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WO2023011428A1 - Ripk1抑制剂的晶型及其酸式盐和其酸式盐的晶型 - Google Patents

Ripk1抑制剂的晶型及其酸式盐和其酸式盐的晶型 Download PDF

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WO2023011428A1
WO2023011428A1 PCT/CN2022/109562 CN2022109562W WO2023011428A1 WO 2023011428 A1 WO2023011428 A1 WO 2023011428A1 CN 2022109562 W CN2022109562 W CN 2022109562W WO 2023011428 A1 WO2023011428 A1 WO 2023011428A1
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compound
formula
crystal form
salt
ray powder
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PCT/CN2022/109562
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English (en)
French (fr)
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周福生
陶元志
赵金柱
兰炯
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劲方医药科技(上海)有限公司
浙江劲方药业有限公司
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Priority to EP22852140.7A priority Critical patent/EP4382528A1/en
Priority to US18/293,374 priority patent/US20240352040A1/en
Priority to CN202280053909.6A priority patent/CN117751120A/zh
Publication of WO2023011428A1 publication Critical patent/WO2023011428A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/23—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/24—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/22—Tricarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the invention relates to the field of medical technology, in particular to a crystal form of a RIPK1 inhibitor, an acid salt thereof and a crystal form of the acid salt thereof.
  • Receptor-interacting protein 1 (RIP1) kinase is a TKL family serine/threonine protein kinase involved in innate immune signaling.
  • RIP1 kinase is a RHIM domain-containing protein with an N-terminal kinase domain and a C-terminal death domain.
  • the RIP1 death domain mediates interactions with other death domain-containing proteins, including Fas and TNFR-1, TRAIL-R1 and TRAIL-R2, and TRADD, whereas the RHIM domain pair binds other RHIM domain-containing proteins Proteins such as TRIF, DAI and RIP3 are critical and achieve their numerous actions through these interactions.
  • RIP1 in cell signaling has been assessed in different conditions, including TLR3, TLR4, TRAIL, FAS, but is best understood in mediating signaling downstream of the death receptor TNFR1.
  • Engagement of TNFR by TNF results in oligomerization and the recruitment of multiple proteins, including linear K63-linked polyubiquitinated RIP1, TRAF2/5, TRADD, and cIAPs, to the cytoplasmic tail of the receptor.
  • This RIP1-dependent complex acts as a scaffolding protein (ie, kinase-independent), termed complex I, which provides a platform for pro-survival signaling through activation of the NF ⁇ B and MAP kinase pathways.
  • DISC death-inducing signaling complex
  • apoptosis is inhibited (eg, FADD/caspase 8 deletion, caspase inhibition, or viral infection)
  • apoptosis is inhibited (eg, FADD/caspase 8 deletion, caspase inhibition, or viral infection)
  • RIP3 can now enter this complex, phosphorylate it through RIP1, and initiate caspase-independent programmed necroptosis through MLKL and PGAM5 activation.
  • programmed necrosis (not to be confused with non-programmed passive necrosis) results in the release of danger-associated molecular patterns (DAMPs) from cells.
  • DAMPs danger-associated molecular patterns
  • RIP3 knockout mice in which RIP1-mediated necroptosis is completely blocked
  • Necrostatin-1 a tool inhibitor of RIP1 kinase activity with poor oral bioavailability
  • RIP1 Dysregulation of kinase-mediated programmed cell death has been implicated in various forms of inflammation.
  • RIP3 knockout mice have been shown to be resistant to inflammatory bowel disease (including ulcerative colitis and Crohn's disease), psoriasis, retinal detachment-induced photoreceptor necrosis, retinitis pigmentosa, bombesin-induced acute pancreatic Inflammation and sepsis/systemic inflammatory response syndrome are protective.
  • Necrostatin-1 has been shown to be effective in attenuating ischemic brain injury, retinal ischemia/reperfusion injury, Huntington's disease, renal ischemia-reperfusion injury, cisplatin-induced renal injury and traumatic brain injury.
  • Other diseases or conditions regulated at least in part by RIP1-dependent apoptosis, necrosis, or cytokine production include, hematological and solid organ malignancies, bacterial and viral infections (including but not limited to tuberculosis and influenza), and lysosomal storage disease (especially Gaucher disease).
  • a potent, selective, small molecule inhibitor of RIP1 kinase activity capable of blocking RIP1-dependent cell necrosis, thereby providing therapeutic effects for diseases or events associated with DAMPs, cell death, and/or inflammation.
  • the technical problem to be solved by the present invention is to overcome the defect that there are few types of RIP1 inhibitors in the prior art. Therefore, a crystal form of the RIPK1 inhibitor and its acid salt and the crystal form of the acid salt are provided.
  • the crystal form of the RIPK1 inhibitor of the present invention and its acid salt and the crystal form of the acid salt have the advantages of low hygroscopicity and good stability, and have a good prospect of being a drug.
  • the first aspect of the present invention provides a crystalline form A of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 10.94 ⁇ 0.2°, 16.43 ⁇ 0.2°, 19.12 ⁇ 0.2° and 19.81 ⁇ 0.2° There are diffraction peaks;
  • the crystal form A of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 21.25 ⁇ 0.2°, 22.32 ⁇ 0.2°, 27.55 ⁇ 0.2°, 20.23 ⁇ 0.2°, and 18.41 ⁇ 0.2°.
  • the crystal form A of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 18.13 ⁇ 0.2°, 33.21 ⁇ 0.2° , 17.86 ⁇ 0.2°, 23.47 ⁇ 0.2°, 26.91 ⁇ 0.2°, and 16.77 ⁇ 0.2°.
  • the crystal form A of the compound of formula I has an X-ray powder diffraction pattern represented by an angle of 2 ⁇ basically as shown in FIG. 1 .
  • the crystalline form A of the compound of formula I has a thermogravimetric analysis (TGA) weight loss of 0.5%-2% (such as 1.1%) at the initial heating to 175 ⁇ 5°C (the The percentage of weight loss mentioned is the percentage of the weight of the sample reduced to the weight of the sample before this weight loss).
  • TGA thermogravimetric analysis
  • the crystalline form A of the compound of formula I has an endothermic peak at 191.6 ⁇ 5°C and/or 240.5 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the compound of formula I are basically as shown in FIG. 2 .
  • the second aspect of the present invention also provides a crystal form B of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 27.64 ⁇ 0.2°, 24.48 ⁇ 0.2°, 3.76 ⁇ 0.2° and 19.30 ⁇ 0.2° There is a diffraction peak at °;
  • the crystal form B of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 16.11 ⁇ 0.2°, 18.48 ⁇ 0.2°, 21.23 ⁇ 0.2°, 17.80 ⁇ 0.2°, and 21.41 ⁇ 0.2°.
  • the crystal form B of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 17.01 ⁇ 0.2°, 28.03 ⁇ 0.2° , 21.96 ⁇ 0.2°, 22.66 ⁇ 0.2°, 30.78 ⁇ 0.2°, and 19.66 ⁇ 0.2°.
  • the crystal form B of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles basically as shown in FIG. 4 .
  • the crystalline form B of the compound of formula I has a weight loss of 1%-3% (for example, 2.2%) in the thermogravimetric analysis diagram at the initial heating to 200 ⁇ 5°C (the weight loss The percentage is the percentage of the weight of the sample reduced to the weight of the sample before this weight loss).
  • the crystalline form B of the compound of formula I has an endothermic peak at 240.1 ⁇ 5° C. in the differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form B of the compound of formula I are basically shown in FIG. 5 .
  • the third aspect of the present invention provides a crystalline form C of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 19.55 ⁇ 0.2°, 29.51 ⁇ 0.2°, 19.99 ⁇ 0.2° and 20.26 ⁇ 0.2° There are diffraction peaks;
  • the crystal form C of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 29.92 ⁇ 0.2°, 23.30 ⁇ 0.2°, 20.57 ⁇ 0.2°, 31.49 ⁇ 0.2°, and 10.11 ⁇ 0.2°.
  • the crystal form C of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 24.93 ⁇ 0.2°, 20.82 ⁇ 0.2° , 11.60 ⁇ 0.2°, 9.77 ⁇ 0.2°, 10.98 ⁇ 0.2° and 26.96 ⁇ 0.2°.
  • the crystal form C of the compound of formula I has an X-ray powder diffraction pattern represented by the angle of 2 ⁇ basically as shown in FIG. 53 .
  • the crystalline form C of the compound of formula I has a weight loss of 3%-4% (for example, 3.2%) in its thermogravimetric analysis diagram at the initial heating to 150 ⁇ 5°C (the weight loss The percentage is the percentage of the weight of the sample reduced to the weight of the sample before this weight loss).
  • the crystalline form C of the compound of formula I has endothermic peaks at one or more of 64.9 ⁇ 5°C, 200.1 ⁇ 5°C and 237.0 ⁇ 5°C in its differential scanning calorimetry .
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form C of the compound of formula I are basically as shown in FIG. 54 .
  • the fourth aspect of the present invention provides a pharmaceutically acceptable salt of the compound of formula I;
  • the pharmaceutically acceptable salt is a salt of the compound of formula I and an acid;
  • the acid is an inorganic acid or an organic acid;
  • the molar ratio of the compound of formula I to the acid is 1:(0.3-2), such as 1:0.3, 1:0.8, 1:0.9, 1:1, 1:1.1 , 1:1.3 or 1:2.
  • the inorganic acid is hydrochloric acid and/or sulfuric acid.
  • the organic acid is fumaric acid, maleic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, cyclamic acid, mucic acid, glycolic acid, malic acid and hippuric acid one or more.
  • the organic acid is one or more of p-toluenesulfonic acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid and cyclamic acid.
  • the organic acid is p-toluenesulfonic acid.
  • the pharmaceutically acceptable salt of the compound of formula I is any of the following pharmaceutically acceptable salts:
  • the pharmaceutically acceptable salts of the compounds of formula I can be prepared by conventional salt-forming reactions in the art.
  • the pharmaceutically acceptable salt of the compound of formula I can be prepared by the following method:
  • the molar ratio of the compound of formula I to hydrochloric acid is 1:2;
  • the molar ratio of the compound of formula I to sulfuric acid is 1:(1-2), for example 1:(1-1.3), for example 1:1, 1:1.1 or 1:2;
  • the molar ratio of the compound of formula I to citric acid is 1:1;
  • the molar ratio of the compound of formula I to maleic acid is 1:(0.5-1), for example 1:0.8;
  • the molar ratio of the compound of formula I to fumaric acid is 1:(0.5-1), for example 1:0.9;
  • the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.1-1), for example 1:(0.3-1), for example 1:0.3 or 1:1;
  • the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:(0.1-1), for example 1:0.9.
  • the molar ratio of the compound of formula I to cyclamic acid is 1:(0.1-1), for example 1:0.9.
  • the fifth aspect of the present invention provides a crystal form A of the hydrochloride salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 8.83 ⁇ 0.2°, 13.24 ⁇ 0.2°, 24.25 ⁇ 0.2° and 18.31 There are diffraction peaks at ⁇ 0.2°; the hydrochloride salt of the compound shown in formula I is as described above;
  • the crystal form A of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 26.66 ⁇ 0.2°, 22.21 ⁇ 0.2°, 4.39 ⁇ 0.2°, 31.19 ⁇ 0.2°, and 19.54 ⁇ 0.2°.
  • the crystal form A of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 35.77 ⁇ 0.2°, 19.71 ⁇ 0.2°, 27.3 ⁇ 0.2°, 32.11 ⁇ 0.2°, 28.38 ⁇ 0.2°, and 21.52 ⁇ 0.2°.
  • the crystal form A of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern represented by an angle of 2 ⁇ basically as shown in FIG. 7 .
  • the crystalline form A of the hydrochloride salt of the compound of formula I has a weight loss of 4%-5.5% (for example, 4.8%) (The weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).
  • the crystalline form A of the hydrochloride salt of the compound of formula I has an endothermic peak at 156.8 ⁇ 5° C. in its differential scanning calorimetry diagram.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the hydrochloride salt of the compound of formula I are basically shown in FIG. 8 .
  • the sixth aspect of the present invention provides a crystal form A of the citrate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 17.87 ⁇ 0.2°, 14.97 ⁇ 0.2°, 17.45 ⁇ 0.2° and 17.01° There are diffraction peaks at ⁇ 0.2°; the citrate of the compound shown in formula I is as described above;
  • the crystal form A of the citrate salt of the compound of formula I wherein, the molar ratio of the compound of formula I to citric acid is 1:1.
  • the crystal form A of the citrate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 4.45 ⁇ 0.2°, 11.14 ⁇ 0.2°, 19.08 ⁇ 0.2°, 8.91 ⁇ 0.2°, and 13.38 ⁇ 0.2°.
  • the crystal form A of the citrate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 21.23 ⁇ 0.2°, 25.56 ⁇ 0.2°, 21.00 ⁇ 0.2°, 24.25 ⁇ 0.2°, 28.48 ⁇ 0.2°, and 29.9 ⁇ 0.2°.
  • the crystal form A of the citrate salt of the compound of formula I has an X-ray powder diffraction pattern represented by an angle of 2 ⁇ basically as shown in FIG. 19 .
  • the crystalline form A of the citrate salt of the compound of formula I has a weight loss of 0.5%-2% (for example, 1.1%) (The weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).
  • the crystalline form A of the citrate salt of the compound of formula I has an endothermic peak at 166.4 ⁇ 5° C. in its differential scanning calorimetry diagram.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the citrate salt of the compound of formula I are basically shown in FIG. 20 .
  • the sixth aspect of the present invention provides a crystalline form A of the maleate salt of a compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 16.47 ⁇ 0.2°, 4.58 ⁇ 0.2°, 10.97 ⁇ 0.2° and There is a diffraction peak at 22.91 ⁇ 0.2°; the maleate of the compound shown in formula I is as described above;
  • the crystalline form A of the maleate salt of the compound of formula I wherein, the molar ratio of the compound of formula I to maleic acid is 1:(0.5-1), for example 1:0.8.
  • the crystalline form A of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 18.2 ⁇ 0.2°, 19.87 ⁇ 0.2°, 24.64 ⁇ 0.2°, 22.35 ⁇ 0.2°, and 20.26 ⁇ 0.2°.
  • the crystal form A of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 19.56 ⁇ 0.2° , 28.43 ⁇ 0.2°, 26.52 ⁇ 0.2°, 15.04 ⁇ 0.2°, 27.52 ⁇ 0.2°, and 18.86 ⁇ 0.2°.
  • the X-ray powder diffraction pattern represented by 2 ⁇ angle of the maleate salt crystal form A of the compound of formula I is basically as shown in FIG. 22 .
  • the crystalline form A of the maleate salt of the compound of formula I has a thermogravimetric analysis figure of 3%-4% (for example, 3.3%) weight loss at 150 ⁇ 5°C, and a weight loss of 3%-4% (for example, 3.3%) at 150°C to The weight loss at 250°C is 10%-15% (eg 13.6%).
  • the crystalline form A of the maleate salt of the compound of formula I has an endothermic peak at 176.0 ⁇ 5°C and/or 210.7 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the maleate salt of the compound of formula I are basically shown in FIG. 23 .
  • the seventh aspect of the present invention provides a crystalline form A of the fumarate salt of the above-mentioned compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 28.83 ⁇ 0.2°, 5.03 ⁇ 0.2°, 16.15 ⁇ 0.2 There are diffraction peaks at ° and 13.11 ⁇ 0.2 °; the fumarate of the compound shown in formula I is as described above;
  • the crystalline form A of the fumarate salt of the compound of formula I wherein, the molar ratio of the compound of formula I to fumaric acid is 1:(0.5-1), for example 1:0.9.
  • the crystalline form A of the fumarate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 22.86 ⁇ 0.2°, 12.39 ⁇ 0.2°, 29.44 ⁇ 0.2°, 17.78 ⁇ 0.2°, and 9.69 ⁇ 0.2°.
  • the crystalline form A of the fumarate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 19.82 ⁇ 0.2°, 10.73 ⁇ 0.2°, 3.25 ⁇ 0.2°, 17.09 ⁇ 0.2°, 6.54 ⁇ 0.2°, and 11.22 ⁇ 0.2°.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the fumarate salt crystal form A of the compound of formula I is basically as shown in FIG. 25 .
  • the crystalline form A of the fumarate salt of the compound of formula I has a thermogravimetric analysis figure with a weight loss of 1%-3% (such as 1.8%) at the initial heating to 150 ⁇ 5°C. (The percentage of described weight loss is the percentage of the weight that sample reduces and the weight of sample before this weight loss).
  • the crystalline form A of the fumarate salt of the compound of formula I has a differential scanning calorimetry at 182.5 ⁇ 5°C, 192.9 ⁇ 5°C, 211.8 ⁇ 5°C and 219.2 ⁇ 5°C There are endothermic peaks at one or more places and/or exothermic peaks at one or more places at 123.0 ⁇ 5°C, 184.8 ⁇ 5°C and 196.9 ⁇ 5°C.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the fumarate salt of the compound of formula I are basically shown in FIG. 26 .
  • the eighth aspect of the present invention provides a crystal form A of the mesylate salt of the above-mentioned compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 5.76 ⁇ 0.2°, 14.75 ⁇ 0.2°, 5.11 ⁇ 0.2 There are diffraction peaks at °, 17.54 ⁇ 0.2 °; the mesylate of the compound shown in formula I is as described above;
  • the crystal form A of the mesylate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 20.29 ⁇ 0.2°, 20.49 ⁇ 0.2°, 16.84 ⁇ 0.2°, 7.51 ⁇ 0.2°, and 16.51 ⁇ 0.2°.
  • the crystal form A of the mesylate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 21.72 ⁇ 0.2° , 19.60 ⁇ 0.2°, 15.51 ⁇ 0.2°, 18.43 ⁇ 0.2°, 15.86 ⁇ 0.2°, and 12.84 ⁇ 0.2°.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form A of the mesylate salt of the compound of formula I is basically as shown in FIG. 28 .
  • the crystalline form A of the mesylate salt of the compound of formula I has a thermogravimetric analysis chart with a weight loss of 2%-4% (such as 2.9%) at the initial heating to 110 ⁇ 5°C. (The percentage of described weight loss is the percentage of the weight that sample reduces and the weight of sample before this weight loss).
  • the crystalline form A of the mesylate salt of the compound of formula I has an endothermic peak at 92.5 ⁇ 5°C and/or 138.6 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the mesylate salt of the compound of formula I are basically shown in FIG. 29 .
  • the ninth aspect of the present invention provides a crystal form B of the mesylate salt of the above-mentioned compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 18.83 ⁇ 0.2°, 16.51 ⁇ 0.2°, 25.51 ⁇ 0.2 There are diffraction peaks at ° and 10.98 ⁇ 0.2 °; the mesylate of the compound shown in formula I is as described above;
  • the crystal form B of the mesylate salt of the compound of formula I wherein, the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.1-1), for example 1:1.
  • the crystal form B of the mesylate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 22.32 ⁇ 0.2°, 5.49 ⁇ 0.2°, 20.34 ⁇ 0.2°, 26.34 ⁇ 0.2°, and 16.94 ⁇ 0.2°.
  • the crystal form B of the mesylate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 19.48 ⁇ 0.2° , 21.35 ⁇ 0.2°, 15.06 ⁇ 0.2°, 19.93 ⁇ 0.2°, 12.75 ⁇ 0.2°, and 18.05 ⁇ 0.2°.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form B of the mesylate salt of the compound of formula I is basically as shown in FIG. 31 .
  • the crystalline form B of the mesylate salt of the compound of formula I has a thermogravimetric analysis chart with a weight loss of 2%-4% (such as 2.8%) at the initial heating to 150 ⁇ 5°C. (The percentage of described weight loss is the percentage of the weight that sample reduces and the weight of sample before this weight loss).
  • the crystalline form B of the mesylate salt of the compound of formula I has an endothermic peak at 171.3 ⁇ 5°C and/or 194.7 ⁇ 5°C in its differential scanning calorimetry diagram.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form B of the mesylate salt of the compound of formula I are basically as shown in FIG. 32 .
  • the tenth aspect of the present invention provides a crystal form C of the mesylate salt of the above-mentioned compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 19.57 ⁇ 0.2°, 19.98 ⁇ 0.2°, 16.50 ⁇ 0.2 ° and 18.20 ⁇ 0.2° have diffraction peaks;
  • the crystal form C of the mesylate salt of the compound of formula I wherein, the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.1-1), for example 1:0.3.
  • the crystal form C of the mesylate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 20.26 ⁇ 0.2°, 23.30 ⁇ 0.2°, 29.52 ⁇ 0.2°, 10.99 ⁇ 0.2°, and 26.94 ⁇ 0.2°.
  • the crystal form C of the mesylate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 22.36 ⁇ 0.2° , 20.86 ⁇ 0.2°, 24.62 ⁇ 0.2°, 24.92 ⁇ 0.2°, 27.41 ⁇ 0.2°, and 18.45 ⁇ 0.2°.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form C of the mesylate salt of the compound of formula I is basically as shown in FIG. 34 .
  • the crystalline form C of the mesylate salt of the compound of formula I has a thermogravimetric analysis chart with a weight loss of 4%-6% (for example, 4.9%) at the initial heating to 150 ⁇ 5°C. (The percentage of described weight loss is the percentage of the weight that sample reduces and the weight of sample before this weight loss).
  • the crystal form C of the mesylate salt of the compound of formula I has a differential scanning calorimetry at one or more of 108.2 ⁇ 5°C, 181.9 ⁇ 5°C and 233.2 ⁇ 5°C There is an endothermic peak.
  • the differential scanning calorimetry and thermogravimetric analysis diagrams of the crystal form C of the mesylate salt of the compound of formula I are basically shown in FIG. 35 .
  • the eleventh aspect of the present invention provides a crystal form A of the p-toluenesulfonate salt of the compound of formula I above, and its X-ray powder diffraction pattern represented by 2 ⁇ angle is at 5.80 ⁇ 0.2°, 19.70 ⁇ 0.2°, 22.36 There are diffraction peaks at ⁇ 0.2° and 11.57 ⁇ 0.2°; the p-toluenesulfonate of the compound shown in formula I is as described above;
  • the crystal form A of the p-toluenesulfonic acid salt of the compound of formula I wherein, the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:(0.1-1), for example 1:0.9 .
  • the crystal form A of the p-toluenesulfonate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles : 27.22 ⁇ 0.2°, 14.81 ⁇ 0.2°, 16.83 ⁇ 0.2°, 27.91 ⁇ 0.2° and 15.18 ⁇ 0.2°.
  • the crystal form A of the p-toluenesulfonate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 19.21 ⁇ 0.2 °, 18.16 ⁇ 0.2°, 13.07 ⁇ 0.2°, 30.66 ⁇ 0.2°, 32.47 ⁇ 0.2°, and 18.47 ⁇ 0.2°.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form A of the p-toluenesulfonate salt of the compound of formula I is basically as shown in FIG. 37 .
  • the crystalline form A of the p-toluenesulfonate salt of the compound of formula I has a thermogravimetric analysis chart with a weight loss of 1%-3% (such as 1.6% at the initial heating to 150 ⁇ 5°C) ) (the percentage of described weight loss is the percentage of the weight that sample reduces and the weight of sample before this weight loss).
  • the crystalline form A of the p-toluenesulfonate salt of the compound of formula I has an endothermic peak at 205.6 ⁇ 5° C. in its differential scanning calorimetry diagram.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystalline form A of the p-toluenesulfonate salt of the compound of formula I are basically shown in FIG. 38 .
  • the twelfth aspect of the present invention provides a crystal form A of the cyclamate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 6.41 ⁇ 0.2°, 16.47 ⁇ 0.2°, 18.57 ⁇ 0.2° and 10.95 ⁇ 0.2 ° place has a diffraction peak; the described cyclamate of the compound shown in formula I is as described above;
  • the crystal form A of the cyclamate salt of the compound of formula I wherein, the molar ratio of the compound of formula I to cyclamate is 1:(0.1-1), for example 1:0.9.
  • the crystal form A of the cyclamate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 18.16 ⁇ 0.2°, 19.58 ⁇ 0.2°, 20.24 ⁇ 0.2°, 22.33 ⁇ 0.2°, and 23.27 ⁇ 0.2°.
  • the crystal form A of the cyclamate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 24.63 ⁇ 0.2°, 26.94 ⁇ 0.2°, 27.39 ⁇ 0.2°, 21.39 ⁇ 0.2°, 20.83 ⁇ 0.2°, and 24.93 ⁇ 0.2°.
  • the crystalline form A of the cyclamate salt of the compound of formula I has an X-ray powder diffraction pattern represented by an angle of 2 ⁇ basically as shown in FIG. 40 .
  • the crystalline form A of the cyclamate salt of the compound of formula I has a thermogravimetric analysis chart with a weight loss of 0.1%-2% (for example, 0.7%) at the initial heating to 150 ⁇ 5°C. (The percentage of described weight loss is the percentage of the weight that sample reduces and the weight of sample before this weight loss).
  • the crystalline form A of the cyclamate salt of the compound of formula I has an endothermic peak at 202.3 ⁇ 5°C and/or 231.3 ⁇ 5°C in its differential scanning calorimetry; and/or Or there is an exothermic peak at 118.2 ⁇ 5°C and/or 205.4 ⁇ 5°C.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the cyclamate salt of the compound of formula I are basically shown in FIG. 41 .
  • the thirteenth aspect of the present invention provides a crystal form A of the sulfate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 14.60 ⁇ 0.2°, 11.67 ⁇ 0.2°, 21.09 ⁇ 0.2° and 13.32° There are diffraction peaks at ⁇ 0.2°; the sulfate salt of the compound shown in formula I is as described above;
  • the crystal form A of the sulfate salt of the compound of formula I wherein the molar ratio of the compound of formula I to sulfuric acid is 1: (1-2), such as 1: (1-1.3), 1 : (1-1.1) or 1:1.
  • the crystal form A of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 17.38 ⁇ 0.2°, 21.65 ⁇ 0.2°, 26.08 ⁇ 0.2°, 23.45 ⁇ 0.2°, and 26.44 ⁇ 0.2°.
  • the crystal form A of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 15.76 ⁇ 0.2°, 8.75 ⁇ 0.2°, 37.29 ⁇ 0.2°, 24.42 ⁇ 0.2°, 22.08 ⁇ 0.2°, and 29.39 ⁇ 0.2°.
  • the crystal form A of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, which is basically shown in FIG. 10 .
  • the crystal form A of the sulfate salt of the compound of formula I has a weight loss of 2%-4% (for example, 3.4%) in the thermogravimetric analysis diagram at the initial heating to 175 ⁇ 5°C (the The percentage of weight loss mentioned is the percentage of the weight of the sample reduced to the weight of the sample before this weight loss).
  • the crystalline form A of the sulfate salt of the compound of formula I has three endothermic peaks at 70.6 ⁇ 5°C, 123.3 ⁇ 5°C and 205.1 ⁇ 5°C in the differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the sulfate salt of the compound of formula I are basically shown in FIG. 11 .
  • the fourteenth aspect of the present invention provides a crystal form D of the sulfate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 14.60 ⁇ 0.2°, 25.31 ⁇ 0.2°, 19.85 ⁇ 0.2° and 20.07° There are diffraction peaks at ⁇ 0.2°; the sulfate salt of the compound shown in formula I is as described above;
  • the crystal form D of the sulfate salt of the compound of formula I wherein the molar ratio of the compound of formula I to sulfuric acid is 1: (1-2), such as 1: (1-1.3), 1 : (1-1.1), 1:1 or 1:1.1.
  • the crystal form D of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 21.06 ⁇ 0.2°, 19.31 ⁇ 0.2°, 18.15 ⁇ 0.2°, 13.18 ⁇ 0.2°, and 6.59 ⁇ 0.2°.
  • the crystal form D of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 15.02 ⁇ 0.2°, 31.39 ⁇ 0.2°, 22.14 ⁇ 0.2°, 24.63 ⁇ 0.2°, 25.63 ⁇ 0.2°, and 9.83 ⁇ 0.2°.
  • the crystal form D of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, basically as shown in FIG. 43 .
  • the crystalline form D of the sulfate salt of the compound of formula I has a thermogravimetric analysis chart with a weight loss of 1%-4% (such as 3%) at the initial heating to 125 ⁇ 5°C (the The percentage of weight loss mentioned is the percentage of the weight of the sample reduced to the weight of the sample before this weight loss).
  • the crystalline form D of the sulfate salt of the compound of formula I has three endothermic peaks at 111.9 ⁇ 5°C, 153.2 ⁇ 5°C and 197.7 ⁇ 5°C in the differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form D of the sulfate salt of the compound of formula I are basically as shown in FIG. 44 .
  • the fifteenth aspect of the present invention provides a crystalline form I of the sulfate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 12.92 ⁇ 0.2°, 26.90 ⁇ 0.2°, 15.86 ⁇ 0.2° and 23.02° There are diffraction peaks at ⁇ 0.2°; the sulfate salt of the compound shown in formula I is as described above;
  • the crystal form I of the sulfate salt of the compound of formula I wherein the molar ratio of the compound of formula I to sulfuric acid is 1: (1-2), such as 1: (1-1.3), 1 : (1-1.1) or 1:1.
  • the crystal form I of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 21.09 ⁇ 0.2°, 14.99 ⁇ 0.2°, 17.26 ⁇ 0.2°, 19.34 ⁇ 0.2°, and 24.61 ⁇ 0.2°.
  • the crystal form I of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 20.79 ⁇ 0.2°, 21.75 ⁇ 0.2°, 18.31 ⁇ 0.2°, 18.47 ⁇ 0.2°, 21.61 ⁇ 0.2°, and 19.75 ⁇ 0.2°.
  • the crystal form I of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by the angle of 2 ⁇ basically as shown in FIG. 46 .
  • the sixteenth aspect of the present invention provides a crystal form B of the sulfate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 25.15 ⁇ 0.2°, 18.71 ⁇ 0.2°, 3.13 ⁇ 0.2° and 23.28 There are diffraction peaks at ⁇ 0.2°; the sulfate salt of the compound shown in formula I is as described above;
  • the crystal form B of the sulfate salt of the compound of formula I wherein the molar ratio of the compound of formula I to sulfuric acid is 1: (1-2), such as 1: (1-1.3), 1 : (1-1.1), 1:1 or 1:1.1.
  • the crystal form B of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 20.27 ⁇ 0.2°, 24.82 ⁇ 0.2°, 15.17 ⁇ 0.2°, 14.82 ⁇ 0.2°, and 23.67 ⁇ 0.2°.
  • the crystal form B of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 21.03 ⁇ 0.2°, 19.05 ⁇ 0.2°, 18.34 ⁇ 0.2°, 12.20 ⁇ 0.2°, 24.18 ⁇ 0.2°, and 17.21 ⁇ 0.2°.
  • the crystal form B of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, which is basically as shown in FIG. 13 .
  • the crystal form B of the sulfate salt of the compound of formula I has a weight loss of 2%-4% (for example, 2.9%) in its thermogravimetric analysis chart at the initial heating to 150 ⁇ 5°C (the The percentage of weight loss mentioned is the percentage of the weight of the sample reduced to the weight of the sample before this weight loss).
  • the crystalline form B of the sulfate salt of the compound of formula I has three endothermic peaks at 77.9 ⁇ 5°C, 118.8 ⁇ 5°C and 196.8 ⁇ 5°C in the differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis chart of the crystal form B of the sulfate salt of the compound of formula I are basically shown in FIG. 14 .
  • the seventeenth aspect of the present invention provides a crystal form C of the sulfate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 5.55 ⁇ 0.2°, 14.72 ⁇ 0.2°, 16.75 ⁇ 0.2° and 27.35 There are diffraction peaks at ⁇ 0.2°; the sulfate salt of the compound shown in formula I is as described above;
  • the sulfate salt of the compound of formula I in the crystal form C of the sulfate salt of the compound of formula I, is a hydrate, and the molar ratio of the compound of formula I to water is 1:( 1-2), such as 1:(1-1.3), another example is 1:(1-1.1), and another example is 1:1.
  • the crystal form C of the sulfate salt of the compound of formula I wherein the molar ratio of the compound of formula I to sulfuric acid is 1:(1-2), such as 1:(1-1.3), 1 :(1-1.1) or 1:1.
  • the sulfate salt of the compound shown in formula I in the crystal form C of the sulfate salt of the compound shown in formula I, is monohydrate, and the sulfate salt of the compound shown in formula I The molar ratio of compound to sulphate shown is 1:1.
  • the crystal form C of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 22.92 ⁇ 0.2°, 20.90 ⁇ 0.2°, 21.13 ⁇ 0.2°, 19.63 ⁇ 0.2°, and 20.37 ⁇ 0.2°.
  • the crystal form C of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 20.72 ⁇ 0.2°, 12.52 ⁇ 0.2°, 19.45 ⁇ 0.2°, 19.96 ⁇ 0.2°, 25.16 ⁇ 0.2°, and 12.75 ⁇ 0.2°.
  • the crystal form C of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by the angle of 2 ⁇ basically as shown in FIG. 16 .
  • the crystal form C of the sulfate salt of the compound of formula I has a weight loss of 3%-4.5% in its thermogravimetric analysis figure when heated to 175 ⁇ 5°C; for example, when heated to 175 ⁇ 5°C It has a weight loss of 3.9% at 5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).
  • the crystalline form C of the sulfate salt of the compound of formula I has three endothermic peaks at 129.2 ⁇ 5°C, 152.8 ⁇ 5°C and 200.2 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form C of the sulfate salt of the compound of formula I are basically shown in FIG. 17 .
  • the crystal form C of the sulfate salt of the compound of formula I has a dynamic moisture adsorption spectrum basically as shown in Figure 55
  • the eighteenth aspect of the present invention provides a crystal form E of the sulfate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 16.39 ⁇ 0.2°, 12.75 ⁇ 0.2°, 14.32 ⁇ 0.2° and 20.28 There are diffraction peaks at ⁇ 0.2°; the sulfate salt of the compound shown in formula I is as described above;
  • the crystal form E of the sulfate salt of the compound of formula I wherein the molar ratio of the compound of formula I to sulfuric acid is 1: (1-2), such as 1: (1-1.3), and For example 1:1.3.
  • the crystal form E of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 17.76 ⁇ 0.2°, 23.45 ⁇ 0.2°, 26.20 ⁇ 0.2°, 17.47 ⁇ 0.2° and 19.76 ⁇ 0.2°;
  • the crystal form E of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 11.46 ⁇ 0.2°, 25.88 ⁇ 0.2°, 21.90 ⁇ 0.2°, 23.00 ⁇ 0.2°, 20.79 ⁇ 0.2°, and 18.25 ⁇ 0.2°.
  • the crystal form E of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles basically as shown in FIG. 47 .
  • the crystal form E of the sulfate salt of the compound of formula I has a weight loss of 5%-6.5% (such as 5.9%) when its thermogravimetric analysis chart is initially heated to 150 ⁇ 5°C (The weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).
  • the crystalline form E of the sulfate salt of the compound of formula I has three endothermic peaks at 82.2 ⁇ 5°C, 138.6 ⁇ 5°C and 205.4 ⁇ 5°C in the differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form E of the sulfate salt of the compound of formula I are basically shown in FIG. 48 .
  • the nineteenth aspect of the present invention provides a crystalline form F of the sulfate salt of the compound of formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 24.91 ⁇ 0.2°, 20.60 ⁇ 0.2°, 27.62 ⁇ 0.2° and 16.04 ⁇ 0.2° has a diffraction peak; the sulfate salt of the compound shown in formula I is as described above;
  • the crystalline form F of the sulfate salt of the compound of formula I wherein the molar ratio of the compound of formula I to sulfuric acid is 1: (1-2), such as 1: (1-1.3), and For example 1:1.1.
  • the crystal form F of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and there are diffraction peaks at one or more of the following 2 ⁇ angles: 24.26 ⁇ 0.2°, 24.14 ⁇ 0.2°, 18.63 ⁇ 0.2°, 17.01 ⁇ 0.2° and 21.53 ⁇ 0.2°;
  • the crystal form F of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 23.10 ⁇ 0.2°, 19.94 ⁇ 0.2°, 19.73 ⁇ 0.2°, 15.29 ⁇ 0.2°, 28.29 ⁇ 0.2°, and 20.12 ⁇ 0.2°.
  • the crystal form F of the sulfate salt of the compound of formula I has an X-ray powder diffraction pattern represented by 2 ⁇ angles substantially as shown in FIG. 50 .
  • the crystalline form F of the sulfate salt of the compound of formula I has a thermogravimetric analysis chart with a weight loss of 5%-7% (such as 6.4%) at the initial heating to 160°C. When heated to 225°C, the weight loss is 6%-8% (for example, 6.9%) (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).
  • the crystalline form F of the sulfate salt of the compound of formula I has two endothermic peaks at 123.6 ⁇ 5°C and 185.2 ⁇ 5°C in its differential scanning calorimetry, and two endothermic peaks at 206.0 ⁇ 5°C. There is an exothermic peak at °C.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form F of the sulfate salt of the compound of formula I are basically shown in FIG. 51 .
  • the crystalline form of the RIPK1 inhibitor of the present invention and the pharmaceutically acceptable salt thereof and the preparation method of the crystalline form of the pharmaceutically acceptable salt thereof can be obtained by many methods as known in the art.
  • the preparation method of the sulfate polymorph including but not limited to the addition of anti-solvent, anti-anti-solvent addition, gas-solid diffusion, gas-liquid infiltration, suspension stirring, slow volatilization, circulation heating and cooling suspension stirring, polymer induction, Grinding and other methods are used to crystallize the sulfate salt sample of the compound of formula I.
  • Addition of anti-solvent Weigh the starting sample of sulfate, dissolve it with a good solvent, add anti-solvent to the clear solution, and stir while adding dropwise until solid precipitates, if no solid precipitates after adding 4.5mL of anti-solvent, stop . A solid was separated by centrifugation and subjected to XRPD testing. Wherein, the volume-to-mass ratio of the good solvent to the initial sulfate sample is 5 to 75 times the amount.
  • Anti-anti-solvent addition Weigh the initial sulfate sample, dissolve it in a good solvent, add the clear solution to the anti-solvent, and stir while adding it dropwise. A solid was separated by centrifugation and subjected to XRPD testing. Wherein, the volume-to-mass ratio of the good solvent to the initial sulfate sample is 5 to 75 times the amount.
  • Suspension and stirring at room temperature Weigh the initial sulfate sample, add solvent, and place the obtained suspension at room temperature for about 5 days under magnetic stirring ( ⁇ 750rpm), centrifuge to separate the solid, and perform XRPD test. Wherein, the volume-mass ratio of the solvent to the sulfate starting sample is 25-50 times.
  • Suspension stirring at 50°C Weigh the initial sulfate sample, add solvent, place the obtained suspension at 50°C under magnetic stirring ( ⁇ 750rpm) for about 3 days, centrifuge the solid and perform XRPD test. Wherein, the volume-to-mass ratio of the solvent to the sulfate starting sample is 30 times the amount.
  • Gas-solid diffusion Weigh the initial sulfate sample into a 3mL vial, add solvent into a 20mL vial, place the 3mL vial in a 20mL vial, and then seal the 20mL vial. After standing at room temperature for ⁇ 7 days, the solid was collected and tested by XRPD. Wherein, the volume-to-mass ratio of the solvent to the sulfate starting sample is 200 times the amount.
  • Gas-liquid diffusion Weigh the initial sulfate sample (20mg) into a 3mL vial, use 0.05-2.2mL solvent to obtain a clear solution, filter the filtrate and transfer it to a 3mL vial, and add about 3mL of anti-solvent to another 20mL vial , place the 3mL vial containing the filtrate open on the 20mL vial, seal the 20mL vial and let stand at room temperature. When solid precipitation was observed, the solid was collected and subjected to XRPD testing.
  • 50-5°C cycle heating and cooling suspension stirring Weigh the initial sulfate sample, add solvent, and stir magnetically ( ⁇ 750rpm) at 50°C for 2 hours. Cool down to 5°C at a rate of 0.1°C/min, and stir at 5°C for 0.5 hours; then raise the temperature to 50°C at a rate of 0.1°C/min, and stir at 50°C for 0.5 hours. After repeating the above steps once, the temperature was lowered to 5°C at a rate of 0.1°C/min and kept at 5°C. Collect the solids for XRPD. Wherein, the volume-to-mass ratio of the solvent to the sulfate starting sample is 25 times the amount.
  • Polymer induction Weigh about 20 mg of each starting sulfate sample into a 3 mL vial, use ⁇ 2.0 mL of solvent to dissolve the solid, add about 2 mg of mixed polymer, and seal the filtrate container with a parafilm Prick 3 to 5 small holes on the vial, place it at room temperature to evaporate slowly, collect the obtained solid and perform XRPD test.
  • mixed high polymer is mixed high polymer A and mixed high polymer B;
  • Mixed high polymer A is polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose and Methyl cellulose (mixed in equal mass),
  • mixed polymer B is polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose (mixed in equal mass).
  • solvents include but are not limited to the solvents listed below, such as alcohols, halogenated hydrocarbons, nitriles, ketones, ethers, sulfoxides, amides, lipids, water, alkanes, aromatics and others their mixed solvents.
  • Alcohols are preferably methanol, ethanol, propanol, isopropanol, butanol; halogenated hydrocarbons are preferably dichloromethane, chloroform; nitriles are preferably acetonitrile.
  • Ketones are preferably acetone, 2-butanone, methyl isobutyl ketone, N-methylpyrrolidone; ethers are preferably methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 1,4- Dioxane, anisole; dimethyl sulfoxide is preferred for sulfoxides; N, N-dimethylformamide, N, N-dimethylacetamide is preferred for amides; ethyl acetate, acetic acid are preferred for lipids Isopropyl ester; alkyl group is preferably n-heptane; aromatic group is preferably toluene, xylene.
  • the twenty-second aspect of the present invention provides a method for preparing the crystal form A of the sulfate salt of the compound of formula I above, which is method a or method b;
  • Method a comprising the steps of: crystallizing the compound of formula I and sulfuric acid in methanol at room temperature to obtain crystal form A of the sulfate salt of the compound of formula I;
  • Method b comprising the steps of: crystallizing the sulfate salt of the above-mentioned compound of formula I in a solvent to obtain crystal form A of the sulfate salt of the compound of formula I;
  • the solvent is C 1-3 alcohol solvent-2 - Methyltetrahydrofuran.
  • the compound of formula I is crystal form A of the compound of formula I.
  • the sulfate salt of the compound of formula I is crystal form C of the sulfate salt of the compound of formula I.
  • the crystallization preferably includes the following steps: dissolving the sulfate salt of the compound of formula I in the C 1-3 alcohol solvent to obtain a mixed solution, adding (For example, the addition method is dropwise) 2-methyltetrahydrofuran (ie anti-solvent addition).
  • the C 1-3 alcohol solvent in the described C 1-3 alcohol solvent-2-methyltetrahydrofuran is preferably methanol, ethanol and iso One or more of propanols, such as methanol.
  • the amount of the C 1-3 alcohol solvent is not specifically limited, and the sulfate salt of the compound of formula I forms a clear solution in the C 1-3 alcohol solvent as a standard.
  • the 2-methyltetrahydrofuran may not be specifically limited, and the mixed solution and 2-methyltetrahydrofuran form a clear solution as a standard.
  • the crystallization preferably includes the following steps: suspending and stirring the compound of formula I and sulfuric acid (for example, the molar ratio of the compound of formula I to sulfuric acid is 1:1) in the methanol for crystallization (i.e. suspension stirring).
  • the crystallization method can be crystallization under stirring (for example, suspension stirring).
  • separation can be carried out according to conventional operating methods in the art, such as centrifugation or filtration.
  • the twenty-third aspect of the present invention provides a crystal form A of the sulfate salt of the compound of formula I prepared according to the preparation method of the crystal form A of the sulfate salt of the compound of formula I.
  • the twenty-fourth aspect of the present invention provides a method for preparing the crystal form C of the sulfate salt of the compound of formula I above, which is method 1 or 2:
  • Method 1 it comprises the steps of: dissolving the compound of formula I in a nitrile solvent with sulfuric acid aqueous solution and then cooling to obtain the crystal form C of the sulfate salt of the compound of formula I;
  • Method 2 it includes the following steps: crystallize the compound of formula I and sulfuric acid in a water-nitrile solvent at room temperature to obtain crystal form C of the sulfate salt of the compound of formula I.
  • the compound of formula I is the crystal form A of the compound of formula I mentioned above.
  • the molar ratio of the compound of formula I to sulfuric acid is 1:(1-2) (eg 1:(1-1.1)).
  • the nitrile solvent in the water-nitrile solvent is preferably acetonitrile.
  • the nitrile solvent is preferably acetonitrile.
  • the mass volume ratio of the compound of formula I to the nitrile solvent is preferably 120-20 mg/ml, such as 100-40 mg/ml.
  • separation can be carried out according to conventional operating methods in the art, such as centrifugation or filtration.
  • the twenty-fifth aspect of the present invention provides a crystal form C of the sulfate salt of the compound of formula I prepared according to the preparation method of the crystal form C of the sulfate salt of the compound of formula I.
  • the twenty-sixth aspect of the present invention provides a method for preparing crystal form D of the sulfate salt of the compound of formula I, which comprises the steps of: forming a suspension of the sulfate salt of the compound of formula I in propanol and performing crystallization (50 °C suspension and stirring) to obtain the crystal form D of the sulfate salt of the compound of formula I.
  • the sulfate salt of the compound of formula I is crystal form C of the sulfate salt of the compound of formula I.
  • the propanol is preferably n-propanol and/or isopropanol, such as n-propanol.
  • the mass volume ratio of the sulfate salt of the compound of formula I to the propanol is preferably 25-40 mg/ml, for example 33.3 mg/ml.
  • separation can be carried out according to conventional operating methods in the art, such as centrifugation or filtration.
  • the twenty-seventh aspect of the present invention provides a crystal form D of the sulfate salt of the compound of formula I prepared according to the above-mentioned preparation method of the crystal form D of the sulfate salt of the compound of formula I.
  • the twenty-eighth aspect of the present invention provides a method for preparing the crystal form E of the sulfate salt of the compound of formula I, which comprises the steps of: monohydrate the sulfate salt of the compound of formula I (such as monohydrate of the sulfate salt of the compound of formula I Form C) forms a suspension in a mixed solvent of ester solvent-water (for example, a mixed solvent of ethyl acetate-water, the volume ratio of the two is 19:1) and performs crystal transformation (suspension and stirring at 50°C) to obtain formula I Form E of the sulfate salt of the compound.
  • a mixed solvent of ester solvent-water for example, a mixed solvent of ethyl acetate-water, the volume ratio of the two is 19:1
  • the twenty-ninth aspect of the present invention provides a crystal form E of the sulfate salt of the compound of formula I prepared according to the preparation method of the crystal form E of the sulfate salt of the compound of formula I.
  • the thirtieth aspect of the present invention provides a method for preparing the crystal form F of the sulfate salt of the compound of formula I, which comprises the steps of: preparing the sulfate monohydrate of the compound of formula I (for example, the sulfate monohydrate of the compound of formula I Form C) is volatilized in a sulfoxide solvent (such as dimethyl sulfoxide (DMSO)) to obtain the crystalline form E of the sulfate salt of the compound of formula I.
  • a sulfoxide solvent such as dimethyl sulfoxide (DMSO)
  • the thirty-first aspect of the present invention provides a crystal form F of the sulfate salt of the compound of formula I prepared according to the preparation method of the crystal form F of the sulfate salt of the compound of formula I.
  • the thirty-second aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective dose of substance A and a pharmaceutically acceptable excipient; said substance A is the crystal form of the above-mentioned compound of formula I (the above-mentioned Crystal form A of the compound of formula I, crystal form B of the compound of formula I above, crystal form C of the compound of formula I above, ), a pharmaceutically acceptable salt of the compound of formula I above or a pharmaceutically acceptable salt of the compound of formula I above
  • the crystal form of acceptable salt (crystal form A of the hydrochloride salt of the above-mentioned formula I compound, the crystal form A of the citrate salt of the above-mentioned formula I compound, the crystal form of the maleate salt of the above-mentioned formula I compound A, the crystal form A of the fumarate salt of the above-mentioned compound of formula I, the crystal form A of the mesylate salt of the above-mentioned compound of formula I, the crystal form B of the mes
  • the thirty-third aspect of the present invention provides a use of substance B in the preparation of medicines for treating and/or preventing diseases, wherein the substance B is the above-mentioned pharmaceutical composition, the crystal form of the above-mentioned compound of formula I (the above-mentioned Crystal form A of the compound of formula I, crystal form B of the compound of formula I above, crystal form C of the compound of formula I above, ), a pharmaceutically acceptable salt of the compound of formula I above or a pharmaceutically acceptable salt of the compound of formula I above
  • the crystal form of acceptable salt (crystal form A of the hydrochloride salt of the above-mentioned formula I compound, the crystal form A of the citrate salt of the above-mentioned formula I compound, the crystal form of the maleate salt of the above-mentioned formula I compound A, the crystal form A of the fumarate salt of the above-mentioned compound of formula I, the crystal form A of the mesylate salt of the above-mentioned compound of formula I, the crystal
  • the disease is preferably a RIPK1-mediated disease, and the disease is preferably one of stroke, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, NASH and heart failure one or more species.
  • the disease is preferably one or more of stroke, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, NASH and heart failure.
  • the dosage of the substance B is an effective therapeutic dosage.
  • the thirty-fourth aspect of the present invention provides a use of substance B in the preparation of RIPK1 inhibitors, wherein the substance B is the above-mentioned pharmaceutical composition, the crystal form A of the above-mentioned compound of formula I, the crystal form A of the above-mentioned compound of formula I Crystal form B, crystal form C of the above-mentioned compound of formula I, pharmaceutically acceptable salts of the above-mentioned compound of formula I, crystal form A of the hydrochloride of the above-mentioned compound of formula I, citrate of the above-mentioned compound of formula I.
  • said RIPK1 inhibitor is preferably an in vivo or in vitro RIPK1 inhibitor.
  • said RIPK1 inhibitor is preferably used to treat a disease or disorder related to RIPK1 (eg a disease or disorder mediated by RIPK1).
  • the diseases or disorders associated with RIPK1 include but are not limited to inflammatory diseases (such as Crohn's disease and ulcerative colitis, inflammatory bowel disease, asthma, graft resistance host disease, chronic obstructive pulmonary disease), autoimmune disease (eg, Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis); destructive bone disease, such as bone resorption disease, osteoarthritis, osteoporosis multiple myeloma-related bone disease); proliferative disorders (eg, acute myeloid leukemia, chronic myeloid leukemia), angiogenic disorders (eg, angiogenesis disorders, including solid tumors, ocular neovascularization, and infantile hemangiomas) , infectious diseases (such as sepsis, septic shock, and shigellosis); neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, am
  • the RIPK1-associated diseases or disorders include but are not limited to pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, nephropathy Glomeronephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia , Thrombocytopenia, Atopic Dermatitis, Chronic Active Hepatitis, Myasthenia Gravis, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Inflammatory Bowel Disease, Ulcerative Colitis, Crohn's Disease, Psoriasis, Graft Anti-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter
  • the disease or disorder associated with RIPK1 is selected from the group consisting of stroke, inflammatory bowel disease, Crohn's disease and ulcerative colitis, allograft rejection, rheumatoid arthritis arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.
  • a preferred condition is selected from ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction.
  • the X-ray powder diffraction characteristic peaks of the polymorphic form of the compound of formula 1 in the present invention are represented by 2 ⁇ angle, wherein " ⁇ 0.20°" is the allowable measurement error range.
  • the polymorphic form of the compound of formula I according to the invention can be used in combination with other active ingredients, provided it does not produce other adverse effects, such as allergic reactions.
  • composition is meant to include a product comprising the specified amounts of each of the specified ingredients, as well as any product resulting, directly or indirectly, from the combination of the specified amounts of each of the specified ingredients.
  • compositions may be particularly specially formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.
  • the pharmaceutical composition can be formulated into a variety of dosage forms for easy administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions) , or injectable dry powder, which can be used immediately after adding the drug vehicle before injection).
  • oral preparations such as tablets, capsules, solutions or suspensions
  • injectable preparations such as injectable solutions or suspensions
  • injectable dry powder which can be used immediately after adding the drug vehicle before injection.
  • the term "therapeutically and/or prophylactically effective amount” is the amount of drug or pharmaceutical preparation that elicits the biological or medical response of a tissue, system, animal or human being sought by the researcher, veterinarian, physician or others.
  • the total daily dosage of the polymorphic form of the compound of formula I and the pharmaceutical composition of the present invention must be decided by the attending physician within the scope of reliable medical judgment.
  • the particular therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; The age, weight, general health, sex and diet of the patient; the timing, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical arts. For example, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.
  • Polymorph or “polymorph” as used in the present invention refers to crystal forms having the same chemical composition but different spatial arrangements of the molecules, atoms and/or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in packing and geometric arrangement and may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution speed and similar properties. Depending on their temperature-stability relationship, the two polymorphs can be monotropic or tautotropic. For a single denaturation system, the relative stability between the two solid phases remains unchanged when the temperature is changed.
  • room temperature or "RT” refers to an ambient temperature of 20 to 25°C (68-77°F).
  • MeOH methanol
  • 2-MeTHF 2-methyltetrahydrofuran
  • EtOH ethanol
  • 1,4-Dioxane 1,4-dioxane
  • IPA isopropanol
  • ACN acetonitrile
  • Acetone acetone
  • DCM dichloromethane
  • MIBK methyl isobutyl ketone: Toluene: toluene
  • EtOAc ethyl acetate
  • n-Heptane n-heptane
  • IPAc isopropyl acetate
  • DMSO dimethyl sulfoxide
  • DMAc dimethylacetamide
  • THF tetrahydrofuran
  • NMP N-methylpyrrolidone.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that: the crystal form of the RIPK1 inhibitor of the present invention and its acid salt and the crystal form of the acid salt have good inhibitory activity on RIPK1 enzyme, high inhibitory activity on U937 cells, low hygroscopicity and The advantages of good stability and good prospect of finished medicine.
  • Figure 1 is the XRPD spectrum of anhydrous crystal form A of the compound of formula I.
  • Fig. 2 is the TGA/DSC spectrum of the anhydrous crystal form A of the compound of formula I.
  • Fig. 3 is the 1 H NMR spectrum of anhydrous crystal form A of the compound of formula I.
  • Fig. 4 is the XRPD spectrum of anhydrous crystal form B of the compound of formula I.
  • Fig. 5 is the TGA/DSC spectrum of the anhydrous crystal form B of the compound of formula I.
  • Fig. 6 is a comparative spectrum of 1 H NMR of anhydrous form B of the compound of formula I and anhydrous form A of the compound of formula I.
  • Fig. 7 is the XRPD pattern of the crystal form A of the hydrochloride salt of the compound of formula I.
  • Fig. 8 is the TGA/DSC spectrum of the crystal form A of the hydrochloride salt of the compound of formula I.
  • Fig. 9 is the 1 H NMR spectrum of the hydrochloride salt form A of the compound of formula I.
  • Figure 10 is the XRPD spectrum of the crystal form A of the sulfate salt of the compound of formula I.
  • Figure 11 is the TGA/DSC spectrum of the crystal form A of the sulfate salt of the compound of formula I.
  • Fig. 12 is the 1 H NMR spectrum of the crystalline form A of the sulfate salt of the compound of formula I.
  • Figure 13 is the XRPD spectrum of the crystal form B of the sulfate salt of the compound of formula I.
  • Figure 14 is the TGA/DSC spectrum of the crystal form B of the sulfate salt of the compound of formula I.
  • Fig. 15 is the 1 H NMR spectrum of the crystal form B of the sulfate salt of the compound of formula I.
  • Fig. 16 is the XRPD spectrum of the crystal form C of the sulfate salt hydrate of the compound of formula I.
  • Figure 17 is the TGA/DSC spectrum of the crystal form C of the sulfate salt hydrate of the compound of formula I.
  • Fig. 18 is a 1 H NMR spectrum of the crystal form C of the sulfate hydrate of the compound of formula I.
  • Figure 19 is the XRPD spectrum of Form A of the citrate salt of the compound of formula I.
  • Figure 20 is a TGA/DSC spectrum of Form A of the citrate salt of the compound of formula I.
  • Fig. 21 is a 1 H NMR spectrum of Form A of the citrate salt of the compound of formula I.
  • Fig. 22 is an XRPD spectrum of the crystalline form A of the maleate salt of the compound of formula I.
  • Figure 23 is the TGA/DSC spectrum of the crystalline form A of the maleate salt of the compound of formula I.
  • Fig. 24 is a 1 H NMR spectrum of Form A of the maleate salt of the compound of formula I.
  • Fig. 25 is the XRPD spectrum of the crystalline form A of the fumarate salt of the compound of formula I.
  • Figure 26 is the TGA/DSC spectrum of the crystalline form A of the fumarate salt of the compound of formula I.
  • Fig. 27 is a 1 H NMR spectrum of the crystal form A of the fumarate salt of the compound of formula I.
  • Fig. 28 is an XRPD spectrum of Form A of the mesylate salt of the compound of formula I.
  • Figure 29 is a TGA/DSC spectrum of Form A of the mesylate salt of the compound of formula I.
  • Fig. 30 is a 1 H NMR spectrum of Form A of the mesylate salt of the compound of formula I.
  • Figure 31 is the XRPD spectrum of Form B of the mesylate salt of the compound of formula I.
  • Figure 32 is a TGA/DSC spectrum of Form B of the mesylate salt of the compound of formula I.
  • Fig. 33 is a 1 H NMR spectrum of Form B of the mesylate salt of the compound of formula I.
  • Fig. 34 is an XRPD spectrum of Form C of the mesylate salt of the compound of formula I.
  • Figure 35 is a TGA/DSC spectrum of Form C of the mesylate salt of the compound of formula I.
  • Fig. 36 is a 1 H NMR spectrum of Form C of the mesylate salt of the compound of formula I.
  • Fig. 37 is an XRPD spectrum of Form A of p-toluenesulfonate salt of the compound of formula I.
  • Figure 38 is a TGA/DSC spectrum of Form A of p-toluenesulfonate salt of the compound of formula I.
  • Fig. 39 is a 1 H NMR spectrum of Form A of p-toluenesulfonate salt of the compound of formula I.
  • Fig. 40 is an XRPD spectrum of Form A of the cyclamate salt of the compound of formula I.
  • Figure 41 is a TGA/DSC spectrum of Form A of the cyclamate salt of the compound of formula I.
  • Fig. 42 is a 1 H NMR spectrum of Form A of the cyclamate salt of the compound of formula I.
  • Figure 43 is the XRPD spectrum of the crystal form D of the sulfate salt of the compound of formula I.
  • Figure 44 is the TGA/DSC spectrum of the crystal form D of the sulfate salt of the compound of formula I.
  • Fig. 45 is the 1 H NMR spectrum of the crystal form D of the sulfate salt of the compound of formula I.
  • Fig. 47 is an XRPD spectrum of the crystal form E of the sulfate salt of the compound of formula I.
  • Figure 48 is the TGA/DSC spectrum of the crystal form E of the sulfate salt of the compound of formula I.
  • Fig. 49 is a 1 H NMR spectrum of the crystal form E of the sulfate salt of the compound of formula I.
  • Fig. 50 is an XRPD spectrum of Form F of the sulfate salt of the compound of formula I.
  • Figure 51 is the TGA/DSC spectrum of the crystal form F of the sulfate salt of the compound of formula I.
  • Fig. 52 is a 1 H NMR spectrum of the crystal form F of the sulfate salt of the compound of formula I.
  • Figure 53 is an XRPD spectrum of Form C of the compound of formula I.
  • Figure 54 is a TGA/DSC spectrum of Form C of the compound of formula I.
  • Figure 55 is the DVS spectrum of Form C prepared in Example 9.
  • the obtained solid samples were analyzed using various detection and analysis methods, such as powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), dynamic moisture adsorption (DVS), hydrogen spectrum Liquid NMR ( 1 H Solution NMR).
  • XRPD powder X-ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVS dynamic moisture adsorption
  • H Solution NMR hydrogen spectrum Liquid NMR
  • Powder X-ray Diffraction (XRPD) XRPD results were collected on PANalytical Empyrean and X’Pert3 X-ray powder diffraction analyzers, and the scanning parameters are shown in Table 1.
  • TGA and DSC Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC): TGA and DSC diagrams were collected on TA Q5000/Discovery 5500 thermogravimetric analyzer and TA Q2000/Discovery 2500 differential scanning calorimeter respectively, the table 2 lists the test parameters.
  • Dynamic moisture adsorption (DVS) Dynamic moisture adsorption (DVS) curves were collected on DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25° C. was corrected with the deliquescence points of LiCl, Mg(NO 3 ) 2 and KCl. DVS test parameters are listed in Table 3.
  • Moisture titration is carried out by the instrument Metrohm 870 KF Titrinoplus, calibrated with ultrapure water, and the titration reagent is R-Composite 5, the manufacturer is Sigma-aldrich. HPLC grade methanol was used to dissolve solid samples.
  • Ion chromatography In the test, a ThermoFisher ICS-1100 ion chromatograph was used to analyze the ion content, and the specific conditions are shown in Table 5.
  • Step 1 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5 Synthesis of -a]pyridin-2-amine: Add 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (4.0g, 18.78mmol ), pinacol diboronate (5.723g, 22.53mmol), potassium acetate (4.601g, 46.95mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane The complex (767mg, 0.939mmol) and 1,4-dioxane (50ml) were replaced with nitrogen three times, reacted overnight at 90°C, cooled to room temperature, filtered with suction, washed the filter cake with ethyl acetate three times to obtain the filtrate, After concentration, the crude product 7-(4,4,5,5-
  • Step 2 Synthesis of methyl 5-bromo-2-vinylnicotinate: under nitrogen protection, methyl 5-bromo-2-chloronicotinate (10g, 39.923mmol), potassium vinyl trifluoroborate (5.348g , 39.923mmol), triethylamine (5.56mL, 39.923mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (585mg, 0.798mmol) was dissolved in 200mL EtOH, nitrogen replacement Three times, react at 80°C for 1 hour, cool to room temperature, filter, and spin the filtrate to dryness.
  • Step 3 Synthesis of 3-bromo-6-(2-fluoro-5-(trifluoromethoxy)benzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one: In a microwave vial, methyl 5-bromo-2-vinylnicotinate (2.5 g, 10.328 mmol) and (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine (4.32 g, 20.656 mmol) were mixed in DMA (75 mL).
  • Step 4 3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-(2-fluoro-5-(trifluoromethoxy) Benzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one synthesis: under nitrogen protection, 3-bromo-6-(2-fluoro-5-(trifluoromethoxy Base) benzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.885g, 4.499mmol), 7-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.602g, 8.998mmol), sodium carbonate ( 1.192g, 11.248mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro
  • the U937 cell line used in the following test examples comes from ATCC, number: CRL-1593.2, batch number: 63479999, culture medium: RPMI-1640+10% FBS.
  • the L929 cell line used in the following test examples is from ATCC, number: CCL-1, batch number: 70001022, culture medium: MEM+10%FBS+1%PS.
  • reagents used, their suppliers, and their catalog numbers are as follows: RPMI-1640, Gibco, 11875-093; FBS, Gibco, 10099-141; Trypsin-EDTA, Gibco, 25200-072; PS, Gibco, 15140-122; CellTiter Glo , Progema, G7573; DMSO, VWR AMRESCO, 0231-500ML; TNF- ⁇ protein (human, recombinant), Peprotech, 300-01A; Q-VD-Oph, MCE, HY-12305; V-bottom plate, Corning, 3894; 384-well low flange white flat bottom microplate, Corning, 3570; RIPK1, Eurofins, 16-022; MOPS, BDH, 441644J; EDTA, Sigma, E5134; Myelin basic protein, Sigma, M1891-25.00MG; Magnesium acetate , Merck, DU008026; ATP (non-radioactively labeled), Sigma, A
  • Test Example 1 Inhibitory activity of the compound of formula I on TNF- ⁇ -induced programmed cell necrosis
  • the compounds to be tested were dissolved in DMSO and diluted with DMSO to form a series of concentration gradients.
  • 5000/well U937 cells were inoculated in 384-well white plate, and the compound of corresponding concentration was added to each well and mixed with the cells evenly, and human TNF- ⁇ and Q-VD-Oph were added at the same time to induce programmed necrosis of the cells, and the cells were placed at 37 °C for 48 hours in a 5% CO 2 incubator.
  • the CellTiter-Glo reagent was used for detection, and the chemiluminescence reading value was detected by a microplate reader after a sufficient cleavage reaction.
  • the compound of formula I had higher inhibitory activity on U937 cells, with an IC 50 value of 6 nM.
  • Test Example 2 Inhibitory Activity of Formula I Compounds on RIPK1 Enzyme
  • the compound to be tested was dissolved in DMSO to prepare a 10mM stock solution, diluted 3.16 times with DMSO to form a series of concentration gradients, and then diluted 50 times with MOPS pH 7.0 buffer solution to prepare a working solution, and 36nM RIPK1 (final concentration), 0.33mg/ml substrate MBP and mix well. Afterwards, 10 mM magnesium ions and 155 ⁇ M phosphorus 33 isotope-labeled ATP were added for reaction, the final concentration of DMSO was 2%, and phosphoric acid was added after 2 hours at room temperature to terminate the reaction. After the final reaction system was processed, it was detected using a liquid scintillation counter.
  • the results after detection were subtracted from the blank control and compared with the reading value of the control group, converted into activity percentage, and the corresponding final concentration of the compound was plotted into a curve, and four-parameter fitting was used to obtain the IC 50 of the compound for inhibiting RIPK1 enzyme activity.
  • the compound of formula I has high inhibitory activity on RIPK1, with an IC 50 value of 39nM.
  • Test Example 3 Inhibitory activity of the compound of formula I on the programmed necrosis of L929 cells induced by TNF- ⁇
  • the compound was dissolved in DMSO, prepared as a 10 mM stock solution, diluted with DMSO according to 3.16 times to form a series of concentration gradients, and then diluted 100 times with the medium to make a working solution.
  • 10,000 cells/well L929 cells were seeded in 384-well white plate, and the corresponding concentration of compound was added to each well and mixed with the cells evenly.
  • 30ng/ml mouse TNF- ⁇ and 15 ⁇ M Z-VAD were added to induce programmed necrosis of the cells.
  • the CellTiter-Glo reagent was used for detection, and the chemiluminescence reading value was detected by a microplate reader after a sufficient cleavage reaction.
  • the compound of formula I had a high inhibitory activity on L929 cells, with an IC 50 value of 3 nM.
  • reaction solution was filtered through a diatomaceous earth pad, and 20 g of activated carbon was added to the filtrate, and the temperature was raised to 100° C. and stirred for 20 minutes. After filtration, the filtrate was concentrated to dryness, methanol (500 mL) was added, slurry was made at room temperature, filtered, and the filter cake was dried at 50°C for 2 hours.
  • the target product was characterized by XRPD, TGA, DSC, 1 H NMR and HPLC.
  • the XPRD is shown in Figure 1.
  • the sample is crystal, named as free base anhydrous form A, and its X-ray powder diffraction data are shown in Table 6 below.
  • the results of TGA/DSC and 1 H NMR (DMSO-d6) are shown in Figure 2 and Figure 3 .
  • TGA results showed that the sample had 1.1% weight loss before 175°C, and DSC results showed two endothermic peaks at 191.6°C and 240.5°C (peak temperature).
  • the free base anhydrous crystal form A (20mg, 0.0424mmol) sample of the compound of formula I obtained in Example 1 and hydrochloric acid (3.09mg, 0.085mmol) of 2 times the molar amount were put into an HPLC vial, and 0.5mL methanol was added to mix to obtain a suspension , magnetically stirred ( ⁇ 750rpm) at room temperature for about 5 days, and magnetically stirred ( ⁇ 750rpm) at 5°C for 4 days. After adding anti-solvent (ethyl acetate) to the obtained clear liquid, the separated solid was vacuum-dried at room temperature for one day to obtain the formula Compound I hydrochloride crystal form A.
  • anti-solvent ethyl acetate
  • the molar ratio of Cl - to API was determined to be 2.0:1 by HPLC and IC test results.
  • the characterization results of XRPD, TGA/DSC and 1 H NMR are shown in Fig. 7, Fig. 8 and Fig. 9, respectively.
  • the X-ray powder diffraction data of the hydrochloride salt form A of the compound of formula I are shown in Table 8 below.
  • TGA showed that the hydrochloride salt form A had a weight loss of 4.8% when heated to 100°C.
  • DSC showed that the sample had an endothermic peak at 156.8°C (peak temperature).
  • the TGA results showed a 3.9% weight loss when heated to 175°C, and the DSC results showed an overlapping endothermic peak at 129.2°C (peak temperature) and 152.8°C (peak temperature), and a relatively high endothermic peak at 200.2°C (peak temperature). Small endothermic peak.
  • 1 H NMR results showed that no solvent residue was detected.
  • the KF test results showed that the water content of the sample was 3.18%.
  • XRPD X-ray powder diffraction data of the anhydrous crystal form A of the sulfate salt of the compound of formula I are shown in Table 10 below.
  • TGA showed a 3.4% weight loss on heating to 175°C.
  • DSC showed three endothermic peaks at 70.6°C, 123.3°C and 205.1°C (peak temperature).
  • 1 H NMR results showed that no solvent residue was detected.
  • Example 2 The free base anhydrous form A (20 mg, 0.0424 mmol) obtained in Example 1 and an equimolar amount of sulfuric acid (4.16 mg, 0.0424 mmol) were added to an HPLC vial, 0.5 mL of methanol was added, and the mixture was suspended and stirred at room temperature for 5 days. It was obtained by vacuum drying at room temperature for 1 day. It was characterized by XRPD, TGA, DSC and 1 H NMR, and each spectrum was basically the same as that in Example 5.
  • the crystal form B of the sulfate salt of the compound of formula I has X-ray powder diffraction data shown in Table 11 below.
  • TGA results show that there is a weight loss of 2.9% when the temperature rises to 150°C.
  • DSC results showed that the sample had three endothermic peaks at 77.9°C, 118.8°C and 196.8°C (peak temperature).
  • 1 H NMR results showed that no solvent residue was detected.
  • Example 4 Weigh about 20 mg of the compound sulfate monohydrate crystal form C of formula I obtained in Example 4 into an HPLC vial, add 0.6 mL of acetonitrile solvent respectively, and place the obtained suspension at 50° C. under magnetic stirring ( ⁇ 750 rpm) for about 3 The next day, the solid was centrifuged and characterized by XRPD, TGA, DSC and 1 H NMR. Each spectrum was basically the same as that in Example 4, and it was the crystal form C of the sulfate monohydrate of the compound of formula I.
  • TGA showed that the citric acid form A sample had a weight loss of 1.1% when heated to 150°C.
  • DSC showed that the sample had a sharp endothermic peak at 166.4°C.
  • 1 H NMR results showed that the molar ratio of citric acid and free base in the sample was 1.0:1.
  • Example 2 Put the free base anhydrous form A (20mg, 0.0424mmol) obtained in Example 1 and an equimolar amount of maleic acid (4.92mg, 0.0424mmol) into an HPLC vial, add 0.5mL of acetone, and suspend and stir at room temperature for 5 days to obtain The solid was dried under vacuum at room temperature for 1 day to obtain Form A of the maleate salt of the compound of formula I.
  • the characterization results of XRPD, TGA/DSC and 1 H NMR are shown in Figure 22, Figure 23 and Figure 24.
  • the X-ray powder diffraction data of the maleic acid crystal form A of the compound of formula I are shown in Table 13 below.
  • TGA showed that the maleate crystal form A sample had a weight loss of 3.3% when heated to 150°C, and a weight loss of 13.6% when heated from 150°C to 250°C.
  • DSC showed that the sample had two endothermic peaks at 176.0°C (onset temperature) and 210.7°C (peak temperature).
  • 1 H NMR results showed that the molar ratio of maleic acid and free base in the sample was 0.8:1.
  • TGA showed that fumarate salt form A had a weight loss of 1.8% when heated to 150°C.
  • DSC showed that the sample had four endothermic peaks at 182.5°C, 192.9°C, 211.8°C and 219.2°C (peak temperature), and three exothermic peaks at 123.0°C, 184.8°C and 196.9°C (peak temperature).
  • 1 HNMR results showed that the molar ratio of fumaric acid and free base in the sample was 0.9:1, and no solvent residue was detected.
  • the X-ray powder diffraction data of the mesylate salt form B are shown in Table 16 below.
  • TGA showed that the mesylate salt Form B had a weight loss of 2.8% when heated to 150°C.
  • DSC showed that the sample had two endothermic peaks at 171.3°C and 194.7°C (peak temperature).
  • 1 H NMR results showed that the molar ratio of methanesulfonic acid to free base in the sample was 1.0:1, and no solvent residue was detected.
  • TGA showed a 0.7% weight loss of cyclamate form A heated to 150°C.
  • DSC showed that the sample had two endothermic peaks at 202.3°C and 231.3°C (peak temperature), and two exothermic peaks at 118.2°C and 205.4°C (peak temperature).
  • 1 H NMR results showed that the molar ratio of cyclamate and free base in the sample was about 0.9:1, and no solvent residue was detected.
  • the X-ray powder diffraction data of the anhydrous crystal form D of the sulfate salt of the compound of formula I are shown in Table 20 below.
  • TGA results show that there is a 3.0% weight loss when the temperature rises to 125°C.
  • DSC results showed that the sample had three endothermic peaks at 111.9°C, 153.2°C and 197.7°C (peak temperature). The results showed that no solvent residue was detected.
  • the sulfate monohydrate crystal form C sample obtained in Example 4 was heated to 130° C. and then cooled to 30° C. to obtain the sulfate crystal form I of the compound of formula I.
  • the XRPD results are shown in Figure 46.
  • Table 21 shows the X-ray powder diffraction data of the sulfate salt crystal form I of the compound of formula I.
  • the crystal form E of the sulfate salt of the compound of formula I has X-ray powder diffraction data shown in Table 22 below. TGA results show that there is a 5.9% weight loss when the temperature rises to 150°C. DSC results showed that the sample had three endothermic peaks at 82.2°C, 138.6°C and 205.4°C (peak temperature).
  • the X-ray powder diffraction data of the sulfate salt crystal form F of the compound of formula I are shown in Table 23 below.
  • TGA results show that there is a 6.4% weight loss when the temperature rises to 160°C, and a 6.9% weight loss when heated from 160°C to 225°C.
  • DSC results showed that the sample had two endothermic peaks at 123.6°C and 185.2°C (peak temperature), and one exothermic peak at 206.0°C (peak temperature).
  • the X-ray powder diffraction data of the free base crystal form C of the compound of formula I are shown in Table 24 below.
  • the XRPD and TGA/DSC results are shown in Figure 53 and Figure 54, showing that the sample has a weight loss of 3.2% when heated to 150°C; there are three endothermic peaks at 64.9°C, 200.1°C and 237.0°C (peak temperature).
  • solvent Solubility (mg/mL) solvent Solubility (mg/mL) Methanol S ⁇ 1.8 Acetonitrile S ⁇ 1.9 ethanol S ⁇ 2.2 n-heptane S ⁇ 1.7 Isopropanol S ⁇ 1.9 water S ⁇ 2.1 acetone S ⁇ 1.8 Dimethyl sulfoxide* 7.7 ⁇ S ⁇ 23.0
  • solvent Solubility (mg/mL) solvent Solubility (mg/mL) Methanol 7.3 ⁇ S ⁇ 22.0 Acetonitrile S ⁇ 2.4 ethanol 2.0 ⁇ S ⁇ 6.7 n-heptane S ⁇ 2.3 Isopropanol* S ⁇ 2.4 water S ⁇ 2.4 acetone S ⁇ 2.4 Dimethyl sulfoxide S>42.0
  • the crystal form C of sulfate monohydrate has a wide range of thermodynamic stability under different water activity conditions at room temperature.
  • the hygroscopicity of the sulfate monohydrate crystal form C sample obtained in Example 9 was evaluated by the DVS test between 0%RH and 95%RH at 25°C.
  • the DVS results are shown in Figure 55.
  • the hygroscopic weight gain of the sulfate monohydrate crystal form C sample is about 0.27% at 25°C/80%RH, indicating that the sample is slightly hygroscopic.
  • the XRPD result shows that after the DVS test, no crystal form change occurs in the sulfate monohydrate crystal form C sample.

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Abstract

公开了一种RIPK1抑制剂的晶型及其酸式盐和其酸式盐的晶型。所述RIPK1抑制剂的晶型及其酸式盐和其酸式盐的晶型具有引湿性低和稳定性好优点，成药前景好。

Description

RIPK1抑制剂的晶型及其酸式盐和其酸式盐的晶型
本申请要求申请日为2021年8月2日的中国专利申请2021108827578的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及医药技术领域，具体涉及一种RIPK1抑制剂的晶型及其酸式盐和其酸式盐的晶型。
背景技术
受体相互作用蛋白1(RIP1)激酶是一种涉及先天免疫信号传导的TKL家族丝氨酸/苏氨酸蛋白激酶。RIP1激酶是一种包含蛋白的RHIM结构域，其具有N端激酶结构域和C端死亡结构域。RIP1死亡结构域介导与其他包含死亡结构域的蛋白的相互作用，所述蛋白包括Fas和TNFR-1，TRAIL-R1和TRAIL-R2和TRADD，而RHIM结构域对结合其他包含RHIM结构域的蛋白非常关键，所述蛋白如TRIF，DAI和RIP3，并通过这些相互作用实现其众多作用。
RIP1在细胞信号传导中的作用已经在不同条件下进行了评估，包括TLR3，TLR4，TRAIL，FAS，但是在死亡受体TNFR1下游介导信号中能够获得最佳理解。通过TNF实现TNFR衔接，导致低聚反应，将多种蛋白，包括线性K63连接的多泛素化RIP1，TRAF2/5，TRADD和cIAPs，募集至受体的胞质尾区。依赖于RIP1的这种复合物作为支架蛋白(即非激酶依赖性)，称作复合物I，它通过激活NFκB和MAP激酶通路为促存活信号传导提供了一个平台。另外，在促进RIP1脱泛素的条件下，TNF与其受体结合(通过例如A20和CYLD蛋白或cIAP抑制)，将导致受体内化和复合物II或DISC(死亡诱导信号复合物)的形成。DISC(包括RIP1、TRADD、FADD和半胱天冬酶8)的形成，导致半胱天冬酶8的激活，还以非RIP1激酶依赖性方式开始程序性凋亡细胞死亡。细胞凋亡很大程度上是一种静止形式的细胞死亡，其参与例如发育和细胞体内稳态等常规过程。
在DISC形成和RIP3表达，但是细胞凋亡被抑制的条件下(如FADD/半胱天冬酶8缺失、半胱天冬酶抑制或病毒感染)，就可能存在第三种RIP1激酶依赖性。现在，RIP3可以进入这种复合物，通过RIP1实现磷酸化，通过MLKL和PGAM5激活开始不依赖半胱天冬酶的程序性坏死细胞凋亡。与细胞凋亡相反，程序性坏死(不要与非程序性被动坏死混淆)导致从细胞释放危险相关分子模式(DAMP)。这些DAMP能够向周围细胞和组织提供一种“危险信号”，诱发促炎反应，包括炎性体激活、细胞因子生成和细胞募集反应。
通过使用RIP3基因敲除小鼠(其中RIP1介导的程序性坏死被完全阻断)和Necrostatin-1(一种具有较差的口服生物利用度的RIP1激酶活性的工具抑制剂)已经证明，RIP1激酶介导的程序性细胞死亡的调节异常与各种炎症有关。RIP3敲除小鼠已经显示对炎性肠病(包括溃疡性结肠炎和克罗恩氏病)，银屑病，视网膜脱离诱导的感光细胞坏死，色素性视网膜炎，蛙皮素诱导的急性胰腺炎和败血症/全身炎症反应综合症具有保护作用。已经显示Necrostatin-1能有效缓解缺血性脑损伤，视网膜缺血/再灌注 损伤，亨廷顿氏病，肾缺血再灌注损伤，顺铂诱导的肾损伤和创伤性脑损伤。至少部分由RIP1依赖性细胞凋亡、坏死或细胞因子生成调节的其他疾病或病症包括，血液和实体器官恶性肿瘤，细菌感染和病毒感染(包括但不限于结核病和流感)和溶酶体贮积症(尤其是戈谢病)。
一种有效的、选择性的、小分子的RIP1激酶活性抑制剂，能够阻断RIP1依赖性细胞坏死，从而能够为与DAMP、细胞死亡和/或炎症有关的疾病或事件提供治疗效果。
发明内容
本发明所要解决技术问题是为了克服现有技术中RIP1抑制剂的种类较少的缺陷，为此，提供了一种RIPK1抑制剂的晶型及其酸式盐和其酸式盐的晶型。本发明的RIPK1抑制剂的晶型及其酸式盐和其酸式盐的晶型具有引湿性低和稳定性好优点，成药前景好。
本发明第一方面提供了一种式I化合物的晶型A，其以2θ角度表示的X-射线粉末衍射图在10.94±0.2°、16.43±0.2°、19.12±0.2°和19.81±0.2°处有衍射峰；
Figure PCTCN2022109562-appb-000001
在某一优选方案中，所述的式I化合物的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.25±0.2°、22.32±0.2°、27.55±0.2°、20.23±0.2°和18.41±0.2°。
优选，所述的式I化合物的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：18.13±0.2°、33.21±0.2°、17.86±0.2°、23.47±0.2°、26.91±0.2°和16.77±0.2°。
在某一优选方案中，所述的式I化合物的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图1所示。
在某一优选方案中，所述的式I化合物的晶型A，其热重分析图(TGA)在起始加热至175±5℃处失重为0.5％-2％(例如1.1％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的晶型A，其差示扫描量热图191.6±5℃和/或240.5±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的晶型A，其差示扫描热图和热重分析图基本如图2所示。
本发明第二方面提还供了一种式I化合物的晶型B，其以2θ角度表示的X-射线粉末衍射图在27.64±0.2°、24.48±0.2°、3.76±0.2°和19.30±0.2°处有衍射峰；
Figure PCTCN2022109562-appb-000002
在某一优选方案中，所述的式I化合物的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：16.11±0.2°、18.48±0.2°、21.23±0.2°、17.80±0.2°和21.41±0.2°。
优选，所述的式I化合物的晶型B，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：17.01±0.2°、28.03±0.2°、21.96±0.2°、22.66±0.2°、30.78±0.2°和19.66±0.2°。
在某一优选方案中，所述的式I化合物的晶型B，其以2θ角度表示的X-射线粉末衍射图基本如图4所示。
在某一优选方案中，所述的式I化合物的晶型B，其热重分析图在起始加热至200±5℃处失重为1％-3％(例如2.2％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的晶型B，其差示扫描量热图240.1±5℃处有一个吸热峰。
在某一优选方案中，所述的式I化合物的晶型B，其差示扫描热图和热重分析图基本如图5所示。
本发明第三方面提供了一种式I化合物的晶型C，其以2θ角度表示的X-射线粉末衍射图在19.55±0.2°、29.51±0.2°、19.99±0.2°和20.26±0.2°处有衍射峰；
Figure PCTCN2022109562-appb-000003
在某一优选方案中，所述的式I化合物的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：29.92±0.2°、23.30±0.2°、20.57±0.2°、31.49±0.2°和10.11±0.2°。
优选，所述的式I化合物的晶型C，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：24.93±0.2°、20.82±0.2°、11.60±0.2°、9.77±0.2°、10.98±0.2°和26.96±0.2°。
在某一优选方案中，所述的式I化合物的晶型C，其以2θ角度表示的X-射线粉末衍射图基本如图53所示。
在某一优选方案中，所述的式I化合物的晶型C，其热重分析图在起始加热至150±5℃处失重为3％-4％(例如3.2％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的晶型C，其差示扫描量热图在64.9±5℃、200.1±5℃和237.0±5℃的一处或多处有吸热峰。
在某一优选方案中，所述的式I化合物的晶型C，其差示扫描热图和热重分析图基本如图54所示。
本发明第四方面提供了一种式I化合物的药学上可接受的盐；所述的药学上可接受的盐为式I化合物与酸形成的盐；所述的酸为无机酸或有机酸；
Figure PCTCN2022109562-appb-000004
在某一优选方案中，所述的式I化合物与所述的酸的摩尔比为1:(0.3-2)，例如1:0.3、1:0.8、1:0.9、1:1、1:1.1、1:1.3或1:2。
在某一优选方案中，所述的无机酸为盐酸和/或硫酸。
在某一优选方案中，所述的有机酸为富马酸、马来酸、柠檬酸、甲磺酸、对甲苯磺酸、环拉酸、粘酸、乙醇酸、苹果酸和马尿酸中的一种或多种。
较佳地，所述的有机酸为对甲苯磺酸、甲磺酸、马来酸、富马酸、柠檬酸和环拉酸中的一种或多种。
更佳地，所述的有机酸为对甲苯磺酸。
在某一优选方案中，所述的式I化合物的药学上可接受的盐为如下任一药学上可接受的盐：
(1)式I化合物的盐酸盐；其中，式I化合物与盐酸的摩尔比为1：2；
(2)式I化合物的硫酸盐；其中，式I化合物与硫酸的摩尔比为1：(1-2)，例如1:(1-1.3)，再例如1：1、1：1.1、1：1.3或1：2；
(3)式I化合物的柠檬酸盐；其中，式I化合物与柠檬酸的摩尔比为1:1；
(4)式I化合物的马来酸盐；其中，式I化合物与马来酸的摩尔比为1:(0.5-1)，例如1:0.8；
(5)式I化合物的富马酸盐；其中，式I化合物与富马酸的摩尔比为1:(0.5-1)，例如1:0.9；
(6)式I化合物的甲磺酸盐；其中，式I化合物与甲磺酸的摩尔比为1:(0.1-1)，例如1:(0.3-1)，再例如1:0.3或1:1；
(7)式I化合物的对甲苯磺酸盐；其中，式I化合物与对甲苯磺酸的摩尔比为1:(0.1-1)，例如1:0.9。
(8)式I化合物的环拉酸盐；其中，式I化合物与环拉酸的摩尔比为1:(0.1-1)，例如1:0.9。
所述的式I化合物的药学上可接受的盐可以通过本领域常规的成盐反应制得。例如所述的式I化合物的药学上可接受的盐可以通过下述方法制得：
将式I化合物与酸在溶剂中进行成盐反应，得到所述的式I化合物的药学上可接受的盐；
其中，当酸为盐酸时，所述的式I化合物与盐酸的摩尔比为1：2；
当酸为硫酸时，所述的式I化合物与硫酸的摩尔比为1：(1-2)，例如1:(1-1.3)，再例如1：1、1：1.1或1：2；
当酸为柠檬酸时，所述的式I化合物与柠檬酸的摩尔比为1:1；
当酸为马来酸时，所述的式I化合物与马来酸的摩尔比为1:(0.5-1)，例如1:0.8；
当酸为富马酸时，所述的式I化合物与富马酸的摩尔比为1:(0.5-1)，例如1:0.9；
当酸为甲磺酸时，所述的式I化合物与甲磺酸的摩尔比为1:(0.1-1)，例如1:(0.3-1)，再例如1:0.3或1:1；
当酸为对甲苯磺酸时，所述的式I化合物与对甲苯磺酸的摩尔比为1:(0.1-1)，例如1:0.9。
当酸为环拉酸时，所述的式I化合物与环拉酸的摩尔比为1:(0.1-1)，例如1:0.9。
本发明第五方面提供了一种式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在8.83±0.2°、13.24±0.2°、24.25±0.2°和18.31±0.2°处有衍射峰；所述的如式I所示的化合物的盐酸 盐如上所述；
Figure PCTCN2022109562-appb-000005
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A；其中，式I化合物与盐酸的摩尔比为1：2。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：26.66±0.2°、22.21±0.2°、4.39±0.2°、31.19±0.2°和19.54±0.2°。
优选，所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：35.77±0.2°、19.71±0.2°、27.3±0.2°、32.11±0.2°、28.38±0.2°和21.52±0.2°。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图7所示。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其热重分析图在起始加热至100±5℃处失重为4％-5.5％(例如4.8％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其差示扫描量热图在156.8±5℃处有一个吸热峰。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其差示扫描热图和热重分析图基本如图8所示。
本发明第六方面提供了一种式I化合物的柠檬酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在17.87±0.2°、14.97±0.2°、17.45±0.2°和17.01±0.2°处有衍射峰；所述的如式I所示的化合物的柠檬酸盐如上所述；
Figure PCTCN2022109562-appb-000006
在某一优选方案中，所述的式I化合物的柠檬酸盐的晶型A；其中，式I化合物与柠檬酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的柠檬酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：4.45±0.2°、11.14±0.2°、19.08±0.2°、8.91±0.2°和13.38±0.2°。
优选，所述的式I化合物的柠檬酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步 还在如下一个或多个2θ角度处有衍射峰：21.23±0.2°、25.56±0.2°、21.00±0.2°、24.25±0.2°、28.48±0.2°和29.9±0.2°。
在某一优选方案中，所述的式I化合物的柠檬酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图19所示。
在某一优选方案中，所述的式I化合物的柠檬酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为0.5％-2％(例如1.1％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的柠檬酸盐的晶型A，其差示扫描量热图在166.4±5℃处有一个吸热峰。
在某一优选方案中，所述的式I化合物的柠檬酸盐的晶型A，其差示扫描热图和热重分析图基本如图20所示。
本发明第六方面提供了一种式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在16.47±0.2°、4.58±0.2°、10.97±0.2°和22.91±0.2°处有衍射峰；所述的如式I所示的化合物的马来酸盐如上所述；
Figure PCTCN2022109562-appb-000007
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A；其中，式I化合物与马来酸的摩尔比为1:(0.5-1)，例如1:0.8。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：18.2±0.2°、19.87±0.2°、24.64±0.2°、22.35±0.2°和20.26±0.2°。
优选，所述的式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：19.56±0.2°、28.43±0.2°、26.52±0.2°、15.04±0.2°、27.52±0.2°和18.86±0.2°。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图22所示。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其热重分析图在150±5℃处失重3％-4％(例如3.3％)，在150℃至250℃处失重为10％-15％(例如13.6％)。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其差示扫描量热图在176.0±5℃和/或210.7±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其差示扫描热图和热重分析图基本如图23所示。
本发明第七方面提供了一种上述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在28.83±0.2°、5.03±0.2°、16.15±0.2°和13.11±0.2°处有衍射峰；所述的如式I所示的化合物的富马酸盐如上所述；
Figure PCTCN2022109562-appb-000008
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A；其中，式I化合物与富马酸的摩尔比为1:(0.5-1)，例如1:0.9。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.86±0.2°、12.39±0.2°、29.44±0.2°、17.78±0.2°和9.69±0.2°。
优选，所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：19.82±0.2°、10.73±0.2°、3.25±0.2°、17.09±0.2°、6.54±0.2°和11.22±0.2°。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图25所示。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为1％-3％(例如1.8％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其差示扫描量热图在182.5±5℃、192.9±5℃、211.8±5℃和219.2±5℃的一处或多处有吸热峰和/或在123.0±5℃、184.8±5℃和196.9±5℃的一处或多处有放热峰。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其差示扫描热图和热重分析图基本如图26所示。
本发明第八方面提供了一种上述的式I化合物的甲磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在5.76±0.2°、14.75±0.2°、5.11±0.2°、17.54±0.2°处有衍射峰；所述的如式I所示的化合物的甲磺酸盐如上所述；
Figure PCTCN2022109562-appb-000009
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型A；其中，式I化合物与甲磺酸的摩尔比为1:(0.1-1)，例如1:1。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍 射图，还在如下一个或多个2θ角度处有衍射峰：20.29±0.2°、20.49±0.2°、16.84±0.2°、7.51±0.2°和16.51±0.2°。
优选，所述的式I化合物的甲磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：21.72±0.2°、19.60±0.2°、15.51±0.2°、18.43±0.2°、15.86±0.2°和12.84±0.2°。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图28所示。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型A，其热重分析图在起始加热至110±5℃处失重为2％-4％(例如2.9％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型A，其差示扫描量热图在92.5±5℃和/或138.6±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型A，其差示扫描热图和热重分析图基本如图29所示。
本发明第九方面提供了一种上述的式I化合物的甲磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图在18.83±0.2°、16.51±0.2°、25.51±0.2°和10.98±0.2°处有衍射峰；所述的如式I所示的化合物的甲磺酸盐如上所述；
Figure PCTCN2022109562-appb-000010
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型B；其中，式I化合物与甲磺酸的摩尔比为1:(0.1-1)，例如1:1。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.32±0.2°、5.49±0.2°、20.34±0.2°、26.34±0.2°和16.94±0.2°。
优选，所述的式I化合物的甲磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：19.48±0.2°、21.35±0.2°、15.06±0.2°、19.93±0.2°、12.75±0.2°和18.05±0.2°。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图基本如图31所示。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型B，其热重分析图在起始加热至150±5℃处失重为2％-4％(例如2.8％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型B，其差示扫描量热图在171.3±5℃和/或194.7±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型B，其差示扫描热图和热重分析图基本如图32所示。
本发明第十方面提供了一种上述的式I化合物的甲磺酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图在19.57±0.2°、19.98±0.2°、16.50±0.2°和18.20±0.2°处有衍射峰；
Figure PCTCN2022109562-appb-000011
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型C；其中，式I化合物与甲磺酸的摩尔比为1:(0.1-1)，例如1:0.3。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.26±0.2°、23.30±0.2°、29.52±0.2°、10.99±0.2°和26.94±0.2°。
优选，所述的式I化合物的甲磺酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：22.36±0.2°、20.86±0.2°、24.62±0.2°、24.92±0.2°、27.41±0.2°和18.45±0.2°。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图基本如图34所示。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型C，其热重分析图在起始加热至150±5℃处失重为4％-6％(例如4.9％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型C，其差示扫描量热图在108.2±5℃、181.9±5℃和233.2±5℃的一处或多处有吸热峰。
在某一优选方案中，所述的式I化合物的甲磺酸盐的晶型C，其差示扫描量热图和热重分析图基本如图35所示。
本发明第十一方面提供了一种上述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在5.80±0.2°、19.70±0.2°、22.36±0.2°和11.57±0.2°处有衍射峰；所述的如式I所示的化合物的对甲苯磺酸盐如上所述；
Figure PCTCN2022109562-appb-000012
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A；其中，式I化合物与对甲苯磺酸的摩尔比为1:(0.1-1)，例如1:0.9。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：27.22±0.2°、14.81±0.2°、16.83±0.2°、27.91±0.2°和15.18±0.2°。
优选，所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：19.21±0.2°、18.16±0.2°、13.07±0.2°、30.66±0.2°、32.47±0.2°和18.47±0.2°。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图37所示。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为1％-3％(例如1.6％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其差示扫描量热图在205.6±5℃处有一个吸热峰。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其差示扫描热图和热重分析图基本如图38所示。
本发明第十二方面提供了一种式I化合物的环拉酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在6.41±0.2°、16.47±0.2°、18.57±0.2°和10.95±0.2°处有衍射峰；所述的如式I所示的化合物的环拉酸盐如上所述；
Figure PCTCN2022109562-appb-000013
在某一优选方案中，所述的式I化合物的环拉酸盐的晶型A；其中，式I化合物与环拉酸的摩尔比为1:(0.1-1)，例如1:0.9。
在某一优选方案中，所述的式I化合物的环拉酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：18.16±0.2°、19.58±0.2°、20.24±0.2°、22.33±0.2°和23.27±0.2°。
在某一优选方案中，所述的式I化合物的环拉酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：24.63±0.2°、26.94±0.2°、27.39±0.2°、21.39±0.2°、20.83±0.2°和24.93±0.2°。
在某一优选方案中，所述的式I化合物的环拉酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图40所示。
在某一优选方案中，所述的式I化合物的环拉酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为0.1％-2％(例如0.7％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的环拉酸盐的晶型A，其差示扫描量热图在202.3±5℃和/或231.3±5℃处有吸热峰；和/或在118.2±5℃和/或205.4±5℃处有放热峰。
在某一优选方案中，所述的式I化合物的环拉酸盐的晶型A，其差示扫描热图和热重分析图基本如图41所示。
本发明第十三方面提供了一种式I化合物的硫酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在14.60±0.2°、11.67±0.2°、21.09±0.2°和13.32±0.2°处有衍射峰；所述的如式I所示的化合物的硫酸盐如上所述；
Figure PCTCN2022109562-appb-000014
在某一优选方案中，所述的式I化合物的硫酸盐的晶型A，其中，式I化合物与硫酸的摩尔比为1：(1-2)，例如1：(1-1.3)、1：(1-1.1)或1:1。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.38±0.2°、21.65±0.2°、26.08±0.2°、23.45±0.2°和26.44±0.2°。
优选，所述的式I化合物的硫酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：15.76±0.2°、8.75±0.2°、37.29±0.2°、24.42±0.2°、22.08±0.2°和29.39±0.2°。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图10所示。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型A，其热重分析图在起始加热至175±5℃处失重为2％-4％(例如3.4％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型A，其差示扫描量热图在70.6±5℃和123.3±5℃和205.1±5℃处有三个吸热峰。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型A，其差示扫描热图和热重分析图基本如图11所示。
本发明第十四方面提供了一种式I化合物的硫酸盐的晶型D，其以2θ角度表示的X-射线粉末衍射图在14.60±0.2°、25.31±0.2°、19.85±0.2°和20.07±0.2°处有衍射峰；所述的如式I所示的化合物的硫酸盐如上所述；
Figure PCTCN2022109562-appb-000015
在某一优选方案中，所述的式I化合物的硫酸盐的晶型D，其中，式I化合物与硫酸的摩尔比为1：(1-2)，例如1：(1-1.3)、1：(1-1.1)、1:1或1:1.1。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型D，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.06±0.2°、19.31±0.2°、18.15±0.2°、13.18±0.2°和6.59±0.2°。
优选，所述的式I化合物的硫酸盐的晶型D，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：15.02±0.2°、31.39±0.2°、22.14±0.2°、24.63±0.2°、25.63±0.2°和9.83±0.2°。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型D，其以2θ角度表示的X-射线粉末衍射图基本如图43所示。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型D，其热重分析图在起始加热至125±5℃处失重为1％-4％(例如3％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型D，其差示扫描量热图在111.9±5℃和153.2±5℃和197.7±5℃处有三个吸热峰。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型D，其差示扫描热图和热重分析图基本如图44所示。
本发明第十五方面提供了一种式I化合物的硫酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图在12.92±0.2°、26.90±0.2°、15.86±0.2°和23.02±0.2°处有衍射峰；所述的如式I所示的化合物的硫酸盐如上所述；
Figure PCTCN2022109562-appb-000016
在某一优选方案中，所述的式I化合物的硫酸盐的晶型I，其中，式I化合物与硫酸的摩尔比为1：(1-2)，例如1：(1-1.3)、1：(1-1.1)或1:1。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.09±0.2°、14.99±0.2°、17.26±0.2°、19.34±0.2°和24.61±0.2°。
优选，所述的式I化合物的硫酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：20.79±0.2°、21.75±0.2°、18.31±0.2°、18.47±0.2°、21.61±0.2°和 19.75±0.2°。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图基本如图46所示。
本发明第十六方面提供了一种式I化合物的硫酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图在25.15±0.2°、18.71±0.2°、3.13±0.2°和23.28±0.2°处有衍射峰；所述的如式I所示的化合物的硫酸盐如上所述；
Figure PCTCN2022109562-appb-000017
在某一优选方案中，所述的式I化合物的硫酸盐的晶型B，其中，式I化合物与硫酸的摩尔比为1：(1-2)，例如1：(1-1.3)、1：(1-1.1)、1:1或1:1.1。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.27±0.2°、24.82±0.2°、15.17±0.2°、14.82±0.2°和23.67±0.2°。
优选，所述的式I化合物的硫酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：21.03±0.2°、19.05±0.2°、18.34±0.2°、12.20±0.2°、24.18±0.2°和17.21±0.2°。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图基本如图13所示。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型B，其热重分析图在起始加热至150±5℃处失重为2％-4％(例如2.9％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型B，其差示扫描量热图在77.9±5℃和118.8±5℃和196.8±5℃处有三个吸热峰。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型B，其差示扫描热图和热重分析图基本如图14所示。
本发明第十七方面提供了一种式I化合物的硫酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图在5.55±0.2°、14.72±0.2°、16.75±0.2°和27.35±0.2°处有衍射峰；所述的如式I所示的化合物的硫酸盐如上所述；
Figure PCTCN2022109562-appb-000018
在某一优选方案中，所述的式I化合物的硫酸盐的晶型C中，所述的式I化合物的硫酸盐为水合物，所述的式I化合物与水的摩尔比为1:(1-2)，例如1:(1-1.3)，又例如1:(1-1.1)，再例如1:1。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型C，其中，式I化合物与硫酸的摩尔比为1:(1-2)，例如1:(1-1.3)、1:(1-1.1)或1:1。
在某一优选方案中，所述的如式I所示的化合物的硫酸盐的晶型C中，所述的如式I所示的化合物的硫酸盐为1水合物，所述的如式I所示的化合物与硫酸盐的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.92±0.2°、20.90±0.2°、21.13±0.2°、19.63±0.2°和20.37±0.2°。
优选，所述的式I化合物的硫酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.72±0.2°、12.52±0.2°、19.45±0.2°、19.96±0.2°、25.16±0.2°和12.75±0.2°。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图基本如图16所示。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型C，其热重分析图在加热至175±5℃时具有3％-4.5％的失重；例如，在加热至175±5℃时具有3.9％的失重(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型C，其差示扫描量热图在129.2±5℃和152.8±5℃和200.2±5℃处有三个吸热峰。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型C，其差示扫描热图和热重分析图基本如图17所示。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型C，其动态水分吸附谱图基本如图55所示
本发明第十八方面提供了一种式I化合物的硫酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图在16.39±0.2°、12.75±0.2°、14.32±0.2°和20.28±0.2°处有衍射峰；所述的如式I所示的化合物的硫酸盐如上所述；
Figure PCTCN2022109562-appb-000019
在某一优选方案中，所述的式I化合物的硫酸盐的晶型E，其中，式I化合物与硫酸的摩尔比为1：(1-2)，例如1：(1-1.3)，又例如1:1.3。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.76±0.2°、23.45±0.2°、26.20±0.2°、17.47±0.2°和19.76±0.2°；
优选，所述的式I化合物的硫酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：11.46±0.2°、25.88±0.2°、21.90±0.2°、23.00±0.2°、20.79±0.2°和18.25±0.2°。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图基本如图47所示。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型E，其热重分析图在起始加热至150±5℃时具有5％-6.5％(例如5.9％)的失重(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型E，其差示扫描量热图在82.2±5℃和138.6±5℃和205.4±5℃处有三个吸热峰。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型E，其差示扫描热图和热重分析图基本如图48所示。
本发明第十九方面提供了一种式I化合物的硫酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图在24.91±0.2°、20.60±0.2°、27.62±0.2°和16.04±0.2°有衍射峰；所述的如式I所示的化合物的硫酸盐如上所述；
Figure PCTCN2022109562-appb-000020
在某一优选方案中，所述的式I化合物的硫酸盐的晶型F，其中，式I化合物与硫酸的摩尔比为1：(1-2)，例如1：(1-1.3)，又例如1:1.1。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：24.26±0.2°、24.14±0.2°、18.63±0.2°、17.01±0.2°和21.53±0.2°；
优选，所述的式I化合物的硫酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：23.10±0.2°、19.94±0.2°、19.73±0.2°、15.29±0.2°、28.29±0.2°和20.12±0.2°。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图基本如图50所示。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型F，其热重分析图在起始加热至160℃处失重为5％-7％(例如6.4％)，从160℃加热至225℃处失重为6％-8％(例如6.9％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型F，其差示扫描量热图在123.6±5℃和185.2±5℃处有两个吸热峰，在206.0±5℃处有一个放热峰。
在某一优选方案中，所述的式I化合物的硫酸盐的晶型F，其差示扫描热图和热重分析图基本如图51所示。
本发明的RIPK1抑制剂的晶型及其药学上可接受的盐和其药学上可接受的盐的晶型的制备方法可以通过如本领域中已知的许多方法来获得结晶形式。
所述硫酸盐多晶型的制备方法：包括但不限于采用反溶剂添加、反反溶剂添加、气固扩散、气液渗透、悬浮搅拌、缓慢挥发、循环升降温悬浮搅拌、高聚物诱导、研磨等方法使式I化合物硫酸盐样品进行结晶。
反溶剂添加：称取硫酸盐起始样品，用良溶剂溶解后，向该澄清溶液中加入反溶剂，边滴加边搅拌至有固体析出，若加入4.5mL反溶剂后仍无固体析出则停止。离心分离析出固体并进行XRPD测试。其中，所述良溶剂与硫酸盐起始样品的体积质量比为5～75倍量。
反反溶剂添加：称取硫酸盐起始样品，用良溶剂溶解后，将该澄清溶液加入反溶剂中，边滴加边搅拌。离心分离析出固体并进行XRPD测试。其中，所述良溶剂与硫酸盐起始样品的体积质量比为5～75倍量。
缓慢挥发：称取硫酸盐样品，加入溶剂，经震荡溶清后，用封口膜封住装有澄清溶液的小瓶并在上面扎5个小孔，放置在室温下缓慢挥发。收集挥发所得固体并进行XRPD测试。其中，所述溶剂与硫酸盐起始样品的体积质量比为50～100倍量。
室温悬浮搅拌：称量硫酸盐起始样品，加入溶剂，得到的悬浊液置于室温下磁力搅拌(～750rpm)约5天，离心分离固体并进行XRPD测试。其中，所述溶剂与硫酸盐起始样品的体积质量比为25～50倍量。
50℃悬浮搅拌：称量硫酸盐起始样品，加入溶剂，得到的悬浊液置于50℃下磁力搅拌(～750rpm)约3天，离心分离固体并进行XRPD测试。其中，所述溶剂与硫酸盐起始样品的体积质量比为30倍量。
缓慢降温：称量硫酸盐起始样品，加入溶剂，在50℃下搅拌约2小时后过滤(孔径0.45μm的PTFE滤膜)取滤液，将所得滤液放置在生化培养箱中，以0.1℃/分钟的降温速度从50℃降温至5℃，收集析出的固体并进行XRPD测试。其中，所述溶剂与硫酸盐起始样品的体积质量比为50倍量。
气固扩散：称取硫酸盐起始样品于3mL小瓶中，另在20mL小瓶中加入溶剂，将3mL小瓶敞口置于20mL小瓶中后，将20mL小瓶密封。室温下静置～7天后收集固体并进行XRPD测试。其中，所述溶剂与硫酸盐起始样品的体积质量比为200倍量。
气液扩散：称取硫酸盐起始样品(20mg)于3mL小瓶中，使用0.05～2.2mL溶剂得到澄清溶液，过滤得滤液转移至3mL小瓶，另取20mL的小瓶向其中加入约3mL的反溶剂，将装有滤液的3mL小瓶敞口置于20mL小瓶后，密封20mL的小瓶并于室温下静置。当观察到有固体析出时，则收集固体并进行XRPD测试。
50～5℃循环升降温悬浮搅拌：称取硫酸盐起始样品，加入溶剂，在50℃下磁力搅拌(～750rpm)2小时。以0.1℃/min的速率降温至5℃，并在5℃下搅拌0.5小时；再以0.1℃/min的速率升温至50℃ C，并在50℃下搅拌0.5小时。重复以上步骤1次后，以0.1℃/min的速率降温至5℃，并保持在5℃。收集固体测XRPD。其中，所述溶剂与硫酸盐起始样品的体积质量比为25倍量。
研磨：称取硫酸盐起始样品于玛瑙研钵中，加入0.05mL的溶剂，手动研磨约15分钟后收集固体测XRPD。其中，溶剂与硫酸盐起始样品的体积质量比为2.5倍量。
高聚物诱导：称取约20mg每份的硫酸盐起始样品于3mL小瓶中，使用～2.0mL溶剂将固体溶清，装入约2mg混合高聚物，用封口膜封住装有滤液的小瓶并在上面扎3～5个小孔，放置在室温下缓慢挥发，收集所得固体并进行XRPD测试。
所述混合高聚物为混合高聚物A和混合高聚物B；混合高聚物A为聚乙烯吡咯烷酮，聚乙烯醇，聚氯乙烯，聚醋酸乙烯酯，羟丙基甲基纤维素和甲基纤维素(等质量混合)，混合高聚物B为聚己酸内酯，聚乙二醇，聚甲基丙烯酸甲酯，海藻酸钠和羟乙基纤维素(等质量混合)。
上述溶剂包括但不限定于下列所列举的溶剂，例如醇类、卤代烃类、腈类、酮类、醚类、亚砜类、酰胺类，脂类，水，烷烃类，芳香类及其它们的混合溶剂。醇类优选甲醇，乙醇，丙醇，异丙醇，丁醇；卤代烃类优选二氯甲烷，氯仿；腈类优选乙腈。酮类优选丙酮，2-丁酮，甲基异丁酮，N-甲基吡咯烷酮；醚类优选甲基叔丁基醚，四氢呋喃，2-甲基四氢呋喃，环戊基甲醚，1,4-二氧六环，苯甲醚；亚砜类优选二甲基亚砜；酰胺类优选N，N-二甲基甲酰胺，N,N-二甲基乙酰胺；脂类优选乙酸乙酯，醋酸异丙酯；烷基类优选正庚烷；芳香类优选甲苯，二甲苯。
本发明第二十二方面提供了一种上述的式I化合物的硫酸盐的晶型A的制备方法，其为方法a或方法b；
方法a，其包括如下步骤：在室温下，将所述的式I化合物与硫酸在甲醇中进行析晶，得到式I化合物的硫酸盐的晶型A；
方法b，其包括如下步骤：将上述的式I化合物的硫酸盐在溶剂中进行析晶，得到式I化合物的硫酸盐的晶型A；所述的溶剂为C 1-3醇类溶剂-2-甲基四氢呋喃。
方法a中，所述的式I化合物为式I化合物的晶型A。
方法b中，所述的式I化合物的硫酸盐为式I化合物的硫酸盐的晶型C。
方法b中，所述的析晶优选包括以下步骤：将所述的式I化合物的硫酸盐溶解在所述的C 1-3醇类溶剂中，得到混合溶液，向所述的混合溶液中加入(例如加入方式为滴加)2-甲基四氢呋喃(即反溶剂添加)。所述的式I化合物的硫酸盐的晶型A的制备方法中，所述的C 1-3醇类溶剂-2-甲基四氢呋喃中的C 1-3醇类溶剂优选为甲醇、乙醇和异丙醇中一种或多种，例如甲醇。
所述的C 1-3醇类溶剂的用量可以不做具体限定，以所述的式I化合物的硫酸盐在C 1-3醇类溶剂中形成澄清溶液为标准。
所述的2-甲基四氢呋喃可以不做具体限定，以所述的混合溶液与2-甲基四氢呋喃形成澄清溶液为标准。
方法a中，所述的析晶优选包括以下步骤：将所述的式I化合物和硫酸(例如式I化合物与硫酸摩尔比为1:1)在所述的甲醇中进行悬浮搅拌析晶(即悬浮搅拌)。
所述的析晶的方式可以在搅拌(例如悬浮搅拌)下进行析晶。
所述的析晶结束后，可按照本领域中的常规操作方法进行分离，例如离心或者过滤。
本发明第二十三方面提供了一种按照上述式I化合物的硫酸盐的晶型A的制备方法制得的式I化合物的硫酸盐的晶型A。
本发明第二十四方面提供了一种上述的式I化合物的硫酸盐的晶型C的制备方法，其为方法1或2：
方法1：其包括如下步骤：将所述的式I化合物在腈类溶剂中与硫酸水溶液溶清后冷却得到式I化合物的硫酸盐的晶型C；
方法2：其包括如下步骤：在室温下，将所述的式I化合物与硫酸在水-腈类溶剂中进行析晶，得到式I化合物的硫酸盐的晶型C。
方法1或2中，所述的式I化合物为上述的式I化合物的晶型A。
方法1中，所述的式I化合物与硫酸的摩尔比为1:(1-2)(例如1:(1-1.1))。
方法2中，所述的水-腈类溶剂中的腈类溶剂优选为乙腈。
方法1中，所述的腈类溶剂优选为乙腈。
方法1或2中，所述的式I化合物与所述的腈类溶剂的质量体积比优选为120-20mg/ml，例如100-40mg/ml。
所述析结晶结束后，可按照本领域中的常规操作方法进行分离，例如离心或者过滤。
本发明第二十五方面提供了一种按照上述的式I化合物的硫酸盐的晶型C的制备方法制得的式I化合物的硫酸盐的晶型C。
本发明第二十六方面提供了一种式I化合物的硫酸盐的晶型D的制备方法，其包括如下步骤：将式I化合物的硫酸盐在丙醇中形成悬浊液进行转晶(50℃悬浮搅拌)得到式I化合物的硫酸盐的晶型D。
所述的式I化合物的硫酸盐为式I化合物的硫酸盐的晶型C。
所述的丙醇优选为正丙醇和/或异丙醇，例如正丙醇。
所述的式I化合物的硫酸盐与所述的丙醇的质量体积比优选为25-40mg/ml，例如33.3mg/ml。
所述重结晶结束后，可按照本领域中的常规操作方法进行分离，例如离心或者过滤。
本发明第二十七方面提供了一种按照上述的式I化合物的硫酸盐的晶型D的制备方法制得的式I化合物的硫酸盐的晶型D。
本发明第二十八方面提供了一种式I化合物的硫酸盐的晶型E的制备方法，其包括如下步骤：将式I化合物的硫酸盐一水合物(例如式I化合物的硫酸盐一水合物晶型C)在酯类溶剂-水的混合溶剂(例如乙酸乙酯-水的混合溶剂，二者体积比19:1)中形成悬浊液进行转晶(50℃悬浮搅拌)得到式I化合物的硫酸盐的晶型E。
本发明第二十九方面提供了一种按照上述的式I化合物的硫酸盐的晶型E的制备方法制得的式I化合物的硫酸盐的晶型E。
本发明第三十方面提供了一种式I化合物的硫酸盐的晶型F的制备方法，其包括如下步骤：将式 I化合物的硫酸盐一水合物(例如式I化合物的硫酸盐一水合物晶型C)在亚砜类溶剂(例如二甲亚砜(DMSO))中进行挥发，得到式I化合物的硫酸盐的晶型E。
本发明第三十一方面提供了一种按照上述的式I化合物的硫酸盐的晶型F的制备方法制得的式I化合物的硫酸盐的晶型F。
本发明第三十二方面提供了一种药物组合物，其包含治疗有效剂量的物质A和药学上可接受的赋形剂；所述的物质A为上述的式I化合物的晶型(上述的式I化合物的晶型A、上述的式I化合物的晶型B、上述的式I化合物的晶型C、)、上述的式I化合物的药学上可接受的盐或上述的式I化合物的药学上可接受的盐的晶型(上述的式I化合物的盐酸盐的晶型A、上述的式I化合物的柠檬酸盐的晶型A、上述的式I化合物的马来酸盐的晶型A、上述的式I化合物的富马酸盐的晶型A、上述的式I化合物的甲磺酸盐的晶型A、上述的式I化合物的甲磺酸盐的晶型B、上述的式I化合物的甲磺酸盐的晶型C、上述的式I化合物的对甲苯磺酸盐的晶型A、上述的式I化合物的环拉酸盐的晶型A、上述的式I化合物的硫酸盐的晶型A、上述的式I化合物的硫酸盐的晶型D、上述的式I化合物的硫酸盐的晶型I、上述的式I化合物的硫酸盐的晶型B、上述的式I化合物的硫酸盐的晶型C、上述的式I化合物的硫酸盐的晶型E或上述的式I化合物的硫酸盐的晶型F)。
本发明第三十三方面提供了一种物质B在制备治疗和/或预防疾病的药物中的用途，所述的物质B为上述的药物组合物、上述的式I化合物的晶型(上述的式I化合物的晶型A、上述的式I化合物的晶型B、上述的式I化合物的晶型C、)、上述的式I化合物的药学上可接受的盐或上述的式I化合物的药学上可接受的盐的晶型(上述的式I化合物的盐酸盐的晶型A、上述的式I化合物的柠檬酸盐的晶型A、上述的式I化合物的马来酸盐的晶型A、上述的式I化合物的富马酸盐的晶型A、上述的式I化合物的甲磺酸盐的晶型A、上述的式I化合物的甲磺酸盐的晶型B、上述的式I化合物的甲磺酸盐的晶型C、上述的式I化合物的对甲苯磺酸盐的晶型A、上述的式I化合物的环拉酸盐的晶型A、上述的式I化合物的硫酸盐的晶型A、上述的式I化合物的硫酸盐的晶型D、上述的式I化合物的硫酸盐的晶型I、上述的式I化合物的硫酸盐的晶型B、上述的式I化合物的硫酸盐的晶型C、上述的式I化合物的硫酸盐的晶型E或上述的式I化合物的硫酸盐的晶型F)。
所述的疾病优选为RIPK1介导的疾病，所述的疾病优选为中风、炎症性肠病、溃疡性结肠炎、克罗恩病、牛皮癣、类风湿性关节炎、NASH和心力衰竭中的一种或多种。
或者，所述的疾病优选为中风、炎症性肠病、溃疡性结肠炎、克罗恩病、牛皮癣、类风湿性关节炎、NASH和心力衰竭中的一种或多种。
所述的物质B的用量为有效治疗量。
本发明第三十四方面提供了一种物质B在制备RIPK1抑制剂中的用途，所述的物质B为上述的药物组合物、上述的式I化合物的晶型A、上述的式I化合物的晶型B、上述的式I化合物的晶型C、上述的式I化合物的药学上可接受的盐、上述的式I化合物的盐酸盐的晶型A、上述的式I化合物的柠檬酸盐的晶型A、上述的式I化合物的马来酸盐的晶型A、上述的式I化合物的富马酸盐的晶型A、上述的式I化合物的甲磺酸盐的晶型A、上述的式I化合物的甲磺酸盐的晶型B、上述的式I化合物 的甲磺酸盐的晶型C、上述的式I化合物的对甲苯磺酸盐的晶型A、上述的式I化合物的环拉酸盐的晶型A、上述的式I化合物的硫酸盐的晶型A、上述的式I化合物的硫酸盐的晶型D、上述的式I化合物的硫酸盐的晶型I、上述的式I化合物的硫酸盐的晶型B、上述的式I化合物的硫酸盐的晶型C、上述的式I化合物的硫酸盐的晶型E或上述的式I化合物的硫酸盐的晶型F。
所述的用途中，所述的RIPK1抑制剂优选为体内或体外RIPK1抑制剂。
所述的用途中，所述的RIPK1抑制剂优选用于治疗与RIPK1相关的疾病或病症(例如由RIPK1介导的疾病或病症)。
所述的与RIPK1相关的疾病或病症(例如由RIPK1介导的疾病或病症)包括但不限于炎性疾病(例如克罗恩病和溃疡性结肠炎，炎性肠病，哮喘，移植物抗宿主病，慢性阻塞性肺病)、自身免疫性疾病(例如格雷夫斯病，类风湿性关节炎，系统性红斑狼疮，牛皮癣；破坏性骨病，如骨吸收疾病，骨关节炎，骨质疏松症，多发性骨髓瘤相关性骨病)；增生性疾病(例如急性髓性白血病，慢性粒细胞白血病)、血管生成障碍(如血管生成障碍、包括实体瘤、眼部新生血管和婴儿血管瘤)、感染性疾病(例如败血症，感染性休克和志贺氏菌病)；神经退行性疾病(例如阿尔茨海默病，帕金森病，肌萎缩侧索硬化症，脑缺血或由创伤性损伤引起的神经退行性疾病)、肿瘤和病毒性疾病(如转移性黑色素瘤，卡波西氏肉瘤，多发性骨髓瘤，成纤维细胞瘤，淋巴细胞瘤，HIV感染和CMV视网膜炎，艾滋病)。
所述的与RIPK1相关疾病或病症(例如由RIPK1介导的疾病或病症)包括但不限于胰腺炎(急性或慢性)，哮喘，过敏症，成人呼吸窘迫综合征，慢性阻塞性肺病，肾小球肾炎，类风湿性关节炎，系统性红斑狼疮，硬皮病，慢性甲状腺炎，格雷夫斯病，自身免疫性胃炎，糖尿病，自身免疫性溶血性贫血，自身免疫性中性粒细胞减少症，血小板减少症，特应性皮炎，慢性活动性肝炎，重症肌无力，肌萎缩侧索硬化症，多发性硬化症，炎症性肠病，溃疡性结肠炎，克罗恩病，牛皮癣，移植物抗宿主病，内毒素引起的炎症反应，结核，动脉粥样硬化，肌肉变性，恶病质，银屑病关节炎，瑞特综合征，痛风，创伤性关节炎，风疹关节炎，急性滑膜炎，胰腺β细胞病；以大量中性粒细胞浸润为特征的疾病；类风湿性脊椎炎，痛风性关节炎和其他关节炎病症，脑疟疾，慢性肺部炎症，矽肺病，肺肉瘤病，骨吸收疾病，同种异体移植排斥，感染引起的发热和肌痛，继发于感染的恶病质，类黄体形成，瘢痕组织形成，溃疡结肠炎，发热，流行性感冒，骨质疏松症，骨关节炎，急性髓性白血病，慢性髓性白血病，转移性黑色素瘤，卡波西氏肉瘤，多发性骨髓瘤，败血症，感染性休克和志贺氏菌病；阿尔茨海默病，帕金森病，脑缺血或创伤性损伤引起的神经退行性疾病；血管生成障碍包括实体瘤，眼部新生血管和婴儿血管瘤；病毒性疾病包括急性肝炎感染(包括甲型肝炎，乙型肝炎和丙型肝炎)，艾滋病毒感染和CMV视网膜炎，艾滋病，ARC或恶性肿瘤和疱疹；中风，心肌缺血，中风心脏病发作，器官缺血，血管增生，心脏和肾脏再灌注损伤，血栓形成，心脏肥大，凝血酶诱导的血小板聚集，内毒素血症和/或中毒性休克综合征，与前列腺素内过氧化物酶合成酶-2相关的病症和寻常型天疱疮。
所述的与RIPK1相关疾病或病症(例如由RIPK1介导的疾病或病症)选自：中风、炎性肠病，克罗恩病和溃疡性结肠炎，同种异体移植排斥，类风湿性关节炎，牛皮癣，强直性脊柱炎，银屑病关节炎和寻常型天疱疮。或者优选的病症选自缺血再灌注损伤，包括由中风引起的脑缺血再灌注损伤和由心 肌梗塞引起的心肌缺血再灌注损伤。
术语定义和说明
本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。
本发明的式1化合物的多晶型物以2θ角度表示的X-射线粉末衍射特征峰，其中“±0.20°”为允许的测量误差范围。
本发明的式I化合物的多晶型物可以与其它活性成分组合使用，只要它不产生其他不利作用，例如过敏反应。
本发明所用的术语“组合物”意指包括包含指定量的各指定成分的产品，以及直接或间接从指定量的各指定成分的组合产生的任何产品。
本领域技术人员可以使用已知的药物载体，将本发明的式I化合物的多晶型物制备成适合的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。
所述的药物组合物可配制成多种剂型，便于给药，例如，口服制剂(如片剂、胶囊剂、溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入药物溶媒后可立即使用)。
本发明所用的术语“治疗和/或预防有效量”是引起研究人员、兽医、医生或其他人所寻求的组织、系统、动物或人的生物学或医学应答的药物或药物制剂的量。
当用于上述治疗和/或预防用途时，本发明式I化合物的多晶型物和药物组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定，所述因素包括所治疗的障碍和该障碍的严重程度；所采用的具体化合物的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、性别和饮食；所采用的具体化合物的给药时间、给药途径和排泄率；治疗持续时间；与所采用的具体化合物组合使用或同时使用的药物；及医疗领域公知的类似因素。例如，本领域的做法是，化合物的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。
本发明所用的“多晶型”或“多晶型物”是指具有相同化学组成，但构成该晶体的分子、原子和/或离子的不同空间排列的晶型。尽管多晶型物具有相同的化学组成，但它们的堆积和几何排列不同，并可能表现出不同的物理性质，如熔点、形状、颜色、密度、硬度、可形变性、稳定性、溶解度、溶出速率和类似性质。根据他们的温度-稳定性关系，两种多晶型物可以是单变性或互变性的。对于单变性体系，在温度变化时，两种固相之间的相对稳定性保持不变。相反，在互变性体系中，存在一个过渡温度，在此两种相的稳定性调换((Theory and Origin of Polymorphism in″Polymorphism in Pharmaceutical Solids″(1999)ISBN：)-8247-0237)。这种化合物以不同晶体结构存在的现象被称作药物多晶型现象。
本文所用的术语″室温″或″RT″是指20至25℃(68-77°F)的环境温度。
缩写说明：MeOH：甲醇；2-MeTHF：2-甲基四氢呋喃；EtOH：乙醇；1,4-Dioxane：1,4-二氧六环；IPA：异丙醇；ACN：乙腈；Acetone：丙酮；DCM:二氯甲烷；MIBK：甲基异丁基酮：Toluene：甲苯；EtOAc：乙酸乙酯；n-Heptane：正庚烷；IPAc：乙酸异丙酯；DMSO：二甲亚砜；MTBE：甲基叔丁基醚；DMAc：二甲基乙酰胺；THF：四氢呋喃；NMP:N-甲基吡咯烷酮。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的RIPK1抑制剂的晶型及其酸式盐和其酸式盐的晶型具有对RIPK1酶的抑制活性好、对U937细胞抑制活性高、引湿性低和稳定性好优点，成药前景好。
附图说明
图1为式I化合物无水晶型A的XRPD谱图。
图2为式I化合物无水晶型A的TGA/DSC谱图。
图3为式I化合物无水晶型A的 1H NMR谱图。
图4为式I化合物无水晶型B的XRPD谱图。
图5为式I化合物无水晶型B的TGA/DSC图谱。
图6为式I化合物无水晶型B与式I化合物无水晶型A的 1H NMR对比谱图。
图7为式I化合物的盐酸盐的晶型A的XRPD谱图。
图8为式I化合物的盐酸盐的晶型A的TGA/DSC谱图。
图9为式I化合物的盐酸盐晶型A的 1H NMR谱图。
图10为式I化合物的硫酸盐的晶型A的XRPD谱图。
图11为式I化合物的硫酸盐的晶型A的TGA/DSC谱图。
图12为式I化合物的硫酸盐的晶型A的 1H NMR谱图。
图13为式I化合物的硫酸盐的晶型B的XRPD谱图。
图14为式I化合物的硫酸盐的晶型B的TGA/DSC谱图。
图15为式I化合物的硫酸盐的晶型B的 1H NMR谱图。
图16为式I化合物的硫酸盐水合物的晶型C的XRPD谱图。
图17为式I化合物的硫酸盐水合物的晶型C的TGA/DSC谱图。
图18为式I化合物的硫酸盐水合物的晶型C的 1H NMR谱图。
图19为式I化合物的柠檬酸盐的晶型A的XRPD谱图。
图20为式I化合物的柠檬酸盐的晶型A的TGA/DSC谱图。
图21为式I化合物的柠檬酸盐的晶型A的 1H NMR谱图。
图22为式I化合物的马来酸盐的晶型A的XRPD谱图。
图23为式I化合物的马来酸盐的晶型A的TGA/DSC谱图。
图24为式I化合物的马来酸盐的晶型A的 1H NMR谱图。
图25为式I化合物的富马酸盐的晶型A的XRPD谱图。
图26为式I化合物的富马酸盐的晶型A的TGA/DSC谱图。
图27为式I化合物的富马酸盐的晶型A的 1H NMR谱图。
图28为式I化合物的甲磺酸盐的晶型A的XRPD谱图。
图29为式I化合物的甲磺酸盐的晶型A的TGA/DSC谱图。
图30为式I化合物的甲磺酸盐的晶型A的 1H NMR谱图。
图31为式I化合物的甲磺酸盐的晶型B的XRPD谱图。
图32为式I化合物的甲磺酸盐的晶型B的TGA/DSC谱图。
图33为式I化合物的甲磺酸盐的晶型B的 1H NMR谱图。
图34为式I化合物的甲磺酸盐的晶型C的XRPD谱图。
图35为式I化合物的甲磺酸盐的晶型C的TGA/DSC谱图。
图36为式I化合物的甲磺酸盐的晶型C的 1H NMR谱图。
图37为式I化合物的对甲苯磺酸盐的晶型A的XRPD谱图。
图38为式I化合物的对甲苯磺酸盐的晶型A的TGA/DSC谱图。
图39为式I化合物的对甲苯磺酸盐的晶型A的 1H NMR谱图。
图40为式I化合物的环拉酸盐的晶型A的XRPD谱图。
图41为式I化合物的环拉酸盐的晶型A的TGA/DSC谱图。
图42为式I化合物的环拉酸盐的晶型A的 1H NMR谱图。
图43为式I化合物的硫酸盐的晶型D的XRPD谱图。
图44为式I化合物的硫酸盐的晶型D的TGA/DSC谱图。
图45为式I化合物的硫酸盐的晶型D的 1H NMR谱图。
图46为式I化合物的硫酸盐的晶型I的XRPD谱图。
图47为式I化合物的硫酸盐的晶型E的XRPD谱图。
图48为式I化合物的硫酸盐的晶型E的TGA/DSC谱图。
图49为式I化合物的硫酸盐的晶型E的 1H NMR谱图。
图50为式I化合物的硫酸盐的晶型F的XRPD谱图。
图51为式I化合物的硫酸盐的晶型F的TGA/DSC谱图。
图52为式I化合物的硫酸盐的晶型F的 1H NMR谱图。
图53为式I化合物的晶型C的XRPD谱图。
图54为式I化合物的晶型C的TGA/DSC谱图。
图55为实施例9制得的晶型C的DVS谱图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
仪器和方法
运用多种检测分析方法对得到的固体样品进行了分析，例如粉末X射线衍射(XRPD)、差示扫描量热法(DSC)和热重分析(TGA)、动态水分吸附(DVS)、氢谱液体核磁( 1H Solution NMR)。
(1)粉末X射线衍射(XRPD)：XRPD结果是在PANalytical Empyrean和X’Pert3 X射线粉末衍射分析仪上采集，扫描参数如表1所示。
表1 XRPD测试参数(I/II)
Figure PCTCN2022109562-appb-000021
(2)热重分析(TGA)和差示扫描量热(DSC)：TGA和DSC图分别在TA Q5000/Discovery 5500热重分析仪和TA Q2000/Discovery 2500差示扫描量热仪上采集，表2列出了测试参数。
表2 TGA和DSC测试参数
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铝盘，敞开 铝盘，压盖
温度范围 RT-350℃ RT-目标温度
加热速率 10℃/min 10℃/min
保护气体 氮气 氮气
(3)动态水分吸附(DVS)：动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl、Mg(NO 3) 2和KCl的潮解点校正。DVS测试参数列于表3。
表3 DVS测试参数
Figure PCTCN2022109562-appb-000022
Figure PCTCN2022109562-appb-000023
(4)氢谱液体核磁( 1H Solution NMR)：氢谱液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d 6作为溶剂。
(5)水分滴定(KF)：水分滴定通过仪器Metrohm 870 KF Titrinoplus进行，以超纯水进行校正，滴定试剂为
Figure PCTCN2022109562-appb-000024
R-Composite 5，生产厂家为Sigma-aldrich。HPLC级甲醇用于溶解固体样品。
(6)高效液相色谱(HPLC)：试验中纯度和溶解度由安捷伦1260高效液相色谱仪测试，分析条件如表4所示。
表4纯度测试的高效液相色谱测试条件
Figure PCTCN2022109562-appb-000025
Figure PCTCN2022109562-appb-000026
(7)离子色谱(IC)：试验中使用ThermoFisher ICS-1100离子色谱仪分析离子含量，具体条件见表5。
表5离子色谱条件和参数
IC ThermoFisher ICS-1100
色谱柱 IonPac AS18 Analytical Column(4×250mm)
流动相 25mM NaOH
进样体积 25μL
流速 1.0mL/min
样品池温度 35℃
柱温 35℃
电流 80mA
运行时间 6.0min(Cl -),11.0min(SO 4 2-)
制备例1式I化合物的制备
Figure PCTCN2022109562-appb-000027
步骤一：7-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺的合成：向250mL圆底烧瓶中加入7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺(4.0g,18.78mmol)，联硼酸频那醇酯(5.723g,22.53mmol),醋酸钾(4.601g,46.95mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(767mg,0.939mmol)和1,4-二氧六环(50ml),氮气置换三次，90℃反应过夜，冷却至室温，抽滤，用乙酸乙酯清洗滤饼三次，得滤液，浓缩后得到粗品7-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(2.6g,Y:78％)。ES-API:[M+H] +＝179.1。
步骤二：5-溴-2-乙烯基烟酸甲酯的合成：氮气保护下，将5-溴-2-氯烟酸甲酯(10g,39.923mmol),乙烯基三氟硼酸钾(5.348g,39.923mmol)，三乙胺(5.56mL,39.923mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(585mg,0.798mmol)溶解在200mL EtOH，氮气置换三次，80℃反应1小时，冷却至室温，过 滤，滤液旋干。将残渣溶解在300mL乙酸乙酯和300mL水中，分离，浓缩有机相，残渣使用自动快速色谱法(EtOAc/PE 0-20％)在硅胶上纯化得到5-溴-2-乙烯基烟酸甲酯(5.186g,Y:54％)。ES-API:[M+H] +＝242.1。
步骤三：3-溴-6-(2-氟-5-(三氟甲氧基)苄基)-7,8-二氢-1,6-萘啶-5(6H)-酮的合成：在微波瓶中，将5-溴-2-乙烯基烟酸甲酯(2.5g,10.328mmol)和(2-氟-5-(三氟甲氧基)苯基)甲胺(4.32g,20.656mmol)在DMA(75mL)中混合。将反应在150℃下微波辐射3小时，冷却至室温，反应液加入100mL乙酸乙酯，然后用水(30mL x 3)和饱和食盐水(30mL x 3)洗涤，浓缩合并的有机层，使用自动快速色谱法(EtOAc/PE 0-20％)在硅胶上纯化得到3-溴-6-(2-氟-5-(三氟甲氧基)苄基)-7,8-二氢-1,6-萘啶-5(6H)-酮(2.356g,Y:54％)。ES-API:[M+H] +＝419.1。
步骤四：3-(2-氨基-[1,2,4]三唑并[1,5-a]吡啶-7-基)-6-(2-氟-5-(三氟甲氧基)苄基)-7,8-二氢-1,6-萘啶-5(6H)-酮的合成：氮气保护下，将3-溴-6-(2-氟-5-(三氟甲氧基)苄基)-7,8-二氢-1,6-萘啶-5(6H)-酮(1.885g,4.499mmol)，7-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(1.602g,8.998mmol)，碳酸钠(1.192g,11.248mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(184mg,0.225mmol)溶解在30mL二氧六环和6mL H 2O中，氮气置换三次，95℃反应过夜。冷却至室温，反应液加入50mL EtOAc，然后用水(30mL x 3)和饱和食盐水(30mL x 3)洗涤，浓缩合并的有机层，残渣使用自动快速色谱法(EtOAc/PE 0-100％，随后，DCM/MeOH 0-4％)在硅胶上纯化得到纯度为95％的淡黄色化合物3-(2-氨基-[1,2,4]三唑并[1,5-a]吡啶-7-基)-6-(2-氟-5-(三氟甲氧基)苄基)-7,8-二氢-1,6-萘啶-5(6H)-酮(式I化合物，1.426g,Y:67％)。ES-API:[M+H] +＝473.0。 1H NMR(400MHz,DMSO-d6)δ9.10(d,J＝2.4Hz,1H),8.64(d,J＝6.8Hz,1H),8.52(d,J＝2.4Hz,1H),7.80(d,J＝1.6Hz,1H),7.40-7.45(m,3H),7.30(dd,J1＝2.0Hz,J2＝6.8Hz,1H),6.10(s,2H),4.82(s,2H),3.73(t,J＝6.8Hz,2H),3.21(t,J＝6.8Hz,2H)。
生物测试
以下测试例中所使用的U937细胞株来源于ATCC，编号：CRL-1593.2，批号：63479999，培养液：RPMI-1640+10％FBS。以下测试例中所使用的L929细胞株来源于ATCC，编号：CCL-1，批号：70001022，培养液：MEM+10％FBS+1％PS。所使用的试剂、其供应商、货号如下：RPMI-1640，Gibco，11875-093；FBS，Gibco，10099-141；Trypsin-EDTA，Gibco，25200-072；PS，Gibco，15140-122；CellTiter Glo，Progema，G7573；DMSO，VWR AMRESCO，0231-500ML；TNF-α蛋白(人，重组)，Peprotech，300-01A；Q-VD-Oph，MCE，HY-12305；V型底板，Corning，3894；384孔低法兰白色平底微孔板，Corning，3570；RIPK1，Eurofins，16-022；MOPS，BDH，441644J；EDTA，Sigma，E5134；髓鞘碱性蛋白，Sigma，M1891-25.00MG；醋酸镁，Merck，DU008026；ATP(非放射性标记)，Sigma，A-7699；ATP(放射性标记)，Hartmann Analytic，DU008054；磷酸，Metlab，DU003000；Z-VAD：上海与昂化工，YA02401。
测试例1：式I化合物对TNF-α诱导的细胞程序性坏死的抑制活性
待测化合物溶解在DMSO中，用DMSO稀释成系列浓度梯度。5000个/孔U937细胞接种于384 孔白板中，各孔中加入相应浓度的化合物与细胞混合均匀，同时加入人TNF-α和Q-VD-Oph诱导细胞发生程序性坏死，将细胞放置于37℃，5％CO 2培养箱中继续培养48小时。检测使用CellTiter-Glo试剂，充分裂解反应后使用酶标仪检测化学发光读值。检测结果使用公式计算存活率SR(％)＝(RLU化合物–RLU空白)/(RLU high control–RLU空白)×100％，存活率和对应的化合物的终浓度绘制成曲线，使用四参数拟合，计算化合物对TNF-α诱导的细胞程序性坏死的抑制IC 50。结果，式I化合物对U937细胞有较高的抑制活性，IC 50值为6nM。
测试例2：式I化合物对RIPK1酶的抑制活性
将待测化合物溶解在DMSO中，制备成10mM的储备液，按照3.16倍用DMSO稀释成系列浓度梯度，之后使用MOPS pH 7.0缓冲溶液稀释50倍制备成工作液，和36nM RIPK1(终浓度)，0.33mg/ml底物MBP混匀。之后加入10mM的镁离子，155μM磷33同位素标记的ATP进行反应，DMSO终浓度为2％，室温反应2小时后加入磷酸终止。最终反应体系经处理后使用液体闪烁计数器进行检测。检测后的结果减去空白对照后和对照组的读值相比换算成活性百分比，和对应的化合物的终浓度绘制成曲线，使用四参数拟合，获得化合物对RIPK1酶活抑制的IC 50。结果，式I化合物对RIPK1具有较高的抑制活性，IC 50值为39nM。
测试例3：式I化合物对TNF-α诱导的L929细胞程序性坏死的抑制活性
化合物溶解在DMSO中，制备成10mM的储备液，按照3.16倍用DMSO稀释成系列浓度梯度，之后使用培养基稀释100倍制成工作液。10000个/孔L929细胞接种于384孔白板中，各孔中加入相应浓度的化合物与细胞混合均匀，同时加入30ng/ml鼠TNF-α和15μM Z-VAD诱导细胞发生程序性坏死，DMSO终浓度为0.2％，将细胞放置于37℃，5％CO2培养箱中继续培养6小时。检测使用CellTiter-Glo试剂，充分裂解反应后使用酶标仪检测化学发光读值。检测结果使用公式计算存活率SR(％)＝(RLU化合物-RLU空白)/(RLU high control-RLU空白)×100％，存活率和对应的化合物的终浓度绘制成曲线，使用四参数拟合，计算化合物对TNF-α诱导的细胞程序性坏死的抑制IC 50。结果，式I化合物对L929细胞具有较高的抑制活性，IC 50值为3nM。
实施例1式I化合物(游离碱)无水晶型A的制备
氮气保护下，将3-溴-6-(2-氟-5-(三氟甲氧基)苄基)-7,8-二氢-1,6-萘啶-5(6H)-酮(制备例1步骤二至三制备106g,252.88mmol)，7-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(制备例1步骤一制备，111.82g,429.89mmol)，碳酸钠(67g,632.2mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(10.3g,12.64mmol)溶解在1.5L二氧六环和300mL H 2O中，氮气置换三次，100℃反应过夜。冷却至室温，反应液用硅藻土垫滤，滤液加入20g活性炭，升温至100℃搅拌20分钟。过滤，滤液浓缩干，加入甲醇(500mL)，室温打浆，过滤，滤饼与50℃下干燥2小时。粗品加入30倍质量体积的二氯甲烷/甲醇＝2:1，15g活性炭，回流搅拌30分钟，趁热过滤，滤液冷却过滤，滤饼用甲醇(500mL)打浆，过滤，滤饼于50℃下干燥4小时，得目标产物3-(2-氨基-[1,2,4]三唑并[1,5-a]吡啶-7-基)-6-(2-氟-5-(三氟甲氧基)苄基)-7,8-二氢-1,6-萘啶-5(6H)-酮(式I化合物，103g，收率：86.5％，纯度为99.03％)。
对目标产物进行XRPD、TGA、DSC、 1H NMR和HPLC表征。XPRD如图1所示，该样品为晶体，命名为游离碱无水晶型A，其X射线粉末衍射数据如下表6所示。TGA/DSC和 1H NMR(DMSO-d6)结果如图2和图3所示。TGA结果显示样品在175℃前有1.1％的失重，DSC结果显示在191.6℃和240.5℃(峰值温度)处有两个吸热峰。
表6
Figure PCTCN2022109562-appb-000028
实施例2式I化合物(游离碱)无水晶型B的制备
对实施例1得到的式I化合物游离碱无水晶型A进行加热试验，使用DSC在氮气保护下将样品加热至210℃并降至室温，得到式I化合物无水晶型B。对所得固体进行了XRPD、TGA、DSC及 1H NMR(DMSO-d6)表征。XRPD和TGA/DSC结果如图4和5所示，其X射线粉末衍射数据如下表7所示。TGA结果显示在200℃前有2.2％的失重，DSC结果显示在240.1℃(峰值温度)处有一个尖锐的吸热峰。游离碱无水晶型B与游离碱无水晶型A的核磁对比图见图6，结果显示两样品核磁图谱一致。
表7
Figure PCTCN2022109562-appb-000029
Figure PCTCN2022109562-appb-000030
实施例3式I化合物的盐酸盐的晶型A的制备
将实施例1得到的式I化合物游离碱无水晶型A(20mg,0.0424mmol)样品和2倍摩尔量的盐酸(3.09mg,0.085mmol)至HPLC小瓶中，加入0.5mL甲醇混合得到悬浊液，室温下磁力搅拌(～750rpm)约5天,5℃下磁力搅拌(～750rpm)4天，对所得澄清液体进行反溶剂(乙酸乙酯)添加后对分离固体，室温真空干燥一天制备得到式I化合物盐酸盐晶型A。通过HPLC和IC测试结果确定Cl -与API的摩尔比为2.0:1。XRPD和TGA/DSC及 1H NMR表征结果分别如图7和图8和图9所示。式I化合物盐酸盐晶型A，其X射线粉末衍射数据如下表8所示。TGA显示盐酸盐晶型A加热至100℃有4.8％的失重。DSC显示该样品在156.8℃(峰值温度)处有一个吸热峰。
表8
Figure PCTCN2022109562-appb-000031
实施例4式I化合物的硫酸盐水合物的晶型C的制备
向100mL圆底烧瓶中加入实施例1制备的式I化合物游离碱无水晶型A(6.15g，13.02mmol)和乙腈(62mL)，油浴升温至80℃。搅拌下逐滴加入10％的硫酸水溶液(14g，14.29mmol)。升温至回流溶清，搅拌下自然冷却至室温，过滤，滤饼用乙腈淋洗，干燥得到式I化合物硫酸盐一水合物晶型C(7.3g，收率：98％)。据HPLC和IC结果确定SO 4 2-与API的摩尔比为1.0:1。XRPD、TGA/DSC、 1H NMR(DMSO-d6)表征结果分别如图16、图17和图18所示，其X射线粉末衍射数据如下表9所示。式I化合物硫酸盐一水合物晶型C的 1H NMR:δ9.14(d,J＝2.4Hz,1H),8.85(d,J＝7.2Hz,1H),8.58(d,J＝2.4Hz,1H),7.97(d,J＝1.6Hz,1H),7.64(d,J＝2.0Hz,1H),7.44(m,3H),4.83(s,2H),3.76(t,J＝6.8Hz,2H),3.24(t,J＝6.8Hz,2H)。TGA结果显示加热至175℃有3.9％的失重，DSC结果显示在129.2℃(峰值温度)和152.8℃(峰值温度)处有一个重叠的吸热峰，在200.2℃(峰值温度)处有一个较小的吸热峰。 1H NMR结果显示未检测出溶剂残留。KF测试结果显示样品水含量为3.18％。
表9
Figure PCTCN2022109562-appb-000032
实施例5式I化合物的硫酸盐的晶型A的制备
称取实施例4得到的式I化合物硫酸盐一水合物晶型C约20mg加至5mL的小瓶内，用0.1～1.5mL的良溶剂甲醇溶解后，向该澄清溶液中加入4.5mL反溶剂2-甲基四氢呋喃，边滴加边搅拌。在加完反溶剂后得到澄清溶液，后在室温下搅拌3天观察到固体析出，离心分离出固体，室温晾干得到式I化合物硫酸盐无水晶型A。据HPLC和IC结果确定SO 4 2-与API的摩尔比为1.0:1。XRPD和TGA/DSC及 1H NMR表征结果如图10、图11和图12所示。式I化合物硫酸盐无水晶型A，其X射线粉末衍 射数据如下表10所示。TGA显示加热至175℃有3.4％的失重。DSC显示在70.6℃，123.3℃和205.1℃(峰值温度)处有三个吸热峰。 1H NMR结果显示未检测出溶剂残留。
表10
Figure PCTCN2022109562-appb-000033
实施例6式I化合物的硫酸盐的晶型A的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的硫酸(4.16mg,0.0424mmol)至HPLC小瓶中，加入0.5mL甲醇，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到。对其进行XRPD、TGA、DSC及 1H NMR表征，各个图谱基本同实施例5中的图谱。
实施例7式I化合物的硫酸盐的晶型B的制备
称取实施例4得到的式I化合物硫酸盐一水合物晶型C约20mg于3mL小瓶中，另在20mL小瓶中加入约4mL二氯甲烷溶剂，将3mL小瓶敞口置于20mL小瓶中后，将20mL小瓶密封。室温下静置～7天后收集固体得到式I化合物硫酸盐晶型B。据HPLC和IC结果确定SO 4 2-与API的摩尔比为1.1:1。XRPD和TGA/DSC及 1H NMR结果如图13和图14和图15所示。式I化合物硫酸盐晶型B，其X射线粉末衍射数据如下表11所示。TGA结果显示升温至150℃有2.9％的失重。DSC结果显示，样品在77.9℃、118.8℃和196.8℃(峰值温度)处有三个吸热峰。 1H NMR结果显示未检测到溶剂残留。
表11
Figure PCTCN2022109562-appb-000034
Figure PCTCN2022109562-appb-000035
实施例8式I化合物的硫酸盐的晶型B的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的硫酸(4.16mg,0.0424mmol)至HPLC小瓶中，加入0.5mL丙酮，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到。对其进行XRPD、TGA、DSC及 1H NMR表征，各个图谱基本同实施例7中的图谱，为式I化合物硫酸盐晶型B。
实施例9式I化合物的硫酸盐水合物的晶型C的制备
称量实施例4得到的式I化合物硫酸盐一水合物晶型C约20mg至HPLC小瓶中，分别加入0.6mL乙腈溶剂，得到的悬浊液置于50℃下磁力搅拌(～750rpm)约3天，离心分离固体对其进行XRPD、TGA、DSC及 1H NMR表征，各个图谱基本同实施例4中的图谱，为式I化合物硫酸盐一水合物晶型C。
实施例10式I化合物的硫酸盐水合物的晶型C的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的硫酸(4.16mg,0.0424mmol)至HPLC小瓶中，加入0.5mL乙腈/水(9:1,v/v)，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到。对其进行XRPD、TGA、DSC及 1H NMR表征，各个图谱基本同实施例4中的图谱，为式I化合物硫酸盐一水合物晶型C。
实施例11式I化合物的柠檬酸盐的晶型A的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的无水柠檬酸(8.15mg,0.0424mmol)至HPLC小瓶中，加入0.5mL乙酸乙酯，室温悬浮搅拌5天，所得固体在室温下真空干 燥1天得到式I化合物柠檬酸盐晶型A。XRPD和TGA/DSC及 1H NMR表征结果如图19、图20和图21所示。式I化合物柠檬酸盐晶型A，其X射线粉末衍射数据如下表12所示。TGA显示柠檬酸晶型A样品加热至150℃有1.1％的失重。DSC显示该样品在166.4℃处有一个尖锐的吸热峰。 1H NMR结果表明样品的柠檬酸和游离碱的摩尔比为1.0:1。
表12
Figure PCTCN2022109562-appb-000036
实施例12式I化合物的马来酸盐的晶型A的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的马来酸(4.92mg,0.0424mmol)至HPLC小瓶中，加入0.5mL丙酮，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到式I化合物马来酸盐晶型A。XRPD和TGA/DSC及 1H NMR表征结果如图22、图23和图24所示。式I化合物马来酸晶型A，其X射线粉末衍射数据如下表13所示。TGA显示马来酸盐晶型A样品加热至150℃有3.3％的失重，从150℃加热至250℃有13.6％的失重。DSC显示该样品在176.0℃(起始温度)和210.7℃(峰值温度)处有两个吸热峰。 1H NMR结果表明样品的马来酸和游离碱的摩尔比为0.8:1。
表13
Figure PCTCN2022109562-appb-000037
Figure PCTCN2022109562-appb-000038
实施例13式I化合物的富马酸盐的晶型A的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的富马酸(4.92mg,0.0424mmol)至HPLC小瓶中，加入0.5mL乙酸乙酯，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到式I化合物富马酸盐晶型A。XRPD和TGA/DSC及 1H NMR表征结果如图25、图26和图27所示。式I化合物富马酸盐晶型A，其X射线粉末衍射数据如下表14所示。TGA显示富马酸盐晶型A加热至150℃有1.8％的失重。DSC显示该样品在182.5℃、192.9℃、211.8℃和219.2℃(峰值温度)处有四个吸热峰，在123.0℃、184.8℃和196.9℃(峰值温度)处有三个放热峰。 1HNMR结果表明样品的富马酸和游离碱的摩尔比为0.9:1，未检测出溶剂残留。
表14
Figure PCTCN2022109562-appb-000039
实施例14式I化合物的甲磺酸盐的晶型A的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的甲磺酸(4.08mg,0.0424mmol)至HPLC小瓶中，加入0.5mL丙酮，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到式I化合物甲磺酸盐晶型A。XRPD和TGA/DSC及 1HNMR表征结果如图28、图29和图30所示。该甲磺酸盐晶型A，其X射线粉末衍射数据如下表15所示。TGA显示甲磺酸盐晶型A加热至110℃有2.9％的失重。DSC显示该样品在92.5℃和138.6℃(峰值温度)处有两个吸热峰。 1H NMR结果表明样品的甲磺酸和游离碱的摩尔比为1.0:1，未检测出溶剂残留。
表15
Figure PCTCN2022109562-appb-000040
实施例15式I化合物的甲磺酸盐的晶型B的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的甲磺酸(4.08mg,0.0424mmol)至HPLC小瓶中，加入0.5mL乙酸乙酯，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到式I化合物甲磺酸盐晶型B。XRPD和TGA/DSC及 1H NMR表征结果如图31、图32和图33所示。该甲磺酸盐晶型B，其X射线粉末衍射数据如下表16所示。TGA显示甲磺酸盐晶型B加热至150℃有2.8％的失重。DSC显示该样品在171.3℃和194.7℃(峰值温度)处有两个吸热峰。 1H NMR结果表明样品的甲磺酸和游离碱的摩尔比为1.0:1，未检测出溶剂残留。
表16
Figure PCTCN2022109562-appb-000041
Figure PCTCN2022109562-appb-000042
实施例16式I化合物的甲磺酸盐的晶型C的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的甲磺酸(4.08mg,0.0424mmol)至HPLC小瓶中，加入0.5mL ACN/H 2O(9:1,v/v)，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到式I化合物甲磺酸盐晶型C。XRPD和TGA/DSC及 1H NMR表征结果如图34、图35和图36所示。式I化合物甲磺酸盐晶型C，其X射线粉末衍射数据如下表17所示。TGA显示甲磺酸盐晶型C加热至150℃有4.9％的失重。DSC显示该样品在108.2℃、181.9℃和233.2℃(峰值温度)处有三个吸热峰。 1H NMR结果表明样品的甲磺酸和游离碱的摩尔比为0.3:1。
表17
Figure PCTCN2022109562-appb-000043
实施例17式I化合物的对甲苯磺酸盐的晶型A的制备
将实施例1得到的将游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的对甲苯磺酸 (7.30mg,0.0424mmol)至HPLC小瓶中，加入0.5mL丙酮，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到式I化合物对甲苯磺酸盐晶型A。XRPD和TGA/DSC及 1H NMR表征结果如图37、图38和图39所示。式I化合物对甲苯磺酸盐晶型A，其X射线粉末衍射数据如下表18所示。TGA显示对甲苯磺酸盐晶型A加热至150℃有1.6％的失重。DSC显示该样品在205.6℃(峰值温度)处有一个吸热峰。 1H NMR(结果表明样品的对甲苯磺酸和游离碱的摩尔比为0.9:1。
表18
Figure PCTCN2022109562-appb-000044
实施例18式I化合物的环拉酸盐的晶型A的制备
将实施例1得到的游离碱无水晶型A(20mg,0.0424mmol)和等摩尔量的环拉酸(7.60mg,0.0424mmol)至HPLC小瓶中，加入0.5mL在EtOAc，室温悬浮搅拌5天，所得固体在室温下真空干燥1天得到式I化合物环拉酸盐晶型A。XRPD和TGA/DSC及 1H NMR表征结果如图40、图41和图42所示。式I化合物环拉酸盐晶型A，其X射线粉末衍射数据如下表19所示。TGA显示环拉酸盐晶型A加热至150℃有0.7％的失重。DSC显示该样品在202.3℃和231.3℃(峰值温度)处有两个吸热峰，在118.2℃和205.4℃(峰值温度)处有两个放热峰。 1H NMR结果表明样品的环拉酸和游离碱的摩尔比约为0.9:1，未检测出溶剂残留。
表19
Figure PCTCN2022109562-appb-000045
实施例19式I化合物的硫酸盐的晶型D的制备
称量实施例4得到的式I化合物硫酸盐一水合物晶型C约20mg至HPLC小瓶中，分别加入0.6mL正丙醇，得到的悬浊液置于50℃下磁力搅拌(～750rpm)约3天，离心分离固体得到式I化合物硫酸盐无水晶型D。据HPLC和IC测试确定SO 4 2-与API的摩尔比为1.1:1。XRPD和TGA/DSC及 1H NMR结果如图43、图44和图45所示。式I化合物硫酸盐无水晶型D，其X射线粉末衍射数据如下表20所示。TGA结果显示升温至125℃有3.0％的失重。DSC结果显示，样品在111.9℃、153.2℃和197.7℃(峰值温度)处有三个吸热峰。结果显示未检测到溶剂残留。
表20
Figure PCTCN2022109562-appb-000046
Figure PCTCN2022109562-appb-000047
实施例20式I化合物的硫酸盐的晶型I的制备
在N 2保护下加热实施例4得到的硫酸盐一水合物晶型C样品至130℃后降温至30℃得到式I化合物硫酸盐晶型I。XRPD结果如图46所示。式I化合物硫酸盐晶型I，其X射线粉末衍射数据如下表21所示。
表21
Figure PCTCN2022109562-appb-000048
实施例21式I化合物的硫酸盐的晶型E的制备
称量实施例4得到的式I化合物硫酸盐一水合物晶型C约20mg至HPLC小瓶中，分别加入 0.5～1.0mL(EtOAc/H 2O(19:1,v/v))溶剂，得到的悬浊液置于室温下磁力搅拌(～750rpm)3天，离心分离固体得到式I化合物硫酸盐晶型E。据HPLC和IC结果确定SO 4 2-与API的摩尔比为1.3:1。XRPD和TGA/DSC及 1H NMR结果如图47、图48和图49所示。式I化合物硫酸盐晶型E，其X射线粉末衍射数据如下表22所示。TGA结果显示升温至150℃有5.9％的失重。DSC结果显示，样品在82.2℃、138.6℃和205.4℃(峰值温度)处有三个吸热峰。
表22
Figure PCTCN2022109562-appb-000049
实施例22式I化合物的硫酸盐的晶型F的制备
称取实施例4得到的式I化合物硫酸盐一水合物晶型C约20mg于3mL小瓶中，另在20mL小瓶中加入约4mL DMSO溶剂，将3mL小瓶敞口置于20mL小瓶中后，将20mL小瓶密封。室温下静置～7天后收集固体得到式I化合物硫酸盐晶型F。据HPLC和IC结果确定SO 4 2-与API的摩尔比为1.1:1。XRPD和TGA/DSC及 1H NMR结果如图50、图51和图52所示。式I化合物硫酸盐晶型F，其X射线粉末衍射数据如下表23所示。TGA结果显示升温至160℃有6.4％的失重，从160℃加热至225℃有6.9％的失重。DSC结果显示，样品在123.6℃和185.2℃(峰值温度)处有两个吸热峰，在206.0℃(峰值温度)处有一个放热峰。
表23
Figure PCTCN2022109562-appb-000050
Figure PCTCN2022109562-appb-000051
实施例23式I化合物的晶型C的制备
称取实施例4得到的式I化合物硫酸盐一水合物晶型C约20mg于3mL小瓶中，使用～2.0mL(EtOH/DMF(9:1,v/v))的溶剂将固体溶清，装入约2mg混合高聚物(由聚己酸内酯，聚乙二醇，聚甲基丙烯酸甲酯，海藻酸钠和羟乙基纤维素等质量混合)，用封口膜封住装有滤液的小瓶并在上面扎3～5个小孔，放置在室温下缓慢挥发，收集所得固体得到式I化合物游离碱晶型C。式I化合物游离碱晶型C，其X射线粉末衍射数据如下表24所示。XRPD和TGA/DSC结果如图53和图54所示，显示样品加热至150℃有3.2％的失重；在64.9℃、200.1℃和237.0℃(峰值温度)处有三个吸热峰。
表24
Figure PCTCN2022109562-appb-000052
Figure PCTCN2022109562-appb-000053
溶解度
室温下测试了由实施例1得到的式I化合物游离碱无水晶型A和由实施例4得到的式I化合物硫酸盐一水合物晶型C在不同溶剂体系中的粗略溶解度。称取～2mg的固体样品加入到HPLC小瓶中，再逐步(依次50/50/200/700μL)加入对应溶剂后震荡直至固体溶清。若溶剂加到1mL后样品仍未溶清，则不再增加溶剂。根据固体样品质量、添加溶剂的体积和观察到的溶解现象计算得到的粗略溶解度范围如表25-1及表25-2所示。
表25-1室温下由实施例1得到的式I化合物游离碱无水晶型A的粗略溶解度
溶剂 溶解度(mg/mL) 溶剂 溶解度(mg/mL)
甲醇 S<1.8 乙腈 S<1.9
乙醇 S<2.2 正庚烷 S<1.7
异丙醇 S<1.9 水 S<2.1
丙酮 S<1.8 二甲亚砜* 7.7<S<23.0
*：在50℃条件下溶清。
表25-2室温下由实施例4得到的式I化合物硫酸盐一水合物晶型C的粗略溶解度
溶剂 溶解度(mg/mL) 溶剂 溶解度(mg/mL)
甲醇 7.3<S<22.0 乙腈 S<2.4
乙醇 2.0<S<6.7 正庚烷 S<2.3
异丙醇* S<2.4 水 S<2.4
丙酮 S<2.4 二甲亚砜 S>42.0
*：在50℃条件下溶清。
无水晶型/水合物间转化关系研究
为了进一步研究硫酸盐无水晶型/水合物晶型间的转化关系。
设置了由实施例5得到的硫酸盐无水晶型A和由实施例19得到的硫酸盐无水晶型D之间的混悬竞争试验，包括在MeOH中5℃、25℃和50℃及在ACN中25℃条件。(试验编号A1至A4)
设置了由实施例4得到的硫酸盐一水合物晶型C和实施例5得到的硫酸盐无水晶型A间的室温混悬竞争试验，包括室温下在不同水活度的ACN/H 2O(a w＝0/0.2/0.4/0.6/.0.8)中的混悬竞争试验。(试验编号B1至B5)
具体步骤如下：1)配制室温下硫酸盐在不同溶剂体系中的饱和溶液；2)将等质量的相应硫酸盐晶型样品(各约5mg)分别加入到1mL的饱和溶液中形成悬浊液；3)分别在相应的温度条件下磁力搅拌；4)分离剩余固体测试XRPD。
试验结果汇总于表26。无水晶型间的混悬竞争试验在不同溶剂体系，不同温度条件下搅拌后均得到无水晶型A；水合物和室温稳定的无水晶型A之间的室温混悬竞争试验，在水活度～0的溶剂体系中搅拌后得到无水晶型A；在水活度～0.2和～0.8之间得到水合物晶型C，表明无水晶型A和水合物晶型C转变的关键水活度点在0～0.2之间；在水中(a w～1)搅拌后得到游离碱晶型A，表明硫酸盐在高水活度(～1)条件下易发生歧化。
结合筛选及热力学关系研究结果，硫酸盐一水合物晶型C在室温不同水活度条件下热力学稳定区间较广。
表26硫酸盐晶型混悬竞争试验结果
试验编号 溶剂(v:v) 温度(℃) 水活度a w 结果
A1 MeOH 5 ～0 硫酸盐无水晶型A
A2 MeOH 25 ～0 硫酸盐无水晶型A
A3 MeOH 50 ～0 硫酸盐无水晶型A
A4 ACN 25 ～0 硫酸盐无水晶型A
B1 ACN 25 ～0 硫酸盐无水晶型A
B2 ACN/H 2O(991:9) 25 ～0.2 硫酸盐一水合物晶型C
B3 ACN/H 2O(978:22) 25 ～0.4 硫酸盐一水合物晶型C
B4 ACN/H 2O(96:4) 25 ～0.6 硫酸盐一水合物晶型C
B5 ACN/H 2O(926:74) 25 ～0.8 硫酸盐一水合物晶型C
B6 H 2O 25 ～1 游离碱晶型A
引湿性
通过25℃下0％RH～95％RH之间的DVS测试对由实施例9得到的硫酸盐一水合物晶型C样品的引湿性进行了评估。DVS结果如图55所示。如结果所示，硫酸盐一水合物晶型C样品在25℃/80％RH时吸湿增重约为0.27％，表明样品略有引湿性。XRPD结果显示DVS测试后硫酸盐一水合物 晶型C样品未发生晶型变化。
固态稳定性
分别称取适量由实施例9或实施例4得到的硫酸盐一水合物晶型C样品在60℃条件下闭口放置24小时，40℃/75％RH条件下敞口放置一周。将不同条件下分离出的固体样品，分别通过XRPD测试晶型变化，HPLC测试纯度评估化学稳定性。评估结果汇总于表27中，硫酸盐一水合物晶型C在稳定性测试前后的XRPD对比结果显示，两批次硫酸盐一水合物晶型C样品在两种测试条件下均未出现HPLC纯度的明显降低，晶型未发生改变，表明其在测试条件下具有较好的理化稳定性。
表27硫酸盐一水合物晶型C的固态稳定性评估结果
Figure PCTCN2022109562-appb-000054
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (13)

  1. 一种式I化合物的晶型，其特征在于，其为式I化合物的晶型A、式I化合物的晶型B或式I化合物的晶型C；
    Figure PCTCN2022109562-appb-100001
    所述的式I化合物的晶型A，其以2θ角度表示的X-射线粉末衍射图在10.94±0.2°、16.43±0.2°、19.12±0.2°和19.81±0.2°处有衍射峰；
    所述的式I化合物的晶型B，其以2θ角度表示的X-射线粉末衍射图在27.64±0.2°、24.48±0.2°、3.76±0.2°和19.30±0.2°处有衍射峰；
    所述的式I化合物的晶型C，其以2θ角度表示的X-射线粉末衍射图在19.55±0.2°、29.51±0.2°、19.99±0.2°和20.26±0.2°处有衍射峰。
  2. 如权利要求1所述的式I化合物的晶型，其特征在于，
    当所述的式I化合物的晶型为式I化合物的晶型A时，所述的式I化合物的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.25±0.2°、22.32±0.2°、27.55±0.2°、20.23±0.2°和18.41±0.2°；
    (2)所述的式I化合物的晶型A，其热重分析图在起始加热至175±5℃处失重为0.5％-2％，例如1.1％；
    (3)所述的式I化合物的晶型A，其差示扫描量热图191.6±5℃和/或240.5±5℃处有吸热峰；
    或，
    当所述的式I化合物的晶型为式I化合物的晶型B时，所述的式I化合物的晶型B满足如下1个或多个条件：
    (1)所述的式I化合物的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：16.11±0.2°、18.48±0.2°、21.23±0.2°、17.80±0.2°和21.41±0.2°；
    (2)所述的式I化合物的晶型B，其热重分析图在起始加热至200±5℃处失重为1％-3％，例如2.2％；
    (3)所述的式I化合物的晶型B，其差示扫描量热图240.1±5℃处有吸热峰；
    或，
    当所述的式I化合物的晶型为式I化合物的晶型C时，所述的式I化合物的晶型C满足如下1个或多个条件：
    (1)所述的式I化合物的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：29.92±0.2°、23.30±0.2°、20.57±0.2°、31.49±0.2°和10.11±0.2°；
    (2)所述的式I化合物的晶型C，其热重分析图在起始加热至150±5℃处失重为3％-4％，例如3.2％；
    (3)所述的式I化合物的晶型C，其差示扫描量热图在64.9±5℃、200.1±5℃和237.0±5℃的一处或多处有吸热峰。
  3. 如权利要求2所述的式I化合物的晶型，其特征在于，
    当所述的式I化合物的晶型为式I化合物的晶型A时，所述的式I化合物的晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：18.13±0.2°、33.21±0.2°、17.86±0.2°、23.47±0.2°、26.91±0.2°和16.77±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图1所示；
    (2)所述的式I化合物的晶型A，其差示扫描热图和热重分析图基本如图2所示；
    或，
    当所述的式I化合物的晶型为式I化合物的晶型B时，所述的式I化合物的晶型B满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.01±0.2°、28.03±0.2°、21.96±0.2°、22.66±0.2°、30.78±0.2°和19.66±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图4所示；
    (2)所述的式I化合物的晶型B，其差示扫描热图和热重分析图基本如图5所示；
    或，
    当所述的式I化合物的晶型为式I化合物的晶型C时，所述的式I化合物的晶型C满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：24.93±0.2°、20.82±0.2°、11.60±0.2°、9.77±0.2°、10.98±0.2°和26.96±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图53所示；
    (2)所述的式I化合物的晶型C，其差示扫描热图和热重分析图基本如图54所示。
  4. 一种式I化合物的药学上可接受的盐，其特征在于，所述的药学上可接受的盐为式I化合物与酸形成的盐；所述的酸为无机酸或有机酸；
    Figure PCTCN2022109562-appb-100002
  5. 如权利要求4所述的式I化合物的药学上可接受的盐，其特征在于，
    所述的式I化合物与所述的酸的摩尔比为1:(0.3-2)；
    和/或，所述的无机酸为盐酸和/或硫酸；
    和/或，所述的有机酸为富马酸、马来酸、柠檬酸、甲磺酸、对甲苯磺酸、环拉酸、粘酸、乙醇酸、 苹果酸和马尿酸中的一种或多种；较佳地，所述的有机酸为对甲苯磺酸、甲磺酸、马来酸、富马酸、柠檬酸和环拉酸中的一种或多种；更佳地，所述的有机酸为对甲苯磺酸。
  6. 如权利要求4所述的式I化合物的药学上可接受的盐，其特征在于，所述的式I化合物的药学上可接受的盐为如下任一药学上可接受的盐：
    (1)式I化合物的盐酸盐；其中，式I化合物与盐酸的摩尔比为1：2；
    (2)式I化合物的硫酸盐；其中，式I化合物与硫酸的摩尔比为1：(1-2)，例如1:(1-1.3)，再例如1：1、1：1.1、1：1.3或1：2；
    (3)式I化合物的柠檬酸盐；其中，式I化合物与柠檬酸的摩尔比为1:1；
    (4)式I化合物的马来酸盐；其中，式I化合物与马来酸的摩尔比为1:(0.5-1)，例如1:0.8；
    (5)式I化合物的富马酸盐；其中，式I化合物与富马酸的摩尔比为1:(0.5-1)，例如1:0.9；
    (6)式I化合物的甲磺酸盐；其中，式I化合物与甲磺酸的摩尔比为1:(0.1-1)，例如1:(0.3-1)，再例如1:0.3或1:1；
    (7)式I化合物的对甲苯磺酸盐；其中，式I化合物与对甲苯磺酸的摩尔比为1:(0.1-1)，例如1:0.9；
    (8)式I化合物的环拉酸盐；其中，式I化合物与环拉酸的摩尔比为1:(0.1-1)，例如1:0.9。
  7. 一种式I化合物的药学上可接受的盐的晶型，其特征在于，所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐的晶型A、式I化合物的柠檬酸盐的晶型A、式I化合物的马来酸盐的晶型A、式I化合物的富马酸盐的晶型A、式I化合物的甲磺酸盐的晶型A、式I化合物的甲磺酸盐的晶型B、式I化合物的甲磺酸盐的晶型C、式I化合物的对甲苯磺酸盐的晶型A、式I化合物的环拉酸盐的晶型A、式I化合物的硫酸盐的晶型A、式I化合物的硫酸盐的晶型D、式I化合物的硫酸盐的晶型I、式I化合物的硫酸盐的晶型B、式I化合物的硫酸盐的晶型C、式I化合物的硫酸盐的晶型E或式I化合物的硫酸盐的晶型F；
    Figure PCTCN2022109562-appb-100003
    所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在8.83±0.2°、13.24±0.2°、24.25±0.2°和18.31±0.2°处有衍射峰；
    所述的式I化合物的柠檬酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在17.87±0.2°、14.97±0.2°、17.45±0.2°和17.01±0.2°处有衍射峰；
    所述的式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在16.47±0.2°、4.58±0.2°、10.97±0.2°和22.91±0.2°处有衍射峰；
    所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在28.83±0.2°、5.03±0.2°、16.15±0.2°和13.11±0.2°处有衍射峰；
    所述的式I化合物的甲磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在5.76±0.2°、 14.75±0.2°、5.11±0.2°和17.54±0.2°处有衍射峰；
    所述的式I化合物的甲磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图在18.83±0.2°、16.51±0.2°、25.51±0.2°和10.98±0.2°处有衍射峰；
    所述的式I化合物的甲磺酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图在19.57±0.2°、19.98±0.2°、16.50±0.2°和18.20±0.2°处有衍射峰；
    所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在5.80±0.2°、19.70±0.2°、22.36±0.2°和11.57±0.2°处有衍射峰；
    所述的式I化合物的环拉酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在6.41±0.2°、16.47±0.2°、18.57±0.2°和10.95±0.2°处有衍射峰；
    所述的式I化合物的硫酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在14.60±0.2°、11.67±0.2°、21.09±0.2°和13.32±0.2°处有衍射峰；
    所述的式I化合物的硫酸盐的晶型D，其以2θ角度表示的X-射线粉末衍射图在14.60±0.2°、25.31±0.2°、19.85±0.2°和20.07±0.2°处有衍射峰；
    所述的式I化合物的硫酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图在12.92±0.2°、26.90±0.2°、15.86±0.2°和23.02±0.2°处有衍射峰；
    所述的式I化合物的硫酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图在25.15±0.2°、18.71±0.2°、3.13±0.2°和23.28±0.2°处有衍射峰；
    所述的式I化合物的硫酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图在5.55±0.2°、14.72±0.2°、16.75±0.2°和27.35±0.2°处有衍射峰；
    所述的式I化合物的硫酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图在16.39±0.2°、12.75±0.2°、14.32±0.2°和20.28±0.2°处有衍射峰；
    所述的式I化合物的硫酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图在24.91±0.2°、20.60±0.2°、27.62±0.2°和16.04±0.2°有衍射峰。
  8. 如权利要求7所述的式I化合物的药学上可接受的盐的晶型，其特征在于，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐的晶型A时，所述的式I化合物的盐酸盐的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：26.66±0.2°、22.21±0.2°、4.39±0.2°、31.19±0.2°和19.54±0.2°；
    (2)所述的式I化合物的盐酸盐的晶型A，其热重分析图在起始加热至100±5℃处失重为4％-5.5％，例如4.8％；
    (3)所述的式I化合物的盐酸盐的晶型A，其差示扫描量热图在156.8±5℃处有吸热峰；
    (4)所述的式I化合物的盐酸盐的晶型A中的式I化合物的盐酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的柠檬酸盐的晶型A时，所述的式 I化合物的柠檬酸盐的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的柠檬酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：4.45±0.2°、11.14±0.2°、19.08±0.2°、8.91±0.2°和13.38±0.2°；
    (2)所述的式I化合物的柠檬酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为0.5％-2％，例如1.1％；
    (3)所述的式I化合物的柠檬酸盐的晶型A，其差示扫描量热图在166.4±5℃处有吸热峰；
    (4)所述的式I化合物的柠檬酸盐的晶型A中的式I化合物的柠檬酸盐如权利要求6所述；或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐的晶型A时，所述的式I化合物的马来酸盐的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：18.2±0.2°、19.87±0.2°、24.64±0.2°、22.35±0.2°和20.26±0.2°；
    (2)所述的式I化合物的马来酸盐的晶型A，其热重分析图在150±5℃处失重3％-4％，例如3.3％；在150℃至250℃处失重为10％-15％，例如13.6％；
    (3)所述的式I化合物的马来酸盐的晶型A，其差示扫描量热图在176.0±5℃和/或210.7±5℃处有吸热峰；
    (4)所述的式I化合物的马来酸盐的晶型A中的式I化合物的马来酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的富马酸盐的晶型A时，所述的式I化合物的富马酸盐的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.86±0.2°、12.39±0.2°、29.44±0.2°、17.78±0.2°和9.69±0.2°；
    (2)所述的式I化合物的富马酸盐的晶型A，其热重分析图在起始加热至150±5℃处的失重为1％-3％，例如1.8％；
    (3)所述的式I化合物的富马酸盐的晶型A，其差示扫描量热图在182.5±5℃、192.9±5℃、211.8±5℃和219.2±5℃的一处或多处有吸热峰，和/或，在123.0±5℃、184.8±5℃和196.9±5℃的一处或多处有放热峰；
    (4)所述的式I化合物的富马酸盐的晶型A中的式I化合物的富马酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的甲磺酸盐的晶型A时，所述的式I化合物的甲磺酸盐的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的甲磺酸盐的晶型A以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.29±0.2°、20.49±0.2°、16.84±0.2°、7.51±0.2°和16.51±0.2°；
    (2)所述的式I化合物的甲磺酸盐的晶型A，其热重分析图在起始加热至110±5℃处失重为2％-4％，例如2.9％；
    (3)所述的式I化合物的甲磺酸盐的晶型A，其差示扫描量热图在92.5±5℃和/或138.6±5℃处有吸热峰；
    (4)所述的式I化合物的甲磺酸盐的晶型A中的式I化合物的甲磺酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的甲磺酸盐的晶型B时，所述的式I化合物的甲磺酸盐的晶型B满足如下1个或多个条件：
    (1)所述的式I化合物的甲磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.32±0.2°、5.49±0.2°、20.34±0.2°、26.34±0.2°和16.94±0.2°；
    (2)所述的式I化合物的甲磺酸盐的晶型B，其热重分析图在起始加热至150±5℃处失重为2％-4％，例如2.8％；
    (3)所述的式I化合物的甲磺酸盐的晶型B，其差示扫描量热图在171.3±5℃和/或194.7±5℃处有吸热峰；
    (4)所述的式I化合物的甲磺酸盐的晶型B中的式I化合物的甲磺酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的甲磺酸盐的晶型C时，所述的式I化合物的甲磺酸盐的晶型C满足如下1个或多个条件：
    (1)所述的式I化合物的甲磺酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.26±0.2°、23.30±0.2°、29.52±0.2°、10.99±0.2°和26.94±0.2°；
    (2)所述的式I化合物的甲磺酸盐的晶型C，其热重分析图在起始加热至150±5℃处失重为4％-6％，例如4.9％；
    (3)所述的式I化合物的甲磺酸盐的晶型C，其差示扫描量热图在108.2±5℃、181.9±5℃和233.2±5℃的一处或多处有吸热峰；
    (4)所述的式I化合物的甲磺酸盐的晶型C中的式I化合物的甲磺酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的对甲苯磺酸盐的晶型A时，所述的式I化合物的对甲苯磺酸盐的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：27.22±0.2°、14.81±0.2°、16.83±0.2°、27.91±0.2°和15.18±0.2°；
    (2)所述的式I化合物的对甲苯磺酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为1％-3％，例如1.6％；
    (3)所述的式I化合物的对甲苯磺酸盐的晶型A，其差示扫描量热图在205.6±5℃处有一个吸热峰；
    (4)所述的式I化合物的对甲苯磺酸盐的晶型A中的式I化合物的对甲苯磺酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的环拉酸盐的晶型A时，所述的式I化合物的环拉酸盐的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的环拉酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：18.16±0.2°、19.58±0.2°、20.24±0.2°、22.33±0.2°和23.27±0.2°；
    (2)所述的式I化合物的环拉酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为0.1％-2％，例如0.7％；
    (3)所述的式I化合物的环拉酸盐的晶型A，其差示扫描量热图在202.3±5℃和/或231.3±5℃处有吸热峰；和/或在118.2±5℃和/或205.4±5℃处有放热峰；
    (4)所述的式I化合物的环拉酸盐的晶型A中的式I化合物的环拉酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型A时，所述的式I化合物的硫酸盐的晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的硫酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.38±0.2°、21.65±0.2°、26.08±0.2°、23.45±0.2°和26.44±0.2°；
    (2)所述的式I化合物的硫酸盐的晶型A，其热重分析图在起始加热至175±5℃处失重为2％-4％，例如3.4％；
    (3)所述的式I化合物的硫酸盐的晶型A，其差示扫描量热图在205.1±5℃处有吸热峰；
    (4)所述的式I化合物的硫酸盐的晶型A中的式I化合物的硫酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型D时，所述的式I化合物的硫酸盐的晶型D满足如下1个或多个条件：
    (1)所述的式I化合物的硫酸盐的晶型D，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.06±0.2°、19.31±0.2°、18.15±0.2°、13.18±0.2°和6.59±0.2°；
    (2)所述的式I化合物的硫酸盐的晶型D，其热重分析图在起始加热至125±5℃处失重为1％-4％，例如3％；
    (3)所述的式I化合物的硫酸盐的晶型D，其差示扫描量热图在111.9±5℃、153.2±5℃和197.7±5℃的一处或多处有吸热峰；
    (4)所述的式I化合物的硫酸盐的晶型D中的式I化合物的硫酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型I时，所述的式I化合物的硫酸盐的晶型I以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.09±0.2°、14.99±0.2°、17.26±0.2°、19.34±0.2°和24.61±0.2°；
    和/或，所述的式I化合物的硫酸盐的晶型I中的式I化合物的硫酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型B时，所述的式I化合物的硫酸盐的晶型B满足如下1个或多个条件：
    (1)所述的式I化合物的硫酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.27±0.2°、24.82±0.2°、15.17±0.2°、14.82±0.2°和23.67±0.2°；
    (2)所述的式I化合物的硫酸盐的晶型B，其热重分析图在起始加热至150±5℃处失重为2％-4％，例如2.9％；
    (3)所述的式I化合物的硫酸盐的晶型B，其差示扫描量热图在77.9±5℃、118.8±5℃和196.8±5℃的一处或多处有吸热峰；
    (4)所述的式I化合物的硫酸盐的晶型B中的式I化合物的硫酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型C时，所述的式I化合物的硫酸盐的晶型C满足如下1个或多个条件：
    (1)所述的式I化合物的硫酸盐的晶型C中，所述的式I化合物的硫酸盐为水合物，所述的式I化合物与水的摩尔比为1:(1-2)，例如1:(1-1.3)，又例如1:(1-1.1)；
    (2)所述的式I化合物的硫酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.92±0.2°、20.90±0.2°、21.13±0.2°、19.63±0.2°和20.37±0.2°；
    (3)所述的式I化合物的硫酸盐的晶型C，其热重分析图在加热至175±5℃时具有3％-4.5％的失重；
    (4)所述的式I化合物的硫酸盐的晶型C，其差示扫描量热图在152.8±5℃处有吸热峰；
    (5)所述的式I化合物的硫酸盐的晶型C，其中，所述的式I化合物与硫酸盐的摩尔比为1：(1-2)，例如1：(1-1.3)、1：(1-1.1)或1:1，再例如1：1、1：1.1、1：1.3或1：2；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型E时，所述的式I化合物的硫酸盐的晶型E满足如下1个或多个条件：
    (1)所述的式I化合物的硫酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：17.76±0.2°、23.45±0.2°、26.20±0.2°、17.47±0.2°和19.76±0.2°；
    (2)所述的式I化合物的硫酸盐的晶型E，其热重分析图在起始加热至150±5℃时具有5％-6.5％的失重，例如5.9％；
    (3)所述的式I化合物的硫酸盐的晶型E，其差示扫描量热图在82.2±5℃、138.6±5℃和205.4±5℃的一处或多处有吸热峰；
    (4)所述的式I化合物的硫酸盐的晶型E中的式I化合物的硫酸盐如权利要求6所述；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型F时，所述的式I化合物的硫酸盐的晶型F满足如下1个或多个条件：
    (1)所述的式I化合物的硫酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图，还在如下一个 或多个2θ角度处有衍射峰：24.26±0.2°、24.14±0.2°、18.63±0.2°、17.01±0.2°和21.53±0.2°；
    (2)所述的式I化合物的硫酸盐的晶型F，其热重分析图在起始加热至160℃处失重为5％-7％，例如6.4％，从160℃加热至225℃处失重为6％-8％，例如6.9％；
    (3)所述的式I化合物的硫酸盐的晶型F，其差示扫描量热图在123.6±5℃和/或185.2±5℃处有吸热峰；和/或，在206.0±5℃处有一个放热峰；
    (4)所述的式I化合物的硫酸盐的晶型F中的式I化合物的硫酸盐如权利要求6所述。
  9. 如权利要求8所述的式I化合物的药学上可接受的盐的晶型，其特征在于，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐的晶型A时，所述的式I化合物的盐酸盐的晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：35.77±0.2°、19.71±0.2°、27.3±0.2°、32.11±0.2°、28.38±0.2°和21.52±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图7所示；
    (2)所述的式I化合物的盐酸盐的晶型A，其差示扫描热图和热重分析图基本如图8所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的柠檬酸盐的晶型A时，所述的式I化合物的柠檬酸盐的晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的柠檬酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：21.23±0.2°、25.56±0.2°、21.00±0.2°、24.25±0.2°、28.48±0.2°和29.9±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图19所示；
    (2)所述的式I化合物的柠檬酸盐的晶型A，其差示扫描热图和热重分析图基本如图20所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐的晶型A时，所述的式I化合物的马来酸盐的晶型A满足如下(1)和/或(2)的条件：
    (1)还在如下一个或多个2θ角度处有衍射峰：19.56±0.2°、28.43±0.2°、26.52±0.2°、15.04±0.2°、27.52±0.2°和18.86±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图22所示；
    (2)所述的式I化合物的马来酸盐的晶型A，其差示扫描热图和热重分析图基本如图23所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的富马酸盐的晶型A时，所述的式I化合物的富马酸盐的晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：19.82±0.2°、10.73±0.2°、3.25±0.2°、17.09±0.2°、6.54±0.2°和11.22±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图25所示；
    (2)所述的式I化合物的富马酸盐的晶型A，其差示扫描热图和热重分析图基本如图26所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的甲磺酸盐的晶型A时，所述的式I化合物的甲磺酸盐的晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的甲磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.72±0.2°、19.60±0.2°、15.51±0.2°、18.43±0.2°、15.86±0.2°和12.84±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图28所示；
    (2)所述的式I化合物的甲磺酸盐的晶型A，其差示扫描热图和热重分析图基本如图29所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的甲磺酸盐的晶型B时，所述的式I化合物的甲磺酸盐的晶型B满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的甲磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：19.48±0.2°、21.35±0.2°、15.06±0.2°、19.93±0.2°、12.75±0.2°和18.05±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图31所示；
    (2)所述的式I化合物的甲磺酸盐的晶型B，其差示扫描热图和热重分析图基本如图32所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的甲磺酸盐的晶型C时，所述的式I化合物的甲磺酸盐的晶型C满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的甲磺酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.36±0.2°、20.86±0.2°、24.62±0.2°、24.92±0.2°、27.41±0.2°和18.45±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图34所示；
    (2)所述的式I化合物的甲磺酸盐的晶型C，其差示扫描热图和热重分析图基本如图35所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的对甲苯磺酸盐的晶型A时，所述的式I化合物的对甲苯磺酸盐的晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：19.21±0.2°、18.16±0.2°、13.07±0.2°、30.66±0.2°、32.47±0.2°和18.47±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图37所示；
    (2)所述的式I化合物的对甲苯磺酸盐的晶型A，其差示扫描热图和热重分析图基本如图38所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的环拉酸盐的晶型A时，所述的式I化合物的环拉酸盐的晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的环拉酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：24.63±0.2°、26.94±0.2°、27.39±0.2°、21.39±0.2°、20.83±0.2°和24.93±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图40所示；
    (2)所述的式I化合物的环拉酸盐的晶型A，其差示扫描热图和热重分析图基本如图41所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型A时，所述的式I化合物的硫酸盐的晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的硫酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：15.76±0.2°、8.75±0.2°、37.29±0.2°、24.42±0.2°、22.08±0.2°和29.39±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图10所示；
    (2)所述的式I化合物的硫酸盐的晶型A，其差示扫描热图和热重分析图基本如图11所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型D时，所述的式I化合物的硫酸盐的晶型D满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的硫酸盐的晶型D，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：15.02±0.2°、31.39±0.2°、22.14±0.2°、24.63±0.2°、25.63±0.2°和9.83±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图43所示；
    (2)所述的式I化合物的硫酸盐的晶型D，其差示扫描热图和热重分析图基本如图44所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型I时，所述的式I化合物的硫酸盐的晶型I以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.79±0.2°、21.75±0.2°、18.31±0.2°、18.47±0.2°、21.61±0.2°和19.75±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图46所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型B时，所述的式I化合物的硫酸盐的晶型B满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的硫酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.03±0.2°、19.05±0.2°、18.34±0.2°、12.20±0.2°、24.18±0.2°和17.21±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图13所示；
    (2)所述的式I化合物的硫酸盐的晶型B，其差示扫描热图和热重分析图基本如图14所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型C时，所述的式I化合物的硫酸盐的晶型C满足如下1个或多个条件：
    (1)所述的式I化合物的硫酸盐的晶型C中，所述式I化合物的硫酸盐为一水合物，所述的式I化合物与硫酸的摩尔比为1：1；
    (2)所述的式I化合物的硫酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.72±0.2°、12.52±0.2°、19.45±0.2°、19.96±0.2°、25.16±0.2°和12.75±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图16所示；
    (3)所述的式I化合物的硫酸盐的晶型C，其差示扫描热图和热重分析图基本如图17所示；
    (4)所述的式I化合物的硫酸盐的晶型C，其动态水分吸附谱图基本如图55所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型E时，所述的式I化合物的硫酸盐的晶型E满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的硫酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：11.46±0.2°、25.88±0.2°、21.90±0.2°、23.00±0.2°、20.79±0.2°和18.25±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图47所示；
    (2)所述的式I化合物的硫酸盐的晶型E，其差示扫描热图和热重分析图基本如图48所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的硫酸盐的晶型F时，所述的式I化合物的硫酸盐的晶型F满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的硫酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：23.10±0.2°、19.94±0.2°、19.73±0.2°、15.29±0.2°、28.29±0.2°和20.12±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图50所示；
    (2)所述的式I化合物的硫酸盐的晶型F，其差示扫描热图和热重分析图基本如图51所示。
  10. 一种如权利要求7-9中任一项所述的式I化合物的药学上可接受的盐的晶型的制备方法，其特征在于，其为所述的式I化合物的硫酸盐的晶型A的制备方法、所述的式I化合物的硫酸盐的晶型C的制备方法、所述的式I化合物的硫酸盐的晶型D的制备方法、所述的式I化合物的硫酸盐的晶型E的制备方法或所述的式I化合物的硫酸盐的晶型F的制备方法；其中，
    所述的式I化合物的硫酸盐的晶型A的制备方法，其为方法a或方法b：
    方法a，其包括如下步骤：在室温下，将所述的式I化合物与硫酸在甲醇中进行析晶，得到式I化合物的硫酸盐的晶型A；
    方法b，其包括如下步骤：将所述的式I化合物的硫酸盐在溶剂中进行析晶，得到式I化合物的硫酸盐的晶型A；所述的溶剂为C 1-3醇类溶剂-2-甲基四氢呋喃；
    所述的式I化合物的硫酸盐的晶型C的制备方法，其为方法1或方法2：
    方法1：其包括如下步骤：将所述的式I化合物在腈类溶剂中与硫酸水溶液溶清后冷却得到式I化合物的硫酸盐的晶型C；
    方法2：其包括如下步骤：在室温下，将所述的式I化合物与硫酸在水-腈类溶剂中进行析晶，得到式I化合物的硫酸盐的晶型C；
    所述的式I化合物的硫酸盐的晶型D的制备方法，其包括如下步骤：将式I化合物的硫酸盐在丙醇中形成悬浊液进行转晶得到式I化合物的硫酸盐的晶型D；
    所述的式I化合物的硫酸盐的晶型E的制备方法，其包括如下步骤：将式I化合物的硫酸盐一水合物在酯类溶剂-水的混合溶剂中形成悬浊液进行转晶得到式I化合物的硫酸盐的晶型E；
    所述的式I化合物的硫酸盐的晶型F的制备方法，其包括如下步骤：将式I化合物的硫酸盐一水合物在亚砜类溶剂中进行挥发，得到式I化合物的硫酸盐的晶型E。
  11. 如权利要求10所述的式I化合物的药学上可接受的盐的晶型的制备方法，其特征在于，
    当所述的式I化合物的药学上可接受的盐的晶型的制备方法为所述的式I化合物的硫酸盐的晶型A的制备方法时，所述的式I化合物的硫酸盐的晶型A的制备方法满足如下1个或多个条件：
    (1)方法a中，所述的式I化合物为式I化合物的晶型A；
    (2)方法b中，所述的析晶包括以下步骤：将所述的式I化合物的硫酸盐溶解在所述的C 1-3醇类溶剂中，得到混合溶液，向所述的混合溶液中加入2-甲基四氢呋喃；所述的C 1-3醇类溶剂-2-甲基四氢呋喃中的C 1-3醇类溶剂为甲醇、乙醇和异丙醇中一种或多种，例如甲醇；
    (3)方法a中，所述的析晶包括以下步骤：将所述的式I化合物和硫酸在所述的甲醇中进行悬浮搅拌析晶；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型的制备方法为所述的式I化合物的硫酸盐的晶型C的制备方法时，所述的式I化合物的硫酸盐的晶型C的制备方法满足如下1个或多个条件：
    (1)方法1或2中，所述的式I化合物为式I化合物的晶型A；
    (2)方法2中，所述的水-腈类溶剂中的腈类溶剂为乙腈；
    (3)方法1中，所述的腈类溶剂为乙腈；
    (4)方法1或2中，所述的式I化合物与所述的腈类溶剂的质量体积比为120-20mg/ml，例如100-40mg/ml；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型的制备方法为所述的式I化合物的硫酸盐的晶型D的制备方法时，所述的式I化合物的硫酸盐的晶型D的制备方法满足如下(1)和/或(2)：
    (1)所述的丙醇为正丙醇和/或异丙醇，例如正丙醇；
    (2)所述的式I化合物的硫酸盐与所述的丙醇的质量体积比优选为25-40mg/ml，例如33.3mg/ml；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型的制备方法为所述的式I化合物的硫酸盐的晶型E的制备方法时，所述的式I化合物的硫酸盐的晶型E的制备方法满足(1)和/或(2)：
    (1)所述的酯类溶剂-水的混合溶剂为乙酸乙酯-水的混合溶剂；
    (2)所述的酯类溶剂-水的混合溶剂中的酯类溶剂与水体积比为19:1；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型的制备方法为所述的式I化合物的硫酸盐的晶型E的制备方法时，所述的式I化合物的硫酸盐的晶型F的制备方法中，所述的亚砜类溶剂为二甲亚砜。
  12. 一种药物组合物，其包含治疗有效剂量的物质A和药学上可接受的赋形剂；所述的物质A为如权利要求1-3中任一项所述的式I化合物的晶型、如权利要求4-6任一项所述的式I化合物的药学 上可接受的盐或如权利要求7-9中任一项所述的式I化合物的药学上可接受的盐的晶型。
  13. 一种物质B在制备治疗和/或预防疾病的药物或RIPK1抑制剂中的用途，所述的物质B为如权利要求12所述的药物组合物、如权利要求1-3中任一项所述的式I化合物的晶型、如权利要求4-6任一项所述的式I化合物的药学上可接受的盐或如权利要求7-9中任一项所述的式I化合物的药学上可接受的盐的晶型；
    所述的疾病优选为RIPK1介导的疾病，所述的疾病优选为中风、炎症性肠病、溃疡性结肠炎、克罗恩病、牛皮癣、类风湿性关节炎、NASH和心力衰竭中的一种或多种；或所述的疾病优选为中风、炎症性肠病、溃疡性结肠炎、克罗恩病、牛皮癣、类风湿性关节炎、NASH和心力衰竭中的一种或多种；
    所述的RIPK1抑制剂优选为体内或体外RIPK1抑制剂。
PCT/CN2022/109562 2021-08-02 2022-08-02 Ripk1抑制剂的晶型及其酸式盐和其酸式盐的晶型 WO2023011428A1 (zh)

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CN105916503A (zh) * 2014-01-14 2016-08-31 米伦纽姆医药公司 杂芳基化合物和其用途
CN110325526A (zh) * 2017-02-28 2019-10-11 伊莱利利公司 异喹啉和萘啶化合物
WO2020192562A1 (zh) * 2019-03-22 2020-10-01 劲方医药科技(上海)有限公司 取代的杂环酰胺类化合物，其制法与医药上的用途
WO2021160109A1 (zh) * 2020-02-13 2021-08-19 劲方医药科技(上海)有限公司 二氢萘啶酮类化合物，其制法与医药上的用途

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CN110325526A (zh) * 2017-02-28 2019-10-11 伊莱利利公司 异喹啉和萘啶化合物
WO2020192562A1 (zh) * 2019-03-22 2020-10-01 劲方医药科技(上海)有限公司 取代的杂环酰胺类化合物，其制法与医药上的用途
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