WO2024051590A1 - 苯并氮杂卓并环化合物盐型、晶型及其应用 - Google Patents

苯并氮杂卓并环化合物盐型、晶型及其应用 Download PDF

Info

Publication number
WO2024051590A1
WO2024051590A1 PCT/CN2023/116489 CN2023116489W WO2024051590A1 WO 2024051590 A1 WO2024051590 A1 WO 2024051590A1 CN 2023116489 W CN2023116489 W CN 2023116489W WO 2024051590 A1 WO2024051590 A1 WO 2024051590A1
Authority
WO
WIPO (PCT)
Prior art keywords
ray powder
diffraction pattern
powder diffraction
crystal form
formula
Prior art date
Application number
PCT/CN2023/116489
Other languages
English (en)
French (fr)
Inventor
张勇
曹程
Original Assignee
上海济煜医药科技有限公司
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 上海济煜医药科技有限公司 filed Critical 上海济煜医药科技有限公司
Publication of WO2024051590A1 publication Critical patent/WO2024051590A1/zh

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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to benzazepine compound salt forms, crystal forms and their applications.
  • Arginine Vasopressin AVP
  • AVP Arginine Vasopressin
  • Metabolic disorders of arginine vasopressin (AVP) can cause hyponatremia, abnormal antidiuretic hormone secretion syndrome, congestive heart failure, cirrhosis, kidney disease, hypertension, edema and other diseases.
  • Arginine vasopressin (AVP) receptor antagonists can inhibit the binding of AVP to the receptor, thus playing a therapeutic role in the above diseases.
  • Arginine vasopressin V2 receptor antagonists represented by tolvaptan can increase free water excretion without affecting electrolyte metabolism, making them ideal drugs for the treatment of the above diseases.
  • marketed AVP V2 receptor antagonists, such as tolvaptan are metabolized by liver metabolic enzymes, which produce a large number of metabolites in the body and lead to severe drug-induced hepatotoxicity.
  • the FDA provides this on the product label of the drug. A black box warning limits its application.
  • the application number is PCT/CN2022/079350, and the application date is March 4, 2022.
  • the patent application provides a new AVP V2 receptor antagonist with the following structure:
  • the invention proposes a maleate salt of the compound represented by formula (I), whose structure is represented by formula (II),
  • the present invention proposes crystal form A of the maleate salt of the compound represented by formula (I) (ie, the compound represented by formula (II)).
  • the X-ray powder diffraction pattern of crystal form A is in the following 2 ⁇ There are characteristic diffraction peaks at the corners: 9.14 ⁇ 0.2°, 12.88 ⁇ 0.2°, 18.31 ⁇ 0.2°, 18.90 ⁇ 0.2°, 20.60 ⁇ 0.2°, 27.61 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.14 ⁇ 0.2°, 12.88 ⁇ 0.2°, 17.19 ⁇ 0.2°, 18.31 ⁇ 0.2°, 18.90 ⁇ 0.2 °, 20.60 ⁇ 0.2°, 21.45 ⁇ 0.2°, 27.61 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.14 ⁇ 0.2°, 12.88 ⁇ 0.2°, 17.19 ⁇ 0.2°, 18.31 ⁇ 0.2°, 18.90 ⁇ 0.2°, 19.70 ⁇ 0.2°, 20.20 ⁇ 0.2°, 20.60 ⁇ 0.2°, 21.45 ⁇ 0.2°, 21.91 ⁇ 0.2°, 27.61 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.14 ⁇ 0.2°, 12.88 ⁇ 0.2°, 17.19 ⁇ 0.2°, 18.31 ⁇ 0.2°, 18.90 ⁇ 0.2 °, 19.70 ⁇ 0.2°, 20.20 ⁇ 0.2°, 20.60 ⁇ 0.2°, 21.45 ⁇ 0.2°, 21.91 ⁇ 0.2°, 25.96 ⁇ 0.2°, 26.53 ⁇ 0.2°, 27.61 ⁇ 0.2°, 29.22 ⁇ 0.2°, 30.20 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A has an X-ray powder diffraction pattern substantially as shown in Figure 1.
  • the X-ray powder diffraction pattern analysis data of Form A is shown in Table 1 below.
  • the present invention also proposes crystal form B of the maleate salt of the compound represented by formula (I) (ie, the compound represented by formula (II)).
  • the X-ray powder diffraction pattern of the crystal form B It has characteristic diffraction peaks at the following 2 ⁇ angles: 8.97 ⁇ 0.2°, 15.73 ⁇ 0.2°, 18.31 ⁇ 0.2°, 20.15 ⁇ 0.2°, 21.12 ⁇ 0.2°, 24.70 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form B has characteristic diffraction peaks at the following 2 ⁇ angles: 7.40 ⁇ 0.2°, 8.97 ⁇ 0.2°, 10.11 ⁇ 0.2°, 13.94 ⁇ 0.2°, 15.73 ⁇ 0.2 °, 18.31 ⁇ 0.2°, 19.02 ⁇ 0.2°, 20.15 ⁇ 0.2°, 21.12 ⁇ 0.2°, 24.70 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form B has an X-ray powder diffraction pattern substantially as shown in Figure 6.
  • the X-ray powder diffraction pattern analysis data of Form B is shown in Table 2 below.
  • the invention also discloses a fumarate salt of the compound represented by formula (I), the structure of which is represented by formula (III),
  • the present invention also discloses crystalline form C of the fumarate salt of the compound represented by formula (I) (ie, the compound represented by formula (III)).
  • the X-ray powder diffraction pattern of crystalline form C is as follows: There are characteristic diffraction peaks at the 2 ⁇ angle: 12.77 ⁇ 0.2°, 14.44 ⁇ 0.2°, 20.00 ⁇ 0.2°, 20.64 ⁇ 0.2°, 21.33 ⁇ 0.2°, 21.87 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form C has characteristic diffraction peaks at the following 2 ⁇ angles: 12.77 ⁇ 0.2°, 13.17 ⁇ 0.2°, 14.44 ⁇ 0.2°, 17.18 ⁇ 0.2°, 20.00 ⁇ 0.2 °, 20.64 ⁇ 0.2°, 21.33 ⁇ 0.2°, 21.87 ⁇ 0.2°, 23.43 ⁇ 0.2°, 25.86 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form C has an X-ray powder diffraction pattern substantially as shown in Figure 9.
  • the X-ray powder diffraction pattern analysis data of Form C is shown in Table 3 below.
  • the present invention proposes a hydrochloride salt of the compound represented by formula (I), whose structure is represented by formula (IV),
  • the present invention proposes crystalline form D of the hydrochloride salt of the compound represented by formula (I) (ie, the compound represented by formula (IV)).
  • the X-ray powder diffraction pattern of the crystalline form D is as follows: There are characteristic diffraction peaks at the 2 ⁇ angle: 8.13 ⁇ 0.2°, 9.27 ⁇ 0.2°, 9.91 ⁇ 0.2°, 13.53 ⁇ 0.2°, 16.37 ⁇ 0.2°, 17.09 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form D has characteristic diffraction peaks at the following 2 ⁇ angles: 8.13 ⁇ 0.2°, 9.27 ⁇ 0.2°, 9.91 ⁇ 0.2°, 12.86 ⁇ 0.2°, 13.53 ⁇ 0.2 °, 16.37 ⁇ 0.2°, 17.09 ⁇ 0.2°, 18.67 ⁇ 0.2°, 21.77 ⁇ 0.2°, 23.81 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form D has an X-ray powder diffraction pattern substantially as shown in Figure 12.
  • the X-ray powder diffraction pattern analysis data of Form D is shown in Table 4 below.
  • the present invention proposes crystalline form E of the hydrochloride salt of the compound represented by formula (I) (ie, the compound represented by formula (IV)).
  • the X-ray powder diffraction pattern of the crystalline form E is as follows: There are characteristic diffraction peaks at the 2 ⁇ angle: 3.86 ⁇ 0.2°, 13.60 ⁇ 0.2°, 14.19 ⁇ 0.2°, 18.06 ⁇ 0.2°, 20.50 ⁇ 0.2°, 21.24 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2 ⁇ angles: 3.86 ⁇ 0.2°, 6.74 ⁇ 0.2°, 11.73 ⁇ 0.2°, 13.60 ⁇ 0.2°, 14.19 ⁇ 0.2°, 18.06 ⁇ 0.2°, 20.50 ⁇ 0.2°, 21.24 ⁇ 0.2°, 23.72 ⁇ 0.2°, 24.06 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form E has an X-ray powder diffraction pattern substantially as shown in Figure 15.
  • the X-ray powder diffraction pattern analysis data of the crystalline form E is shown in Table 5 below.
  • the present invention also proposes crystal form F of the hydrochloride salt of the compound represented by formula (I) (ie, the compound represented by formula (IV)).
  • the X-ray powder diffraction pattern of the crystal form F is in There are characteristic diffraction peaks at the following 2 ⁇ angles: 5.84 ⁇ 0.2°, 11.77 ⁇ 0.2°, 13.29 ⁇ 0.2°, 17.82 ⁇ 0.2°, 20.49 ⁇ 0.2°, 20.94 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2 ⁇ angles: 5.84 ⁇ 0.2°, 11.77 ⁇ 0.2°, 13.29 ⁇ 0.2°, 14.34 ⁇ 0.2°, 17.82 ⁇ 0.2°, 18.67 ⁇ 0.2°, 20.49 ⁇ 0.2°, 20.94 ⁇ 0.2°, 23.02 ⁇ 0.2°, 23.68 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form F has an X-ray powder diffraction pattern substantially as shown in Figure 18.
  • the X-ray powder diffraction pattern analysis data of the crystalline form F is shown in Table 6 below.
  • the present invention also proposes a sulfate salt of the compound represented by formula (I), whose structure is represented by formula (V),
  • the present invention also proposes the crystalline form G of the sulfate of the compound represented by formula (I) (ie, the compound represented by formula (V)).
  • the X-ray powder diffraction pattern of the crystalline form G is as follows: There are characteristic diffraction peaks at the 2 ⁇ angle: 10.30 ⁇ 0.2°, 13.02 ⁇ 0.2°, 16.60 ⁇ 0.2°, 18.53 ⁇ 0.2°, 20.67 ⁇ 0.2°, 22.26 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2 ⁇ angles: 6.46 ⁇ 0.2°, 10.30 ⁇ 0.2°, 13.02 ⁇ 0.2°, 16.60 ⁇ 0.2°, 17.66 ⁇ 0.2°, 18.53 ⁇ 0.2°, 19.98 ⁇ 0.2°, 20.67 ⁇ 0.2°, 22.26 ⁇ 0.2°, 23.62 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form G has an X-ray powder diffraction pattern substantially as shown in Figure 21.
  • the X-ray powder diffraction pattern analysis data of the sulfate crystal form G is shown in Table 7 below.
  • the present invention also proposes a succinate salt of the compound represented by formula (I), whose structure is represented by formula (VI),
  • the present invention also proposes crystalline form H of the succinate salt of the compound represented by formula (I) (ie, the compound represented by formula (VI)).
  • the X-ray powder diffraction pattern of the crystalline form H is in There are characteristic diffraction peaks at the following 2 ⁇ angles: 10.30 ⁇ 0.2°, 14.63 ⁇ 0.2°, 18.59 ⁇ 0.2°, 20.13 ⁇ 0.2°, 21.83 ⁇ 0.2°, 22.30 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2 ⁇ angles: 10.30 ⁇ 0.2°, 12.91 ⁇ 0.2°, 14.63 ⁇ 0.2°, 18.59 ⁇ 0.2°, 19.41 ⁇ 0.2°, 20.13 ⁇ 0.2°, 20.69 ⁇ 0.2°, 21.83 ⁇ 0.2°, 22.30 ⁇ 0.2°, 23.65 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form H has an X-ray powder diffraction pattern substantially as shown in Figure 24.
  • the X-ray powder diffraction pattern analysis data of the crystalline form H is as shown in Table 8 below.
  • the present invention also proposes the succinate crystal form J of the compound represented by formula (I) (ie, the compound represented by formula (VI)).
  • the X-ray powder diffraction pattern of the crystal form J is in There are characteristic diffraction peaks at the following 2 ⁇ angles: 9.61 ⁇ 0.2°, 11.56 ⁇ 0.2°, 12.93 ⁇ 0.2°, 17.12 ⁇ 0.2°, 17.71 ⁇ 0.2°, 19.95 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form J has characteristic diffraction peaks at the following 2 ⁇ angles: 9.61 ⁇ 0.2°, 11.56 ⁇ 0.2°, 12.93 ⁇ 0.2°, 13.76 ⁇ 0.2°, 17.12 ⁇ 0.2°, 17.71 ⁇ 0.2°, 19.51 ⁇ 0.2°, 19.95 ⁇ 0.2°, 21.83 ⁇ 0.2°, 22.42 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form J has an X-ray powder diffraction pattern substantially as shown in Figure 27.
  • the X-ray powder diffraction pattern analysis data of the crystal form J is shown in Table 9 below.
  • the present invention also proposes a glycolate salt of the compound represented by formula (I), whose structure is represented by formula (VII),
  • the present invention also proposes crystal form K of the glycolate salt of the compound represented by formula (I) (ie, the compound represented by formula (VII)).
  • the X-ray powder diffraction pattern of the crystal form K is in There are characteristic diffraction peaks at the following 2 ⁇ angles: 12.51 ⁇ 0.2°, 15.99 ⁇ 0.2°, 18.71 ⁇ 0.2°, 20.18 ⁇ 0.2°, 20.59 ⁇ 0.2°, 21.64 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form K has characteristic diffraction peaks at the following 2 ⁇ angles: 12.51 ⁇ 0.2°, 13.62 ⁇ 0.2°, 15.99 ⁇ 0.2°, 16.65 ⁇ 0.2°, 18.71 ⁇ 0.2°, 20.18 ⁇ 0.2°, 20.59 ⁇ 0.2°, 21.64 ⁇ 0.2°, 22.62 ⁇ 0.2°, 24.53 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form K has an X-ray powder diffraction pattern substantially as shown in Figure 30.
  • the X-ray powder diffraction pattern analysis data of the crystal form K is shown in Table 10 below.
  • the present invention also proposes a benzoate salt of the compound represented by formula (I), whose structure is represented by formula (VIII),
  • the present invention also proposes the benzoic acid eutectic crystal form L of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form L has characteristic diffraction peaks at the following 2 ⁇ angles: 8.14 ⁇ 0.2°, 8.76 ⁇ 0.2°, 9.55 ⁇ 0.2°, 12.62 ⁇ 0.2°, 16.43 ⁇ 0.2°, 18.05 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2 ⁇ angles: 8.14 ⁇ 0.2°, 8.76 ⁇ 0.2°, 9.55 ⁇ 0.2°, 12.62 ⁇ 0.2°, 16.43 ⁇ 0.2°, 17.68 ⁇ 0.2°, 18.05 ⁇ 0.2°, 18.95 ⁇ 0.2°, 19.32 ⁇ 0.2°, 19.73 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form L has an X-ray powder diffraction pattern substantially as shown in Figure 33.
  • the X-ray powder diffraction pattern analysis data of the crystal form L is shown in Table 11 below.
  • the present invention also proposes the benzoic acid eutectic crystal form M of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form M has characteristic diffraction peaks at the following 2 ⁇ angles: 9.31 ⁇ 0.2°, 13.77 ⁇ 0.2°, 14.54 ⁇ 0.2°, 19.84 ⁇ 0.2°, 20.34 ⁇ 0.2°, 21.70 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form M has characteristic diffraction peaks at the following 2 ⁇ angles: 9.31 ⁇ 0.2°, 13.77 ⁇ 0.2°, 14.54 ⁇ 0.2°, 16.55 ⁇ 0.2°, 17.66 ⁇ 0.2°, 18.68 ⁇ 0.2°, 19.84 ⁇ 0.2°, 20.34 ⁇ 0.2°, 21.70 ⁇ 0.2°, 23.32 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form M has an X-ray powder diffraction pattern substantially as shown in Figure 36.
  • the X-ray powder diffraction pattern analysis data of the crystal form M is as shown in Table 12 below.
  • the present invention also proposes the crystalline form N of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystalline form N has a characteristic diffraction peak at the following 2 ⁇ angle: 10.38 ⁇ 0.2°. , 13.54 ⁇ 0.2°, 14.41 ⁇ 0.2°, 16.32 ⁇ 0.2°, 18.10 ⁇ 0.2°, 19.05 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form N has characteristic diffraction peaks at the following 2 ⁇ angles: 10.38 ⁇ 0.2°, 13.54 ⁇ 0.2°, 14.41 ⁇ 0.2°, 15.90 ⁇ 0.2°, 16.32 ⁇ 0.2°, 18.10 ⁇ 0.2°, 19.05 ⁇ 0.2°, 22.14 ⁇ 0.2°, 22.91 ⁇ 0.2°, 23.66 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form N has an X-ray powder diffraction pattern substantially as shown in Figure 39.
  • the X-ray powder diffraction pattern analysis data of the crystal form N is shown in Table 13 below.
  • the present invention also proposes the crystalline form O of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystalline form O has a characteristic diffraction peak at the following 2 ⁇ angle: 4.75 ⁇ 0.2°. , 9.65 ⁇ 0.2°, 15.70 ⁇ 0.2°, 16.88 ⁇ 0.2°, 18.00 ⁇ 0.2°, 18.97 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2 ⁇ angles: 4.75 ⁇ 0.2°, 9.65 ⁇ 0.2°, 15.70 ⁇ 0.2°, 16.88 ⁇ 0.2°, 18.00 ⁇ 0.2°, 18.97 ⁇ 0.2°, 19.89 ⁇ 0.2°, 21.86 ⁇ 0.2°, 22.67 ⁇ 0.2°, 24.30 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form O has an X-ray powder diffraction pattern substantially as shown in Figure 42.
  • the X-ray powder diffraction pattern analysis data of the crystal form O is as shown in Table 14 below.
  • the present invention also proposes the crystalline form P of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystalline form P has a characteristic diffraction peak at the following 2 ⁇ angle: 13.07 ⁇ 0.2°. , 17.98 ⁇ 0.2°, 21.64 ⁇ 0.2°, 23.78 ⁇ 0.2°, 26.36 ⁇ 0.2°, 33.13 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form P has an X-ray powder diffraction pattern substantially as shown in Figure 45.
  • the X-ray powder diffraction pattern analysis data of the crystal form P is shown in Table 15 below.
  • the present invention also proposes a crystalline form Q of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystalline form Q has a characteristic diffraction peak at the following 2 ⁇ angle: 3.48 ⁇ 0.2°. , 10.60 ⁇ 0.2°, 12.32 ⁇ 0.2°, 15.41 ⁇ 0.2°, 16.60 ⁇ 0.2°, 17.09 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form Q has characteristic diffraction peaks at the following 2 ⁇ angles: 3.48 ⁇ 0.2°, 10.60 ⁇ 0.2°, 12.32 ⁇ 0.2°, 15.41 ⁇ 0.2°, 16.60 ⁇ 0.2°, 17.09 ⁇ 0.2°, 17.75 ⁇ 0.2°, 18.79 ⁇ 0.2°, 20.49 ⁇ 0.2°, 21.40 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form Q has an X-ray powder diffraction pattern substantially as shown in Figure 48.
  • the X-ray powder diffraction pattern analysis data of the crystal form Q is shown in Table 16 below.
  • the present invention also proposes the crystalline form R of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystalline form R has a characteristic diffraction peak at the following 2 ⁇ angle: 6.70 ⁇ 0.2°. , 13.30 ⁇ 0.2°, 18.15 ⁇ 0.2°, 21.39 ⁇ 0.2°, 22.97 ⁇ 0.2°, 26.71 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form R has an X-ray powder diffraction pattern substantially as shown in Figure 50.
  • the X-ray powder diffraction pattern analysis data of the crystal form R is shown in Table 17 below.
  • the present invention also proposes a crystalline form S of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystalline form S has a characteristic diffraction peak at the following 2 ⁇ angle: 14.97 ⁇ 0.2°. , 15.34 ⁇ 0.2°, 17.97 ⁇ 0.2°, 22.81 ⁇ 0.2°, 23.54 ⁇ 0.2°, 24.69 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form S has an X-ray powder diffraction pattern substantially as shown in Figure 53.
  • the X-ray powder diffraction pattern analysis data of the crystal form S is shown in Table 18 below.
  • the present invention also proposes a crystalline form T of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystalline form T has a characteristic diffraction peak at the following 2 ⁇ angle: 15.84 ⁇ 0.2°. , 17.03 ⁇ 0.2°, 17.60 ⁇ 0.2°, 20.01 ⁇ 0.2°, 22.22 ⁇ 0.2°, 22.82 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form T has characteristic diffraction peaks at the following 2 ⁇ angles: 13.64 ⁇ 0.2°, 14.70 ⁇ 0.2°, 15.84 ⁇ 0.2°, 17.03 ⁇ 0.2°, 17.60 ⁇ 0.2°, 19.01 ⁇ 0.2°, 20.01 ⁇ 0.2°, 22.22 ⁇ 0.2°, 22.82 ⁇ 0.2°, 24.45 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form T has an X-ray powder diffraction pattern substantially as shown in Figure 56.
  • the X-ray powder diffraction pattern analysis data of the crystal form T is shown in Table 19 below.
  • the present invention also proposes a crystalline form U of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystalline form U has a characteristic diffraction peak at the following 2 ⁇ angle: 8.01 ⁇ 0.2° , 9.27 ⁇ 0.2°, 12.68 ⁇ 0.2°, 16.15 ⁇ 0.2°, 17.94 ⁇ 0.2°, 19.31 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form U has characteristic diffraction peaks at the following 2 ⁇ angles: 8.01 ⁇ 0.2°, 9.27 ⁇ 0.2°, 12.68 ⁇ 0.2°, 16.15 ⁇ 0.2°, 17.94 ⁇ 0.2°, 19.31 ⁇ 0.2°, 22.16 ⁇ 0.2°, 22.82 ⁇ 0.2°, 23.80 ⁇ 0.2°, 24.08 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form U has an X-ray powder diffraction pattern substantially as shown in Figure 59.
  • the X-ray powder diffraction pattern analysis data of the crystal form U is shown in Table 20 below.
  • API or “free state” both refer to the free base form of the compound represented by formula (I).
  • Crystalline form or “crystalline form” refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Clathrate, eutectic, salt, salt solvate, salt hydrate. Crystalline forms of substances can be obtained by a number of methods known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in nanopores or capillaries, crystallization on a surface or template, e.g., on a polymer, Crystallization in the presence of additives such as co-crystallized antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding and solvent drop milling, etc.
  • additives such as co-crystallized antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding and solvent drop milling, etc.
  • Amorphous or “amorphous form” refers to a substance formed when particles (molecules, atoms, ions) of matter are arranged in a three-dimensional space without periodicity, and is characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline matter. Amorphous forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, solid dispersion technology, etc.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol , ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylacetamide Methylformamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol , propanol, 2-propanone, pyridine,
  • Antisolvent refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent.
  • the antisolvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid than the solvent.
  • Solidvate means that the crystal has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice, where the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetrachloro Carbon dioxide, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylacetamide Methylformamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2 -Acetone, pyridine, tetrahydrofuran, toluene
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, or in the crystal lattice, or both on the surface and in the crystal lattice is water.
  • the hydrate may or may not have a solvent other than water on the surface of the substance, or in the crystal lattice, or both on the surface and in the crystal lattice.
  • Crystalline or amorphous forms can be identified through a variety of technical methods, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • solution calorimetry solution calorimetry
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect changes in crystal form, crystallinity, crystal structure state and other information, and is a common method for identifying crystal forms.
  • the peak position of the XRPD spectrum mainly depends on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the Figures of the invention. At the same time, the measurement of 2 ⁇ of the XRPD spectrum may have experimental errors.
  • the measurement of 2 ⁇ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2 ⁇ cannot be regarded as absolute. According to the conditions of the instrument used in the test of the present invention, there is an error tolerance of ⁇ 0.2° for the diffraction peak.
  • Differential scanning calorimetry is a technique that measures the energy difference between a sample and an inert reference substance (commonly used ⁇ -Al 2 O 3 ) as the temperature changes by continuously heating or cooling under program control.
  • the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by a DSC pattern having characteristic peak positions substantially as shown in the DSC patterns provided in the Figures herein. At the same time, the DSC spectrum may have experimental errors.
  • the peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the instrument used in the test of the present invention, there is an error tolerance of ⁇ 3°C for the melting peak.
  • Glass transition refers to the transition of amorphous materials between the highly elastic state and the glassy state. It is an inherent property of the material; its corresponding transition temperature is the glass transition temperature (Tg), which is an important characteristic of amorphous materials. physical properties. The glass transition is a phenomenon related to molecular motion. Therefore, the glass transition temperature (Tg) mainly depends on the structure of the substance and is relatively insensitive to experimental details.
  • the glass transition temperature (Tg) of the amorphous form of the present invention is determined by differential scanning calorimetry (DSC) and is characterized by having a glass transition temperature of 107.44°C. According to the conditions of the instrument used in the test of the present invention, there is an error tolerance of ⁇ 3°C for the glass transition temperature.
  • DSC Differential scanning calorimetry
  • Solids with the same chemical composition often form isomers, or variants, with different crystal structures under different thermodynamic conditions. This phenomenon is called polymorphism or polymorphism.
  • variants can transform into each other, a phenomenon called crystalline transformation. Due to the transformation of the crystal form, the mechanical, electrical, magnetic and other properties of the crystal will undergo tremendous changes.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric analysis is a technique that measures the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition. It can be inferred that the crystals contain crystal water or crystallization solvent. Case.
  • the mass change displayed by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA is slightly different between different instruments and different samples. According to the conditions of the instrument used in the test of the present invention, there is an error tolerance of ⁇ 0.3% for the mass change.
  • 2 ⁇ values in X-ray powder diffraction patterns are all in degrees (°).
  • a peak refers to a feature that can be identified by a person skilled in the art and is not attributable to background noise.
  • substantially as shown in the drawings means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95% of the X-ray powder diffraction pattern or DSC pattern or TGA result %, or at least 99% of the peaks are shown in its plot.
  • substantially pure means that a crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, the The percentage of other crystal forms in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, Or less than 0.1%, or less than 0.01%.
  • substantially free means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • Relative intensity refers to the ratio of the intensity of the other peaks to the intensity of the first strong peak among all diffraction peaks in the X-ray powder diffraction pattern (XRPD) when the intensity of the first strong peak is 100%.
  • the words "about” or “approximately” when or whether they are used mean within 10%, suitably within 5% and especially within 1% of a given value or range. .
  • the term “about” or “approximately” means within an acceptable standard error of the mean. Whenever a number with a value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+ Numbers within /-10% of the value are explicitly disclosed, where "+/-" means plus or minus.
  • Figure 1 is an XRPD pattern of maleate crystal form A according to an embodiment of the present invention
  • Figure 2 is a DSC and TGA diagram of maleate crystal form A according to an embodiment of the present invention
  • Figure 3 is an NMR chart of the maleate crystal form A according to an embodiment of the present invention: (a) comparison with the free state; (b) integration result;
  • Figure 4 is a DVS curve of maleate crystal form A according to an embodiment of the present invention.
  • Figure 5 is an XRPD pattern before and after the DVS test of maleate crystal form A according to an embodiment of the present invention
  • Figure 6 is an XRPD pattern of maleate crystal form B according to an embodiment of the present invention.
  • Figure 7 is a DSC and TGA diagram of maleate crystal form B according to an embodiment of the present invention.
  • Figure 8 is an NMR pattern of maleate crystal form B according to an embodiment of the present invention.
  • Figure 9 is an XRPD pattern of fumarate crystal form C according to an embodiment of the present invention.
  • Figure 10 is a DSC and TGA diagram of fumarate crystal form C according to an embodiment of the present invention.
  • Figure 11 is an NMR diagram of fumarate crystal form C according to an embodiment of the present invention: (a) comparison diagram with the free state; (b) integration result;
  • Figure 12 is an XRPD pattern of hydrochloride crystal form D according to an embodiment of the present invention.
  • Figure 13 is a DSC and TGA diagram of hydrochloride crystal form D according to an embodiment of the present invention.
  • Figure 14 is an NMR diagram of hydrochloride crystal form D according to an embodiment of the present invention: (a) comparison diagram with the free state; (b) integration result;
  • Figure 15 is an XRPD pattern of hydrochloride crystal form E according to an embodiment of the present invention.
  • Figure 16 is a DSC and TGA diagram of the hydrochloride crystal form E according to an embodiment of the present invention.
  • Figure 17 is an NMR chart of the hydrochloride crystal form E according to an embodiment of the present invention: (a) comparison with the free state; (b) integration result;
  • Figure 18 is an XRPD pattern of hydrochloride crystal form F according to an embodiment of the present invention.
  • Figure 19 is a DSC and TGA diagram of hydrochloride crystal form F according to an embodiment of the present invention.
  • Figure 20 is an NMR chart of the hydrochloride crystal form F according to an embodiment of the present invention: (a) comparison with the free state; (b) integration result;
  • Figure 21 is an XRPD pattern of sulfate crystal form G according to an embodiment of the present invention.
  • Figure 22 is a DSC and TGA chart of sulfate crystal form G according to an embodiment of the present invention.
  • Figure 23 is an NMR diagram of sulfate crystal form G according to an embodiment of the present invention: (a) comparison diagram with the free state; (b) integration result;
  • Figure 24 is an XRPD pattern of succinate crystal form H according to an embodiment of the present invention.
  • Figure 25 is a DSC and TGA diagram of succinate crystal form H according to an embodiment of the present invention.
  • Figure 26 is an NMR diagram of succinate crystal form H according to an embodiment of the present invention: (a) comparison diagram with the free state; (b) integration result;
  • Figure 27 is an XRPD pattern of succinate crystal form J according to an embodiment of the present invention.
  • Figure 28 is a DSC and TGA diagram of succinate crystal form J according to an embodiment of the present invention.
  • Figure 29 is an NMR chart of the succinate crystal form J according to an embodiment of the present invention: (a) comparison with the free state; (b) integration result;
  • Figure 30 is an XRPD pattern of glycolate crystal form K according to an embodiment of the present invention.
  • Figure 31 is a DSC and TGA diagram of glycolate crystal form K according to an embodiment of the present invention.
  • Figure 32 is an NMR pattern of glycolate crystal form K according to an embodiment of the present invention: (a) comparison with the free state; (b) integration result;
  • Figure 33 is an XRPD pattern of the benzoic acid eutectic crystal form L according to an embodiment of the present invention.
  • Figure 34 is a DSC and TGA diagram of benzoic acid eutectic crystal form L according to an embodiment of the present invention.
  • Figure 35 is an NMR chart of the benzoic acid eutectic crystal form L according to an embodiment of the present invention: (a) comparison chart with the free state; (b) integration result;
  • Figure 36 is an XRPD pattern of the benzoic acid eutectic crystal form M according to an embodiment of the present invention.
  • Figure 37 is a DSC and TGA diagram of the benzoic acid eutectic crystal form M according to an embodiment of the present invention.
  • Figure 38 is an NMR chart of the benzoic acid eutectic crystal form M according to an embodiment of the present invention: (a) comparison with the free state; (b) integration result;
  • Figure 39 is an XRPD pattern of Form N according to an embodiment of the present invention.
  • Figure 40 is a DSC and TGA diagram of crystal form N according to an embodiment of the present invention.
  • Figure 41 is an NMR pattern of Form N according to an embodiment of the present invention.
  • Figure 42 is an XRPD pattern of Form O according to an embodiment of the present invention.
  • Figure 43 is a DSC and TGA diagram of crystalline form O according to an embodiment of the present invention.
  • Figure 44 is an NMR pattern of Form O according to an embodiment of the present invention.
  • Figure 45 is an XRPD pattern of crystal form P according to an embodiment of the present invention.
  • Figure 46 is a DSC and TGA diagram of crystal form P according to an embodiment of the present invention.
  • Figure 47 is an NMR pattern of crystal form P according to an embodiment of the present invention.
  • Figure 48 is an XRPD pattern of crystalline form Q according to an embodiment of the present invention.
  • Figure 49 is a DSC and TGA diagram of crystalline form Q according to an embodiment of the present invention.
  • Figure 50 is an XRPD pattern of crystalline form R according to an embodiment of the present invention.
  • Figure 51 is a DSC and TGA diagram of crystalline form R according to an embodiment of the present invention.
  • Figure 52 is an NMR pattern of crystalline form R according to an embodiment of the present invention.
  • Figure 53 is an XRPD pattern of crystal form S according to an embodiment of the present invention.
  • Figure 54 is a DSC and TGA diagram of crystalline form S according to an embodiment of the present invention.
  • Figure 55 is an NMR pattern of crystalline form S according to an embodiment of the present invention.
  • Figure 56 is an XRPD pattern of crystalline form T according to an embodiment of the present invention.
  • Figure 57 is a DSC and TGA diagram of crystalline form T according to an embodiment of the present invention.
  • Figure 58 is an NMR pattern of crystalline form T according to an embodiment of the present invention.
  • Figure 59 is an XRPD pattern of Form U according to an embodiment of the present invention.
  • Figure 60 is a DSC and TGA diagram of crystalline form U according to an embodiment of the present invention.
  • Figure 61 is an NMR diagram of crystalline form U according to an embodiment of the present invention: (a) comparison diagram with the free state; (b) integration result;
  • Figure 62 is an XRPD pattern of the stability study of maleate crystal form A according to an embodiment of the present invention.
  • Figure 63 is an XRPD pattern of the stability study of fumarate crystal form C according to an embodiment of the present invention.
  • Figure 64 is an XRPD pattern of a stability study of Form N according to an embodiment of the present invention.
  • Figure 65 is an XRPD pattern of a stability study of Form S according to an embodiment of the present invention.
  • Figure 66 is an XRPD comparison chart of the remaining solid after the maleate crystal form A is shaken in the medium for 24 hours according to an embodiment of the present invention
  • Figure 67 is an XRPD comparison chart of the remaining solid after the fumarate crystal Form C is shaken in the medium for 24 hours according to an embodiment of the present invention.
  • the raw materials used in the present invention are all commercially available unless otherwise specified.
  • Test basis "Chinese Pharmacopoeia” 2020 edition, Part 4, General Chapter 0451.
  • Sample preparation Place the sample in the center of the groove of the sample holder, and make the surface of the sample flush with the surface of the sample holder.
  • thermogravimetric analyzer is TA Discovery 55 (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.
  • 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.
  • Dynamic moisture adsorption-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.
  • the model of the polarizing microscope is Nikon Ci-POL (Nikon, JP). Place a small amount of sample on a glass slide and select an appropriate lens to observe the sample morphology.
  • the high performance liquid chromatography model is LC-2030C 3D Plus (Shimadzu, JP), and the test conditions are shown in Table 21.
  • HPLC conditions used when testing the maleate content are shown in Table 22 below.
  • the ion chromatography model is ICS 5000 (Thermo Fisher, US), and the instrument parameters are shown in Table 23.
  • Different crystal forms are used as starting materials, and a certain amount of sample is added to the selected single solvent or binary solvent until a suspension is formed. After suspending and stirring at room temperature for a certain period of time, the suspension is centrifuged and the solid is vacuum dried at room temperature.
  • Different crystal forms are used as starting materials, and a certain amount of sample is added to the selected solvent until a suspension is formed. After suspending and stirring at 50°C for 1 day, the suspension is centrifuged and the solid is vacuum dried at room temperature.
  • Thermal crystallization was performed using Instec HCS424GXY hot stage (Instec Inc., USA). 6-8mg sample was placed on the glass piece and placed on the hot stage, heated to the target temperature at a rate of 20°C/min, and kept at a constant temperature for 5-10 minutes. Then naturally cool to room temperature to obtain a solid.
  • the configuration process of biological media is shown in Table 24.
  • Samples of different crystal forms were added to the biological medium and shaken at a constant temperature of 37°C for 24 hours. Samples were taken at 0.5 hours, 2 hours and 24 hours respectively.
  • the sampled solutions were filtered with a 0.22 ⁇ m water-based filter membrane. Some samples with higher concentrations were appropriately treated with diluent. Dilute, use HPLC to measure the signal peak area of the solution, and finally calculate the concentration of the compound in the solution based on the peak area, the HPLC standard curve of the raw material, and the dilution factor.
  • the 24h supernatant was taken to test its pH value, and the remaining solid was subjected to XRPD testing.
  • intermediate I-2 (19.00g, 46.68mmol) was dissolved in anhydrous N,N-dimethylformamide (187mL), and sodium carbonate (14.84g, 140.00mmol) and 2- (2-bromoethyl)isoindoline-1,3-dione (23.71g, 93.36mmol) was stirred at 90°C overnight under argon protection. After cooling, the reaction solution was diluted with ethyl acetate (500 mL), washed with water (150 mL ⁇ 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-3.
  • intermediate I-3 (20.00g, 34.48mmol) was dissolved in dimethyl sulfoxide/water (130mL/13mL), and sodium chloride (16.70g, 28.60mmol) was added. After the system was replaced with argon three times, it was stirred at 150°C for 10 hours under argon protection. After cooling, the reaction solution was diluted with ethyl acetate (400 mL), washed with water (150 mL ⁇ 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-4.
  • intermediate I-6 (150 mg, 0.40 mmol) was dissolved in anhydrous methanol (20 mL), and magnesium chips (2.00 g, 83.33 mmol) were added. The nitrogen was replaced three times, and the mixture was stirred at 70°C overnight under a nitrogen atmosphere (balloon). After cooling, filter through diatomaceous earth, concentrate the filtrate to dryness, add methylene chloride/methanol mixture (10/1, 50mL) to dissolve, wash with saturated ammonium chloride aqueous solution (20mL ⁇ 3), and wash with water (20mL ⁇ 2) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-7. The crude product was directly used in the next reaction.
  • LCMS analysis method Chromatographic column: Waters acquisition UPLC CSH 2.1 ⁇ 50mm, 1.7 ⁇ m.
  • Mobile phase A: water (0.01% trifluoroacetic acid)
  • B acetonitrile (0.01% trifluoroacetic acid).
  • Mass spectrometry scan range 100–1000.
  • Example 2 Inhibition IC 50 test of compounds of formula (I) on vasopressin-induced vasopressin receptor V2R activation
  • HeLa cell line stably expressing human vasopressin receptor V2R (HeLa-V2R): constructed by Shanghai Jikai Gene Chemical Technology Co., Ltd. using lentiviral infection method, and stably expressing human V2R was verified by qPCR.
  • DMEM cell culture medium Brand: Gibco, product number: 11995065; Fetal bovine serum: Brand: Gibco, product number: FND500; 0.25% trypsin: Brand: Gibco, product number: 25200072; Puromycin Dihydrochloride: Brand: Gibco, product number: A1113803; cAMP-GS HIRANGE KIT: Brand: Cisbio, product number: 62AM6PEC; IBMX: Brand: Sigma, product number: i5879; Vasopressin AVP: Customized by Gill Biochemical (Shanghai) Co., Ltd.
  • HeLa-V2R cells were incubated and cultured in DMEM medium supplemented with 10% fetal bovine serum at 37 degrees and 5% CO2 . 2 ⁇ g/mL puromycin was added to the medium to continuously select cells expressing V2R. On the day of the experiment, digest the cells with trypsin, wash the cells twice with the stimulation buffer in the cAMP-GS HIRANGE kit, resuspend and count, prepare to 1.6X10 6 cells/ml, and add IBMX to a final concentration of 0.5mM.
  • cAMP standard sample (3-fold dilution starting from 5.6 ⁇ M, 10 concentration points), and transfer 10 ⁇ L cAMP standard to the corresponding well of the 384-well plate.
  • lysis buffer in the cAMP-GS HIRANGE kit to dilute the cAMP-d2 fluorescent and anti-cAMP antibody probes provided in the kit 20 times.
  • Envision microplate reader for sample testing The HTRF method in Detection of fluorescence intensity at 615nm and 665nm. Two duplicate holes are made for each sample to be tested, and 32 duplicate holes are made for each of Min and Max.
  • Table 25 Evaluation of compounds on the inhibition of cAMP increase in human cervical cancer cells (Human V2R Hela-Stable cell line OE2)
  • the compound represented by formula (I) can be formed into 6 salts, namely hydrochloride, sulfate, maleate, fumarate, succinate and glycolate.
  • Method 1 Weigh 513.6 mg of the compound of formula (I) and 1 equivalent of maleic acid, add 16 mL of isopropyl alcohol, stir at room temperature for 2 days, centrifuge the suspension, and place the solid in a vacuum at 40°C Dry for 3 days. 611.5 mg of maleate crystal form A was obtained.
  • Method 2 Add methanol (30mL, 10.0v/w) to the jacketed reactor R1 at room temperature; replace nitrogen 3 times; add free amine (3.0g, 1w, 5.82mmol) to the jacketed reactor R1 at room temperature. ,1.0eq.), start stirring; stir until the solution is clear; in the jacketed reactor R2, configure the isopropyl alcohol solution of maleic acid: at 25-30°C, maleic acid (0.71g, 0.236w, 6.11mmol , 1.05eq) was dissolved in isopropanol (60mL, 20.0v/w); add the prepared maleic acid/isopropyl alcohol solution dropwise into reaction kettle R1, control the internal temperature to 20-30°C, and drop the time 20 minutes; after the dropwise addition is completed, react at 20-30°C for 2-5 hours; filter, wash the filter cake once with isopropyl alcohol (9mL, 3.0v/w), and dry to obtain maleate crystal form A.
  • Method 3 Add 10L of methanol to the 100L reaction kettle, add 4.2kg of free base, add 6.8L of methanol, raise the temperature to 60°C, dissolve 993g of maleic acid in 33.6L of isopropyl alcohol, slowly add the above solution dropwise, and cool to 25°C, filtered to obtain 4.7kg maleate crystal form A.
  • Maleate crystal form A was characterized, and the characterization results are shown in Figures 1 to 5.
  • the XRPD ( Figure 1) results show that the maleate crystal form A is a solid with good crystallinity.
  • TGA ( Figure 2) results show that maleate crystal form A has a weight loss of 0.5% during heating to 150°C and may decompose above 200°C.
  • the DSC ( Figure 2) results show that maleate crystal form A has an endothermic peak at 229°C.
  • the DVS ( Figure 4) results show that the maleate crystal form A gained weight by 0.09% at 80% RH, gained 0.23% at 95% RH, and lost 0.24% at 0% RH, indicating that the maleate crystal form A has almost no hygroscopicity;
  • the XRPD ( Figure 5) results show that the crystal form of the sample after the DVS test has not changed. It can be seen that the maleate crystal form A is an amorphous form with good crystallinity and has almost no hygroscopicity.
  • maleate crystal form A Dissolve 21.7 mg of maleate crystal form A in 0.5 mL of DMF, add 1.5 mL of isopropyl alcohol, heat to 60°C, slowly cool to 15°C, and filter to obtain maleate crystal form B.
  • the XRPD ( Figure 6) results show that Form B is a solid with good crystallinity.
  • TGA ( Figure 7) results show that crystal form B has a weight loss of 9.7% when heated from room temperature to 170°C, and decomposition may occur above 220°C.
  • the DSC ( Figure 7) results show that crystal form B has an endothermic signal corresponding to desolvation at around 145°C and an endothermic peak at around 234°C.
  • the NMR ( Figure 8) results are basically consistent with the raw materials.
  • the solvent peaks of DMF can be seen at 2.73, 2.89 and 7.95 ppm. According to the integration results, the ratio of compound to DMF is 1:0.9, and the DMF content is basically consistent with the weight loss of TGA.
  • Thermal crystallization experimental results show that crystalline form B is heated to 170°C to desolvate and then crystallized into crystalline form A. In summary, Form B is a DMF solvate.
  • the XRPD ( Figure 9) results show that fumarate crystal form C is a solid with good crystallinity.
  • the TGA ( Figure 10) results show that the sample has a weight loss of 0.7% during heating to 150°C and may decompose after 190°C.
  • the DSC ( Figure 10) results show that there is an endothermic signal around 217°C.
  • the XRPD ( Figure 12) results show that the hydrochloride crystal form D is a solid with good crystallinity.
  • the TGA ( Figure 13) results show that the sample has a weight loss of 1.6% during heating to 150°C (corresponding to a weight loss of 0.5 water molecules); decomposition may occur after 230°C.
  • the DSC ( Figure 13) results show that there are endothermic signals around 71°C and 262°C.
  • the XRPD ( Figure 15) results show that the hydrochloride crystal form E is a solid with poor crystallinity.
  • the TGA ( Figure 16) results show that the sample continues to lose weight during the heating process.
  • the DSC ( Figure 16) results show that there are endothermic signals around 89°C and 201°C.
  • the NMR ( Figure 17) results show that compared with the free state, the 1.50-1.90ppm, 2.98ppm, 3.07ppm, 6.90ppm and 7.08ppm peaks are shifted, suggesting that the sample forms a salt; the solvent peak of cyclohexane is visible at 1.39ppm , suggesting that a small amount of cyclohexane solvent remains in the sample.
  • the hydrochloride crystal form E may be anhydrous or hydrate that absorbs water.
  • the XRPD ( Figure 18) results show that the hydrochloride crystal form F is a solid with good crystallinity.
  • the TGA ( Figure 19) results show that the sample has a weight loss of 0.5% during heating to 150°C and may decompose after 230°C.
  • the DSC ( Figure 19) results show that there are endothermic signals around 316°C and 320°C.
  • the XRPD ( Figure 21) results show that the sulfate crystal form G is a solid with good crystallinity.
  • the TGA ( Figure 22) results show that the sample has a weight loss of 3.7% during heating to 150°C and may decompose after 240°C.
  • the DSC ( Figure 22) results show that there are endothermic signals around 282°C and 298°C.
  • sulfate crystal form G may be anhydrous or hydrate that absorbs water.
  • the XRPD ( Figure 24) results show that the succinate crystal form H is a solid with good crystallinity.
  • the TGA ( Figure 25) results show that the sample has a weight loss of 0.2% during heating to 120°C and may decompose after 170°C.
  • the DSC ( Figure 25) results show that there is an endothermic signal around 186°C.
  • the XRPD ( Figure 27) results show that the succinate crystal form J is a solid with good crystallinity.
  • the TGA ( Figure 28) results show that the sample has a weight loss of 0.6% during heating to 150°C and may decompose after 170°C.
  • the DSC results show that there is an endothermic signal around 177°C.
  • the XRPD ( Figure 30) results show that glycolate crystal form K is a solid with good crystallinity.
  • the TGA ( Figure 31) results show that the sample has a weight loss of 0.7% during heating to 70°C, and continues to lose weight during the subsequent heating process, and may decompose after 150°C.
  • the DSC results show that there is an endothermic signal around 98°C.
  • glycolate crystal form K may be anhydrous/hydrate.
  • the XRPD ( Figure 33) results show that the benzoic acid eutectic crystal form L is a solid with good crystallinity.
  • the TGA ( Figure 34) results show that the sample has a weight loss of 1.6% during heating to 100°C and may decompose after 135°C.
  • the DSC ( Figure 34) results show that there are endothermic signals around 165°C and 177°C.
  • the NMR ( Figure 35) results show that compared with the free state, there is no peak shift, suggesting that the sample has not formed a salt and may form a eutectic; the signal peak of benzoic acid can be seen at 7.0 ⁇ 8.5ppm.
  • API and benzene The ratio of formic acid is 1:1; the solvent peak of isopropyl alcohol is visible at 1.04 ppm, indicating that a small amount of isopropyl alcohol solvent remains in the sample.
  • the benzoic acid eutectic crystal form L is an anhydrous form.
  • the XRPD ( Figure 36) results show that the benzoic acid eutectic crystal form M is a solid with poor crystallinity.
  • the TGA ( Figure 37) results show that the sample has a weight loss of 1.0% during heating to 100°C and may decompose after 135°C.
  • the DSC ( Figure 37) results show that there is an endothermic signal around 175°C.
  • the NMR ( Figure 38) results show that compared with the free state, there is no peak shift, suggesting that the sample has not formed a salt and may form a eutectic; the signal peak of benzoic acid can be seen at 7.0 ⁇ 8.5ppm.
  • the raw material and benzene The ratio of formic acid is 1:1; the solvent peak of cyclohexane is visible at 1.39 ppm, indicating that a small amount of cyclohexane solvent remains in the sample.
  • the benzoic acid eutectic crystal form M is an anhydrous form.
  • the XRPD ( Figure 39) results show that Form N is a solid with good crystallinity.
  • the TGA ( Figure 40) results show that crystal form N has a weight loss of 0.6% during heating to 150°C and may decompose above 300°C.
  • the DSC ( Figure 40) results show that Form N has a melting endothermic peak at around 208°C.
  • the NMR ( Figure 41) results show that the solvent peak of toluene is visible at 2.30 ppm, suggesting that the sample contains a small amount of toluene solvent residue.
  • Form N is an amorphous form.
  • the XRPD ( Figure 42) results show that Form O is a solid with good crystallinity.
  • the TGA ( Figure 43) results show that crystal form O has a weight loss of 2.6% during heating to 200°C and may decompose above 300°C.
  • the DSC ( Figure 43) results show that crystal form O has an exothermic peak at around 196°C, an endothermic signal at around 190°C, and a melting endothermic peak at around 208°C.
  • Thermal crystallization experimental results show that Form O recrystallizes into Form N after desolvation.
  • the XRPD ( Figure 45) results show that Form P is a solid with good crystallinity and obvious preferred orientation.
  • the TGA ( Figure 46) results show that crystal form P has a weight loss of 3.3% during heating to 175°C and may decompose above 300°C.
  • the DSC ( Figure 46) results show that crystal form P has an exothermic peak at around 158°C, an endothermic signal at around 145°C, and a melting endothermic peak at around 211°C.
  • Thermal crystallization experimental results show that crystal form P recrystallizes into crystal form N after desolvation.
  • the NMR ( Figure 47) results show that this sample has no obvious organic solvent peak.
  • Form P is a hydrate.
  • the XRPD ( Figure 48) results show that Form Q is a solid with good crystallinity.
  • TGA ( Figure 49) results show that crystalline form Q has a weight loss of 4.6% during heating to 180°C and may decompose above 300°C.
  • the DSC ( Figure 49) results show that crystal form Q has an exothermic peak at around 181°C, endothermic signals at around 171°C and 198°C, and a melting endothermic peak at around 207°C.
  • Thermal crystallization experimental results show that crystal form Q recrystallizes into crystal form N after desolvation.
  • the XRPD ( Figure 50) results show that Form R is a solid with good crystallinity.
  • the TGA ( Figure 51) results show that the crystal form R has a weight loss of 3.7% during heating to 150°C and may decompose above 300°C.
  • the DSC ( Figure 51) results show that the crystal form R has an exothermic peak at around 161°C, an endothermic signal at around 154°C, and a melting endothermic peak at around 211°C.
  • Thermal crystallization experimental results show that Form R recrystallizes into Form N after desolvation.
  • the NMR ( Figure 52) results showed that there was no obvious organic solvent peak.
  • Form R is a hydrate.
  • the XRPD ( Figure 53) results show that Form S is a solid with good crystallinity.
  • the TGA ( Figure 54) results show that crystalline form S has a weight loss of 3.6% during heating to 150°C and may decompose above 300°C.
  • the DSC ( Figure 54) results show that crystal form S has an exothermic peak at around 155°C, an endothermic signal at around 126°C, and a melting endothermic peak at around 210°C.
  • Thermal crystallization experimental results show that crystal form S recrystallizes into crystal form N after desolvation.
  • Form S is a hydrate. See Figure 55 for NMR.
  • the XRPD ( Figure 56) results show that Form T is a solid with good crystallinity.
  • the TGA ( Figure 57) results show that crystalline form T has a weight loss of 6.7% during heating to 200°C and may decompose above 300°C.
  • the DSC ( Figure 57) results show that crystal form T has an exothermic peak at around 191°C, an endothermic signal at around 186°C, and a melting endothermic peak at around 209°C.
  • the NMR ( Figure 58) results show that the structure of the compound has not changed.
  • the solvent peaks of dichloromethane and a small amount of dioxane are visible at 5.76 ppm and 3.57 ppm. According to the integration results, the ratio of the compound to dichloromethane is 1:0.25.
  • the crystal form T is a solvate of methylene chloride or an anhydrous substance containing methylene chloride in the crystal.
  • the XRPD ( Figure 59) results show that it is a solid with good crystallinity.
  • the TGA ( Figure 60) results show that the sample has a weight loss of 18.0% during heating to 130°C, corresponding to a weight loss of approximately 2 propionic acid molecules.
  • the DSC ( Figure 60) results show that there are endothermic signals around 109°C, 121°C and 204°C.
  • the NMR ( Figure 61) results show that compared with the free state, there is no peak shift, indicating that the sample has not formed a salt; the signal peaks of propionic acid can be seen at 0.99ppm and 2.20ppm.
  • the ratio of API to propionic acid is 1:2; the solvent peak of cyclohexane is visible at 1.39 ppm, indicating that a small amount of cyclohexane solvent remains in the sample.
  • Form U is a propionic acid solvate.
  • Dynamic solubility determination was performed in three biological media (FaSSIF, FeSSIF and FaSSGF), and the results are shown in Table 29 below and Figures 66 and 67.
  • references to the terms “one embodiment,” “some embodiments,” “an example,” “specific examples,” or “some examples” or the like means that specific features are described in connection with the embodiment or example. , structures, materials or features are included in at least one embodiment or example of the invention. In this specification, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine different embodiments or examples and features of different embodiments or examples described in this specification unless they are inconsistent with each other.

Abstract

一种苯并氮杂卓并环化合物盐型、晶型及其应用，具体涉及式(I)所示化合物的马来酸盐，所述马来酸盐的结构如式(II)所示。

Description

苯并氮杂卓并环化合物盐型、晶型及其应用
本发明主张如下优先权：
申请号CN 202211080826.4，申请日2022年09月05日。
技术领域
本发明属药物化学领域，具体地，本发明涉及苯并氮杂卓并环化合物盐型、晶型及其应用。
背景技术
激素在人体内环境稳态的调节过程中发挥了重要作用，其中精氨酸加压素(Arginine Vasopressin，AVP)与人体水钠代谢的调节密切相关。精氨酸加压素(AVP)的代谢紊乱可引起低钠血症、抗利尿激素分泌异常综合征、充血性心力衰竭、肝硬化、肾脏疾病、高血压以及浮肿等多种疾病。精氨酸加压素(AVP)受体拮抗剂可抑制AVP与受体的结合，从而对上述疾病起到治疗作用。以托伐普坦为代表的精氨酸加压素V2受体拮抗剂可以在增加自由水排出的同时不影响电解质的代谢，从而成为治疗上述疾病的理想药物。但上市的AVP V2受体拮抗剂，如托伐普坦通过肝脏代谢酶进行代谢，其在体内产生大量的代谢产物并导致了严重的药物诱导肝毒性，FDA在该药物商品标签上给出了黑框警告，限制了它的应用。
申请号为PCT/CN2022/079350，申请日为2022年03月04日的专利申请中，提供了一种新的AVP V2受体拮抗剂，结构如下所示
发明内容
在本发明的一方面，本发明提出了式(I)所示化合物的马来酸盐，其结构如式(II)所示，
在本发明的另一方面，本发明提出了式(I)所示化合物的马来酸盐(即式(II)所示化合物)晶型A，晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.14±0.2°、12.88±0.2°、18.31±0.2°、18.90±0.2°、20.60±0.2°、27.61±0.2°。
在本发明的一些方案中，晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.14±0.2°、12.88±0.2°、17.19±0.2°、18.31±0.2°、18.90±0.2°、20.60±0.2°、21.45±0.2°、27.61±0.2°。
在本发明的一些方案中，晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.14±0.2°、 12.88±0.2°、17.19±0.2°、18.31±0.2°、18.90±0.2°、19.70±0.2°、20.20±0.2°、20.60±0.2°、21.45±0.2°、21.91±0.2°、27.61±0.2°。
在本发明的一些方案中，晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.14±0.2°、12.88±0.2°、17.19±0.2°、18.31±0.2°、18.90±0.2°、19.70±0.2°、20.20±0.2°、20.60±0.2°、21.45±0.2°、21.91±0.2°、25.96±0.2°、26.53±0.2°、27.61±0.2°、29.22±0.2°、30.20±0.2°。
在本发明的一些方案中，晶型A的X射线粉末衍射图谱具有基本上如图1所示的X射线粉末衍射图谱。
在本发明的一些方案中，晶型A的X射线粉末衍射图谱解析数据如下表1所示。
表1
在本发明的另一方面，本发明还提出了式(I)所示化合物的马来酸盐(即式(II)所示化合物)晶型B，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.97±0.2°、15.73±0.2°、18.31±0.2°、20.15±0.2°、21.12±0.2°、24.70±0.2°。
在本发明的一些方案中，晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.40±0.2°、8.97±0.2°、10.11±0.2°、13.94±0.2°、15.73±0.2°、18.31±0.2°、19.02±0.2°、20.15±0.2°、21.12±0.2°、24.70±0.2°。
在本发明的一些方案中，晶型B的X射线粉末衍射图谱具有基本上如图6所示的X射线粉末衍射图谱。
在本发明的一些方案中，晶型B的X射线粉末衍射图谱解析数据如下表2所示。
表2
在本发明的另一方面，本发明还公开了一种式(I)所示化合物的富马酸盐，其结构如式(III)所示，
在本发明的另一方面，本发明还公开了式(I)所示化合物的富马酸盐(即式(III)所示化合物)晶型C，晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.77±0.2°、14.44±0.2°、20.00±0.2°、20.64±0.2°、21.33±0.2°、21.87±0.2°。
在本发明的一些方案中，晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.77±0.2°、13.17±0.2°、14.44±0.2°、17.18±0.2°、20.00±0.2°、20.64±0.2°、21.33±0.2°、21.87±0.2°、23.43±0.2°、25.86±0.2°。
在本发明的一些方案中，晶型C的X射线粉末衍射图谱具有基本上如图9所示的X射线粉末衍射图谱。
在本发明的一些方案中，晶型C的X射线粉末衍射图谱解析数据如下表3所示。
表3
在本发明的另一方面，本发明提出了一种式(I)所示化合物的盐酸盐，其结构如式(IV)所示，
在本发明的另一方面，本发明提出了式(I)所示化合物的盐酸盐(即式(IV)所示化合物)晶型D，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.13±0.2°、9.27±0.2°、9.91±0.2°、13.53±0.2°、16.37±0.2°、17.09±0.2°。
在本发明的一些方案中，晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.13±0.2°、9.27±0.2°、9.91±0.2°、12.86±0.2°、13.53±0.2°、16.37±0.2°、17.09±0.2°、18.67±0.2°、21.77±0.2°、23.81±0.2°。
在本发明的一些方案中，晶型D的X射线粉末衍射图谱具有基本上如图12所示的X射线粉末衍射图谱。
在本发明的一些方案中，晶型D的X射线粉末衍射图谱解析数据如下表4所示。
表4

在本发明的另一方面，本发明提出了式(I)所示化合物的盐酸盐(即式(IV)所示化合物)晶型E，所述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.86±0.2°、13.60±0.2°、14.19±0.2°、18.06±0.2°、20.50±0.2°、21.24±0.2°。
在本发明的一些方案中，所述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.86±0.2°、6.74±0.2°、11.73±0.2°、13.60±0.2°、14.19±0.2°、18.06±0.2°、20.50±0.2°、21.24±0.2°、23.72±0.2°、24.06±0.2°。
在本发明的一些方案中，所述晶型E的X射线粉末衍射图谱具有基本上如图15所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型E的X射线粉末衍射图谱解析数据如下表5所示。
表5

在本发明的另一方面，本发明还提出了式(I)所示化合物的盐酸盐(即式(IV)所示化合物)晶型F，所述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.84±0.2°、11.77±0.2°、13.29±0.2°、17.82±0.2°、20.49±0.2°、20.94±0.2°。
在本发明的一些方案中，所述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.84±0.2°、11.77±0.2°、13.29±0.2°、14.34±0.2°、17.82±0.2°、18.67±0.2°、20.49±0.2°、20.94±0.2°、23.02±0.2°、23.68±0.2°。
在本发明的一些方案中，所述晶型F的X射线粉末衍射图谱具有基本上如图18所示的X射线粉末衍射图谱。
在本发明的一些方案中，所示晶型F的X射线粉末衍射图谱解析数据如下表6所示。
表6
在本发明的另一方面，本发明还提出了一种式(I)所示化合物的硫酸盐，其结构如式(V)所示，
在本发明的另一方面，本发明还提出了式(I)所示化合物的硫酸盐(即式(V)所示化合物)晶型G，所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.30±0.2°、13.02±0.2°、16.60±0.2°、18.53±0.2°、20.67±0.2°、22.26±0.2°。
在本发明的一些方案中，所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.46±0.2°、10.30±0.2°、13.02±0.2°、16.60±0.2°、17.66±0.2°、18.53±0.2°、19.98±0.2°、20.67±0.2°、22.26±0.2°、23.62±0.2°。
在本发明的一些方案中，所述晶型G的X射线粉末衍射图谱具有基本上如图21所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述硫酸盐晶型G的X射线粉末衍射图谱解析数据如下表7所示。
表7
在本发明的另一方面，本发明还提出了一种式(I)所示化合物的琥珀酸盐，其结构如式(VI)所示，
在本发明的另一方面，本发明还提出了式(I)所示化合物的琥珀酸盐(即式(VI)所示化合物)晶型H，所述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.30±0.2°、14.63±0.2°、18.59±0.2°、20.13±0.2°、21.83±0.2°、22.30±0.2°。
在本发明的一些方案中，所述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.30±0.2°、12.91±0.2°、14.63±0.2°、18.59±0.2°、19.41±0.2°、20.13±0.2°、20.69±0.2°、21.83±0.2°、22.30±0.2°、23.65±0.2°。
在本发明的一些方案中，所述晶型H的X射线粉末衍射图谱具有基本上如图24所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型H的X射线粉末衍射图谱解析数据如下表8所示。
表8

在本发明的另一方面，本发明还提出了式(I)所示化合物(即式(VI)所示化合物)的琥珀酸盐晶型J，所述晶型J的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.61±0.2°、11.56±0.2°、12.93±0.2°、17.12±0.2°、17.71±0.2°、19.95±0.2°。
在本发明的一些方案中，所述晶型J的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.61±0.2°、11.56±0.2°、12.93±0.2°、13.76±0.2°、17.12±0.2°、17.71±0.2°、19.51±0.2°、19.95±0.2°、21.83±0.2°、22.42±0.2°。
在本发明的一些方案中，所述晶型J的X射线粉末衍射图谱具有基本上如图27所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型J的X射线粉末衍射图谱解析数据如下表9所示。
表9
在本发明的另一方面，本发明还提出了一种式(I)所示化合物的乙醇酸盐，其结构如式(VII)所示，
在本发明的另一方面，本发明还提出了式(I)所示化合物的乙醇酸盐(即式(VII)所示化合物)晶型K，所述晶型K的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.51±0.2°、15.99±0.2°、18.71±0.2°、20.18±0.2°、20.59±0.2°、21.64±0.2°。
在本发明的一些方案中，所述晶型K的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.51±0.2°、13.62±0.2°、15.99±0.2°、16.65±0.2°、18.71±0.2°、20.18±0.2°、20.59±0.2°、21.64±0.2°、22.62±0.2°、24.53±0.2°。
在本发明的一些方案中，所述晶型K的X射线粉末衍射图谱具有基本上如图30所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型K的X射线粉末衍射图谱解析数据如下表10所示。
表10

在本发明的另一方面，本发明还提出了一种式(I)所示化合物的苯甲酸盐，其结构如式(VIII)所示，
在本发明的另一方面，本发明还提出了式(I)所示化合物的苯甲酸共晶晶型L，所述晶型L的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.14±0.2°、8.76±0.2°、9.55±0.2°、12.62±0.2°、16.43±0.2°、18.05±0.2°。
在本发明的一些方案中，所述晶型L的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.14±0.2°、8.76±0.2°、9.55±0.2°、12.62±0.2°、16.43±0.2°、17.68±0.2°、18.05±0.2°、18.95±0.2°、19.32±0.2°、19.73±0.2°。
在本发明的一些方案中，所述晶型L的X射线粉末衍射图谱具有基本上如图33所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型L的X射线粉末衍射图谱解析数据如下表11所示。
表11

在本发明的另一方面，本发明还提出了式(I)所示化合物的苯甲酸共晶晶型M，所述晶型M的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.31±0.2°、13.77±0.2°、14.54±0.2°、19.84±0.2°、20.34±0.2°、21.70±0.2°。
在本发明的一些方案中，所述晶型M的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.31±0.2°、13.77±0.2°、14.54±0.2°、16.55±0.2°、17.66±0.2°、18.68±0.2°、19.84±0.2°、20.34±0.2°、21.70±0.2°、23.32±0.2°。
在本发明的一些方案中，所述晶型M的X射线粉末衍射图谱具有基本上如图36所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型M的X射线粉末衍射图谱解析数据如下表12所示。
表12
在本发明的另一方面，本发明还提出了式(I)所示化合物的晶型N，所述晶型N的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.38±0.2°、13.54±0.2°、14.41±0.2°、16.32±0.2°、18.10±0.2°、19.05±0.2°。
在本发明的一些方案中，所述晶型N的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.38±0.2°、13.54±0.2°、14.41±0.2°、15.90±0.2°、16.32±0.2°、18.10±0.2°、19.05±0.2°、22.14±0.2°、22.91±0.2°、23.66±0.2°。
在本发明的一些方案中，所述晶型N的X射线粉末衍射图谱具有基本上如图39所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型N的X射线粉末衍射图谱解析数据如下表13所示。
表13
在本发明的另一方面，本发明还提出了式(I)所示化合物的晶型O，所述晶型O的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.75±0.2°、9.65±0.2°、15.70±0.2°、16.88±0.2°、18.00±0.2°、18.97±0.2°。
在本发明的一些方案中，所述晶型O的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰： 4.75±0.2°、9.65±0.2°、15.70±0.2°、16.88±0.2°、18.00±0.2°、18.97±0.2°、19.89±0.2°、21.86±0.2°、22.67±0.2°、24.30±0.2°。
在本发明的一些方案中，所述晶型O的X射线粉末衍射图谱具有基本上如图42所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型O的X射线粉末衍射图谱解析数据如下表14所示。
表14
在本发明的另一方面，本发明还提出了式(I)所示化合物的晶型P，所述晶型P的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.07±0.2°、17.98±0.2°、21.64±0.2°、23.78±0.2°、26.36±0.2°、33.13±0.2°。
在本发明的一些方案中，所述晶型P的X射线粉末衍射图谱具有基本上如图45所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型P的X射线粉末衍射图谱解析数据如下表15所示。
表15

在本发明的另一方面，本发明还提出了式(I)所示化合物的晶型Q，所述晶型Q的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.48±0.2°、10.60±0.2°、12.32±0.2°、15.41±0.2°、16.60±0.2°、17.09±0.2°。
在本发明的一些方案中，所述晶型Q的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.48±0.2°、10.60±0.2°、12.32±0.2°、15.41±0.2°、16.60±0.2°、17.09±0.2°、17.75±0.2°、18.79±0.2°、20.49±0.2°、21.40±0.2°。
在本发明的一些方案中，所述晶型Q的X射线粉末衍射图谱具有基本上如图48所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型Q的X射线粉末衍射图谱解析数据如下表16所示。
表16

在本发明的另一方面，本发明还提出了式(I)所示化合物的晶型R，所述晶型R的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.70±0.2°、13.30±0.2°、18.15±0.2°、21.39±0.2°、22.97±0.2°、26.71±0.2°。
在本发明的一些方案中，所述晶型R的X射线粉末衍射图谱具有基本上如图50所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型R的X射线粉末衍射图谱解析数据如下表17所示。
表17

在本发明的另一方面，本发明还提出了式(I)所示化合物的晶型S，所述晶型S的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.97±0.2°、15.34±0.2°、17.97±0.2°、22.81±0.2°、23.54±0.2°、24.69±0.2°。
在本发明的一些方案中，所述晶型S的X射线粉末衍射图谱具有基本上如图53所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型S的X射线粉末衍射图谱解析数据如下表18所示。
表18

在本发明的另一方面，本发明还提出了式(I)所示化合物的晶型T，所述晶型T的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.84±0.2°、17.03±0.2°、17.60±0.2°、20.01±0.2°、22.22±0.2°、22.82±0.2°。
在本发明的一些方案中，所述晶型T的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.64±0.2°、14.70±0.2°、15.84±0.2°、17.03±0.2°、17.60±0.2°、19.01±0.2°、20.01±0.2°、22.22±0.2°、22.82±0.2°、24.45±0.2°。
在本发明的一些方案中，所述晶型T的X射线粉末衍射图谱具有基本上如图56所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型T的X射线粉末衍射图谱解析数据如下表19所示。
表19

在本发明的另一方面，本发明还提出了式(I)所示化合物的晶型U，所述晶型U的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.01±0.2°、9.27±0.2°、12.68±0.2°、16.15±0.2°、17.94±0.2°、19.31±0.2°。
在本发明的一些方案中，所述晶型U的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.01±0.2°、9.27±0.2°、12.68±0.2°、16.15±0.2°、17.94±0.2°、19.31±0.2°、22.16±0.2°、22.82±0.2°、23.80±0.2°、24.08±0.2°。
在本发明的一些方案中，所述晶型U的X射线粉末衍射图谱具有基本上如图59所示的X射线粉末衍射图谱。
在本发明的一些方案中，所述晶型U的X射线粉末衍射图谱解析数据如下表20所示。
表20

定义和说明
除非另有说明，本发明使用的所有技术和科学术语与本发明所属领域的普通技术人员所通常理解的具有相同含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。尽管在本发明的实践或者测试中可以使用与本发明所述相似或者相同的任何方法和物质，但是本发明中描述的是优选的方法、设备和物质。
“API”或“游离态”均是指式(I)所示化合物的游离碱形式。
“晶型”或“结晶形式”是指具有高度规则化学结构的固体，包括，但不限于，单组分或者多组分晶体，和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，熔体结晶、熔体冷却、溶剂结晶、在限定的空间中结晶，例如，在纳米孔或者毛细管中，在表面或者模板上结晶，例如，在聚合物上，在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、反应结晶、反溶剂添加、研磨和溶剂滴研磨等。
“无定形”或“无定形形式”是指物质的质点(分子、原子、离子)在三维空间排列无周期性时形成的物质，其特征是具有漫射的不具尖峰的X射线粉末衍射图。无定形是固体物质的一种特殊的物理形式，其局部有序的结构特征，提示其与晶型物质有着千丝万缕的联系。物质的无定形形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，骤冷法、反溶剂絮凝法、球磨法、喷雾干燥法、冷冻干燥法、湿法制粒法和固体分散体技术等等。
“溶剂”是指一种物质(典型地是一种液体)，该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二 甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、l-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。
“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体；其可以是与溶剂相同的液体但是处于不同温度，或者它可以是与溶剂不同的液体。
“溶剂化物”是指晶体在表面上、或在晶格中、或者在表面上和在晶格中具有溶剂，其中，所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、或在晶格中、或者在表面上和在晶格中的溶剂是水。在物质的表面上、或在晶格中、或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。
晶型或无定形可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施例中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本发明试验所用仪器状况，衍射峰存在±0.2°的误差容限。
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al2O3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施例中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本发明试验所用仪器状况，熔化峰存在±3℃的误差容限。
玻璃态转变是指非晶态物质在高弹态和玻璃态之间的转变，是该物质的固有性质；它所对应的转变温度为玻璃化转变温度(Tg)，是非晶态物质的一个重要物理性质。玻璃化转变是与分子运动有关的现象，因而，玻璃化转变温度(Tg)主要取决于物质的结构，而对实验细节等相对不敏感。在一些实施例中，本发明所述无定形的玻璃化转变温度(Tg)通过差示扫描量热法(DSC)测定，其特征在于具有107.44℃的玻璃化转变温度。根据本发明试验所用仪器状况，玻璃化转变温度存在±3℃的误差容限。
差示扫描量热(DSC)还可用于检测分析晶型是否有转晶或混晶现象。
化学组成相同的固体，在不同的热力学条件下，常会形成晶体结构不同的同质异构体，或称为变体，这种现象称为同质多晶或同质多相现象。当温度和压力条件变化时，变体之间会发生相互转变，此现象称为晶型转变。由于晶型转变，晶体的力学、电学、磁学等性能会发生巨大的变化。当晶型转变的温度在可测范围内时，在差示扫描量热(DSC)图上可观察到这一转变过程，其特征在于，DSC图具有反映这一转变过程的放热峰，且同时具有两个或多个吸热峰，分别为转变前后的不同晶型的特征吸热峰。本发明化合物的晶型或无定形在适当条件下可发生晶型转变
热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。根据本发明试验所用的仪器状况，质量变化存在±0.3％的误差容限。
在本发明的上下文中，X射线粉末衍射图中的2θ值均以度(°)为单位。
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。
术语“基本上如图所示”是指X射线粉末衍射图或DSC图或TGA结果中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。
“基本上纯净的”是指一种晶型基本上不含另外一种或多种晶型，即晶型的纯度至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或晶型中含有其它晶型，所述其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
“基本上不含”是指一种或多种其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于4％，或少于3％，或少于2％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
“相对强度”是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
附图说明
图1是根据本发明实施例的马来酸盐晶型A的XRPD图；
图2是根据本发明实施例的马来酸盐晶型A的DSC和TGA图；
图3是根据本发明实施例的马来酸盐晶型A的NMR图：(a)与游离态对比图；(b)积分结果；
图4是根据本发明实施例的马来酸盐晶型A的DVS曲线；
图5是根据本发明实施例的马来酸盐晶型A的DVS测试前后的XRPD图；
图6是根据本发明实施例的马来酸盐晶型B的XRPD图；
图7是根据本发明实施例的马来酸盐晶型B的DSC和TGA图；
图8是根据本发明实施例的马来酸盐晶型B的NMR图；
图9是根据本发明实施例的富马酸盐晶型C的XRPD图；
图10是根据本发明实施例的富马酸盐晶型C的DSC和TGA图；
图11是根据本发明实施例的富马酸盐晶型C的NMR图：(a)与游离态对比图；(b)积分结果；
图12是根据本发明实施例的盐酸盐晶型D的XRPD图；
图13是根据本发明实施例的盐酸盐晶型D的DSC和TGA图；
图14是根据本发明实施例的盐酸盐晶型D的NMR图：(a)与游离态对比图；(b)积分结果；
图15是根据本发明实施例的盐酸盐晶型E的XRPD图；
图16是根据本发明实施例的盐酸盐晶型E的DSC和TGA图；
图17是根据本发明实施例的盐酸盐晶型E的NMR图：(a)与游离态对比图；(b)积分结果；
图18是根据本发明实施例的盐酸盐晶型F的XRPD图；
图19是根据本发明实施例的盐酸盐晶型F的DSC和TGA图；
图20是根据本发明实施例的盐酸盐晶型F的NMR图：(a)与游离态对比图；(b)积分结果；
图21是根据本发明实施例的硫酸盐晶型G的XRPD图；
图22是根据本发明实施例的硫酸盐晶型G的DSC和TGA图；
图23是根据本发明实施例的硫酸盐晶型G的NMR图：(a)与游离态对比图；(b)积分结果；
图24是根据本发明实施例的琥珀酸盐晶型H的XRPD图；
图25是根据本发明实施例的琥珀酸盐晶型H的DSC和TGA图；
图26是根据本发明实施例的琥珀酸盐晶型H的NMR图：(a)与游离态对比图；(b)积分结果；
图27是根据本发明实施例的琥珀酸盐晶型J的XRPD图；
图28是根据本发明实施例的琥珀酸盐晶型J的DSC和TGA图；
图29是根据本发明实施例的琥珀酸盐晶型J的NMR图：(a)与游离态对比图；(b)积分结果；
图30是根据本发明实施例的乙醇酸盐晶型K的XRPD图；
图31是根据本发明实施例的乙醇酸盐晶型K的DSC和TGA图；
图32是根据本发明实施例的乙醇酸盐晶型K的NMR图：(a)与游离态对比图；(b)积分结果；
图33是根据本发明实施例的苯甲酸共晶晶型L的XRPD图；
图34是根据本发明实施例的苯甲酸共晶晶型L的DSC和TGA图；
图35是根据本发明实施例的苯甲酸共晶晶型L的NMR图：(a)与游离态对比图；(b)积分结果；
图36是根据本发明实施例的苯甲酸共晶晶型M的XRPD图；
图37是根据本发明实施例的苯甲酸共晶晶型M的DSC和TGA图；
图38是根据本发明实施例的苯甲酸共晶晶型M的NMR图：(a)与游离态对比图；(b)积分结果；
图39是根据本发明实施例的晶型N的XRPD图；
图40是根据本发明实施例的晶型N的DSC和TGA图；
图41是根据本发明实施例的晶型N的NMR图；
图42是根据本发明实施例的晶型O的XRPD图；
图43是根据本发明实施例的晶型O的DSC和TGA图；
图44是根据本发明实施例的晶型O的NMR图；
图45是根据本发明实施例的晶型P的XRPD图；
图46是根据本发明实施例的晶型P的DSC和TGA图；
图47是根据本发明实施例的晶型P的NMR图；
图48是根据本发明实施例的晶型Q的XRPD图；
图49是根据本发明实施例的晶型Q的DSC和TGA图；
图50是根据本发明实施例的晶型R的XRPD图；
图51是根据本发明实施例的晶型R的DSC和TGA图；
图52是根据本发明实施例的晶型R的NMR图；
图53是根据本发明实施例的晶型S的XRPD图；
图54是根据本发明实施例的晶型S的DSC和TGA图；
图55是根据本发明实施例的晶型S的NMR图；
图56是根据本发明实施例的晶型T的XRPD图；
图57是根据本发明实施例的晶型T的DSC和TGA图；
图58是根据本发明实施例的晶型T的NMR图；
图59是根据本发明实施例的晶型U的XRPD图；
图60是根据本发明实施例的晶型U的DSC和TGA图；
图61是根据本发明实施例的晶型U的NMR图：(a)与游离态对比图；(b)积分结果；
图62是根据本发明实施例的马来酸盐晶型A稳定性研究的XRPD图；
图63是根据本发明实施例的富马酸盐晶型C稳定性研究的XRPD图；
图64是根据本发明实施例的晶型N稳定性研究的XRPD图；
图65是根据本发明实施例的晶型S稳定性研究的XRPD图；
图66是根据本发明实施例的马来酸盐晶型A在介质中振荡24h后剩余固体XRPD对比图；
图67是根据本发明实施例的富马酸盐晶型C在介质中振荡24h后剩余固体XRPD对比图。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
本发明所使用的原料如无特殊说明，均来自市售。
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
一般分析方法：
1、核磁分析(1H NMR)
将若干毫克固体样品溶解于二甲基亚砜-d6溶剂中，在Bruker AVANCE-III(Bruker,GER)上进行核磁分析。
2、X射线粉末衍射(XRPD)
仪器型号：Bruker D8ADVANCE(仪器唯一性编号：IARC-031-PXRD-01)。
检测依据：《中国药典》2020版第四部通则0451。
样品制备：将样品置于样品架凹槽中央，将样品表面与样品架表面相平。
实验条件：CuKa40kv 40mA，发散狭缝0.6mm，索拉狭缝4.0°，连续扫描，探测器：LynxEye。
步长：0.02°。
扫描速度：4°/min。
3、热重分析(TGA)
热重分析仪的型号为TA Discovery 55(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。
4、差式扫描量热分析(DSC)
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。
5、动态水分吸脱附分析(DVS)
动态水分吸脱附分析采用DVS Intrinsic(SMS，UK)进行测定。测试采用梯度模式，湿度变化为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。
6、偏光显微镜分析(PLM)
偏光显微镜的型号为Nikon Ci-POL(Nikon,JP)。将少量样品放置在载玻片上，选择合适的镜头观察样品形貌。
7、高效液相色谱(HPLC)
高效液相色谱型号为LC-2030C 3D Plus(Shimadzu，JP)，测试条件如表21所示。
表21

马来酸盐含量测试时采用的HPLC的条件如下表22所示。
表22
8、离子色谱(IC)
离子色谱型号为ICS 5000(Thermo Fisher，US)，仪器参数如表23所示。
表23
一般试验方法：
1、原料溶解度测试
称取20mg左右样品，加入EP管中，室温下(～25℃)逐次加入一定量溶剂，搅拌溶液并观察固体是否完全溶解，若加到10.0mL溶剂后仍未溶清，则停止实验。根据固体完全溶解时所用的溶剂体积估算化合物在该溶剂中的溶解度。
2、反应结晶法
2.1 1当量投料
将26mg(0.05mmol)左右样品和1当量的酸性化合物加入至一定量所选溶剂中，室温混悬2天，将悬浮液离心分离，并将固体室温真空干燥。若溶液澄清，将溶液置于冰箱(﹣15℃)中； 若有固相析出，离心除去上清液，室温真空干燥。若冷却后仍无固相析出，向溶液中滴加反溶剂，直至有固体析出。
2.2 2当量投料
将26mg(0.05mmol)左右样品和2当量的酸性化合物加入至一定量所选溶剂中，室温混悬2天，将悬浮液离心分离，并将固体室温真空干燥。
3、溶剂挥发法
将原料溶解度测试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，或分别称取20mg左右原料，在一定量的不良溶剂中滴加适量所选溶剂至完全溶解，将溶液在室温静置挥发，直至溶剂挥发完全。
4、悬浮法
4.1、室温悬浮
采用不同晶型作为起始物，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。
4.2、50℃悬浮
采用不同晶型作为起始物，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1天后，将悬浮液离心分离，并将固体室温真空干燥。
5、溶析结晶法
5.1溶析结晶法
称取20mg左右样品，室温下滴加一定量良溶剂使样品完全溶解或配置为良溶剂的饱和溶液，将溶液滴加至5-10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或-15℃冰箱，将有固体析出的体系离心分离后，并将固体室温真空干燥。
5.2二元溶剂正滴法
称取20mg左右样品，室温下滴加一定量良溶剂使样品完全溶解或配置为良溶剂的饱和溶液，再滴加不良溶剂至有固体析出。室温搅拌15min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或-15℃冰箱，将有固体析出的体系离心分离后，并将固体室温真空干燥。
6、降温法
6.1、单一溶剂降温
称取20mg左右样品，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4℃进一步冷却，如仍无足量固体析出，将溶液置于-15℃进一步冷却。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。
6.2、二元溶剂降温
称取20mg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。如仍无足量固体析出，将溶液置于-15℃进一步冷却。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。
7、气相扩散法
称取20mg左右样品溶解于良溶剂中或配置为良溶剂的饱和溶液，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。
8、固体气相扩散
称取约20mg左右无定型样品置于室温或低温所选溶剂气氛中7天，定期观察玻璃小瓶中固体性状，对固体进行XRPD测试。
9、热转晶
热转晶采用Instec HCS424GXY热台(Instec Inc.，USA)进行，将6-8mg样品置于玻璃片放在热台上，以20℃/min的速率加热至目标温度，并恒温5-10min，然后自然降温冷却至室温得固体。
10、竞争性水活度悬浮实验
称取等量的所选晶型样品，加入到一定体积不同水含量的水/异丙醇饱和溶液(0％、30％、60％，水体积百分比)中，于室温和60℃下悬浮搅拌一定时间。将悬浮液离心分离，对湿样进行XRPD表征。
11、稳定性研究
称取20mg左右样品置于称量瓶中，分别放置在高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)下，于7天和15天取样进行XRPD表征。
12、溶解度测试
生物介质的配置过程如表24所示。不同晶型的样品加入生物介质中在37℃恒温震荡24h，分别于0.5h，2h和24h取样，将取样的溶液用0.22μm水系滤膜过滤，对部分浓度较高的样品用稀释剂进行适当稀释，用HPLC测量溶液的信号峰面积，最后根据峰面积、原料的HPLC标准曲线和稀释倍数计算溶液中化合物的浓度。此外，取24h上清液测试其pH值，对剩余固体进行XRPD测试。
表24
实施例1式(I)所示化合物的制备
在室温下，将对甲苯磺酰氯(21.9g,115mmol)加入到7-氯-1,2,3,4-四氢苯并[B]氮杂卓-5-酮(15g,76.7mmol)的吡啶(150mL)溶液中。反应液于室温反应16小时。减压浓缩，将反应物倒入水(200mL)中，用乙酸乙酯(100mL×3)萃取，合并有机相。有机相经过饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂，残余物经硅胶色谱法分离纯化得中间体I-1。
LC-MS(ESI)[M+H]+349.9。
1H NMR(400MHz,CDCl3)δ7.66(d,J＝2.4Hz,1H),7.58(d,J＝8.3Hz,2H),7.47(dd,J＝8.6,2.5Hz,1H),7.43(d,J＝8.5Hz,1H),7.28(d,J＝8.0Hz,2H),3.83(t,J＝6.5Hz,2H),2.43(s,3H),2.40–2.35(m,2H),2.00–1.91(m,2H).
在25℃下，将中间体I-1(37.00g,106.00mmol)溶于无水四氢呋喃(350mL)中，氩气保护及冰水浴冷却下，分批加入氢化钠(6.36g,60％wt,159.00mmol)。保持冰水浴冷却搅拌1小时后，加入碳酸二甲酯(19.08g,212.00mmol)，升温到50℃搅拌24小时。冷却后将反应液缓慢倒入冷的饱和氯化铵水溶液(500mL)中，浓缩除去大部分四氢呋喃，过滤。滤饼用清水洗涤，再用石油醚打浆，过滤，滤饼抽干，得到中间体I-2。
LC-MS(ESI)[M+H]+408.0。
在25℃下，将中间体I-2(19.00g,46.68mmol)溶于无水N,N-二甲基甲酰胺(187mL)中，依次加入碳酸钠(14.84g,140.00mmol)和2-(2-溴乙基)异吲哚啉-1,3-二酮(23.71g,93.36mmol)，氩气保护下90℃搅拌过夜。反应液冷却后加乙酸乙酯(500mL)稀释，水洗(150mL×3)，饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-3。
LC-MS(ESI)[M+H]+581.2。
在25℃下，将中间体I-3(20.00g,34.48mmol)溶于二甲基亚砜/水(130mL/13mL)中，加入氯化钠(16.70g,28.60mmol)。体系氩气置换三次后，氩气保护下150℃搅拌10小时。反应液冷却后加乙酸乙酯(400mL)稀释，水洗(150mL×3)，饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-4。
LC-MS(ESI)[M+H]+523.2。
在25℃下，将中间体I-4(200mg,0.38mmol)溶于乙醇(7mL)，加入85％水合肼(0.35mL)，反应液于35℃搅拌4小时。减压浓缩除去大部分乙醇，加入乙酸乙酯(50mL)稀释，依次用水(20mL×3)和饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品中间体I-5。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H]+375.2。
在25℃下，将中间体I-5(170mg,0.45mmol)溶于甲醇(10mL)，冰水浴冷却下缓慢加入硼氢化钠(190mg,5.00mmol)。反应液室温搅拌1小时后，减压浓缩除掉大部分甲醇，加乙酸乙酯(50mL)稀释，依次用水(20mL×3)和饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩得粗品中间体I-6。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H]+377.2。
在25℃下，将中间体I-6(150mg,0.40mmol)溶于无水甲醇(20mL)，加入镁屑(2.00g,83.33mmol)。置换氮气三次，氮气氛围(气球)下70℃搅拌过夜。冷却后，垫硅藻土过滤，滤液浓缩干，加二氯甲烷/甲醇混合液(10/1,50mL)溶解，用饱和氯化铵水溶液(20mL×3)洗涤，水(20mL×2)洗，无水硫酸钠干燥，过滤。滤液减压浓缩得粗品中间体I-7。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H]+223.0。
在25℃下，将中间体I-7(7.30g,32.89mmol)和三乙胺(10.10g,100.00mmol)溶于无水二氯甲烷(100mL)中。在氩气保护及冰水浴冷却下，缓慢加入氯甲酸-9-芴基甲酯(12.73g,49.33mmol)，于25℃搅拌16小时。室温减压浓缩，用石油醚打浆，过滤，滤饼用水(20mL)洗，抽干得到中间体I-47。
LC-MS(ESI)[M+H]+444.8。
室温下，将6-氨基烟酸甲酯(1.0g,6.57mmol)溶于吡啶(20mL)中，加入2-三氟甲基苯甲酰氯(1.51g,7.25mmol)，加料完毕后，反应混合物室温搅拌1h。将反应混合物倒入冰水(100mL)中，用乙酸乙酯(50mL×3)萃取，合并有机相用水(50mL×5)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶色谱法分离纯化得到中间体I-12。
LC-MS(ESI)[M+H]+325.0。
室温下，将中间体I-12(1.35g,4.16mmol)溶于四氢呋喃(10mL)中，加入氢氧化钠(499mg,12.5mmol)的水(2mL)溶液，加料完毕后，反应混合物70℃搅拌反应1小时，反应完毕后，用1N盐酸调节反应液pH＝5～6。过滤，固体干燥得中间体I-13。
LC-MS(ESI)[M+H]+311.0。
在25℃下，将中间体I-47(4.70g,10.58mmol)溶于无水四氢呋喃(35mL)中，依次加入吡啶(8.37g,106.00mmol)，中间体I-13(4.92g,15.87mmol)和1-丙基磷酸酐(50％wt乙酸乙酯溶液,20.00g,31.74mmol)，氩气保护下65℃搅拌过夜。将反应液冷却后，浓缩除去大部分四氢呋喃，加乙酸乙酯(150mL)稀释。依次用1N盐酸(100mL×2)洗涤，饱和碳酸氢钠水溶液(100mL×3)洗涤，水(100mL)洗，饱和氯化钠水溶液(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-48A(Rt＝1.541min)。
LCMS分析方法：色谱柱：Waters acquity UPLC CSH 2.1×50mm,1.7μm。
流动相：A:水(0.01％三氟乙酸)B:乙腈(0.01％三氟乙酸)。
洗脱梯度：5％-95％B，0.7分钟；95％B 0.8分钟；然后5％B 0.5分钟。
流动速率：1.0mL/min。
色谱柱温度：60℃。
质谱扫描范围：100–1000。
中间体I-48A(Rt＝1.541min)LC-MS(ESI)[M+H]+737.3。
在25℃下，将中间体I-48A(14mg,0.019mmol)溶于N,N-二甲基甲酰胺(3mL)，加入吡咯烷(35.50mg,0.50mmol)，25℃搅拌1小时。加乙酸乙酯(20mL)稀释，水(10mL×3)洗，无水硫酸钠干燥，过滤。滤液减压浓缩，经C18反相色谱法(甲酸体系)分离纯化得到化合物8。
LC-MS(ESI)[M+H]+515.2。
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.13–7.90(m,2H),7.88–7.52(m,6H),7.09(dd,J＝8.3,2.7Hz,1H),6.89(d,J＝8.3Hz,1H),4.90(dt,J＝13.7,3.3Hz,1H),4.14(d,J＝9.2Hz,1H),3.80–3.35(m,1H),3.15–3.03(m,1H),3.03–2.92(m,1H),2.66(t,J＝12.7Hz,1H),2.09(dd,J＝12.1,4.1Hz,2H),1.86–1.64(m,2H),1.64–1.51(m,1H)。
化合物8经SFC手性拆分得到化合物10A(Rt＝1.424min)。
手性拆分方法：
仪器：MGⅡpreparative SFC(SFC-14)。
色谱柱：ChiralPak AD,250×30mm I.D.,10μm。
流动相：A:二氧化碳B:乙醇(0.1％氨水)。
洗脱梯度：35％B。
流动速率：80mL/min。
背压：100bar。
柱温：38℃。
检测波长：220nm。
循环时间：～8min。
手性分析方法：
仪器：Waters UPC2 analytical SFC(SFC-H)。
色谱柱：ChiralPak AD,150×4.6mm I.D.,3μm。
流动相：A:二氧化碳B:乙醇(0.05％二乙胺)。
洗脱梯度：40％B。
流动速率：2.5mL/min。
背压：1500psi。
柱温：35℃。
检测波长：220nm。
化合物10A：
Rt＝1.424min。
LC-MS(ESI)[M+H]+515.2。
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.30–7.88(m,2H),7.88–7.55(m,6H),7.10(dd,J＝8.4,2.7Hz,1H),6.89(d,J＝8.3Hz,1H),4.90(dt,J＝13.5,3.2Hz,1H),4.14(d,J＝9.2Hz,1H),3.40–3.39(m,1H),3.13–2.90(m,2H),2.66(t,J＝12.3Hz,1H),2.16–2.05(m,2H),1.87–1.49(m,3H)。
实施例2式(I)化合物对加压素诱导的血管加压素受体V2R激活的抑制IC50测试
(1)细胞
稳定表达人加压素受体V2R的HeLa细胞系(HeLa-V2R)：由上海吉凯基因化学技术有限公司利用慢病毒感染方法构建，经qPCR验证稳定表达人V2R。
(2)试剂
DMEM细胞培养基：品牌：Gibco，货号：11995065；胎牛血清：品牌：吉泰，货号：FND500；0.25％胰酶：品牌：Gibco，货号：25200072；Puromycin Dihydrochloride:品牌：Gibco，货号：A1113803；cAMP-GS HIRANGE KIT：品牌：Cisbio，货号：62AM6PEC；IBMX:品牌：Sigma，货号：i5879；加压素AVP：吉尔生化(上海)有限公司定制。
(3)测试方法
HeLa-V2R细胞用添加10％胎牛血清的DMEM培养基在37度、5％CO2条件下孵育培养，培养基中添加2μg/mL puromycin持续筛选表达V2R的细胞。实验当天用胰酶消化细胞，用cAMP-GS HIRANGE试剂盒中的stimulation buffer洗细胞2次，重悬计数后配制成1.6X106个细胞/ml，加入IBMX至终浓度为0.5mM。转移5μL细胞悬液/孔至384孔板，在相应孔中分别加入2.5μL不同浓度的待测化合物(10μM起3倍稀释，10个浓度梯度)或DMSO(最小值Min、最大值Max对照)。室温孵育30分钟后，测试化合物孔及最大值孔中加入2.5μL加压素AVP溶液至终浓度2.25nM，最小值孔中加入2.5μL stimulation buffer，25度孵育60分钟。同时配制cAMP标准品样品(从5.6μM开始3倍稀释，10个浓度点)，转移10μL cAMP标准品至384孔板相应孔。用cAMP-GS HIRANGE试剂盒中的lysis buffer稀释试剂盒中提供的cAMP-d2荧光和anti-cAMP抗体探针20倍，各取5μL依次加入384孔板中各孔，混匀后简单离心，25度孵育2小时后检测。样品检测用Envision酶标仪 中的HTRF方法，检测615nm及665nm处的荧光强度。每个待测样品做两个复孔，Min、Max各做32个复孔。
(4)数据处理
计算各孔样品665nm与615nm波长处的荧光强度比值FI665/615。以标准品浓度对数为X，FI665/615X1000为Y值，用Prism 8.0软件中“log(inhibitor)vs response–variable slope(four parameters)“模型拟合获得标准曲线。以测试孔FI665/615X1000为Y值，在Prism 8.0软件中根据上述标准曲线计算出各个样品对应的cAMP浓度。
％Inhibition(抑制百分率)计算公式如下：
其中为所有最大值孔中cAMP浓度的平均计算值；为所有最小值孔中cAMP浓度平均计算值；Ccmpd是待测化合物的cAMP浓度计算值。
以％Inhibition(抑制百分率)为Y值，化合物浓度对数值为X，在Prism 8.0软件中用“log(inhibitor)vs response–variable slope(four parameters)“模型做非线性回归，计算IC50，其中Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))。
实验结果如表25所示：
表25：化合物对人宫颈癌细胞(Human V2R Hela-Stable cell line OE2)内cAMP增加抑制的评价
实施例3盐型筛选
选取15种酸性化合物进行盐型筛选，方法为反应结晶法，结果如下表26和表27所示。
表26溶液混悬法(1当量)盐型初筛实验
注：“*”代表在悬浮后澄清，置于-15℃有固体析出；“**”代表在悬浮和降温至-15℃后澄清，加入正庚烷后有固体析出。
表27溶液混悬法(2当量)盐型初筛实验
由上表可知，式(I)所示化合物可成6种盐，分别为盐酸盐、硫酸盐、马来酸盐、富马酸盐、琥珀酸盐和乙醇酸盐。
实施例4马来酸盐晶型A的制备
方法一：称取513.6mg式(I)所示化合物和1当量的马来酸，加入16mL异丙醇，室温条件下搅拌2天，将悬浮液离心分离，并将固体置于40℃中真空干燥3天。获得611.5mg马来酸盐晶型A。
方法二：室温下，向夹套反应釜R1中加入甲醇(30mL，10.0v/w)；置换氮气3次；室温下，向夹套反应釜R1中加入游离胺(3.0g,1w，5.82mmol,1.0eq.)，开始搅拌；搅拌至溶清；在夹套反应釜R2中，配置马来酸的异丙醇溶液：25-30℃下，马来酸(0.71g，0.236w，6.11mmol，1.05eq)溶解在异丙醇(60mL，20.0v/w)中；将配置好的马来酸/异丙醇溶液滴加到反应釜R1中，控制内温20-30℃，滴加时间20分钟；滴加完毕后，20-30℃反应2-5h；过滤，滤饼用异丙醇(9mL，3.0v/w)洗涤一次,干燥得到马来酸盐晶型A。
方法三：100L反应釜中加入甲醇10L，加入游离碱4.2kg，补加6.8L甲醇，升温至60℃，马来酸993g溶于异丙醇中33.6L，慢慢滴加上述溶液，降温至25℃，过滤得到4.7kg马来酸盐晶型A。
对马来酸盐晶型A进行表征，表征结果如图1至图5所示。XRPD(图1)结果显示马来酸盐晶型A为结晶性好的固体。TGA(图2)结果显示马来酸盐晶型A在加热至150℃过程中有0.5％的失重，在200℃以上可能发生分解。DSC(图2)结果显示马来酸盐晶型A在229℃有吸热峰。NMR(图3)结果显示，与游离态相比，1.50～1.90ppm、2.98ppm、3.07ppm、4.11ppm、6.90ppm和7.08ppm峰发生偏移，暗示该样品成盐；在6.03ppm可见马来酸的信号峰，根据积分结果计算，原料与马来酸的比例为1:1；在1.04ppm可见异丙醇的溶剂峰，暗示样品有少量异丙醇溶剂残留。DVS(图4)结果显示马来酸盐晶型A在80％RH下增重0.09％，在95％RH下增重0.23％，在0％RH下失重0.24％，表明马来酸盐晶型A几乎无引湿性；XRPD(图5)结果显示DVS测试后的样品并未发生晶型改变。可知，马来酸盐晶型A为结晶性好的无水晶型，并且几乎无引湿性。
实施例5马来酸盐晶型B的制备
21.7mg马来酸盐晶型A溶于0.5mL DMF,加入异丙醇1.5mL,加热至60℃，慢慢降温至15℃，过滤得到马来酸盐晶型B。
XRPD(图6)结果显示晶型B为结晶性好的固体。TGA(图7)结果显示晶型B从室温加热至170℃过程中有9.7％的失重，在220℃以上可能发生分解。DSC(图7)结果显示晶型B在145℃左右有对应脱溶剂的吸热信号，在234℃左右有吸热峰。NMR(图8)结果与原料基本一致，在2.73、2.89和7.95ppm处可见DMF的溶剂峰，根据积分结果计算，化合物与DMF的比例为1:0.9，DMF含量与TGA失重基本一致。热转晶实验结果显示，晶型B加热至170℃脱溶剂后转晶为晶型A。综上所述，晶型B为DMF溶剂合物。
实施例6富马酸盐晶型C的制备
25.6mg式(I)所示化合物加入异丙醇0.8mL,加入富马酸1当量，室温搅拌2天，离心得到富马酸盐晶型C。
XRPD(图9)结果显示富马酸盐晶型C为结晶性好的固体。TGA(图10)结果显示样品在加热至150℃过程中有0.7％的失重，在190℃后可能发生分解。DSC(图10)结果显示在217℃左右有吸热信号。NMR(图11)结果显示，与游离态相比，1.50～1.90ppm、2.98ppm、3.07ppm、4.11ppm、6.90ppm和7.08ppm峰发生偏移，暗示该样品成盐；在6.57ppm可见富马酸的信号峰，根据积分结果计算，API与富马酸的比例为1:1；在1.04ppm可见异丙醇的溶剂峰，暗示样品有少量异丙醇溶剂残留。综上所述，富马酸盐晶型C为无水晶型。
实施例7盐酸盐晶型D的制备
25.3mg式(I)所示化合物加入异丙醇0.8mL,加入浓盐酸1当量，室温搅拌2天，离心得到盐酸盐晶型D。
XRPD(图12)结果显示盐酸盐晶型D为结晶性好的固体。TGA(图13)结果显示样品在加热至150℃过程中有1.6％的失重(对应0.5个水分子的失重量)；在230℃后可能发生分解。DSC(图13)结果显示在71℃和262℃左右有吸热信号。NMR(图14)结果显示，与游离态相比，1.50～1.90ppm、2.98ppm、3.07ppm、4.11ppm、6.90ppm和7.08ppm多个峰发生偏移，暗示该样品成盐；在1.04ppm可见异丙醇的溶剂峰，暗示样品有少量异丙醇溶剂残留。热转晶实验结果表明，盐酸盐晶型D在加热至150℃后转变为盐酸盐晶型F。离子色谱结果表明，盐酸盐晶型D的成盐比例为1:1。综上所述，盐酸盐晶型D为水合物。
实施例8盐酸盐晶型E的制备
25.3mg式(I)所示化合物加入环己烷1.0mL,加入浓盐酸1当量，室温搅拌2天，离心得到盐酸盐晶型E。
XRPD(图15)结果显示盐酸盐晶型E为结晶性差的固体。TGA(图16)结果显示样品在加热过程中持续失重。DSC(图16)结果显示在89℃和201℃左右有吸热信号。NMR(图17)结果显示，与游离态相比，1.50～1.90ppm、2.98ppm、3.07ppm、6.90ppm和7.08ppm峰发生偏移，暗示该样品成盐；在1.39ppm可见环己烷的溶剂峰，暗示样品有少量环己烷溶剂残留。综上所述，盐酸盐晶型E可能为吸附水的无水物或水合物。
实施例9盐酸盐晶型F的制备
25.4mg晶型N加入异丙醇0.8ml，加入1当量盐酸，室温条件下搅拌2天，将悬浮液离心分离，并将固体室温真空干燥得到盐酸盐晶型F。
XRPD(图18)结果显示盐酸盐晶型F为结晶性好的固体。TGA(图19)结果显示样品在加热至150℃过程中有0.5％的失重，在230℃后可能发生分解。DSC(图19)结果显示在316℃和320℃左右有吸热信号。NMR(图20)结果显示，与游离态相比，1.50～1.90ppm、2.98ppm、3.07ppm、4.11ppm、6.90ppm和7.08ppm峰发生偏移，暗示该样品成盐；在1.04ppm可见异丙醇的溶剂峰，暗示样品有少量异丙醇溶剂残留。离子色谱结果表明，盐酸盐晶型F的成盐比例为1:1。综上所述，盐酸盐晶型F为无水晶型。
实施例10硫酸盐晶型G的制备
26.1mg式(I)所示化合物加入环己烷1.0mL,加入浓硫酸1当量，室温搅拌2天，离心得到硫酸盐晶型G。
XRPD(图21)结果显示硫酸盐晶型G为结晶性好的固体。TGA(图22)结果显示样品在加热至150℃过程中有3.7％的失重，在240℃后可能发生分解。DSC(图22)结果显示在282℃和298℃左右有吸热信号。NMR(图23)结果显示，与游离态相比，1.50～1.90ppm、2.98ppm、3.07ppm、6.90ppm和7.08ppm峰发生偏移，暗示该样品成盐；在1.39ppm可见环己烷的溶剂峰，暗示样品有极少量环己烷溶剂残留。综上所述，硫酸盐晶型G可能为吸附水的无水物或水合物。
实施例11琥珀酸盐晶型H的制备
24.1mg式(I)所示化合物加入0.8ml异丙醇，加入1当量琥珀酸，室温搅拌2天，离心得到琥珀酸盐晶型H。
XRPD(图24)结果显示琥珀酸盐晶型H为结晶性好的固体。TGA(图25)结果显示样品在加热至120℃过程中有0.2％的失重，在170℃后可能发生分解。DSC(图25)结果显示在186℃左右有吸热信号。NMR(图26)结果显示，与游离态相比，1.50～1.90ppm、2.98ppm、3.07ppm、4.11ppm、6.90ppm和7.08ppm峰发生偏移，暗示该样品成盐；在2.39ppm可见琥珀酸的信号峰，根据积分结果计算，API与琥珀酸的比例为1:1；在1.04ppm可见异丙醇的溶剂峰，暗示样品有少量异丙醇溶剂残留。综上所述，琥珀酸盐晶型H为无水晶型。
实施例12琥珀酸盐晶型J的制备
24.7mg式(I)所示化合物加入1.0mL甲基叔丁基醚，加入1当量琥珀酸，室温搅拌2天，离心得到琥珀酸盐晶型J。
XRPD(图27)结果显示琥珀酸盐晶型J为结晶性好的固体。TGA(图28)结果显示样品在加热至150℃过程中有0.6％的失重，在170℃后可能发生分解。DSC结果显示在177℃左右有吸热信号。NMR(图29)结果显示，与游离态相比，1.50～1.90ppm、2.98ppm、3.07ppm、4.11ppm、6.90ppm和7.08ppm峰发生偏移，暗示该样品成盐；在2.39ppm可见琥珀酸的信号峰，根据积分结果计算，API与琥珀酸的比例为1:1；在1.10ppm可见甲基叔丁基醚的溶剂峰，暗示样品有少量甲基叔丁基醚溶剂残留。综上所述，琥珀酸盐晶型J为无水晶型。
实施例13乙醇酸盐晶型K的制备
25.9mg式(I)所示化合物加入1.0mL甲基叔丁基醚，加入1当量乙醇酸，室温搅拌2天，离心得到乙醇酸盐晶型K。
XRPD(图30)结果显示乙醇酸盐晶型K为结晶性好的固体。TGA(图31)结果显示样品在加热至70℃过程中有0.7％的失重，并在之后的加热过程中连续失重，在150℃后可能发生分解。DSC结果显示在98℃左右有吸热信号。NMR(图32)结果显示，与游离态相比，2.98ppm、3.07ppm、4.11ppm、6.90ppm和7.08ppm峰发生偏移，暗示该样品成盐；在3.87ppm可见乙醇酸的信号峰；在1.10ppm可见甲基叔丁基醚的溶剂峰，暗示样品有极少量甲基叔丁基醚溶剂残留。综上所述，乙醇酸盐晶型K可能为无水物/水合物。
实施例14苯甲酸共晶晶型L的制备
24.7mg式(I)所示化合物加入0.8mL异丙醇，加入1当量苯甲酸，室温搅拌2天，离心得到苯甲酸共晶晶型L。
XRPD(图33)结果显示苯甲酸共晶晶型L为结晶性好的固体。TGA(图34)结果显示样品在加热至100℃过程中有1.6％的失重，在135℃后可能发生分解。DSC(图34)结果显示在165℃和177℃左右有吸热信号。NMR(图35)结果显示，与游离态相比，没有峰发生偏移，暗示该样品未成盐，可能形成共晶；在7.0～8.5ppm可见苯甲酸的信号峰，根据积分结果计算，API与苯甲酸的比例为1:1；在1.04ppm可见异丙醇的溶剂峰，暗示样品有少量异丙醇溶剂残留。综上所述，苯甲酸共晶晶型L为无水晶型。
实施例15苯甲酸共晶晶型M的制备
25.2mg式(I)所示化合物加入1.0mL环己烷，加入1当量苯甲酸，室温搅拌2天，离心得到苯甲酸共晶晶型M。
XRPD(图36)结果显示苯甲酸共晶晶型M为结晶性差的固体。TGA(图37)结果显示样品在加热至100℃过程中有1.0％的失重，在135℃后可能发生分解。DSC(图37)结果显示在175℃左右有吸热信号。NMR(图38)结果显示，与游离态相比，没有峰发生偏移，暗示该样品未成盐，可能形成共晶；在7.0～8.5ppm可见苯甲酸的信号峰，根据积分结果计算，原料与苯甲酸的比例为1:1；在1.39ppm可见环己烷的溶剂峰，暗示样品有少量环己烷溶剂残留。综上所述，苯甲酸共晶晶型M为无水晶型。
实施例16晶型N的制备
20.4mg式(I)所示化合物加入甲苯0.5mL,50℃悬浮搅拌一天，离心得到晶型N。
XRPD(图39)结果显示晶型N为结晶性好的固体。TGA(图40)结果显示晶型N在加热至150℃过程中有0.6％的失重，在300℃以上可能发生分解。DSC(图40)结果显示晶型N在208℃左右有一个熔融吸热峰。NMR(图41)结果显示在2.30ppm可见甲苯的溶剂峰，暗示该样品含有少量甲苯溶剂残留。综上所述，晶型N为无水晶型。
实施例17晶型O的制备
19.5mg式(I)所示化合物溶于0.6mL乙醇中，慢慢加入正庚烷9.0mL，悬浮搅拌15分钟，离心得到晶型O。
XRPD(图42)结果显示晶型O为结晶性好的固体。TGA(图43)结果显示晶型O在加热至200℃过程中有2.6％的失重，在300℃以上可能发生分解。DSC(图43)结果显示晶型O在196℃左右有一个放热峰；在190℃左右有一个吸热信号，在208℃左右有熔融吸热峰。热转晶实验结果表明晶型O在脱溶剂后重结晶为晶型N。NMR(图44)结果显示该样品在1.06ppm可见乙醇的溶剂峰；根据积分结果计算，化合物与乙醇的比例为1:0.25，该比例与TGA的失重相符(理论失重量为2.2％)。综上所述，晶型O为乙醇/正丙醇溶剂合物，或者晶体内包藏乙醇/正丙醇的无水物。
实施例18晶型P的制备
20.9mg式(I)所示化合物加入1.4mL乙腈和1.0mL水溶解，将溶液在室温静置挥发，直至溶剂挥发完全，离心得到晶型P。
XRPD(图45)结果显示晶型P为结晶性好且有明显择优取向的固体。TGA(图46)结果显示晶型P在加热至175℃过程中有3.3％的失重，在300℃以上可能发生分解。DSC(图46)结果显示晶型P在158℃左右有一个放热峰；在145℃左右有一个吸热信号，在211℃左右有熔融吸热峰。热转晶实验结果表明晶型P在脱溶剂后重结晶为晶型N。NMR(图47)结果显示该样品无明显的有机溶剂峰。综上所述，晶型P为水合物。
实施例19晶型Q的制备
式(I)所示化合物19.9mg，溶于乙醚4.5mL，在室温敞口静置，直至溶剂完全挥发得到晶型Q。
XRPD(图48)结果显示晶型Q为结晶性好的固体。TGA(图49)结果显示晶型Q在加热至180℃过程中有4.6％的失重，在300℃以上可能发生分解。DSC(图49)结果显示晶型Q在181℃左右有一个放热峰；在171℃、198℃左右有吸热信号，在207℃左右有熔融吸热峰。热转晶实验结果表明晶型Q在脱溶剂后重结晶为晶型N。
实施例20晶型R的制备
19.9mg式(I)所示化合物室温下滴加乙腈0.8mL至完全溶解，再滴加水3.0mL至有固体析出。室温悬浮15min后，将体系离心分离后室温真空干燥，得到晶型R。
XRPD(图50)结果显示晶型R为结晶性好的固体。TGA(图51)结果显示晶型R在加热至150℃过程中有3.7％的失重，在300℃以上可能发生分解。DSC(图51)结果显示晶型R在161℃左右有一个放热峰；在154℃左右有一个吸热信号，在211℃左右有熔融吸热峰。热转晶实验结果表明晶型R在脱溶剂后重结晶为晶型N。NMR(图52)结果显示无明显的有机溶剂峰存在。综上所述，晶型R为水合物。
实施例21晶型S的制备
取400.0mg式(I)所示化合物于玻璃小瓶中，加入10.5mL异丙醇/水(1/6,v/v)的混合溶剂，置于50℃下悬浮1天。将所得固体离心分离，在40℃真空干燥1天，得到晶型S。
XRPD(图53)结果显示晶型S为结晶性好的固体。TGA(图54)结果显示晶型S在加热至150℃过程中有3.6％的失重，在300℃以上可能发生分解。DSC(图54)结果显示晶型S在155℃左右有一个放热峰；在126℃左右有一个吸热信号，在210℃左右有熔融吸热峰。热转晶实验结果表明晶型S在脱溶剂后重结晶为晶型N。综上所述，晶型S为水合物。NMR见图55。
实施例22晶型T的制备
20.4mg式(I)所示化合物溶于二氯甲烷0.1mL中，室温敞口挥发至干，得到晶型T。
XRPD(图56)结果显示晶型T为结晶性较好的固体。TGA(图57)结果显示晶型T在加热至200℃过程中有6.7％的失重，在300℃以上可能发生分解。DSC(图57)结果显示晶型T在191℃左右有一个放热峰；在186℃左右有一个吸热信号，在209℃左右有熔融吸热峰。NMR(图58)结果显示化合物结构没有发生变化，在5.76ppm和3.57ppm可见二氯甲烷和少量二氧六环的溶剂峰；根据积分结果计算，化合物与二氯甲烷的比例为1:0.25。综上所述，晶型T为二氯甲烷的溶剂合物或晶体内包藏二氯甲烷的无水物。
实施例23晶型U的制备
23.5mg式(I)所示化合物加入1.0mL环己烷，加入1当量丙酸，室温条件下搅拌2天，将悬浮液离心分离，并将固体室温真空干燥得晶型U。
XRPD(图59)结果显示其为结晶性好的固体。TGA(图60)结果显示样品在加热至130℃过程中有18.0％的失重，对应约2个丙酸分子的失重量。DSC(图60)结果显示在109℃、121℃和204℃左右有吸热信号。NMR(图61)结果显示，与游离态相比，没有峰发生偏移，暗示该样品未成盐；在0.99ppm和2.20ppm可见丙酸的信号峰，根据积分结果计算，API与丙酸的比例为1:2；在1.39ppm可见环己烷的溶剂峰，暗示样品有少量环己烷溶剂残留。综上所述，晶型U为丙酸溶剂合物。
实施例24稳定性研究
对马来酸盐晶型A、富马酸盐晶型C、晶型N、晶型S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7天和15天取样进行XRPD表征，结果如表28、图62-65所示。XRPD结果显示，马来酸盐晶型A和富马酸盐晶型C在高温、高湿、光照、加速条件下15天均稳定，没有发生晶型转变。
表28
实施例25生物介质溶解度测试
在3种生物介质(FaSSIF、FeSSIF和FaSSGF)中进行动态溶解度测定，结果如下表29和图66、67所示。
表29

*该样品在FaSSGF中先溶清后振荡24h析出固体为无定型。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (26)

  1. 一种式(I)所示化合物的马来酸盐，其结构如式(II)所示，
  2. 式(I)所示化合物的马来酸盐晶型A，其中，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.14±0.2°、12.88±0.2°、18.31±0.2°、18.90±0.2°、20.60±0.2°、27.61±0.2°；
    任选地，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.14±0.2°、12.88±0.2°、17.19±0.2°、18.31±0.2°、18.90±0.2°、20.60±0.2°、21.45±0.2°、27.61±0.2°；
    任选地，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.14±0.2°、12.88±0.2°、17.19±0.2°、18.31±0.2°、18.90±0.2°、19.70±0.2°、20.20±0.2°、20.60±0.2°、21.45±0.2°、21.91±0.2°、27.61±0.2°；
    任选地，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.14±0.2°、12.88±0.2°、17.19±0.2°、18.31±0.2°、18.90±0.2°、19.70±0.2°、20.20±0.2°、20.60±0.2°、21.45±0.2°、21.91±0.2°、25.96±0.2°、26.53±0.2°、27.61±0.2°、29.22±0.2°、30.20±0.2°；
    任选地，所述晶型A的X射线粉末衍射图谱具有基本上如图1所示的X射线粉末衍射图谱。
  3. 式(I)所示化合物的马来酸盐晶型B，其中，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.97±0.2°、15.73±0.2°、18.31±0.2°、20.15±0.2°、21.12±0.2°、24.70±0.2°；
    任选地，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.40±0.2°、8.97±0.2°、10.11±0.2°、13.94±0.2°、15.73±0.2°、18.31±0.2°、19.02±0.2°、20.15±0.2°、21.12±0.2°、24.70±0.2°；
    任选地，所述晶型B的X射线粉末衍射图谱具有基本上如图6所示的X射线粉末衍射图谱。
  4. 一种式(I)所示化合物的富马酸盐，其结构如式(III)所示，
  5. 式(I)所示化合物的富马酸盐晶型C，其中，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.77±0.2°、14.44±0.2°、20.00±0.2°、20.64±0.2°、21.33±0.2°、21.87±0.2°；
    任选地，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.77±0.2°、13.17±0.2°、14.44±0.2°、17.18±0.2°、20.00±0.2°、20.64±0.2°、21.33±0.2°、21.87±0.2°、23.43±0.2°、25.86±0.2°；
    任选地，所述晶型C的X射线粉末衍射图谱具有基本上如图9所示的X射线粉末衍射图谱。
  6. 一种式(I)所示化合物的盐酸盐，其结构如式(IV)所示，
  7. 式(I)所示化合物的盐酸盐晶型D，其中，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.13±0.2°、9.27±0.2°、9.91±0.2°、13.53±0.2°、16.37±0.2°、17.09±0.2°；
    任选地，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.13±0.2°、9.27±0.2°、9.91±0.2°、12.86±0.2°、13.53±0.2°、16.37±0.2°、17.09±0.2°、18.67±0.2°、21.77±0.2°、23.81±0.2°；
    任选地，所述晶型D的X射线粉末衍射图谱具有基本上如图12所示的X射线粉末衍射图谱。
  8. 式(I)所示化合物的盐酸盐晶型E，其中，所述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.86±0.2°、13.60±0.2°、14.19±0.2°、18.06±0.2°、20.50±0.2°、21.24±0.2°；
    任选地，所述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.86±0.2°、6.74±0.2°、11.73±0.2°、13.60±0.2°、14.19±0.2°、18.06±0.2°、20.50±0.2°、21.24±0.2°、23.72±0.2°、24.06±0.2°；
    任选地，所述晶型E的X射线粉末衍射图谱具有基本上如图15所示的X射线粉末衍射图谱。
  9. 式(I)所示化合物的盐酸盐晶型F，其中，所述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.84±0.2°、11.77±0.2°、13.29±0.2°、17.82±0.2°、20.49±0.2°、20.94±0.2°；
    任选地，所述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.84±0.2°、11.77±0.2°、13.29±0.2°、14.34±0.2°、17.82±0.2°、18.67±0.2°、20.49±0.2°、20.94±0.2°、23.02±0.2°、23.68±0.2°；
    任选地，所述晶型F的X射线粉末衍射图谱具有基本上如图18所示的X射线粉末衍射图谱。
  10. 一种式(I)所示化合物的硫酸盐，其结构如式(V)所示，
  11. 式(I)所示化合物的硫酸盐晶型G，其中，所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.30±0.2°、13.02±0.2°、16.60±0.2°、18.53±0.2°、20.67±0.2°、22.26±0.2°；
    任选地，所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.46±0.2°、10.30±0.2°、13.02±0.2°、16.60±0.2°、17.66±0.2°、18.53±0.2°、19.98±0.2°、20.67±0.2°、22.26±0.2°、23.62±0.2°；
    任选地，所述晶型G的X射线粉末衍射图谱具有基本上如图21所示的X射线粉末衍射图谱。
  12. 一种式(I)所示化合物的琥珀酸盐，其结构如式(VI)所示，
  13. 式(I)所示化合物的琥珀酸盐晶型H，其中，所述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.30±0.2°、14.63±0.2°、18.59±0.2°、20.13±0.2°、21.83±0.2°、22.30±0.2°；
    任选地，所述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.30±0.2°、12.91±0.2°、14.63±0.2°、18.59±0.2°、19.41±0.2°、20.13±0.2°、20.69±0.2°、21.83±0.2°、22.30±0.2°、23.65±0.2°；
    任选地，所述晶型H的X射线粉末衍射图谱具有基本上如图24所示的X射线粉末衍射图谱。
  14. 式(I)所示化合物的琥珀酸盐晶型J，其中，所述晶型J的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.61±0.2°、11.56±0.2°、12.93±0.2°、17.12±0.2°、17.71±0.2°、19.95±0.2°；
    任选地，所述晶型J的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.61±0.2°、11.56±0.2°、12.93±0.2°、13.76±0.2°、17.12±0.2°、17.71±0.2°、19.51±0.2°、19.95±0.2°、21.83±0.2°、22.42±0.2°；
    任选地，所述晶型J的X射线粉末衍射图谱具有基本上如图27所示的X射线粉末衍射图谱。
  15. 一种式(I)所示化合物的乙醇酸盐，其结构如式(VII)所示，
  16. 式(I)所示化合物的乙醇酸盐晶型K，其中，所述晶型K的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.51±0.2°、15.99±0.2°、18.71±0.2°、20.18±0.2°、20.59±0.2°、21.64±0.2°；
    任选地，所述晶型K的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.51±0.2°、13.62±0.2°、15.99±0.2°、16.65±0.2°、18.71±0.2°、20.18±0.2°、20.59±0.2°、21.64±0.2°、22.62±0.2°、24.53±0.2°；
    任选地，所述晶型K的X射线粉末衍射图谱具有基本上如图30所示的X射线粉末衍射图谱。
  17. 一种式(I)所示化合物的苯甲酸盐，其结构如式(VIII)所示，
  18. 式(I)所示化合物的苯甲酸共晶晶型M，其中，所述晶型M的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.31±0.2°、13.77±0.2°、14.54±0.2°、19.84±0.2°、20.34±0.2°、21.70±0.2°；
    任选地，所述晶型M的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.31±0.2°、13.77±0.2°、 14.54±0.2°、16.55±0.2°、17.66±0.2°、18.68±0.2°、19.84±0.2°、20.34±0.2°、21.70±0.2°、23.32±0.2°；
    任选地，所述晶型M的X射线粉末衍射图谱具有基本上如图36所示的X射线粉末衍射图谱。
  19. 式(I)所示化合物的晶型N，其中，所述晶型N的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.38±0.2°、13.54±0.2°、14.41±0.2°、16.32±0.2°、18.10±0.2°、19.05±0.2°；
    任选地，所述晶型N的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.38±0.2°、13.54±0.2°、14.41±0.2°、15.90±0.2°、16.32±0.2°、18.10±0.2°、19.05±0.2°、22.14±0.2°、22.91±0.2°、23.66±0.2°；
    任选地，所述晶型N的X射线粉末衍射图谱具有基本上如图39所示的X射线粉末衍射图谱。
  20. 式(I)所示化合物的晶型O，其中，所述晶型O的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.75±0.2°、9.65±0.2°、15.70±0.2°、16.88±0.2°、18.00±0.2°、18.97±0.2°；
    任选地，所述晶型O的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.75±0.2°、9.65±0.2°、15.70±0.2°、16.88±0.2°、18.00±0.2°、18.97±0.2°、19.89±0.2°、21.86±0.2°、22.67±0.2°、24.30±0.2°；
    任选地，所述晶型O的X射线粉末衍射图谱具有基本上如图42所示的X射线粉末衍射图谱。
  21. 式(I)所示化合物的晶型P，其中，所述晶型P的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.07±0.2°、17.98±0.2°、21.64±0.2°、23.78±0.2°、26.36±0.2°、33.13±0.2°；
    任选地，所述晶型P的X射线粉末衍射图谱具有基本上如图45所示的X射线粉末衍射图谱。
  22. 式(I)所示化合物的晶型Q，其中，所述晶型Q的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.48±0.2°、10.60±0.2°、12.32±0.2°、15.41±0.2°、16.60±0.2°、17.09±0.2°；
    任选地，所述晶型Q的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.48±0.2°、10.60±0.2°、12.32±0.2°、15.41±0.2°、16.60±0.2°、17.09±0.2°、17.75±0.2°、18.79±0.2°、20.49±0.2°、21.40±0.2°；
    任选地，所述晶型Q的X射线粉末衍射图谱具有基本上如图48所示的X射线粉末衍射图谱。
  23. 式(I)所示化合物的晶型R，其中，所述晶型R的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.70±0.2°、13.30±0.2°、18.15±0.2°、21.39±0.2°、22.97±0.2°、26.71±0.2°；
    任选地，所述晶型R的X射线粉末衍射图谱具有基本上如图50所示的X射线粉末衍射图谱。
  24. 式(I)所示化合物的晶型S，其中，所述晶型S的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.97±0.2°、15.34±0.2°、17.97±0.2°、22.81±0.2°、23.54±0.2°、24.69±0.2°；
    任选地，所述晶型S的X射线粉末衍射图谱具有基本上如图53所示的X射线粉末衍射图谱。
  25. 式(I)所示化合物的晶型T，其中，所述晶型T的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.84±0.2°、17.03±0.2°、17.60±0.2°、20.01±0.2°、22.22±0.2°、22.82±0.2°；
    任选地，所述晶型T的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.64±0.2°、14.70±0.2°、15.84±0.2°、17.03±0.2°、17.60±0.2°、19.01±0.2°、20.01±0.2°、22.22±0.2°、22.82±0.2°、24.45±0.2°；
    任选地，所述晶型T的X射线粉末衍射图谱具有基本上如图56所示的X射线粉末衍射图谱。
  26. 式(I)所示化合物的晶型U，其中，所述晶型U的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.01±0.2°、9.27±0.2°、12.68±0.2°、16.15±0.2°、17.94±0.2°、19.31±0.2°；
    任选地，所述晶型U的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.01±0.2°、9.27±0.2°、12.68±0.2°、16.15±0.2°、17.94±0.2°、19.31±0.2°、22.16±0.2°、22.82±0.2°、23.80±0.2°、24.08±0.2°；
    任选地，所述晶型U的X射线粉末衍射图谱具有基本上如图59所示的X射线粉末衍射图谱。
PCT/CN2023/116489 2022-09-05 2023-09-01 苯并氮杂卓并环化合物盐型、晶型及其应用 WO2024051590A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211080826 2022-09-05
CN202211080826.4 2022-09-05

Publications (1)

Publication Number Publication Date
WO2024051590A1 true WO2024051590A1 (zh) 2024-03-14

Family

ID=90192008

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/116489 WO2024051590A1 (zh) 2022-09-05 2023-09-01 苯并氮杂卓并环化合物盐型、晶型及其应用

Country Status (1)

Country Link
WO (1) WO2024051590A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5258510A (en) * 1989-10-20 1993-11-02 Otsuka Pharma Co Ltd Benzoheterocyclic compounds
CN1106802A (zh) * 1993-07-29 1995-08-16 美国氰胺公司 三环苯并吖庚因(氮杂䓬)后叶加压素拮抗剂
US5532235A (en) * 1995-01-17 1996-07-02 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US20070185323A1 (en) * 2004-03-02 2007-08-09 Samir Zard Method of preparing benzazepines and derivatives thereof
CN101258134A (zh) * 2005-03-11 2008-09-03 欧加农股份有限公司 2-(4-氧代-4h-喹唑啉-3-基)乙酰胺衍生物及其作为加压素v3拮抗剂的用途
WO2022184172A1 (zh) * 2021-03-05 2022-09-09 上海济煜医药科技有限公司 新型苯并氮杂卓并环衍生物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5258510A (en) * 1989-10-20 1993-11-02 Otsuka Pharma Co Ltd Benzoheterocyclic compounds
CN1106802A (zh) * 1993-07-29 1995-08-16 美国氰胺公司 三环苯并吖庚因(氮杂䓬)后叶加压素拮抗剂
US5532235A (en) * 1995-01-17 1996-07-02 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US20070185323A1 (en) * 2004-03-02 2007-08-09 Samir Zard Method of preparing benzazepines and derivatives thereof
CN101258134A (zh) * 2005-03-11 2008-09-03 欧加农股份有限公司 2-(4-氧代-4h-喹唑啉-3-基)乙酰胺衍生物及其作为加压素v3拮抗剂的用途
WO2022184172A1 (zh) * 2021-03-05 2022-09-09 上海济煜医药科技有限公司 新型苯并氮杂卓并环衍生物

Similar Documents

Publication Publication Date Title
CN109721527B (zh) 一种新型抗pd-l1化合物、其应用及含其的组合物
WO2017193914A1 (zh) 克立硼罗游离形式的晶型及其制备方法和用途
EP3176173B1 (en) Crystalline free bases of c-met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof
WO2024051590A1 (zh) 苯并氮杂卓并环化合物盐型、晶型及其应用
WO2021098850A1 (zh) 一种核蛋白抑制剂的晶型及其应用
JP6193762B2 (ja) １−｛（２Ｓ）−２−アミノ−４−［２，４−ビス（トリフルオロメチル）−５，８−ジヒドロピリド［３，４−ｄ］ピリミジン−７（６Ｈ）−イ
CA3033456C (en) Crystal forms and salt forms of 7h-pyrrolo[2,3-d]pyrimidine compounds and preparation method thereof
TW202412793A (zh) 苯並氮雜卓並環化合物鹽型、晶型及其應用
WO2023231996A1 (zh) 羟肟酸酯化合物及其盐的结晶形式与制备方法
WO2024067784A1 (zh) 双环类化合物的无定形、结晶固体及其制备方法
CN116554177B (zh) 一种含氮杂环化合物的盐型、晶型及其应用
JP7289017B2 (ja) ピロリジニルウレア誘導体の結晶及びその使用
TWI824626B (zh) Ripk1抑制劑的晶型及其酸式鹽和其酸式鹽的晶型
WO2018209667A1 (zh) 多环杂环化合物的晶型、其制备方法、应用及组合物
WO2023078440A1 (zh) 吡嗪类衍生物的盐的晶型及其制备方法
WO2024002353A1 (zh) 一种含氮桥杂环衍生物的可药用盐、晶型及其制备方法
WO2023025271A1 (zh) 吡嗪类衍生物的晶型及其制备方法
WO2024027825A1 (zh) 一种cdk抑制剂及其磷酸盐的多晶型
WO2023246854A1 (zh) 一种硼酸酯衍生物的结晶、其制备方法及用途
WO2021023271A1 (zh) 作为前列环素受体激动剂的化合物的晶型及其制备方法
WO2023246858A1 (zh) 一种硼酸酯衍生物的可药用盐、其结晶形式及用途
WO2023143112A1 (zh) 氮杂苯并八元环化合物的盐型、晶型及其应用
TW202404961A (zh) 苯并［ｃ］色滿化合物的可藥用鹽、其多晶型及用途
CN117466908A (zh) 腺苷受体抑制剂的晶体形式及其制备方法和用途
TW202333672A (zh) Ｒｏｃｋ抑制劑的鹽及鹽的晶型、組合物和藥物用途

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: 23862284

Country of ref document: EP

Kind code of ref document: A1