mg,0.40mmol,1.0eq)溶于二氯甲烷(10mL)中，加入三氟乙酸(10mL)，所得溶液在环境温度下搅拌1h。浓缩反应液，将残余物溶解在二氯甲烷(10mL)中，再次浓缩，得到的三氟乙酸盐固体直接用于下一阶段。将上述的三氟乙酸盐溶于二氯甲烷(10mL)中，加入三乙胺(1mL)和市售的1f(117.6mg,0.60mmol,1.5eq)。所得混合液在环境温度下搅拌1h后，加入醋酸硼氢化钠(508.80mg,2.40mmol,6.0eq)，继续搅拌16h。反应液用饱和碳酸氢钠溶液淬灭，用二氯甲烷/甲醇(10/1,100mL)萃取3次。合并有机相，用无水硫酸钠干燥，浓缩。粗品经制备TLC(二氯甲烷/甲醇(v/v)＝6/1)分离后，得到1g。(307.00mg，收率82.9％)。LC-MS MS-ESI(m/z)926.0[M+H]+。
第四步
将中间体1g(307.00mg,0.33mmol,1.0eq)溶于四氢呋喃(10mL)中，加入水(10mL)和氢氧化锂一水合物(277.20mg,6.60mmol,20.0eq)，所得溶液在环境温度下搅拌16h。浓缩除去四氢呋喃，用1M盐酸调pH至5-6。过滤收集固体，干燥得到类白色固体I。(84.00mg，收率27.9％)。LC-MS MS-ESI(m/z)912.0[M+H]+。1H-NMR(400MHz,DMSO-d6)δppm 9.89(s,2H),8.38(d,J＝8.4Hz,2H),7.49(t,J＝8.0Hz,2H),7.14(d,J＝7.4Hz,2H),3.90(s,6H),3.48-3.41(m, 4H),3.33(s,2H),3.24(s,3H),2.78-2.70(m,4H),2.69-2.62(m,4H),2.56-2.51(m,4H),1.89-1.83(m,2H),1.75-1.69(m,4H),1.58-1.22(m,16H),1.12(s,2H).
实施例2式(I)所示化合物的不同晶型的制备
2.1挥发法
1)单溶剂挥发法
取适量式(I)样品溶解在不同溶剂中，将所得澄清溶液在室温敞口静置，直至溶剂完全挥发得到固体，所得湿样直接进行XRPD测试。结果如表8所示。
表8单溶剂挥发结晶结果
2)二元溶剂挥发法
将约20mg的式(I)样品溶解于一定体积的混合溶剂中，过滤后将滤液在室温下敞口静置，直至溶剂完全挥发得到固体。所得湿样直接进行XRPD测试。结果如表9所示。
表9二元溶剂挥发结晶结果

2.2悬浮法
以式(I)样品的不同晶型作为原料，选择不同的溶剂进行室温(～25℃)以及50℃的悬浮实验。
1)式(I)的Form A样品的室温悬浮
称取一定量式(I)的Form A样品，分别在所选单一和二元溶剂中室温悬浮7天。结果如表10所示。
表10 Form A室温悬浮结晶结果

2)式(I)的Form A样品的50℃悬浮
称取一定量式(I)的Form A样品，在不同溶剂中于50℃悬浮24h，结果如表11所示。
表11 Form A的50℃悬浮结晶结果

3)式(I)的Form B样品的室温悬浮
称取一定量式(I)的Form B样品，在所选单一溶剂中室温悬浮1天，结果如表12所示。
表12 Form A的室温悬浮结晶结果
4)式(I)的Form C样品的室温悬浮
称取一定量式(I)的Form C样品，在所选单一溶剂中室温悬浮1天，结果如表13所示。
表13 Form C的室温悬浮结晶结果
5)式(I)的Form A和Form D样品的室温悬浮
称取一定量式(I)的Form A和Form D样品，在所选单一溶剂中室温悬浮1天后固液离心分离，40℃真空干燥1天，结果如表14所示。
表14 Form A和Form D的室温悬浮结晶结果
2.3溶析结晶法
1)二元溶剂反滴法
称取一定量式(I)样品，分别选用N,N′-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、或者四氢呋喃作为良溶剂，与多种不良溶剂组合，用反滴法进行二元溶剂的溶析结晶实验，结果如表15所示。
表15溶析结晶法之二元溶剂反滴法结晶结果

2)二元溶剂正滴法
称取一定量式(I)样品，分别选用N,N′-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、或者四氢呋喃作为良溶剂，与多种不良溶剂组合，用正滴法进行二元溶剂的溶析结晶实验，结果如表16所示。
表16溶析结晶法之二元溶剂正滴法结晶结果

2.4降温法
1)单一溶剂降温法
称取一定量式(I)样品，采用二氧六环进行单一溶剂降温结晶实验，结果如表17所示。
表17单一溶剂降温结晶结果
1)二元溶剂降温法
称取一定量式(I)样品，分别采用N,N′-二甲基甲酰胺或二甲基亚砜作为良溶剂与多种反溶剂组合，在50℃下进行二元溶剂的降温结晶实验，结果如表18所示。
表18单二元溶剂降温结晶结果
2.5气相扩散法
称取一定量式(I)样品，室温下滴加适量良溶剂使样品完全溶解；分别取过滤后约含20mg样品的溶液将其置于不良溶剂气氛中室温静置，直至有固体析出。用注射器将有固体析出的体系中的溶液移除，对湿样进行XRPD测试。结果如表19所示。
表19气相扩散法结晶结果
2.6热转晶法
1)在线变温
以不同晶型为原料，用在线变温XRPD加热至目标温度，并恒温20min，然后于该温度进行在线XRPD测试，结果如表20所示。
表20在线变温XPRD热转晶法结晶结果
2)热台热转晶
将6-8mg Form F置于玻璃片放在热台上，以20℃/min的速率加热至120℃，并恒温20min，然后自然降温冷却至室温后对固体进行XRPD测试，结果如表21所示。
表21热台热转晶结晶结果
实施例3式(I)所示化合物Form B晶型的吸湿性研究
本发明根据前述的动态水蒸汽吸脱附分析(DVS)方法，评价Form B晶型的吸湿性，测试完成后，对样品进行XRPD分析确认固体形态是否发生变化，结果见表22所示。
表22式(I)化合物Form B晶型的吸湿性研究结果

附：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重；aDVS数据见图22；bDVS测试前后XPRD数
据叠合比较见图23。
实验结论：本发明的式(I)所示化合物的Form B晶型具有吸湿性，DVS测试前后的晶型保持一致。
实施例4式(I)所示化合物Form B晶型的固体稳定性研究
对式(I)所示化合物Form B样品进行高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)条件下的稳定性研究，分别于17天和22天取样进行XRPD表征，结果如表23所示。
表23 Form B稳定性研究结果a


a XPRD数据叠合比较见图24
实验结论：XRPD结果显示，Form B在高温、高湿、光照、加速条件下17天和22天均稳定，没有发生晶型转变。

Claims (16)

  1. 式(I)所示化合物的晶型，其特征在于选自Form A晶型、Form B晶型、Form C晶型、Form D晶型、Form E晶型、Form F晶型和Form G晶型，
    所述Form A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、13.85±0.2°；
    所述Form B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.70±0.2°、9.54±0.2°、13.90±0.2°；
    所述Form C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.10±0.2°、12.30±0.2°；
    所述Form D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.45±0.2°、12.95±0.2°、13.65±0.2°；
    所述Form E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.81±0.2°、13.73±0.2°、15.89±0.2°；
    所述Form F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.73±0.2°、9.07±0.2°；
    所述Form G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.75±0.2°、17.72±0.2°。
  2. 根据权利要求1所述的晶型，其特征在于，所述Form A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、13.85±0.2°、17.25±0.2°；优选地，所述Form A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、12.70±0.2°、13.85±0.2°、15.30±0.2°、17.25±0.2°、25.06±0.2°；更优选地，所述Form A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.39±0.2°、9.28±0.2°、10.75±0.2°、11.46±0.2°、12.70±0.2°、12.93±0.2°、 13.85±0.2°、14.55±0.2°、15.30±0.2°、16.30±0.2°、16.83±0.2°、17.25±0.2°、18.52±0.2°、18.94±0.2°、20.37±0.2°、20.83±0.2°、21.65±0.2°、22.97±0.2°、24.18±0.2°、25.06±0.2°、25.94±0.2°、27.40±0.2°、28.96±0.2°、29.88±0.2°、30.78±0.2°、32.50±0.2°、33.16±0.2°；
    还要优选地，所述Form A晶型的XPRD谱图如图1所示。
  3. 根据权利要求1-2任一项所述的晶型，其特征在于，所述Form A晶型具有如下一项或两项特征：
    (1)Form A晶型的差示扫描量热曲线在40℃有吸热信号；优选Form A晶型的DSC谱图如图2所示；
    (2)Form A晶型的热重分析曲线在加热至100℃过程中有0.9％的失重；优选Form A晶型的TGA谱图如图3所示。
  4. 根据权利要求1所述的晶型，其特征在于，所述Form B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.70±0.2°、9.54±0.2°、13.90±0.2°、17.48±0.2°；
    优选地，所述Form B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.70±0.2°、9.54±0.2°、13.90±0.2°、16.93±0.2°、17.48±0.2°、17.72±0.2°；
    更优选地，所述Form B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.40±0.2°、5.70±0.2°、6.52±0.2°、7.78±0.2°、8.11±0.2°、8.74±0.2°、9.54±0.2°、11.46±0.2°、12.66±0.2°、12.94±0.2°、13.35±0.2°、13.90±0.2°、14.83±0.2°、15.33±0.2°、15.80±0.2°、16.93±0.2°、17.48±0.2°、17.72±0.2°、18.47±0.2°、18.66±0.2°、19.11±0.2°、19.61±0.2°、20.24±0.2°、20.77±0.2°、21.45±0.2°、22.07±0.2°、22.91±0.2°、23.55±0.2°、24.28±0.2°、25.09±0.2°、25.41±0.2°、25.91±0.2°、26.16±0.2°、27.19±0.2°、27.99±0.2°、28.58±0.2°、29.38±0.2°、29.97±0.2°、31.30±0.2°、32.04±0.2°、32.95±0.2°、33.23±0.2°、33.91±0.2°、34.25±0.2°、34.88±0.2°、35.35±0.2°、36.06±0.2°、37.34±0.2°、38.19±0.2°、39.46±0.2°、42.23±0.2°、44.02±0.2°；
    还要优选地，所述Form B晶型的XPRD谱图如图4所示。
  5. 根据权利要求1或4所述的晶型，其特征在于，所述Form B晶型具有如下一项或两项特征：
    (1)Form B晶型的差示扫描量热曲线在31℃有吸热信号；优选Form B晶型的DSC谱图如图5所示；
    (2)Form B晶型的热重分析曲线在加热至150℃过程中有1.0％的失重；优选Form B晶型的TGA谱图如图6所示。
  6. 根据权利要求1所述的晶型，其特征在于，所述Form C晶型的X射线粉末 衍射图谱在下列2θ角处具有特征衍射峰：6.10±0.2°、12.30±0.2°、13.22±0.2°、15.00±0.2°；
    优选地，所述Form C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.10±0.2°、9.89±0.2°、10.68±0.2°、12.30±0.2°、13.22±0.2°、13.90±0.2°、15.00±0.2°、15.82±0.2°、16.63±0.2°、17.86±0.2°、18.13±0.2°、18.68±0.2°、19.98±0.2°、20.41±0.2°、21.84±0.2°、22.77±0.2°、23.79±0.2°、24.14±0.2°、24.53±0.2°、26.10±0.2°、26.52±0.2°、26.91±0.2°、27.50±0.2°、28.21±0.2°、30.06±0.2°、31.18±0.2°、32.28±0.2°、33.12±0.2°；
    更优选地，所述Form C晶型的XPRD谱图如图7所示。
  7. 根据权利要求1或6任一项所述的晶型，其特征在于，所述Form C晶型具有如下一项或两项特征：
    (1)Form C晶型的差示扫描量热曲线在33℃、158℃、213℃有吸热信号；优选Form C晶型的DSC谱图如图8所示；
    (2)Form C晶型的热重分析曲线在加热至250℃过程中有9.8％的失重；优选Form C晶型的TGA谱图如图9所示。
  8. 根据权利要求1所述的晶型，其特征在于，所述Form D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.45±0.2°、10.98±0.2°、12.95±0.2°、13.41±0.2°、13.65±0.2°、16.30±0.2°；
    优选地，所述Form D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.45±0.2°、9.41±0.2°、10.13±0.2°、10.98±0.2°、11.59±0.2°、12.95±0.2°、13.41±0.2°、13.65±0.2°、14.42±0.2°、15.55±0.2°、15.79±0.2°、16.30±0.2°、16.89±0.2°、17.50±0.2°、17.97±0.2°、18.26±0.2°、18.81±0.2°、19.49±0.2°、19.73±0.2°、20.02±0.2°、20.35±0.2°、20.66±0.2°、21.38±0.2°、21.67±0.2°、22.07±0.2°、22.75±0.2°、23.82±0.2°、24.66±0.2°、25.87±0.2°、26.52±0.2°、26.84±0.2°、27.50±0.2°、28.76±0.2°、29.35±0.2°、29.71±0.2°、31.40±0.2°、31.95±0.2°、32.81±0.2°、33.29±0.2°、34.17±0.2°、36.99±0.2°、38.16±0.2°、39.46±0.2°；
    更优选地，所述Form D晶型的XPRD谱图如图10所示。
  9. 根据权利要求1或8所述的晶型，其特征在于，所述Form D晶型具有如下一项或两项特征：
    (1)Form D晶型的差示扫描量热曲线在70℃、199℃有吸热信号；优选FormD晶型的DSC谱图如图11所示；
    (2)Form D晶型的热重分析曲线在加热至150℃过程中有2.5％的失重；优选Form D晶型的TGA谱图如图12所示。
  10. 根据权利要求1所述的晶型，其特征在于，所述Form E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.81±0.2°、13.11±0.2°、13.73±0.2°、15.49±0.2°、15.89±0.2°、19.37±0.2°；
    优选地，所述Form E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.81±0.2°、9.93±0.2°、10.59±0.2°、11.59±0.2°、13.11±0.2°、13.73±0.2°、15.49±0.2°、15.89±0.2°、16.58±0.2°、17.15±0.2°、17.69±0.2°、18.19±0.2°、19.12±0.2°、19.37±0.2°、20.91±0.2°、21.40±0.2°、22.16±0.2°、23.97±0.2°、25.32±0.2°、25.94±0.2°、26.67±0.2°、27.50±0.2°、29.00±0.2°、30.13±0.2°、31.07±0.2°、32.57±0.2°、33.65±0.2°、35.92±0.2°、37.48±0.2°、39.50±0.2°、42.10±0.2°；
    更优选地，所述Form E晶型的XPRD谱图如图13所示。
  11. 根据权利要求1或10所述的晶型，其特征在于，所述Form E晶型具有如下一项或两项特征：
    (1)Form E晶型的差示扫描量热曲线在40℃、151℃、174℃、191℃有吸热信号；优选Form E晶型的DSC谱图如图14所示；
    (2)Form E晶型的热重分析曲线在加热至150℃过程中有2.7％的失重；优选Form E晶型的TGA谱图如图15所示。
  12. 根据权利要求1所述的晶型，其特征在于，所述Form F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.73±0.2°、9.07±0.2°、13.33±0.2°、18.17±0.2°、19.20±0.2°；
    优选地，所述Form F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.32±0.2°、6.73±0.2°、9.07±0.2°、13.33±0.2°、17.04±0.2°、17.81±0.2°、18.17±0.2°、19.20±0.2°、21.08±0.2°、21.30±0.2°；
    更优选地，所述Form F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.56±0.2°、6.32±0.2°、6.73±0.2°、7.82±0.2°、9.07±0.2°、10.41±0.2°、11.65±0.2°、12.66±0.2°、13.33±0.2°、13.62±0.2°、14.63±0.2°、15.00±0.2°、15.24±0.2°、15.58±0.2°、16.08±0.2°、16.47±0.2°、17.04±0.2°、17.81±0.2°、18.17±0.2°、18.68±0.2°、19.20±0.2°、19.98±0.2°、20.45±0.2°、21.08±0.2°、21.30±0.2°、21.97±0.2°、22.62±0.2°、22.80±0.2°、23.50±0.2°、23.85±0.2°、24.09±0.2°、24.39±0.2°、24.77±0.2°、25.72±0.2°、26.29±0.2°、26.83±0.2°、27.44±0.2°、28.12±0.2°、28.89±0.2°、29.16±0.2°、29.51±0.2°、30.46±0.2°、31.47±0.2°、32.06±0.2°、32.81±0.2°；
    还要优选地，所述Form F晶型的XPRD谱图如图16所示。
  13. 根据权利要求1或12所述的晶型，其特征在于，所述Form F晶型具有如下 一项或两项特征：
    (1)Form F晶型的差示扫描量热曲线在102℃、151℃、174℃有吸热信号；优选Form F晶型的DSC谱图如图17所示；
    (2)Form F晶型的热重分析曲线在加热至100℃过程中有7.8％的失重；优选Form F晶型的TGA谱图如图18所示。
  14. 根据权利要求1所述的晶型，其特征在于，所述Form G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.75±0.2°、17.72±0.2°、18.47±0.2°、19.22±0.2°；
    优选地，所述Form G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.2°、14.10±0.2°、14.75±0.2°、15.49±0.2°、17.06±0.2°、17.72±0.2°、18.47±0.2°、19.22±0.2°、24.61±0.2°；
    更优选地，所述Form G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.2°、8.02±0.2°、8.21±0.2°、8.50±0.2°、8.97±0.2°、9.49±0.2°、9.99±0.2°、10.67±0.2°、11.04±0.2°、11.69±0.2°、12.78±0.2°、13.64±0.2°、14.10±0.2°、14.75±0.2°、15.49±0.2°、16.08±0.2°、16.50±0.2°、17.06±0.2°、17.72±0.2°、18.47±0.2°、18.86±0.2°、19.22±0.2°、19.73±0.2°、20.20±0.2°、20.94±0.2°、21.29±0.2°、21.53±0.2°、22.83±0.2°、23.46±0.2°、24.24±0.2°、24.61±0.2°、24.99±0.2°、25.73±0.2°、26.58±0.2°、27.50±0.2°、28.54±0.2°、29.13±0.2°、29.77±0.2°、30.43±0.2°、31.14±0.2°、31.95±0.2°、32.57±0.2°、33.55±0.2°、35.05±0.2°、36.42±0.2°、36.80±0.2°、38.82±0.2°、40.87±0.2°；
    还要优选地，所述Form G晶型的XPRD谱图如图19所示。
  15. 根据权利要求1或14任一项所述的晶型，其特征在于，所述Form G晶型具有如下一项或两项特征：
    (1)Form G晶型的差示扫描量热曲线在152℃、175℃有吸热信号；优选Form G晶型的DSC谱图如图20所示；
    (2)Form G晶型的热重分析曲线在加热至150℃过程中有0.6％的失重；优选Form G晶型的TGA谱图如图21所示。
  16. 根据权利要求1-15任一项所述的晶型在制备用于治疗免疫调节相关疾病药物中的应用。
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