WO2019085927A1 - Salt and crystal of fgfr4 inhibitor, preparation method and use thereof - Google Patents

Salt and crystal of fgfr4 inhibitor, preparation method and use thereof Download PDF

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Publication number
WO2019085927A1
WO2019085927A1 PCT/CN2018/112891 CN2018112891W WO2019085927A1 WO 2019085927 A1 WO2019085927 A1 WO 2019085927A1 CN 2018112891 W CN2018112891 W CN 2018112891W WO 2019085927 A1 WO2019085927 A1 WO 2019085927A1
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compound
formula
xrpd pattern
diffraction peaks
salt
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PCT/CN2018/112891
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French (fr)
Chinese (zh)
Inventor
何雷
李响
林青
陈中科
余俊
杜祖银
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江苏豪森药业集团有限公司
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Priority to CN201880009211.8A priority Critical patent/CN110234649B/en
Publication of WO2019085927A1 publication Critical patent/WO2019085927A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of crystal forms, and in particular relates to a pharmaceutically acceptable salt of a compound of the formula (I), a crystalline form of a pharmaceutically acceptable salt, a preparation method and use thereof.
  • the fibroblast growth factor receptor belongs to the receptor tyrosine kinase transmembrane receptor and includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4.
  • FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions.
  • FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.
  • FGFR4 a member of the FGFR receptor family, forms dimers on the cell membrane by binding to its ligand, fibroblast growth factor 19 (FGF19), and the formation of these dimers can cause critical tyrosine in FGFR4's own cells.
  • FGF19 fibroblast growth factor 19
  • the phosphorylation of the amino acid residue activates multiple downstream signaling pathways in the cell, and these intracellular signaling pathways play an important role in cell proliferation, survival, and anti-apoptosis.
  • FGFR4 is overexpressed in many cancers and is a predictor of malignant invasion of tumors. Decreasing and reducing FGFR4 expression can reduce cell proliferation and promote apoptosis.
  • FGFR4 expression or high expression is also closely related to many other tumors, such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.
  • liver cancer ranks first in the world in China, with new and dead patients accounting for about half of the total number of liver cancers worldwide each year. At present, the incidence of liver cancer in China is about 28.7/100,000. In 2012, there were 394,770 new cases, which became the third most serious malignant tumor after gastric cancer and lung cancer.
  • the onset of primary liver cancer is a multi-factor, multi-step complex process with strong invasiveness and poor prognosis. Surgical treatments such as hepatectomy and liver transplantation can improve the survival rate of some patients, but only limited patients can undergo surgery, and most patients have a poor prognosis due to recurrence and metastasis after surgery. Sorafenib is the only liver cancer treatment drug approved on the market.
  • FGFR4 is a major carcinogenic factor in liver cancer, and its development of small molecule inhibitors has great clinical application potential.
  • FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia.
  • target related side effects Such as target related side effects.
  • Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition.
  • Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects.
  • One aspect of the invention provides a pharmaceutically acceptable salt of a compound of formula (I).
  • a second aspect of the invention provides a crystalline form of the hydrochloride salt of a compound of formula (I).
  • a third aspect of the invention provides a crystalline form of a sulfate salt of a compound of formula (I).
  • a fourth aspect of the invention provides a crystalline form of the methanesulfonate salt of the compound of formula (I).
  • a fifth aspect of the invention provides a crystalline form of a besylate salt of a compound of formula (I).
  • a sixth aspect of the invention provides a crystalline form of the ethanesulfonate salt of the compound of formula (I).
  • a seventh aspect of the invention provides a crystalline form of the oxalate salt of the compound of formula (I).
  • An eighth aspect of the invention provides a crystalline form of the maleate salt of the compound of formula (I).
  • a ninth aspect of the invention provides a crystalline form of the p-toluenesulfonate salt of the compound of formula (I).
  • a tenth aspect of the invention provides a pharmaceutical composition of a pharmaceutically acceptable salt crystalline form of a compound of formula (I).
  • An eleventh aspect of the invention provides a process for the preparation of a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I).
  • the twelfth aspect of the invention provides the use of a pharmaceutically acceptable salt crystalline form of a compound of formula (I).
  • the "pharmaceutically acceptable salt” of the present invention may be any salt as long as it forms a non-toxic salt with the compound of the formula (I).
  • examples include, but are not limited to, salts with various inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, carbonates, bicarbonates, perchloric acids.
  • Salts, etc. salts with organic acids such as citrate, tartrate, fumarate, succinate, maleate, acetate, malate, benzoate, p-toluate, Methanesulfonate, besylate, p-toluenesulfonate, ethanesulfonate, isethionate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, camphorsulfonate, trifluoromethyl Sulfonate, trifluoroacetate, lactate, oxalate, salicylate, phenylacetate, mandelate, formate, acetate, trifluoroacetate, propionate, Oxalate, glycolate, hydroxymaleate, methyl maleate, adipate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, niacin Salt, isonicotinate, cholate, aspartate or glutamate.
  • organic acids
  • the present invention provides a process for the preparation of a pharmaceutically acceptable salt of a compound of formula (I), which is obtained by reacting a compound of formula (I) with an acid in a solvent.
  • the solvent includes an organic solvent or an inorganic solvent selected from the group consisting of an alcohol solvent, a ketone solvent, an ester solvent, dichloromethane, acetonitrile, chloroform, or a mixed solvent thereof, preferably water or ethyl formate.
  • an organic solvent or an inorganic solvent selected from the group consisting of an alcohol solvent, a ketone solvent, an ester solvent, dichloromethane, acetonitrile, chloroform, or a mixed solvent thereof, preferably water or ethyl formate.
  • an organic solvent or an inorganic solvent selected from the group consisting of an alcohol solvent, a ketone solvent, an ester solvent, dichloromethane, acetonitrile, chloroform, or a mixed solvent thereof, preferably water or ethyl formate.
  • a mixed solvent thereof preferably water or ethyl formate.
  • the acid includes an organic acid or inorganic acid including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, perchloric acid, etc.; organic acids include, but are not limited to, citric acid , tartaric acid, fumaric acid, succinic acid, maleic acid, acetic acid, malic acid, benzoic acid, p-toluic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, isethionic acid, 1 -naphthalenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, lactic acid, oxalic acid, salicylic acid, phenylacetic acid, mandelic acid, formic acid,
  • the present invention provides a hydrochloride salt form of the compound of formula (I).
  • the present invention provides the hydrochloride salt form I of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.8, 9.9, 11.0, 16.7 and 25.3;
  • the XRPD pattern of the hydrochloride salt form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.8, 8.2, 9.9, 11.0, 12.1, 12.4, 13.0, 14.0, 16.7, 18.5, 19.0, 22.3. , 25.3, 25.8, 26.2, and 27.7 diffraction peaks.
  • the present invention provides a process for the preparation of the salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethyl acetate.
  • the present invention provides a salt form II of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.0, 6.5, 15.7 and 23.8.
  • the XRPD pattern of the hydrochloride salt form II comprises 2 ⁇ 0.2°: 6.0, 6.5, 8.4, 11.7, 12.1, 13.2, 14.6, 15.7, 16.7, 17.7, 18.7, 19.1, 20.0, 22.5, Diffraction peaks of 23.0, 23.8, 24.5, and 25.6.
  • the present invention provides a process for the preparation of the salt form II of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethanol.
  • the hydrochloride salt form II of the compound of the formula (I) provided by the invention has good stability and is allowed to stand at 40 ° C for 1 month, and the degradation is ⁇ 0.5%.
  • the present invention provides the hydrochloride salt form III of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form III of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.1, 7.0, 9.2, 10.2 and 21.0;
  • the XRPD pattern of the hydrochloride salt form III comprises 2 ⁇ 0.2°: 6.1, 7.0, 9.2, 10.2, 12.4, 14.4, 16.4, 16.9, 18.6, 19.5, 21.0, 24.6, 25.6, and 26.2. Diffraction peaks.
  • the present invention provides a process for the preparation of the salt form III of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in dichloromethane.
  • the present invention provides the hydrochloride salt form IV of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form IV of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.1, 7.8, 9.5, 11.9 and 25.0;
  • the XRPD pattern of the hydrochloride salt form IV comprises 2 ⁇ 0.2° of: 5.9, 6.1, 7.8, 8.8, 9.5, 10.0, 11.9, 12.4, 15.5, 21.2, 23.6, 25.0, 26.5 and 32.5. Diffraction peaks.
  • the present invention provides a process for the preparation of the salt form IV of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in acetonitrile.
  • the present invention provides a hydrochloride salt form V of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.5, 12.0, 13.2, 16.5 and 23.6;
  • the XRPD pattern of the hydrochloride salt form V of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.5, 8.8, 11.5, 12.0, 13.2, 14.4, 14.8, 15.2, 16.5, 20.3, 21.3, 23.6. , 25.3 and 27.0 diffraction peaks.
  • the present invention provides a process for the preparation of the salt form V of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethyl acetate.
  • the present invention provides a sulfate form of the compound of formula (I).
  • the present invention provides a sulfate form I of the compound of formula (I).
  • the XRPD pattern of the sulfate form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.6, 6.4, 7.6, 13.4 and 27.1;
  • the XRPD pattern of the sulfate form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.6, 6.4, 7.6, 11.3, 12.1, 12.4, 13.4, 14.1, 15.3, 18.1, 19.0, 20.9, Diffraction peaks of 21.5, 24.5, 24.9, and 27.1.
  • the present invention provides a process for the preparation of the sulfate form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in ethyl acetate.
  • the present invention provides a sulfate form II of the compound of formula (I).
  • the XRPD pattern of the sulfate form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.8, 6.1, 6.5, 9.0, 13.0 and 23.9;
  • the XRPD pattern of the sulfate form II of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.8, 6.1, 6.5, 7.8, 9.0, 11.8, 13.0, 14.6, 15.4, 16.0, 16.6, 17.4, Diffraction peaks of 18.1, 19.8, 21.6, 22.1, 23.0, and 23.9.
  • the present invention provides a process for the preparation of the sulfate form II of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in acetonitrile.
  • the present invention provides a sulfate form III of the compound of formula (I).
  • the XRPD pattern of the sulfate form III of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.6, 7.8, 15.5, 18.1, 25.0 and 27.1;
  • the XRPD pattern of the sulfate form III of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.6, 7.8, 9.5, 11.5, 12.2, 12.6, 13.6, 14.3, 15.5, 17.1, 18.1, 18.7, Diffraction peaks of 19.1, 19.8, 21.1, 21.6, 23.2, 24.6, 25.0 and 27.1.
  • the present invention provides a process for the preparation of the sulfate form III of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in acetone.
  • the present invention provides a sulfate form IV of the compound of formula (I).
  • the XRPD pattern of the sulfate form IV of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.2, 6.6, 9.8, 20.5 and 23.3;
  • the XRPD pattern of the sulfate form IV of the compound of the formula (I) comprises 2 ⁇ 0.2° of: 5.2, 6.6, 8.7, 9.8, 11.3, 13.4, 16.5, 20.5, 23.3, 25.4, 26.7 and 28.8. Diffraction peaks.
  • the invention provides a process for the preparation of the sulfate form IV of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in dichloromethane.
  • the present invention provides a sulfate form V of the compound of formula (I).
  • the XRPD pattern of the sulfate form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.8, 6.3, 13.5, 24.0 and 24.8;
  • the XRPD pattern of the sulfate form V of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.8, 6.3, 13.5, 14.5, 14.9, 16.8, 17.4, 18.1, 19.4, 20.5, 20.9, 22.8, Diffraction peaks of 24.0, 24.8, 26.7, 28.3 and 31.8.
  • the present invention provides a process for the preparation of the sulfate form V of the compound of the formula (I), wherein the compound of the formula (I) is reacted with sulfuric acid in acetonitrile and stirred for a long period of time.
  • the present invention provides a crystalline form of the mesylate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.2, 7.8, 9.6, 13.8, 18.9 and 25.6;
  • the XRPD pattern of the methanesulfonate salt form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.2, 7.8, 9.6, 12.5, 13.8, 14.6, 15.4, 16.1, 18.9, 19.4, 20.5, Diffraction peaks of 21.0, 22.4, 23.3, 24.0, 25.1, 25.6, 26.6 and 27.9.
  • the present invention provides a process for the preparation of the methanesulfonate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with methanesulfonic acid in acetonitrile.
  • the present invention provides a crystalline form II of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.5, 8.2, 13.7, 17.3, 20.9 and 25.1;
  • the XRPD pattern of the methanesulfonate salt form II of the compound of the formula (I) comprises 2 ⁇ 0.2° of: 7.5, 8.2, 11.5, 13.7, 15.1, 17.3, 20.0, 20.9, 23.0, 25.1 and 28.9. Diffraction peaks.
  • the invention provides a preparation method of the methanesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is reacted with methanesulfonic acid in ethanol.
  • the methanesulfonate salt form II of the compound of the formula (I) provided by the present invention is a solvate crystal form, and the crystal contains ethanol and water.
  • the present invention provides a crystalline form III of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form III of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.2, 13.5, 16.3, 19.5, 22.0 and 24.2;
  • the XRPD pattern of the methanesulfonate salt form III of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.2, 6.9, 11.1, 12.5, 13.5, 14.7, 16.3, 17.2, 18.4, 19.5, 20.4, Diffraction peaks of 22.0, 24.2, 24.8, and 30.4.
  • the invention provides a preparation method of the methanesulfonate salt form III of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by crystallizing in a humidity of 92.5%.
  • the present invention provides a crystalline form IV of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form IV of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.1, 9.0, 11.0, 13.6, 14.8, 22.3 and 23.8;
  • the XRPD pattern of the methanesulfonate salt form IV of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.1, 6.9, 9.0, 11.0, 13.6, 14.8, 18.4, 18.9, 20.6, 22.3, 23.8 and Diffraction peak of 25.4.
  • the invention provides a preparation method of the methanesulfonate salt form IV of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in isobutanol.
  • the methanesulfonate salt form IV of the compound of the formula (I) provided by the present invention is an isobutanol solvate crystal form.
  • the present invention provides a crystalline form V of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.1, 7.9, 9.4, 15.9, 19.2 and 24.5;
  • the XRPD pattern of the methanesulfonate form V of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.1, 7.9, 9.4, 10.1, 12.2, 12.6, 13.3, 14.3, 15.9, 17.2, 19.1. Diffraction peaks of 21.8, 22.8, 23.7, 24.5, 27.3 and 29.1.
  • the invention provides a preparation method of the methanesulfonate salt form V of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in isopropanol.
  • the methanesulfonate form V of the compound of the formula (I) provided by the present invention is an isopropanol solvate crystal form.
  • the present invention provides a mesylate salt form VI of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form VI of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.6, 8.6, 13.7, 17.5, 22.1, 23.7 and 28.8;
  • the XRPD pattern of the methanesulfonate salt form VI of the compound of the formula (I) comprises 2 ⁇ 0.2°: 7.6, 8.6, 11.4, 13.7, 15.1, 17.5, 18.5, 18.8, 20.1, 21.1, 22.1, Diffraction peaks of 23.1, 23.7, 24.5, 25.7 and 28.8.
  • the invention provides a preparation method of the methanesulfonate salt form VI of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in ethyl formate.
  • the mesylate salt form VI of the compound of the formula (I) provided by the present invention is an ethyl formate solvate crystal form.
  • the present invention provides a mesylate salt form VII of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form VII of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.2, 7.1, 10.4, 14.1 and 23.3;
  • the XRPD pattern of the methanesulfonate salt form VII of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.2, 7.1, 10.4, 12.0, 13.2, 14.1, 16.0, 17.2, 18.7, 23.3, and 30.2. Diffraction peak
  • the invention provides a preparation method of the methanesulfonate salt form VII of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in ethyl acetate for a long time.
  • the present invention provides the methanesulfonate salt form VIII of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form VIII of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.9, 6.4, 13.6, 16.9, 24.1 and 25.0;
  • the XRPD pattern of the mesylate salt form VIII comprises 2 ⁇ 0.2°: 5.9, 6.4, 13.6, 14.6, 15.1, 16.9, 17.6, 18.2, 19.6, 20.6, 21.0, 22.7, 24.1, 25.0. , diffraction peaks of 26.8, 28.4, and 31.9.
  • the invention provides a preparation method of the methanesulfonate salt form VIII of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in acetone for a long time.
  • the methanesulfonate salt form VIII of the compound of the formula (I) provided by the invention contains no solvent and melts and degrades at 172 ° C, and the crystal form has good stability under the conditions of high humidity RH 92.5% and high temperature 40 ° C. After storage for 1 month, the related substances increased by ⁇ 0.5%.
  • the present invention provides a crystalline form of the besylate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.4, 5.9, 7.1, 10.4, 14.8, 17.6 and 21.9;
  • the XRPD pattern of the benzenesulfonate salt form I comprises 2 ⁇ 0.2°: 5.4, 5.9, 6.8, 7.1, 8.3, 8.7, 10.4, 11.7, 14.0, 14.8, 15.1, 17.6, 20.9, 21.9 , diffraction peaks of 23.7, 24.8, and 26.6.
  • the invention provides a preparation method of the benzenesulfonate salt form I of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in ethanol.
  • the present invention provides a crystalline form II of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 4.4, 6.0, 9.3, 11.5, 17.5, 21.0 and 26.0;
  • the XRPD pattern of the benzenesulfonate salt form II comprises 2 ⁇ 0.2°: diffraction of 4.4, 6.0, 9.3, 11.5, 14.8, 15.3, 17.5, 20.0, 21.0, 21.9, 22.7, 24.6 and 26.0. peak.
  • the invention provides a preparation method of the benzenesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in tetrahydrofuran.
  • the present invention provides a crystalline form III of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form III of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.7, 8.3, 8.6, 17.2, 23.2 and 26.0;
  • the XRPD pattern of the benzenesulfonate salt form III comprises 2? ⁇ 0.2°: diffraction of 7.7, 8.3, 8.6, 11.6, 13.8, 14.5, 17.2, 18.3, 18.9, 20.8, 21.8, 23.2 and 26.0. peak.
  • the invention provides a preparation method of the benzenesulfonate salt form III of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in dichloromethane.
  • the present invention provides a crystalline form IV of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form IV of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.7, 6.4, 13.0, 14.4 and 23.8;
  • the XRPD pattern of the benzenesulfonate salt form IV of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.7, 6.4, 12.0, 13.0, 14.4, 15.6, 16.5, 17.5, 18.6, 21.0, 21.7, Diffraction peaks of 23.2, 23.8, 26.0, 26.6, and 30.0.
  • the invention provides a preparation method of the benzenesulfonate salt form IV of the compound of the formula (I), wherein the benzenesulfonate of the compound of the formula (I) is obtained by stirring and crystallizing in acetonitrile for a long time.
  • the present invention provides a form V of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate crystal form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.7, 7.5, 10.3, 14.3 and 25.1;
  • the XRPD pattern of the benzenesulfonate crystal form V comprises 2 ⁇ 0.2°: 5.7, 7.5, 10.3, 11.0, 11.3, 11.7, 13.8, 14.3, 16.3, 16.6, 17.8, 18.3, 19.0, 20.1 , diffraction peaks of 23.4, 25.1 and 27.5.
  • the invention provides a preparation method of the benzenesulfonate salt form V of the compound of the formula (I), wherein the benzenesulfonate of the compound of the formula (I) is obtained by stirring and crystallizing in a 75% aqueous solution of ethanol for a long time.
  • the present invention provides a crystalline form VI of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form VI of the compound of the formula (I) contains 2 ⁇ 0.2°: diffraction peaks of 6.0, 7.4, 13.5, 18.6, 23.6 and 24.5;
  • the XRPD pattern of the benzenesulfonate salt form VI of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.0, 7.4, 11.6, 12.2, 12.8, 13.5, 14.8, 16.5, 17.5, 18.6, 20.4, Diffraction peaks of 21.0, 21.6, 22.7, 23.6, 24.5, 25.9, 26.7 and 27.5.
  • the invention provides a preparation method of the benzenesulfonate salt form VI of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in acetone.
  • the benzenesulfonate salt form VI of the compound of the formula (I) provided by the invention has no solvent and has a melting point of 162 ° C, which is very suitable for the development of pharmaceutical preparations, the highest yield of the preparation process is 95%, and the preparation process has good reproducibility. It is especially suitable for industrial production.
  • the present invention provides a benzenesulfonate salt form VII of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form VII of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.9, 7.1, 9.7, 15.0, 16.4 and 23.7;
  • the XRPD pattern of the benzenesulfonate salt form VII of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.9, 7.1, 9.7, 11.9, 12.9, 13.4, 15.0, 16.4, 18.3, 18.8, 20.5, Diffraction peaks of 21.2, 21.9, 22.8, and 23.7.
  • the invention provides a preparation method of the benzenesulfonate salt form VII of the compound of the formula (I), wherein the besylate salt of the compound of the formula (I) is obtained by crystallizing in 92.5% RH.
  • the present invention provides a crystalline form of the ethanesulfonate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the ethanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the ethyl sulfonate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.5, 8.3 and 17.9;
  • the XRPD pattern of the ethyl sulfonate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.5, 8.3, 10.5, 12.9, 17.9, 23.5 and 25.0.
  • the invention provides a preparation method of the ethyl sulfonate salt form I of the compound of the formula (I), which is obtained by reacting the compound of the formula (I) with ethanesulfonic acid in ethanol.
  • the present invention provides a crystalline form II of the ethanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the ethanesulfonate salt form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.0, 6.6, 12.1 and 24.1;
  • the XRPD pattern of the ethanesulfonate salt form II of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.8, 6.0, 6.6, 8.5, 12.1, 13.3, 14.7, 15.4, 16.3, 16.8, 17.3, Diffraction peaks of 19.1, 22.1, 23.3 and 24.1.
  • the invention provides a preparation method of the ethyl sulfonate salt form II of the compound of the formula (I), wherein the ethanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in ethyl acetate for a long time.
  • the present invention provides a crystalline form III of the ethanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the ethanesulfonate salt form III of the compound of the formula (I) contains 2 ⁇ 0.2°: diffraction peaks of 6.0, 7.6, 12.2, 13.6 and 18.3;
  • the XRPD pattern of the ethanesulfonate salt form III contains diffraction peaks of 2 ⁇ 0.2°: 6.0, 7.6, 9.4, 12.2, 13.6, 14.4, 15.2, 16.6, 17.2, 18.4, 19.3 and 20.4.
  • the invention provides a preparation method of the ethyl sulfonate salt form III of the compound of the formula (I), wherein the ethanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in dichloromethane for a long time.
  • the present invention provides a crystalline form of the oxalate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the compound of formula (I).
  • the XRPD pattern of the oxalate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 4.1, 6.9, 7.9, 14.5, 19.4, 23.8 and 27.0;
  • the XRPD pattern of the oxalate salt form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 4.1, 6.9, 7.9, 11.7, 12.2, 13.0, 13.9, 14.5, 15.0, 16.4, 17.6, 19.4. , diffraction peaks of 20.3, 21.0, 23.8, 25.5, 26.0, and 27.0.
  • the present invention provides a process for the preparation of the oxalate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with oxalic acid in dichloromethane.
  • the present invention provides a crystalline form I of the compound of formula (I) having a melting point of about 150 °C.
  • the present invention provides a crystalline form II of the compound of formula (I).
  • the XRPD pattern of the compound oxalate crystal form II of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 4.0, 6.8, 7.7, 8.1, 16.7 and 23.7;
  • the XRPD pattern of the compound oxalate crystal form II of the formula (I) comprises 2 ⁇ 0.2°: 4.0, 6.8, 7.7, 8.1, 14.6, 16.7, 17.4, 17.9, 20.9, 21.4, 22.1, 22.7. , diffraction peaks of 23.7 and 27.7.
  • the invention provides a preparation method of the compound (I) compound oxalate crystal form II, wherein the compound oxalate salt of the formula (I) is obtained by beating and crystallizing in acetone.
  • the present invention provides a crystalline form II of the compound of formula (I) having a melting point of about 154 °C.
  • the present invention provides a crystalline form of the maleate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the maleate salt of the compound of formula (I).
  • the XRPD pattern of the maleate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.6, 8.1, 10.8, 13.8, 23.0 and 26.3;
  • the XRPD pattern of the maleate salt form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.6, 6.4, 8.1, 10.8, 11.6, 12.4, 12.9, 13.3, 13.8, 14.7, 15.5, Diffraction peaks of 16.7, 17.4, 17.8, 18.0, 18.6, 20.1, 21.1, 22.6, 23.0, 23.8, 24.8, 26.3 and 28.1.
  • the present invention provides a process for the preparation of the crystalline form I of the compound of the formula (I), wherein the compound of the formula (I) is co-crystallized with maleic acid in a dichloromethane/ethyl acetate system.
  • the invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in ethyl acetate and stirred at room temperature for 7 days.
  • the maleate salt form I is obtained.
  • the invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in dichloromethane, and ethyl acetate and malay are added. The crystal form I seed crystal is crystallized to obtain the maleate salt form I.
  • the invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in dichloromethane, and n-heptane and malay are added. The crystal form I seed crystal was stirred to obtain a crystal form I sample.
  • the present invention provides a compound of formula (I), maleate salt Form I, having a maleic acid content of from about 27% to about 33%, preferably from about 29% to about 31%, most preferably from about 30%.
  • the compound of the formula (I) provided by the present invention is free of water and an organic solvent, and is allowed to stand under high humidity (RH 92.5%) and high temperature (40 ° C) conditions for 6 months without substantially degrading.
  • the present invention provides a compound of formula (I), maleate salt form I, having a melting point of 114 °C.
  • the compound of the formula (I) provided by the invention has simple preparation process and good process reproducibility, and is particularly suitable for industrial production and pharmaceutical preparation research.
  • the present invention provides a crystalline form of the p-toluenesulfonate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the p-toluenesulfonate salt form I of the compound of the formula (I) contains diffraction peaks of 2 ⁇ 0.2°: 7.6, 13.5, 15.0, 20.6 and 23.5;
  • the XRPD pattern of the crystalline form I of the p-toluenesulfonate salt of the compound of the formula (I) comprises 2 ⁇ 0.2°: 7.6, 8.5, 10.1, 11.9, 13.0, 13.5, 15.0, 16.5, 17.0, 17.4, 18.4. Diffraction peaks of 18.7, 20.6, 20.9, 23.5, 24.1, 25.7 and 26.6.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in ethyl acetate.
  • the present invention provides a crystalline form II of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form II comprises 2 ⁇ 0.2°: diffraction peaks of 7.5, 8.1, 13.1, 20.7 and 22.9;
  • the XRPD pattern of the p-toluenesulfonate salt form II of the compound of the formula (I) comprises 2 ⁇ 0.2°: 7.5, 8.1, 13.1, 13.5, 16.5, 16.9, 17.7, 19.9, 20.7, 21.1, 22.9. , diffraction peaks of 24.9, 25.5, and 28.7.
  • the invention provides a preparation method of the p-toluenesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is obtained by beating and crystallizing the p-toluenesulfonate in ethanol.
  • the present invention provides a crystalline form III of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the compound p-toluenesulfonate crystal form III of the formula (I) comprises diffraction peaks of 2 ⁇ 0.2°: 8.3, 12.8, 14.7, 16.6 and 24.3;
  • the XRPD pattern of the p-toluenesulfonate salt form III of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.4, 6.9, 8.3, 8.8, 9.1, 10.5, 10.8, 11.4, 12.1, 12.8, 14.7. Diffraction peaks of 15.5, 16.6, 17.2, 17.8, 18.5, 18.8, 19.3, 19.9, 20.4, 22.1, 22.4, 23.4, 23.9, 24.3, 25.4, 25.8, 26.8, 27.5, 28.4 and 29.6.
  • the invention provides a preparation method of the p-toluenesulfonate salt form III of the compound of the formula (I), wherein the compound of the formula (I) is obtained by crystallizing the p-toluenesulfonate in water for a long time.
  • the present invention provides a crystalline form IV of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IV comprises 2 ⁇ 0.2° as diffraction peaks of 7.3, 14.4, 21.2, 23.5 and 25.3;
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IV comprises 2 ⁇ ⁇ 0.2°: 5.7, 7.3, 10.1, 10.6, 11.7, 14.4, 16.1, 16.6, 17.2, 18.5, 18.9 Diffraction of 19.9, 20.6, 21.2, 22.3, 22.9, 23.5, 24.4, 25.3, 25.8, 26.9, 27.4, 28.1, 29.2, 30.1, 31.0, 31.6, 32.5, 33.1, 33.6, 34.5, 35.5, 367, 38.9 and 42.7 peak.
  • the invention provides a preparation method of the p-toluenesulfonate salt form IV of the compound of the formula (I), wherein the compound of the formula (I) is obtained by slurrying and translating p-toluenesulfonate in ethyl acetate.
  • the present invention provides a crystalline form V of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the tosylate salt form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 8.1, 10.2, 11.0, 19.4 and 24.1;
  • the XRPD pattern of the p-toluenesulfonate crystal form V of the compound of the formula (I) comprises 2 ⁇ 0.2°: 8.1, 8.5, 9.0, 10.2, 11.0, 13.8, 14.8, 16.6, 17.0, 17.5, 18.3. Diffraction peaks of 19.4, 20.6, 22.1, 23.0, 24.1, 25.8, 28.1, 30.1 and 30.7.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form V of the compound of the formula (I), wherein the compound of the formula (I) is p-crystallized by p-toluenesulfonate in dichloromethane/ethyl acetate.
  • the present invention provides a crystalline form VI of the compound p-toluenesulfonate of formula (I).
  • the XRPD pattern of the compound p-toluenesulfonate form VI of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.2, 12.5, 16.5 and 21.0;
  • the XRPD pattern of the compound of the formula (I) on the p-toluenesulfonate form VI comprises 2 ⁇ 0.2°: 6.8, 7.2, 7.7, 10.0, 10.4, 11.6, 12.5, 14.3, 16.5, 17.1, 17.5. Diffraction peaks of 18.2, 19.2, 19.7, 21.0, 21.7, 23.5, 23.7, 24.4, 25.3, 26.8 and 29.4.
  • the invention provides a preparation method of the p-toluenesulfonate salt form VI of the compound of the formula (I), wherein the compound of the formula (I) is obtained by slurrying and translating the p-toluenesulfonate in acetone/ethyl acetate.
  • the present invention provides a compound of formula (I) p-toluenesulfonate Form VII.
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VII comprises 2 ⁇ 0.2°: diffraction peaks of 5.7, 6.9, 9.9 and 17.6;
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VII comprises 2 ⁇ 0.2°: 5.7, 6.9, 7.4, 8.7, 9.9, 11.5, 12.5, 14.6, 15.7, 17.6, 23.6. , diffraction peaks of 24.7 and 26.5.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form VII of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in ethanol.
  • the present invention provides a compound of formula (I) p-toluenesulfonate Form VIII.
  • the XRPD pattern of the compound of formula (I) p-toluenesulfonate Form VIII comprises 2 ⁇ 0.2°: diffraction peaks of 4.2, 5.9, 7.2, 9.0 and 25.3;
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VIII comprises 2 ⁇ ⁇ 0.2°: 4.2, 5.9, 7.2, 9.0, 10.3, 11.0, 14.3, 15.2, 16.6, 18.9, 19.7 Diffraction peaks of 19.9, 21.0, 22.1, 23.6, 25.3, 26.2, 29.5 and 31.1.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form VIII of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in acetone.
  • the present invention provides a crystalline form IX of the compound p-toluenesulfonate of formula (I).
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IX comprises 2 ⁇ 0.2°: diffraction peaks of 7.0, 7.7, 9.4, 12.9 and 15.4;
  • the XRPD pattern of the p-toluenesulfonate salt form IX of the compound of the formula (I) comprises 2 ⁇ 0.2°: 7.0, 7.7, 9.4, 10.8, 12.2, 12.9, 13.7, 15.4, 18.0, 20.5, 21.9. , diffraction peaks of 23.2, 26.7 and 28.0.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form IX of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in methanol.
  • the salts of the present invention have good physicochemical properties, especially in terms of solubility, stability and wettability, and particularly preferred salts of the present invention Its crystal form is particularly excellent in the above properties.
  • the crystal form of the invention has good stability, no hygroscopicity, good solubility, good adaptability in the preparation process, good drug dissolution behavior, and good bioavailability of the drug in the body.
  • the corresponding crystal form preparation process is simple, the yield is high, and it is suitable for industrial production. Therefore, the salt and crystal form of the compound of the formula (I) of the present invention are very suitable for pharmaceutical preparation applications and have good clinical application prospects. ⁇
  • Fig. 1 is an X-ray powder diffraction pattern of the hydrochloride salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 2 is an X-ray powder diffraction pattern of the hydrochloride salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 3 is an X-ray powder diffraction pattern of the hydrochloride salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 5 is an X-ray powder diffraction pattern of the hydrochloride salt form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 6 is an X-ray powder diffraction pattern of the sulfate form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 7 is an X-ray powder diffraction pattern of the sulfate form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 8 is an X-ray powder diffraction pattern of the sulfate form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 9 is an X-ray powder diffraction pattern of the sulfate form IV of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 10 is an X-ray powder diffraction pattern of the sulfate form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 11 is an X-ray powder diffraction pattern of the mesylate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 12 is a DSC chart of the methanesulfonate salt form I of the compound of formula (I);
  • Figure 13 is a TGA spectrum of the mesylate salt form I of the compound of formula (I);
  • Fig. 14 is an X-ray powder diffraction pattern of the mesylate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 15 is an X-ray powder diffraction pattern of the mesylate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 16 is an X-ray powder diffraction pattern of the mesylate salt form IV of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 17 is an X-ray powder diffraction pattern of the methanesulfonate crystal form V of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 18 is an X-ray powder diffraction pattern of the mesylate salt form VI of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 19 is an X-ray powder diffraction pattern of the mesylate salt form VII of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 20 is an X-ray powder diffraction pattern of the mesylate salt form VIII of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 21 is a DSC chart of the methanesulfonate salt form VIII of the compound of formula (I);
  • Figure 22 is a TGA spectrum of the methanesulfonate salt form VIII of the compound of formula (I);
  • Figure 23 is an X-ray powder diffraction pattern of the form I of the besylate salt of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Fig. 24 is an X-ray powder diffraction pattern of the benzenesulfonate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 25 is an X-ray powder diffraction pattern of the benzenesulfonate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 26 is an X-ray powder diffraction pattern of the form of the besylate salt of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 27 is an X-ray powder diffraction pattern of the form of the besylate salt form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 28 is an X-ray powder diffraction pattern of the form of the besylate salt form VI of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 29 is an X-ray powder diffraction pattern of the benzenesulfonate salt form VII of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 30 is an X-ray powder diffraction pattern of the ethanesulfonate salt form I of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 31 is an X-ray powder diffraction pattern of the ethanesulfonate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 32 is an X-ray powder diffraction pattern of the ethanesulfonate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 33 is an X-ray powder diffraction pattern of the oxalate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 34 is a DSC chart of the oxalate salt form I of the compound of formula (I);
  • Figure 35 is a TGA spectrum of the oxalate salt form I of the compound of formula (I);
  • Figure 36 is an X-ray powder diffraction pattern of the compound oxalate crystal form II of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 37 is a DSC spectrum of the compound oxalate salt form II of the formula (I);
  • Figure 38 is a TGA pattern of the oxalate salt form II of the compound of formula (I);
  • Figure 39 is an X-ray powder diffraction pattern of the maleate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 40 is a DSC spectrum of the maleate salt form I of the compound of formula (I)
  • Figure 41 is an X-ray powder diffraction pattern of the compound (I) p-tolylate Form I, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 42 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form II, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 43 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form III, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 44 is an X-ray powder diffraction pattern of the compound of the formula (I) versus toluene salt form IV, wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 45 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form V, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 46 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form VI, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 47 is an X-ray powder diffraction pattern of the compound of the formula (I) versus toluene salt crystal form VII, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 48 is an X-ray powder diffraction pattern of the compound of the formula (I), p-toluate, Form VIII, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 49 is an X-ray powder diffraction pattern of the compound of the formula (I), p-toluate, Form IX, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • the second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone
  • the third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate
  • EtOAc EtOAc
  • Step 5 (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide
  • oxalate salt of the compound of the formula (I) was weighed into the reactor, and 10.0 mL of acetone was added thereto at room temperature, and the mixture was stirred for 3 days, and the suspension was filtered to obtain a solid, i.e., oxalate crystal form II.
  • Example 35 Preparation of the crystalline form I of the p-toluenesulfonate salt of the compound of formula (I)
  • the compound of formula (I) is p-toluenesulfonate Form I.
  • the sample of the methanesulfonate salt form VIII and the maleate salt form I of the compound of the formula (I) provided by the present invention is placed under the conditions of high temperature 40 ° C and high humidity (RH 92.5%) at 0, 1, respectively. At 2, 3, and 6 months, samples were taken to investigate the relevant substances. The specific test results are shown in Table 2.
  • TR-FRET fluorescence resonance energy transfer
  • Adding 1 to 5 uL of the substrate mixture comprises a final concentration of the substrate polypeptide of 5 to 50 nM and a final concentration of ATP of 10 to 200 uM.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the enzymatic activities of the specific examples are shown in Table 3.
  • TR-FRET fluorescence resonance energy transfer
  • Adding 1 to 5 uL of the substrate mixture comprises a final concentration of the substrate polypeptide of 5 to 50 nM and a final concentration of ATP of 10 to 200 uM.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the enzymatic activities of the specific examples are shown in Table 3.
  • the method of the present study the inhibition of a test compound CellTiter-Glo proliferation of Hep 3B cells, derived compounds inhibit cell proliferation and half maximal inhibitory concentration IC 50 activity.
  • the plate reader measures the chemiluminescence signal values of the plates.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the cell activity of the specific examples is shown in Table 4.
  • the method of the present study the inhibition of a test compound on the CellTiter-Glo HuH-7 cell proliferation, and to obtain the compound inhibited cell proliferation half maximal inhibitory concentration IC 50 activity.
  • the plate reader measures the chemiluminescence signal values of the plates.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the cell activity of the specific examples is shown in Table 4.
  • the method of the present study the inhibition of a test compound on the CellTiter-Glo SK-HEP-1 cell proliferation, the compounds inhibit cell proliferation and draw half maximal inhibitory concentration IC 50 activity.
  • the cells/mL were cultured in an incubator for 16 to 24 hours (37 ° C, 5% CO 2 ).
  • the plate reader measures the chemiluminescence signal values of the plates.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the cell activity of the specific examples is shown in Table 4.
  • the rat pharmacokinetic test of the preferred embodiment of the present invention was carried out using SD rats (Shanghai Jiesijie Experimental Animal Co., Ltd.).
  • ⁇ Mode of administration single oral administration.
  • Formulation formulation 0.5% CMC and 1% Tween 80, sonicated.
  • ⁇ Sampling points 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.
  • the plasma sample was added to 160 uL of acetonitrile precipitate in 40 ⁇ L, and mixed for 500 to 2000 ⁇ g for 5 to 20 minutes.
  • Time/minute Liquid A B liquid 0.01 80% 20% 0.5 80% 20% 1.2 10% 90% 2.6 10% 90% 2.7 80% 20% 3.8 80% 20%
  • FBS fetal bovine serum
  • the cells are covered with 80-90% of the bottom of the culture flask, they are passaged. After passage, the cells are continuously cultured in a CO2 incubator. This process is repeated until the number of cells meets the in vivo efficacy requirements.
  • the cultured cells were collected, counted by a fully automatic cell counter, and the cells were resuspended in PBS according to the counting results to prepare a cell suspension (density: 7 ⁇ 10 7 /mL), which was placed in an ice box for use.
  • mice were labeled with a one-time large mouse universal ear tag before inoculation, and the skin of the inoculated site was disinfected with 75% medical alcohol.
  • test nude mice were inoculated in turn (the inoculation site was placed subcutaneously inoculated with 0.1 mL of cell suspension on the right side of the right side of the nude mouse).
  • tumors were counted on days 14-16 after inoculation, and tumor size was calculated.
  • tumor volume (mm3) length (mm) ⁇ width (mm) ⁇ width (mm) / 2
  • the administration of the test drug (administration method: oral administration, administration dose: 30 mg/kg, administration volume: 10 mL/kg, administration frequency: 2 times/day, administration period: 14 days) , solvent: 0.5% CMC / 1% Tween 80).
  • the tumor was dosed twice a week after the test drug was administered, and weighed.

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Abstract

The present invention relates to a salt and crystal of an FGFR4 inhibitor, a preparation method and the use thereof. In particular, the present invention relates to a crystal form of a pharmaceutically acceptable salt of a compound of formula (I) and a preparation method therefor, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form and the use of same in the treatment of cancers.

Description

FGFR4抑制剂的盐、晶体、制备方法及其用途Salt, crystal, preparation method and use thereof of FGFR4 inhibitor 技术领域Technical field
本发明属于晶型技术领域，具体涉及式(I)化合物可药用盐、可药用盐的晶型及其制备方法和用途。The invention belongs to the technical field of crystal forms, and in particular relates to a pharmaceutically acceptable salt of a compound of the formula (I), a crystalline form of a pharmaceutically acceptable salt, a preparation method and use thereof.
背景技术Background technique
成纤维细胞生长因子受体(FGFR)属于受体酪氨酸激酶跨膜受体，包括4个受体亚型，分别为FGFR1、FGFR2、FGFR3和FGFR4。FGFR调节细胞增殖、生存、分化和迁移等多种功能，在人体发育和成人各项机体功能中发挥重要作用。FGFR在多种人类肿瘤中表现异常，包括基因扩增、突变和过表达，是肿瘤靶向治疗研究的重要靶点。The fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor and includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.
FGFR4是FGFR受体家族中的一员，通过与其配体成纤维细胞生长因子19(FGF19)的结合，在细胞膜上形成二聚体，这些二聚体的形成可引起FGFR4自身细胞内关键的酪氨酸残基磷酸化，从而激活细胞内多个下游信号通路，这些细胞内信号通路在细胞增殖、生存及抗凋亡过程中起重要作用。FGFR4在许多癌症中过表达，是肿瘤恶性侵袭的预测因素。减少和降低FGFR4表达能减少细胞增生和促进细胞凋亡。最近越来越多的研究表明约三分之一左右的肝癌患者FGF19/FGFR4信号通路持续激活，是导致该部分患者肝癌发生的主要致癌因素。同时FGFR4表达或高表达也和许多其他肿瘤的密切相关，如胃癌、前列腺癌、皮肤癌、卵巢癌、肺癌、乳腺癌、结肠癌等。FGFR4, a member of the FGFR receptor family, forms dimers on the cell membrane by binding to its ligand, fibroblast growth factor 19 (FGF19), and the formation of these dimers can cause critical tyrosine in FGFR4's own cells. The phosphorylation of the amino acid residue activates multiple downstream signaling pathways in the cell, and these intracellular signaling pathways play an important role in cell proliferation, survival, and anti-apoptosis. FGFR4 is overexpressed in many cancers and is a predictor of malignant invasion of tumors. Decreasing and reducing FGFR4 expression can reduce cell proliferation and promote apoptosis. Recently, more and more studies have shown that about one-third of liver cancer patients with continuous activation of FGF19/FGFR4 signaling pathway are the main carcinogenic factors leading to liver cancer in this part of patients. At the same time, FGFR4 expression or high expression is also closely related to many other tumors, such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.
肝癌发病率在我国高居全球之首，每年新发和死亡患者约占全球肝癌总数的一半。目前我国肝癌的发病率约为28.7/10万，2012年有394770例新发病例，成为死亡率仅次于胃癌、肺癌的第三大恶性肿瘤。原发性肝癌发病是多因素、多步骤的复杂过程，其侵袭性强，预后差。手术治疗如肝切除和肝移植可提高部分病人的生存率，但只有有限病人可以进行手术治疗，并且手术后大多数病人由于复发和转移仍预后较差。Sorafenib是目前市场上批准的唯一一个肝癌治疗药物，临床也只能延长3个月左右的总体生存期，治疗效果并不理想，因此迫切需要开发靶向新分子的肝癌系统治疗药物。FGFR4作为相当一部分肝癌的主要致癌因素，其小分子抑制剂的开发具有重大的临床应用潜力。The incidence of liver cancer ranks first in the world in China, with new and dead patients accounting for about half of the total number of liver cancers worldwide each year. At present, the incidence of liver cancer in China is about 28.7/100,000. In 2012, there were 394,770 new cases, which became the third most serious malignant tumor after gastric cancer and lung cancer. The onset of primary liver cancer is a multi-factor, multi-step complex process with strong invasiveness and poor prognosis. Surgical treatments such as hepatectomy and liver transplantation can improve the survival rate of some patients, but only limited patients can undergo surgery, and most patients have a poor prognosis due to recurrence and metastasis after surgery. Sorafenib is the only liver cancer treatment drug approved on the market. It can only prolong the overall survival period of about 3 months, and the treatment effect is not satisfactory. Therefore, it is urgent to develop a liver cancer system treatment drug targeting new molecules. FGFR4 is a major carcinogenic factor in liver cancer, and its development of small molecule inhibitors has great clinical application potential.
目前已有一些FGFR抑制剂作为抗肿瘤药物进入临床研究阶段，但这些都主要是针对FGFR1、2和3的抑制剂，对FGFR4的活性抑制较弱，且FGFR1-3的抑制具有高血磷症等靶点相关副作用。FGFR4高选择性抑制剂能有效治疗FGFR4信号通路异常导致的癌症疾病，并可避免FGFR1-3抑制导致的高血磷症等相关副作用，针对FGFR4的高选择性小分子抑制剂在肿瘤靶向治疗领域具有重大应用前景。At present, some FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia. Such as target related side effects. Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition. Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects.
发明内容Summary of the invention
本发明一方面提供了式(I)化合物的可药用盐。One aspect of the invention provides a pharmaceutically acceptable salt of a compound of formula (I).
本发明第二方面提供了式(I)化合物盐酸盐的晶型。A second aspect of the invention provides a crystalline form of the hydrochloride salt of a compound of formula (I).
本发明第三方面提供了式(I)化合物硫酸盐的晶型。A third aspect of the invention provides a crystalline form of a sulfate salt of a compound of formula (I).
本发明第四方面提供了式(I)化合物甲磺酸盐的晶型。A fourth aspect of the invention provides a crystalline form of the methanesulfonate salt of the compound of formula (I).
本发明第五方面提供了式(I)化合物苯磺酸盐的晶型。A fifth aspect of the invention provides a crystalline form of a besylate salt of a compound of formula (I).
本发明第六方面提供了式(I)化合物乙磺酸盐的晶型。A sixth aspect of the invention provides a crystalline form of the ethanesulfonate salt of the compound of formula (I).
本发明第七方面提供了式(I)化合物草酸盐的晶型。A seventh aspect of the invention provides a crystalline form of the oxalate salt of the compound of formula (I).
本发明第八方面提供了式(I)化合物马来酸盐的晶型。An eighth aspect of the invention provides a crystalline form of the maleate salt of the compound of formula (I).
本发明第九方面提供了式(I)化合物对甲苯磺酸盐的晶型。A ninth aspect of the invention provides a crystalline form of the p-toluenesulfonate salt of the compound of formula (I).
本发明第十方面提供了式(I)化合物可药用盐晶型的药物组合物。A tenth aspect of the invention provides a pharmaceutical composition of a pharmaceutically acceptable salt crystalline form of a compound of formula (I).
本发明第十一方面提供了式(I)化合物可药用盐晶型的制备方法。An eleventh aspect of the invention provides a process for the preparation of a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I).
本发明第十二方面提供了式(I)化合物可药用盐晶型的用途。The twelfth aspect of the invention provides the use of a pharmaceutically acceptable salt crystalline form of a compound of formula (I).
化合物(R)-N-(5-氰基-4-((1-甲氧基丙烷-2-基)氨基)吡啶-2-基)-7-甲酰基-6-((2-羰基-1,3-噁吖庚环-3-基)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-甲酰胺(以下简称为式(I)化合物)，最早公开于豪森专利PCT/CN2017/084564，该化合物对FGFR4激酶活性具有很强的抑制作用，并具有非常高的选择性，是新一代FGFR4抑制剂药物，其化学结构式如下：Compound (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-) 1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (hereinafter referred to as a compound of formula (I)) It was first disclosed in Hausen patent PCT/CN2017/084564. This compound has strong inhibitory effect on FGFR4 kinase activity and has very high selectivity. It is a new generation of FGFR4 inhibitor drug, and its chemical structure is as follows:
Figure PCTCN2018112891-appb-000001
Figure PCTCN2018112891-appb-000001
本发明所述的“可药用盐”可为任何盐，只要它能与式(I)化合物形成无毒盐即可。其例子包括但不限于：与各种无机酸形成的盐如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐、碳酸盐、碳酸氢盐、高氯酸盐等；与有机酸形成的盐如柠檬酸盐、酒石酸盐、富马酸盐、琥珀酸盐、马来酸盐、醋酸盐、苹果酸盐、苯甲酸盐、对甲苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、乙磺酸盐、羟乙基磺酸盐、1-萘磺酸盐、2-萘磺酸盐、樟脑磺酸盐、三氟甲磺酸盐、三氟乙酸盐、乳酸盐、草酸盐、水杨酸盐、苯乙酸盐、扁桃酸盐、甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、草酸盐、羟乙酸盐、羟基马来酸盐、甲基马来酸盐、己二酸盐、肉桂酸盐、抗坏血酸盐、水杨酸盐、2-乙酸基苯甲酸盐、烟酸盐、异烟酸盐、胆酸盐、天冬氨酸盐或谷氨酸盐。在一些情况下，盐可为含水物、水合物、与醇等的溶剂化物等。The "pharmaceutically acceptable salt" of the present invention may be any salt as long as it forms a non-toxic salt with the compound of the formula (I). Examples include, but are not limited to, salts with various inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, carbonates, bicarbonates, perchloric acids. Salts, etc.; salts with organic acids such as citrate, tartrate, fumarate, succinate, maleate, acetate, malate, benzoate, p-toluate, Methanesulfonate, besylate, p-toluenesulfonate, ethanesulfonate, isethionate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, camphorsulfonate, trifluoromethyl Sulfonate, trifluoroacetate, lactate, oxalate, salicylate, phenylacetate, mandelate, formate, acetate, trifluoroacetate, propionate, Oxalate, glycolate, hydroxymaleate, methyl maleate, adipate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, niacin Salt, isonicotinate, cholate, aspartate or glutamate. In some cases, the salt may be a hydrate, a hydrate, a solvate with an alcohol or the like, and the like.
本发明提供了式(I)化合物可药用盐的制备方法，将式(I)化合物与酸在溶剂中反应得到。The present invention provides a process for the preparation of a pharmaceutically acceptable salt of a compound of formula (I), which is obtained by reacting a compound of formula (I) with an acid in a solvent.
所述溶剂包括有机溶剂或无机溶剂，所述有机溶剂选自醇溶剂、酮溶剂、酯类溶剂、二氯甲烷、乙腈、氯仿、中的一种或几种混合溶剂，优选水、甲酸乙酯、乙酸乙酯、乙醇、二氯甲烷、乙腈、丙酮、异丁醇中的一种或几种混合溶剂。The solvent includes an organic solvent or an inorganic solvent selected from the group consisting of an alcohol solvent, a ketone solvent, an ester solvent, dichloromethane, acetonitrile, chloroform, or a mixed solvent thereof, preferably water or ethyl formate. One or a mixture of one of ethyl acetate, ethanol, dichloromethane, acetonitrile, acetone, and isobutanol.
所述酸包括有机溶酸或无机酸，所述无机酸包括但不限于盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸、高氯酸等；有机酸包括但不限于柠檬酸、酒石酸、富马酸、琥珀酸、马来酸、醋酸、苹果酸、苯甲酸、对甲苯甲酸、甲磺酸、苯磺酸、对甲苯磺酸、乙磺酸、羟乙基磺酸、1-萘磺酸、2-萘磺酸、樟脑磺酸、三氟甲磺酸、三氟乙酸、乳酸、草酸、水杨酸、苯乙酸、扁桃酸、甲酸、乙酸、三氟乙酸、丙酸、草酸、羟乙酸、羟基马来酸、甲基马来酸、己二酸、肉桂酸、 抗坏血酸、水杨酸、2-乙酸基苯甲酸、烟酸、异烟酸、胆酸、天冬氨酸或谷氨酸。The acid includes an organic acid or inorganic acid including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, perchloric acid, etc.; organic acids include, but are not limited to, citric acid , tartaric acid, fumaric acid, succinic acid, maleic acid, acetic acid, malic acid, benzoic acid, p-toluic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, isethionic acid, 1 -naphthalenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, lactic acid, oxalic acid, salicylic acid, phenylacetic acid, mandelic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, Oxalic acid, glycolic acid, hydroxymaleic acid, methyl maleic acid, adipic acid, cinnamic acid, ascorbic acid, salicylic acid, 2-acetic acid benzoic acid, nicotinic acid, isonicotinic acid, cholic acid, aspartic acid Or glutamic acid.
本发明提供了式(I)化合物盐酸盐晶型。The present invention provides a hydrochloride salt form of the compound of formula (I).
本发明提供了式(I)化合物盐酸盐晶型I。The present invention provides the hydrochloride salt form I of the compound of formula (I).
所述式(I)化合物盐酸盐晶型I的XRPD图谱中包含2θ±0.2°为：5.8、9.9、11.0、16.7和25.3的衍射峰；The XRPD pattern of the hydrochloride salt form I of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.8, 9.9, 11.0, 16.7 and 25.3;
优选的，所述式(I)化合物盐酸盐晶型I的XRPD图谱中包含2θ±0.2°为：5.8、8.2、9.9、11.0、12.1、12.4、13.0、14.0、16.7、18.5、19.0、22.3、25.3、25.8、26.2和27.7的衍射峰。Preferably, the XRPD pattern of the hydrochloride salt form I of the compound of the formula (I) comprises 2θ±0.2°: 5.8, 8.2, 9.9, 11.0, 12.1, 12.4, 13.0, 14.0, 16.7, 18.5, 19.0, 22.3. , 25.3, 25.8, 26.2, and 27.7 diffraction peaks.
本发明提供了式(I)化合物盐酸盐晶型I制备方法，式(I)化合物与盐酸在乙酸乙酯中反应得到。The present invention provides a process for the preparation of the salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethyl acetate.
本发明提供了式(I)化合物盐酸盐晶型II。The present invention provides a salt form II of the compound of formula (I).
所述式(I)化合物盐酸盐晶型II的XRPD图谱中包含2θ±0.2°为：6.0、6.5、15.7和23.8的衍射峰。The XRPD pattern of the hydrochloride salt form II of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.0, 6.5, 15.7 and 23.8.
优选的，所述盐酸盐晶型II的XRPD图谱中包含2θ±0.2°为：6.0、6.5、8.4、11.7、12.1、13.2、14.6、15.7、16.7、17.7、18.7、19.1、20.0、22.5、23.0、23.8、24.5和25.6的衍射峰。Preferably, the XRPD pattern of the hydrochloride salt form II comprises 2θ±0.2°: 6.0, 6.5, 8.4, 11.7, 12.1, 13.2, 14.6, 15.7, 16.7, 17.7, 18.7, 19.1, 20.0, 22.5, Diffraction peaks of 23.0, 23.8, 24.5, and 25.6.
本发明提供了式(I)化合物盐酸盐晶型II制备方法，式(I)化合物与盐酸在乙醇中反应得到。The present invention provides a process for the preparation of the salt form II of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethanol.
本发明提供的式(I)化合物盐酸盐晶型II，具有良好的稳定性，在40℃条件下放置1个月，降解≤0.5％。The hydrochloride salt form II of the compound of the formula (I) provided by the invention has good stability and is allowed to stand at 40 ° C for 1 month, and the degradation is ≤ 0.5%.
本发明提供了式(I)化合物盐酸盐晶型III。The present invention provides the hydrochloride salt form III of the compound of formula (I).
所述式(I)化合物盐酸盐晶型III的XRPD图谱中包含2θ±0.2°为：6.1、7.0、9.2、10.2和21.0的衍射峰；The XRPD pattern of the hydrochloride salt form III of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.1, 7.0, 9.2, 10.2 and 21.0;
优选的，所述盐酸盐晶型III的XRPD图谱中包含2θ±0.2°为：6.1、7.0、9.2、10.2、12.4、14.4、16.4、16.9、18.6、19.5、21.0、24.6、25.6和26.2的衍射峰。Preferably, the XRPD pattern of the hydrochloride salt form III comprises 2θ±0.2°: 6.1, 7.0, 9.2, 10.2, 12.4, 14.4, 16.4, 16.9, 18.6, 19.5, 21.0, 24.6, 25.6, and 26.2. Diffraction peaks.
本发明提供了式(I)化合物盐酸盐晶型III制备方法，式(I)化合物与盐酸在二氯甲烷中反应得到。The present invention provides a process for the preparation of the salt form III of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in dichloromethane.
本发明提供了式(I)化合物盐酸盐晶型IV。The present invention provides the hydrochloride salt form IV of the compound of formula (I).
所述式(I)化合物盐酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：6.1、7.8、9.5、11.9和25.0的衍射峰；The XRPD pattern of the hydrochloride salt form IV of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.1, 7.8, 9.5, 11.9 and 25.0;
优选的，所述盐酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：5.9、6.1、7.8、8.8、9.5、10.0、11.9、12.4、15.5、21.2、23.6、25.0、26.5和32.5的衍射峰。Preferably, the XRPD pattern of the hydrochloride salt form IV comprises 2θ±0.2° of: 5.9, 6.1, 7.8, 8.8, 9.5, 10.0, 11.9, 12.4, 15.5, 21.2, 23.6, 25.0, 26.5 and 32.5. Diffraction peaks.
本发明提供了式(I)化合物盐酸盐晶型IV制备方法，式(I)化合物与盐酸在乙腈中反应得到。The present invention provides a process for the preparation of the salt form IV of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in acetonitrile.
本发明提供了式(I)化合物盐酸盐晶型V。The present invention provides a hydrochloride salt form V of the compound of formula (I).
所述式(I)化合物盐酸盐晶型V的XRPD图谱中包含2θ±0.2°为：6.5、12.0、13.2、16.5和23.6的衍射峰；The XRPD pattern of the hydrochloride salt form V of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.5, 12.0, 13.2, 16.5 and 23.6;
优选的，所述式(I)化合物盐酸盐晶型V的XRPD图谱中包含2θ±0.2°为：6.5、8.8、11.5、12.0、13.2、14.4、14.8、15.2、16.5、20.3、21.3、23.6、25.3和27.0的衍射峰。Preferably, the XRPD pattern of the hydrochloride salt form V of the compound of the formula (I) comprises 2θ±0.2°: 6.5, 8.8, 11.5, 12.0, 13.2, 14.4, 14.8, 15.2, 16.5, 20.3, 21.3, 23.6. , 25.3 and 27.0 diffraction peaks.
本发明提供了式(I)化合物盐酸盐晶型V制备方法，式(I)化合物与盐酸在乙酸乙酯中反应得到。The present invention provides a process for the preparation of the salt form V of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethyl acetate.
本发明提供了式(I)化合物硫酸盐晶型。The present invention provides a sulfate form of the compound of formula (I).
本发明提供了式(I)化合物硫酸盐晶型I。The present invention provides a sulfate form I of the compound of formula (I).
所述式(I)化合物硫酸盐晶型I的XRPD图谱中包含2θ±0.2°为：5.6、6.4、7.6、13.4和27.1的衍射峰；The XRPD pattern of the sulfate form I of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.6, 6.4, 7.6, 13.4 and 27.1;
优选的，所述式(I)化合物硫酸盐晶型I的XRPD图谱中包含2θ±0.2°为：5.6、6.4、7.6、11.3、12.1、12.4、13.4、14.1、15.3、18.1、19.0、20.9、21.5、24.5、24.9和27.1的衍射峰。Preferably, the XRPD pattern of the sulfate form I of the compound of the formula (I) comprises 2θ±0.2°: 5.6, 6.4, 7.6, 11.3, 12.1, 12.4, 13.4, 14.1, 15.3, 18.1, 19.0, 20.9, Diffraction peaks of 21.5, 24.5, 24.9, and 27.1.
本发明提供了式(I)化合物硫酸盐晶型I的制备方法，式(I)化合物与硫酸在乙酸乙酯中反应得到。The present invention provides a process for the preparation of the sulfate form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in ethyl acetate.
本发明提供了式(I)化合物硫酸盐晶型II。The present invention provides a sulfate form II of the compound of formula (I).
所述式(I)化合物硫酸盐晶型II的XRPD图谱中包含2θ±0.2°为：5.8、6.1、6.5、9.0、13.0和23.9的衍射峰；The XRPD pattern of the sulfate form II of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.8, 6.1, 6.5, 9.0, 13.0 and 23.9;
优选的，所述式(I)化合物硫酸盐晶型II的XRPD图谱中包含2θ±0.2°为：5.8、6.1、6.5、7.8、9.0、11.8、13.0、14.6、15.4、16.0、16.6、17.4、18.1、19.8、21.6、22.1、23.0和23.9的衍射峰。Preferably, the XRPD pattern of the sulfate form II of the compound of the formula (I) comprises 2θ±0.2°: 5.8, 6.1, 6.5, 7.8, 9.0, 11.8, 13.0, 14.6, 15.4, 16.0, 16.6, 17.4, Diffraction peaks of 18.1, 19.8, 21.6, 22.1, 23.0, and 23.9.
本发明提供了式(I)化合物硫酸盐晶型II的制备方法，式(I)化合物与硫酸在乙腈中反应得到。The present invention provides a process for the preparation of the sulfate form II of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in acetonitrile.
本发明提供了式(I)化合物硫酸盐晶型III。The present invention provides a sulfate form III of the compound of formula (I).
所述式(I)化合物硫酸盐晶型III的XRPD图谱中包含2θ±0.2°为：6.6、7.8、15.5、18.1、25.0和27.1的衍射峰；The XRPD pattern of the sulfate form III of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.6, 7.8, 15.5, 18.1, 25.0 and 27.1;
优选的，所述式(I)化合物硫酸盐晶型III的XRPD图谱中包含2θ±0.2°为：6.6、7.8、9.5、11.5、12.2、12.6、13.6、14.3、15.5、17.1、18.1、18.7、19.1、19.8、21.1、21.6、23.2、24.6、25.0和27.1的衍射峰。Preferably, the XRPD pattern of the sulfate form III of the compound of the formula (I) comprises 2θ±0.2°: 6.6, 7.8, 9.5, 11.5, 12.2, 12.6, 13.6, 14.3, 15.5, 17.1, 18.1, 18.7, Diffraction peaks of 19.1, 19.8, 21.1, 21.6, 23.2, 24.6, 25.0 and 27.1.
本发明提供了式(I)化合物硫酸盐晶型III的制备方法，式(I)化合物与硫酸在丙酮中反应得到。The present invention provides a process for the preparation of the sulfate form III of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in acetone.
本发明提供了式(I)化合物硫酸盐晶型IV。The present invention provides a sulfate form IV of the compound of formula (I).
所述式(I)化合物硫酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：5.2、6.6、9.8、20.5和23.3的衍射峰；The XRPD pattern of the sulfate form IV of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.2, 6.6, 9.8, 20.5 and 23.3;
优选的，所述式(I)化合物硫酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：5.2、6.6、8.7、9.8、11.3、13.4、16.5、20.5、23.3、25.4、26.7和28.8的衍射峰。Preferably, the XRPD pattern of the sulfate form IV of the compound of the formula (I) comprises 2θ±0.2° of: 5.2, 6.6, 8.7, 9.8, 11.3, 13.4, 16.5, 20.5, 23.3, 25.4, 26.7 and 28.8. Diffraction peaks.
本发明提供了式(I)化合物硫酸盐晶型IV的制备方法，式(I)化合物与硫酸在二氯甲烷中反应得到。The invention provides a process for the preparation of the sulfate form IV of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in dichloromethane.
本发明提供了式(I)化合物硫酸盐晶型V。The present invention provides a sulfate form V of the compound of formula (I).
所述式(I)化合物硫酸盐晶型V的XRPD图谱中包含2θ±0.2°为：5.8、6.3、13.5、24.0和24.8的衍射峰；The XRPD pattern of the sulfate form V of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.8, 6.3, 13.5, 24.0 and 24.8;
优选的，所述式(I)化合物硫酸盐晶型V的XRPD图谱中包含2θ±0.2°为：5.8、6.3、13.5、14.5、14.9、16.8、17.4、18.1、19.4、20.5、20.9、22.8、24.0、24.8、26.7、28.3和31.8的衍射峰。Preferably, the XRPD pattern of the sulfate form V of the compound of the formula (I) comprises 2θ±0.2°: 5.8, 6.3, 13.5, 14.5, 14.9, 16.8, 17.4, 18.1, 19.4, 20.5, 20.9, 22.8, Diffraction peaks of 24.0, 24.8, 26.7, 28.3 and 31.8.
本发明提供了式(I)化合物硫酸盐晶型V的制备方法，式(I)化合物与硫酸在乙腈中反应并长时间搅拌得到。The present invention provides a process for the preparation of the sulfate form V of the compound of the formula (I), wherein the compound of the formula (I) is reacted with sulfuric acid in acetonitrile and stirred for a long period of time.
本发明提供了式(I)化合物甲磺酸盐晶型。The present invention provides a crystalline form of the mesylate salt of the compound of formula (I).
本发明提供了式(I)化合物甲磺酸盐晶型I。The present invention provides a crystalline form I of the methanesulfonate salt of the compound of formula (I).
所述式(I)化合物甲磺酸盐晶型I的XRPD图谱中包含2θ±0.2°为：6.2、7.8、9.6、13.8、18.9和25.6的衍射峰；The XRPD pattern of the methanesulfonate salt form I of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.2, 7.8, 9.6, 13.8, 18.9 and 25.6;
优选的，所述式(I)化合物甲磺酸盐晶型I的XRPD图谱中包含2θ±0.2°为：6.2、7.8、9.6、12.5、13.8、14.6、15.4、16.1、18.9、19.4、20.5、21.0、22.4、23.3、24.0、25.1、25.6、26.6和27.9的衍射峰.Preferably, the XRPD pattern of the methanesulfonate salt form I of the compound of the formula (I) comprises 2θ±0.2°: 6.2, 7.8, 9.6, 12.5, 13.8, 14.6, 15.4, 16.1, 18.9, 19.4, 20.5, Diffraction peaks of 21.0, 22.4, 23.3, 24.0, 25.1, 25.6, 26.6 and 27.9.
本发明提供了式(I)化合物甲磺酸盐晶型I的制备方法，式(I)化合物与甲磺酸在乙腈中反应得到。The present invention provides a process for the preparation of the methanesulfonate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with methanesulfonic acid in acetonitrile.
本发明提供了式(I)化合物甲磺酸盐晶型II。The present invention provides a crystalline form II of the methanesulfonate salt of the compound of formula (I).
所述式(I)化合物甲磺酸盐晶型II的XRPD图谱中包含2θ±0.2°为：7.5、8.2、13.7、17.3、20.9和25.1的衍射峰；The XRPD pattern of the methanesulfonate salt form II of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 7.5, 8.2, 13.7, 17.3, 20.9 and 25.1;
优选的，所述式(I)化合物甲磺酸盐晶型II的XRPD图谱中包含2θ±0.2°为：7.5、8.2、11.5、13.7、15.1、17.3、20.0、20.9、23.0、25.1和28.9的衍射峰。Preferably, the XRPD pattern of the methanesulfonate salt form II of the compound of the formula (I) comprises 2θ±0.2° of: 7.5, 8.2, 11.5, 13.7, 15.1, 17.3, 20.0, 20.9, 23.0, 25.1 and 28.9. Diffraction peaks.
本发明提供了式(I)化合物甲磺酸盐晶型II的制备方法，式(I)化合物与甲磺酸在乙醇中反应得到。The invention provides a preparation method of the methanesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is reacted with methanesulfonic acid in ethanol.
本发明提供的式(I)化合物甲磺酸盐晶型II，为溶剂化物晶型，晶体中含有乙醇和水。The methanesulfonate salt form II of the compound of the formula (I) provided by the present invention is a solvate crystal form, and the crystal contains ethanol and water.
本发明提供了式(I)化合物甲磺酸盐晶型III。The present invention provides a crystalline form III of the methanesulfonate salt of the compound of formula (I).
所述式(I)化合物甲磺酸盐晶型III的XRPD图谱中包含2θ±0.2°为：6.2、13.5、16.3、19.5、22.0和24.2的衍射峰；The XRPD pattern of the methanesulfonate salt form III of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.2, 13.5, 16.3, 19.5, 22.0 and 24.2;
优选的，所述式(I)化合物甲磺酸盐晶型III的XRPD图谱中包含2θ±0.2°为：6.2、6.9、11.1、12.5、13.5、14.7、16.3、17.2、18.4、19.5、20.4、22.0、24.2、24.8和30.4的衍射峰。Preferably, the XRPD pattern of the methanesulfonate salt form III of the compound of the formula (I) comprises 2θ±0.2°: 6.2, 6.9, 11.1, 12.5, 13.5, 14.7, 16.3, 17.2, 18.4, 19.5, 20.4, Diffraction peaks of 22.0, 24.2, 24.8, and 30.4.
本发明提供了式(I)化合物甲磺酸盐晶型III的制备方法，式(I)化合物甲磺酸盐在湿度92.5％环境中放置转晶得到。The invention provides a preparation method of the methanesulfonate salt form III of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by crystallizing in a humidity of 92.5%.
本发明提供了式(I)化合物甲磺酸盐晶型IV。The present invention provides a crystalline form IV of the methanesulfonate salt of the compound of formula (I).
所述式(I)化合物甲磺酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：5.1、9.0、11.0、13.6、14.8、22.3和23.8的衍射峰；The XRPD pattern of the methanesulfonate salt form IV of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.1, 9.0, 11.0, 13.6, 14.8, 22.3 and 23.8;
优选的，所述式(I)化合物甲磺酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：5.1、6.9、9.0、11.0、13.6、14.8、18.4、18.9、20.6、22.3、23.8和25.4的衍射峰。Preferably, the XRPD pattern of the methanesulfonate salt form IV of the compound of the formula (I) comprises 2θ±0.2°: 5.1, 6.9, 9.0, 11.0, 13.6, 14.8, 18.4, 18.9, 20.6, 22.3, 23.8 and Diffraction peak of 25.4.
本发明提供了式(I)化合物甲磺酸盐晶型IV的制备方法，式(I)化合物甲磺酸盐在异丁醇中打浆转晶得到。The invention provides a preparation method of the methanesulfonate salt form IV of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in isobutanol.
本发明提供的式(I)化合物甲磺酸盐晶型IV，为异丁醇溶剂化物晶型。The methanesulfonate salt form IV of the compound of the formula (I) provided by the present invention is an isobutanol solvate crystal form.
本发明提供了式(I)化合物甲磺酸盐晶型V。The present invention provides a crystalline form V of the methanesulfonate salt of the compound of formula (I).
所述式(I)化合物甲磺酸盐晶型V的XRPD图谱中包含2θ±0.2°为：6.1、7.9、9.4、15.9、19.2和24.5的衍射峰；The XRPD pattern of the methanesulfonate form V of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.1, 7.9, 9.4, 15.9, 19.2 and 24.5;
优选的，所述式(I)化合物甲磺酸盐晶型V的XRPD图谱中包含2θ±0.2°为：6.1、7.9、9.4、10.1、12.2、12.6、13.3、14.3、15.9、17.2、19.1、21.8、22.8、23.7、24.5、27.3和29.1的衍射峰。Preferably, the XRPD pattern of the methanesulfonate form V of the compound of the formula (I) comprises 2θ±0.2°: 6.1, 7.9, 9.4, 10.1, 12.2, 12.6, 13.3, 14.3, 15.9, 17.2, 19.1. Diffraction peaks of 21.8, 22.8, 23.7, 24.5, 27.3 and 29.1.
本发明提供了式(I)化合物甲磺酸盐晶型V的制备方法，式(I)化合物甲磺酸盐在异丙醇中打浆转晶得到。The invention provides a preparation method of the methanesulfonate salt form V of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in isopropanol.
本发明提供的式(I)化合物甲磺酸盐晶型V，为异丙醇溶剂化物晶型。The methanesulfonate form V of the compound of the formula (I) provided by the present invention is an isopropanol solvate crystal form.
本发明提供了式(I)化合物甲磺酸盐晶型VI。The present invention provides a mesylate salt form VI of the compound of formula (I).
所述式(I)化合物甲磺酸盐晶型VI的XRPD图谱中包含2θ±0.2°为：7.6、8.6、13.7、17.5、22.1、23.7和28.8的衍射峰；The XRPD pattern of the methanesulfonate salt form VI of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 7.6, 8.6, 13.7, 17.5, 22.1, 23.7 and 28.8;
优选的，所述式(I)化合物甲磺酸盐晶型VI的XRPD图谱中包含2θ±0.2°为：7.6、8.6、11.4、13.7、15.1、17.5、18.5、18.8、20.1、21.1、22.1、23.1、23.7、24.5、25.7和28.8的衍射峰。Preferably, the XRPD pattern of the methanesulfonate salt form VI of the compound of the formula (I) comprises 2θ±0.2°: 7.6, 8.6, 11.4, 13.7, 15.1, 17.5, 18.5, 18.8, 20.1, 21.1, 22.1, Diffraction peaks of 23.1, 23.7, 24.5, 25.7 and 28.8.
本发明提供了式(I)化合物甲磺酸盐晶型VI的制备方法，式(I)化合物甲磺酸盐在甲酸乙酯中打浆转晶得到。The invention provides a preparation method of the methanesulfonate salt form VI of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in ethyl formate.
本发明提供的式(I)化合物甲磺酸盐晶型VI，为甲酸乙酯溶剂化物晶型。The mesylate salt form VI of the compound of the formula (I) provided by the present invention is an ethyl formate solvate crystal form.
本发明提供了式(I)化合物甲磺酸盐晶型VII。The present invention provides a mesylate salt form VII of the compound of formula (I).
所述式(I)化合物甲磺酸盐晶型VII的XRPD图谱中包含2θ±0.2°为：6.2、7.1、10.4、14.1和23.3的衍射峰；The XRPD pattern of the methanesulfonate salt form VII of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.2, 7.1, 10.4, 14.1 and 23.3;
优选的，所述式(I)化合物甲磺酸盐晶型VII的XRPD图谱中包含2θ±0.2°为：6.2、7.1、10.4、12.0、13.2、14.1、16.0、17.2、18.7、23.3、和30.2的衍射峰；Preferably, the XRPD pattern of the methanesulfonate salt form VII of the compound of the formula (I) comprises 2θ±0.2°: 6.2, 7.1, 10.4, 12.0, 13.2, 14.1, 16.0, 17.2, 18.7, 23.3, and 30.2. Diffraction peak
本发明提供了式(I)化合物甲磺酸盐晶型VII的制备方法，式(I)化合物甲磺酸盐在乙酸乙酯中长时间搅拌转晶得到。The invention provides a preparation method of the methanesulfonate salt form VII of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in ethyl acetate for a long time.
本发明提供了式(I)化合物甲磺酸盐晶型VIII。The present invention provides the methanesulfonate salt form VIII of the compound of formula (I).
所述式(I)化合物甲磺酸盐晶型VIII的XRPD图谱中包含2θ±0.2°为：5.9、6.4、13.6、16.9、24.1和25.0的衍射峰；The XRPD pattern of the methanesulfonate salt form VIII of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.9, 6.4, 13.6, 16.9, 24.1 and 25.0;
优选的，所述甲磺酸盐晶型VIII的XRPD图谱中包含2θ±0.2°为：5.9、6.4、13.6、14.6、15.1、16.9、17.6、18.2、19.6、20.6、21.0、22.7、24.1、25.0、26.8、28.4和31.9的衍射峰。Preferably, the XRPD pattern of the mesylate salt form VIII comprises 2θ±0.2°: 5.9, 6.4, 13.6, 14.6, 15.1, 16.9, 17.6, 18.2, 19.6, 20.6, 21.0, 22.7, 24.1, 25.0. , diffraction peaks of 26.8, 28.4, and 31.9.
本发明提供了式(I)化合物甲磺酸盐晶型VIII的制备方法，式(I)化合物甲磺酸盐在丙酮中长时间搅拌转晶得到。The invention provides a preparation method of the methanesulfonate salt form VIII of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in acetone for a long time.
本发明提供的式(I)化合物甲磺酸盐晶型VIII，不含溶剂，在172℃时熔化降解，该晶型具有良好的稳定性，在高湿RH92.5％和高温40℃条件下储存1个月，有关物质增加＜0.5％。The methanesulfonate salt form VIII of the compound of the formula (I) provided by the invention contains no solvent and melts and degrades at 172 ° C, and the crystal form has good stability under the conditions of high humidity RH 92.5% and high temperature 40 ° C. After storage for 1 month, the related substances increased by <0.5%.
本发明提供了式(I)化合物苯磺酸盐晶型。The present invention provides a crystalline form of the besylate salt of the compound of formula (I).
本发明提供了式(I)化合物苯磺酸盐晶型I。The present invention provides a crystalline form I of the besylate salt of the compound of formula (I).
所述式(I)化合物苯磺酸盐晶型I的XRPD图谱中包含2θ±0.2°为：5.4、5.9、7.1、10.4、14.8、17.6和21.9的衍射峰；The XRPD pattern of the benzenesulfonate salt form I of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.4, 5.9, 7.1, 10.4, 14.8, 17.6 and 21.9;
优选的，所述苯磺酸盐晶型I的XRPD图谱中包含2θ±0.2°为：5.4、5.9、6.8、7.1、8.3、8.7、10.4、11.7、14.0、14.8、15.1、17.6、20.9、21.9、23.7、24.8和26.6的衍射峰。Preferably, the XRPD pattern of the benzenesulfonate salt form I comprises 2θ±0.2°: 5.4, 5.9, 6.8, 7.1, 8.3, 8.7, 10.4, 11.7, 14.0, 14.8, 15.1, 17.6, 20.9, 21.9 , diffraction peaks of 23.7, 24.8, and 26.6.
本发明提供了式(I)化合物苯磺酸盐晶型I的制备方法，式(I)化合物与苯磺酸在乙醇中反应得到。The invention provides a preparation method of the benzenesulfonate salt form I of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in ethanol.
本发明提供了式(I)化合物苯磺酸盐晶型II。The present invention provides a crystalline form II of the besylate salt of the compound of formula (I).
所述式(I)化合物苯磺酸盐晶型II的XRPD图谱中包含2θ±0.2°为：4.4、6.0、9.3、11.5、17.5、21.0和26.0的衍射峰；The XRPD pattern of the benzenesulfonate salt form II of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 4.4, 6.0, 9.3, 11.5, 17.5, 21.0 and 26.0;
优选的，所述苯磺酸盐晶型II的XRPD图谱中包含2θ±0.2°为：4.4、6.0、9.3、11.5、14.8、15.3、17.5、20.0、21.0、21.9、22.7、24.6和26.0的衍射峰。Preferably, the XRPD pattern of the benzenesulfonate salt form II comprises 2θ±0.2°: diffraction of 4.4, 6.0, 9.3, 11.5, 14.8, 15.3, 17.5, 20.0, 21.0, 21.9, 22.7, 24.6 and 26.0. peak.
本发明提供了式(I)化合物苯磺酸盐晶型II的制备方法，式(I)化合物与苯磺酸在四氢呋喃中反应得到。The invention provides a preparation method of the benzenesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in tetrahydrofuran.
本发明提供了式(I)化合物苯磺酸盐晶型III。The present invention provides a crystalline form III of the besylate salt of the compound of formula (I).
所述式(I)化合物苯磺酸盐晶型III的XRPD图谱中包含2θ±0.2°为：7.7、8.3、8.6、17.2、23.2和26.0的衍射峰；The XRPD pattern of the benzenesulfonate salt form III of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 7.7, 8.3, 8.6, 17.2, 23.2 and 26.0;
优选的，所述苯磺酸盐晶型III的XRPD图谱中包含2θ±0.2°为：7.7、8.3、 8.6、11.6、13.8、14.5、17.2、18.3、18.9、20.8、21.8、23.2和26.0的衍射峰。Preferably, the XRPD pattern of the benzenesulfonate salt form III comprises 2?±0.2°: diffraction of 7.7, 8.3, 8.6, 11.6, 13.8, 14.5, 17.2, 18.3, 18.9, 20.8, 21.8, 23.2 and 26.0. peak.
本发明提供了式(I)化合物苯磺酸盐晶型III的制备方法，式(I)化合物与苯磺酸在二氯甲烷中反应得到。The invention provides a preparation method of the benzenesulfonate salt form III of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in dichloromethane.
本发明提供了式(I)化合物苯磺酸盐晶型IV。The present invention provides a crystalline form IV of the besylate salt of the compound of formula (I).
所述式(I)化合物苯磺酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：5.7、6.4、13.0、14.4和23.8的衍射峰；The XRPD pattern of the benzenesulfonate salt form IV of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.7, 6.4, 13.0, 14.4 and 23.8;
优选的，所述式(I)化合物苯磺酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：5.7、6.4、12.0、13.0、14.4、15.6、16.5、17.5、18.6、21.0、21.7、23.2、23.8、26.0、26.6和30.0的衍射峰。Preferably, the XRPD pattern of the benzenesulfonate salt form IV of the compound of the formula (I) comprises 2θ±0.2°: 5.7, 6.4, 12.0, 13.0, 14.4, 15.6, 16.5, 17.5, 18.6, 21.0, 21.7, Diffraction peaks of 23.2, 23.8, 26.0, 26.6, and 30.0.
本发明提供了式(I)化合物苯磺酸盐晶型IV的制备方法，式(I)化合物苯磺酸盐在乙腈中长时间搅拌转晶得到。The invention provides a preparation method of the benzenesulfonate salt form IV of the compound of the formula (I), wherein the benzenesulfonate of the compound of the formula (I) is obtained by stirring and crystallizing in acetonitrile for a long time.
本发明提供了式(I)化合物苯磺酸盐晶型V。The present invention provides a form V of the besylate salt of the compound of formula (I).
所述式(I)化合物苯磺酸盐晶型V的XRPD图谱中包含2θ±0.2°为：5.7、7.5、10.3、14.3和25.1的衍射峰；The XRPD pattern of the benzenesulfonate crystal form V of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.7, 7.5, 10.3, 14.3 and 25.1;
优选的，所述苯磺酸盐晶型V的XRPD图谱中包含2θ±0.2°为：5.7、7.5、10.3、11.0、11.3、11.7、13.8、14.3、16.3、16.6、17.8、18.3、19.0、20.1、23.4、25.1和27.5的衍射峰。Preferably, the XRPD pattern of the benzenesulfonate crystal form V comprises 2θ±0.2°: 5.7, 7.5, 10.3, 11.0, 11.3, 11.7, 13.8, 14.3, 16.3, 16.6, 17.8, 18.3, 19.0, 20.1 , diffraction peaks of 23.4, 25.1 and 27.5.
本发明提供了式(I)化合物苯磺酸盐晶型V的制备方法，式(I)化合物苯磺酸盐在75％乙醇水溶液中长时间搅拌转晶得到。The invention provides a preparation method of the benzenesulfonate salt form V of the compound of the formula (I), wherein the benzenesulfonate of the compound of the formula (I) is obtained by stirring and crystallizing in a 75% aqueous solution of ethanol for a long time.
本发明提供了式(I)化合物苯磺酸盐晶型VI。The present invention provides a crystalline form VI of the besylate salt of the compound of formula (I).
所述式(I)化合物苯磺酸盐晶型VI的XRPD图谱中包含2θ±0.2°为：6.0、7.4、13.5、18.6、23.6和24.5的衍射峰；The XRPD pattern of the benzenesulfonate salt form VI of the compound of the formula (I) contains 2θ±0.2°: diffraction peaks of 6.0, 7.4, 13.5, 18.6, 23.6 and 24.5;
优选的，所述式(I)化合物苯磺酸盐晶型VI的XRPD图谱中包含2θ±0.2°为：6.0、7.4、11.6、12.2、12.8、13.5、14.8、16.5、17.5、18.6、20.4、21.0、21.6、22.7、23.6、24.5、25.9、26.7和27.5的衍射峰。Preferably, the XRPD pattern of the benzenesulfonate salt form VI of the compound of the formula (I) comprises 2θ±0.2°: 6.0, 7.4, 11.6, 12.2, 12.8, 13.5, 14.8, 16.5, 17.5, 18.6, 20.4, Diffraction peaks of 21.0, 21.6, 22.7, 23.6, 24.5, 25.9, 26.7 and 27.5.
本发明提供了式(I)化合物苯磺酸盐晶型VI的制备方法，式(I)化合物与苯磺酸在丙酮中反应得到。The invention provides a preparation method of the benzenesulfonate salt form VI of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in acetone.
本发明提供的式(I)化合物苯磺酸盐晶型VI，不含溶剂，其熔点为162℃，非常适合药物制剂开发，制备工艺收率最高，达到95％，并且制备工艺重现性好，特别适合工业化生产。The benzenesulfonate salt form VI of the compound of the formula (I) provided by the invention has no solvent and has a melting point of 162 ° C, which is very suitable for the development of pharmaceutical preparations, the highest yield of the preparation process is 95%, and the preparation process has good reproducibility. It is especially suitable for industrial production.
本发明提供了式(I)化合物苯磺酸盐晶型VII。The present invention provides a benzenesulfonate salt form VII of the compound of formula (I).
所述式(I)化合物苯磺酸盐晶型VII的XRPD图谱中包含2θ±0.2°为：5.9、7.1、9.7、15.0、16.4和23.7的衍射峰；The XRPD pattern of the benzenesulfonate salt form VII of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.9, 7.1, 9.7, 15.0, 16.4 and 23.7;
优选的，所述式(I)化合物苯磺酸盐晶型VII的XRPD图谱中包含2θ±0.2°为：5.9、7.1、9.7、11.9、12.9、13.4、15.0、16.4、18.3、18.8、20.5、21.2、21.9、22.8和23.7的衍射峰。Preferably, the XRPD pattern of the benzenesulfonate salt form VII of the compound of the formula (I) comprises 2θ±0.2°: 5.9, 7.1, 9.7, 11.9, 12.9, 13.4, 15.0, 16.4, 18.3, 18.8, 20.5, Diffraction peaks of 21.2, 21.9, 22.8, and 23.7.
本发明提供了式(I)化合物苯磺酸盐晶型VII的制备方法，式(I)化合物苯磺酸盐在92.5％RH中放置转晶得到。The invention provides a preparation method of the benzenesulfonate salt form VII of the compound of the formula (I), wherein the besylate salt of the compound of the formula (I) is obtained by crystallizing in 92.5% RH.
本发明提供了式(I)化合物乙磺酸盐晶型。The present invention provides a crystalline form of the ethanesulfonate salt of the compound of formula (I).
本发明提供了式(I)化合物乙磺酸盐晶型I。The present invention provides a crystalline form I of the ethanesulfonate salt of the compound of formula (I).
所述式(I)化合物乙磺酸盐晶型I的XRPD图谱中包含2θ±0.2°为：7.5、8.3和17.9的衍射峰；The XRPD pattern of the ethyl sulfonate salt form I of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 7.5, 8.3 and 17.9;
优选的，所述式(I)化合物乙磺酸盐晶型I的XRPD图谱中包含2θ±0.2°为： 7.5、8.3、10.5、12.9、17.9、23.5和25.0的衍射峰。Preferably, the XRPD pattern of the ethyl sulfonate salt form I of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 7.5, 8.3, 10.5, 12.9, 17.9, 23.5 and 25.0.
本发明提供了式(I)化合物乙磺酸盐晶型I的制备方法，式(I)化合物与乙磺酸在乙醇中反应得到。The invention provides a preparation method of the ethyl sulfonate salt form I of the compound of the formula (I), which is obtained by reacting the compound of the formula (I) with ethanesulfonic acid in ethanol.
本发明提供了式(I)化合物乙磺酸盐晶型II。The present invention provides a crystalline form II of the ethanesulfonate salt of the compound of formula (I).
所述式(I)化合物乙磺酸盐晶型II的XRPD图谱中包含2θ±0.2°为：6.0、6.6、12.1和24.1的衍射峰；The XRPD pattern of the ethanesulfonate salt form II of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 6.0, 6.6, 12.1 and 24.1;
优选的，所述式(I)化合物乙磺酸盐晶型II的XRPD图谱中包含2θ±0.2°为：5.8、6.0、6.6、8.5、12.1、13.3、14.7、15.4、16.3、16.8、17.3、19.1、22.1、23.3和24.1的衍射峰。Preferably, the XRPD pattern of the ethanesulfonate salt form II of the compound of the formula (I) comprises 2θ±0.2°: 5.8, 6.0, 6.6, 8.5, 12.1, 13.3, 14.7, 15.4, 16.3, 16.8, 17.3, Diffraction peaks of 19.1, 22.1, 23.3 and 24.1.
本发明提供了式(I)化合物乙磺酸盐晶型II的制备方法，式(I)化合物乙磺酸盐在乙酸乙酯中长时间搅拌转晶得到。The invention provides a preparation method of the ethyl sulfonate salt form II of the compound of the formula (I), wherein the ethanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in ethyl acetate for a long time.
本发明提供了式(I)化合物乙磺酸盐晶型III。The present invention provides a crystalline form III of the ethanesulfonate salt of the compound of formula (I).
所述式(I)化合物乙磺酸盐晶型III的XRPD图谱中包含2θ±0.2°为：6.0、7.6、12.2、13.6和18.3的衍射峰；The XRPD pattern of the ethanesulfonate salt form III of the compound of the formula (I) contains 2θ±0.2°: diffraction peaks of 6.0, 7.6, 12.2, 13.6 and 18.3;
优选的，所述乙磺酸盐晶型III的XRPD图谱中包含2θ±0.2°为：6.0、7.6、9.4、12.2、13.6、14.4、15.2、16.0、17.2、18.4、19.3和20.4的衍射峰。Preferably, the XRPD pattern of the ethanesulfonate salt form III contains diffraction peaks of 2θ±0.2°: 6.0, 7.6, 9.4, 12.2, 13.6, 14.4, 15.2, 16.6, 17.2, 18.4, 19.3 and 20.4.
本发明提供了式(I)化合物乙磺酸盐晶型III的制备方法，式(I)化合物乙磺酸盐在二氯甲烷中长时间搅拌转晶得到。The invention provides a preparation method of the ethyl sulfonate salt form III of the compound of the formula (I), wherein the ethanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in dichloromethane for a long time.
本发明提供了式(I)化合物草酸盐晶型。The present invention provides a crystalline form of the oxalate salt of the compound of formula (I).
本发明提供了式(I)化合物草酸盐晶型I。The present invention provides a crystalline form I of the compound of formula (I).
所述式(I)化合物草酸盐晶型I的XRPD图谱中包含2θ±0.2°为：4.1、6.9、7.9、14.5、19.4、23.8和27.0的衍射峰；The XRPD pattern of the oxalate salt form I of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 4.1, 6.9, 7.9, 14.5, 19.4, 23.8 and 27.0;
优选的，所述式(I)化合物草酸盐晶型I的XRPD图谱中包含2θ±0.2°为：4.1、6.9、7.9、11.7、12.2、13.0、13.9、14.5、15.0、16.4、17.6、19.4、20.3、21.0、23.8、25.5、26.0和27.0的衍射峰。Preferably, the XRPD pattern of the oxalate salt form I of the compound of the formula (I) comprises 2θ±0.2°: 4.1, 6.9, 7.9, 11.7, 12.2, 13.0, 13.9, 14.5, 15.0, 16.4, 17.6, 19.4. , diffraction peaks of 20.3, 21.0, 23.8, 25.5, 26.0, and 27.0.
本发明提供了式(I)化合物草酸盐晶型I的制备方法，式(I)化合物与草酸在二氯甲烷中反应得到。The present invention provides a process for the preparation of the oxalate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with oxalic acid in dichloromethane.
本发明提供了式(I)化合物草酸盐晶型I，其熔点约150℃。The present invention provides a crystalline form I of the compound of formula (I) having a melting point of about 150 °C.
本发明提供了式(I)化合物草酸盐晶型II。The present invention provides a crystalline form II of the compound of formula (I).
所述式(I)化合物草酸盐晶型II的XRPD图谱中包含2θ±0.2°为：4.0、6.8、7.7、8.1、16.7和23.7的衍射峰；The XRPD pattern of the compound oxalate crystal form II of the formula (I) contains 2θ±0.2° as diffraction peaks of 4.0, 6.8, 7.7, 8.1, 16.7 and 23.7;
优选的，所述式(I)化合物草酸盐晶型II的XRPD图谱中包含2θ±0.2°为：4.0、6.8、7.7、8.1、14.6、16.7、17.4、17.9、20.9、21.4、22.1、22.7、23.7和27.7的衍射峰。Preferably, the XRPD pattern of the compound oxalate crystal form II of the formula (I) comprises 2θ±0.2°: 4.0, 6.8, 7.7, 8.1, 14.6, 16.7, 17.4, 17.9, 20.9, 21.4, 22.1, 22.7. , diffraction peaks of 23.7 and 27.7.
本发明提供了式(I)化合物草酸盐晶型II的制备方法，式(I)化合物草酸盐在丙酮中打浆转晶得到。The invention provides a preparation method of the compound (I) compound oxalate crystal form II, wherein the compound oxalate salt of the formula (I) is obtained by beating and crystallizing in acetone.
本发明提供了式(I)化合物草酸盐晶型II，其熔点约154℃。The present invention provides a crystalline form II of the compound of formula (I) having a melting point of about 154 °C.
本发明提供了式(I)化合物马来酸盐晶型。The present invention provides a crystalline form of the maleate salt of the compound of formula (I).
本发明提供了式(I)化合物马来酸盐晶型I。The present invention provides a crystalline form I of the maleate salt of the compound of formula (I).
所述式(I)化合物马来酸盐晶型I的XRPD图谱中包含2θ±0.2°为：5.6、8.1、10.8、13.8、23.0和26.3的衍射峰；The XRPD pattern of the maleate salt form I of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 5.6, 8.1, 10.8, 13.8, 23.0 and 26.3;
优选的，所述式(I)化合物马来酸盐晶型I的XRPD图谱中包含2θ±0.2°为：5.6、6.4、8.1、10.8、11.6、12.4、12.9、13.3、13.8、14.7、15.5、16.7、17.4、17.8、18.0、18.6、20.1、21.1、22.6、23.0、23.8、24.8、26.3和28.1的衍射峰。Preferably, the XRPD pattern of the maleate salt form I of the compound of the formula (I) comprises 2θ±0.2°: 5.6, 6.4, 8.1, 10.8, 11.6, 12.4, 12.9, 13.3, 13.8, 14.7, 15.5, Diffraction peaks of 16.7, 17.4, 17.8, 18.0, 18.6, 20.1, 21.1, 22.6, 23.0, 23.8, 24.8, 26.3 and 28.1.
本发明提供了式(I)化合物马来酸盐晶型I的制备方法，式(I)化合物与马来酸在二氯甲烷/乙酸乙酯体系中共结晶得到。The present invention provides a process for the preparation of the crystalline form I of the compound of the formula (I), wherein the compound of the formula (I) is co-crystallized with maleic acid in a dichloromethane/ethyl acetate system.
本发明还提供了式(I)化合物马来酸盐晶型I的另一种制备方法，具体为将式(I)化合物与马来酸置于在乙酸乙酯中，在室温下搅拌7天得到马来酸盐晶型I。The invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in ethyl acetate and stirred at room temperature for 7 days. The maleate salt form I is obtained.
本发明还提供了式(I)化合物马来酸盐晶型I的另一种制备方法，具体为将式(I)化合物与马来酸置于二氯甲烷中，加入乙酸乙酯及马来酸盐晶型I晶种析晶，得到马来酸盐晶型I。The invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in dichloromethane, and ethyl acetate and malay are added. The crystal form I seed crystal is crystallized to obtain the maleate salt form I.
本发明还提供了式(I)化合物马来酸盐晶型I的另一种制备方法，具体为将式(I)化合物与马来酸置于二氯甲烷中，加入正庚烷和马来酸盐晶型I晶种，搅拌得到晶型I样品。The invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in dichloromethane, and n-heptane and malay are added. The crystal form I seed crystal was stirred to obtain a crystal form I sample.
本发明提供的式(I)化合物马来酸盐晶型I，马来酸的含量约为27％-33％，优选29％-31％，最优选30％。The present invention provides a compound of formula (I), maleate salt Form I, having a maleic acid content of from about 27% to about 33%, preferably from about 29% to about 31%, most preferably from about 30%.
本发明提供的式(I)化合物马来酸盐晶型I，不含水和有机溶剂，在高湿(RH92.5％)和高温(40℃)条件下放置6个月，基本不发生降解。The compound of the formula (I) provided by the present invention, Form I, is free of water and an organic solvent, and is allowed to stand under high humidity (RH 92.5%) and high temperature (40 ° C) conditions for 6 months without substantially degrading.
本发明提供的式(I)化合物马来酸盐晶型I，其熔点为114℃。The present invention provides a compound of formula (I), maleate salt form I, having a melting point of 114 °C.
本发明提供的式(I)所示化合物马来酸盐晶型I制备工艺简单，工艺重现性好，特别适合工业化生产和药物制剂研究。The compound of the formula (I) provided by the invention has simple preparation process and good process reproducibility, and is particularly suitable for industrial production and pharmaceutical preparation research.
本发明提供了式(I)化合物对甲苯磺酸盐晶型。The present invention provides a crystalline form of the p-toluenesulfonate salt of the compound of formula (I).
本发明提供了式(I)化合物对甲苯磺酸盐晶型I。The present invention provides a crystalline form I of the p-toluenesulfonate salt of the compound of formula (I).
所述式(I)化合物对甲苯磺酸盐晶型I的XRPD图谱中包含2θ±0.2°为：7.6、13.5、15.0、20.6和23.5的衍射峰；The XRPD pattern of the p-toluenesulfonate salt form I of the compound of the formula (I) contains diffraction peaks of 2θ±0.2°: 7.6, 13.5, 15.0, 20.6 and 23.5;
优选的，所述式(I)化合物对甲苯磺酸盐晶型I的XRPD图谱中包含2θ±0.2°为：7.6、8.5、10.1、11.9、13.0、13.5、15.0、16.5、17.0、17.4、18.4、18.7、20.6、20.9、23.5、24.1、25.7和26.6的衍射峰。Preferably, the XRPD pattern of the crystalline form I of the p-toluenesulfonate salt of the compound of the formula (I) comprises 2θ±0.2°: 7.6, 8.5, 10.1, 11.9, 13.0, 13.5, 15.0, 16.5, 17.0, 17.4, 18.4. Diffraction peaks of 18.7, 20.6, 20.9, 23.5, 24.1, 25.7 and 26.6.
本发明提供了式(I)化合物对甲苯磺酸盐晶型I的制备方法，式(I)化合物与对甲苯磺酸在乙酸乙酯中反应得到。The present invention provides a process for the preparation of the p-toluenesulfonate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in ethyl acetate.
本发明提供了式(I)化合物对甲苯磺酸盐晶型II。The present invention provides a crystalline form II of the p-toluenesulfonate salt of the compound of formula (I).
所述式(I)化合物对甲苯磺酸盐晶型II的XRPD图谱中包含2θ±0.2°为：7.5、8.1、13.1、20.7和22.9的衍射峰；The XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form II comprises 2θ±0.2°: diffraction peaks of 7.5, 8.1, 13.1, 20.7 and 22.9;
优选的，所述式(I)化合物对甲苯磺酸盐晶型II的XRPD图谱中包含2θ±0.2°为：7.5、8.1、13.1、13.5、16.5、16.9、17.7、19.9、20.7、21.1、22.9、24.9、25.5和28.7的衍射峰。Preferably, the XRPD pattern of the p-toluenesulfonate salt form II of the compound of the formula (I) comprises 2θ±0.2°: 7.5, 8.1, 13.1, 13.5, 16.5, 16.9, 17.7, 19.9, 20.7, 21.1, 22.9. , diffraction peaks of 24.9, 25.5, and 28.7.
本发明提供了式(I)化合物对甲苯磺酸盐晶型II的制备方法，式(I)化合物对甲苯磺酸盐在乙醇中打浆转晶得到。The invention provides a preparation method of the p-toluenesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is obtained by beating and crystallizing the p-toluenesulfonate in ethanol.
本发明提供了式(I)化合物对甲苯磺酸盐晶型III。The present invention provides a crystalline form III of the p-toluenesulfonate salt of the compound of formula (I).
所述式(I)化合物对甲苯磺酸盐晶型III的XRPD图谱中包含2θ±0.2°为：8.3、12.8、14.7、16.6和24.3的衍射峰；The XRPD pattern of the compound p-toluenesulfonate crystal form III of the formula (I) comprises diffraction peaks of 2θ±0.2°: 8.3, 12.8, 14.7, 16.6 and 24.3;
优选的，所述式(I)化合物对甲苯磺酸盐晶型III的XRPD图谱中包含2θ±0.2°为：5.4、6.9、8.3、8.8、9.1、10.5、10.8、11.4、12.1、12.8、14.7、15.5、16.6、17.2、17.8、18.5、18.8、19.3、19.9、20.4、22.1、22.4、23.4、23.9、24.3、25.4、25.8、26.8、27.5、28.4和29.6的衍射峰。Preferably, the XRPD pattern of the p-toluenesulfonate salt form III of the compound of the formula (I) comprises 2θ±0.2°: 5.4, 6.9, 8.3, 8.8, 9.1, 10.5, 10.8, 11.4, 12.1, 12.8, 14.7. Diffraction peaks of 15.5, 16.6, 17.2, 17.8, 18.5, 18.8, 19.3, 19.9, 20.4, 22.1, 22.4, 23.4, 23.9, 24.3, 25.4, 25.8, 26.8, 27.5, 28.4 and 29.6.
本发明提供了式(I)化合物对甲苯磺酸盐晶型III的制备方法，式(I)化合物对甲苯磺酸盐在水中长时间搅拌转晶得到。The invention provides a preparation method of the p-toluenesulfonate salt form III of the compound of the formula (I), wherein the compound of the formula (I) is obtained by crystallizing the p-toluenesulfonate in water for a long time.
本发明提供了式(I)化合物对甲苯磺酸盐晶型IV。The present invention provides a crystalline form IV of the p-toluenesulfonate salt of the compound of formula (I).
所述式(I)化合物对甲苯磺酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：7.3、14.4、21.2、23.5和25.3的衍射峰；The XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IV comprises 2θ±0.2° as diffraction peaks of 7.3, 14.4, 21.2, 23.5 and 25.3;
优选的，所述式(I)化合物对甲苯磺酸盐晶型IV的XRPD图谱中包含2θ±0.2°为：5.7、7.3、10.1、10.6、11.7、14.4、16.1、16.6、17.2、18.5、18.9、19.9、20.6、21.2、22.3、22.9、23.5、24.4、25.3、25.8、26.9、27.4、28.1、29.2、30.1、31.0、31.6、32.5、33.1、33.6、34.5、35.5、367、38.9和42.7的衍射峰。Preferably, the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IV comprises 2θ ± 0.2°: 5.7, 7.3, 10.1, 10.6, 11.7, 14.4, 16.1, 16.6, 17.2, 18.5, 18.9 Diffraction of 19.9, 20.6, 21.2, 22.3, 22.9, 23.5, 24.4, 25.3, 25.8, 26.9, 27.4, 28.1, 29.2, 30.1, 31.0, 31.6, 32.5, 33.1, 33.6, 34.5, 35.5, 367, 38.9 and 42.7 peak.
本发明提供了式(I)化合物对甲苯磺酸盐晶型IV的制备方法，式(I)化合物对甲苯磺酸盐在乙酸乙酯中打浆转晶得到。The invention provides a preparation method of the p-toluenesulfonate salt form IV of the compound of the formula (I), wherein the compound of the formula (I) is obtained by slurrying and translating p-toluenesulfonate in ethyl acetate.
本发明提供了式(I)化合物对甲苯磺酸盐晶型V。The present invention provides a crystalline form V of the p-toluenesulfonate salt of the compound of formula (I).
所述对式(I)化合物甲苯磺酸盐晶型V的XRPD图谱中包含2θ±0.2°为：8.1、10.2、11.0、19.4和24.1的衍射峰；The XRPD pattern of the tosylate salt form V of the compound of the formula (I) contains 2θ±0.2° as diffraction peaks of 8.1, 10.2, 11.0, 19.4 and 24.1;
优选的，所述式(I)化合物对甲苯磺酸盐晶型V的XRPD图谱中包含2θ±0.2°为：8.1、8.5、9.0、10.2、11.0、13.8、14.8、16.6、17.0、17.5、18.3、19.4、20.6、22.1、23.0、24.1、25.8、28.1、30.1和30.7的衍射峰。Preferably, the XRPD pattern of the p-toluenesulfonate crystal form V of the compound of the formula (I) comprises 2θ±0.2°: 8.1, 8.5, 9.0, 10.2, 11.0, 13.8, 14.8, 16.6, 17.0, 17.5, 18.3. Diffraction peaks of 19.4, 20.6, 22.1, 23.0, 24.1, 25.8, 28.1, 30.1 and 30.7.
本发明提供了式(I)化合物对甲苯磺酸盐晶型V的制备方法，式(I)化合物对甲苯磺酸盐在二氯甲烷/乙酸乙酯中打浆转晶得到。The present invention provides a process for the preparation of the p-toluenesulfonate salt form V of the compound of the formula (I), wherein the compound of the formula (I) is p-crystallized by p-toluenesulfonate in dichloromethane/ethyl acetate.
本发明提供了式(I)化合物对甲苯磺酸盐晶型VI。The present invention provides a crystalline form VI of the compound p-toluenesulfonate of formula (I).
所述式(I)化合物对甲苯磺酸盐晶型VI的XRPD图谱中包含2θ±0.2°为：7.2、12.5、16.5和21.0的衍射峰；The XRPD pattern of the compound p-toluenesulfonate form VI of the formula (I) contains 2θ±0.2° as diffraction peaks of 7.2, 12.5, 16.5 and 21.0;
优选的，所述式(I)化合物对甲苯磺酸盐晶型VI的XRPD图谱中包含2θ±0.2°为：6.8、7.2、7.7、10.0、10.4、11.6、12.5、14.3、16.5、17.1、17.5、18.2、19.2、19.7、21.0、21.7、23.5、23.7、24.4、25.3、26.8和29.4的衍射峰。Preferably, the XRPD pattern of the compound of the formula (I) on the p-toluenesulfonate form VI comprises 2θ±0.2°: 6.8, 7.2, 7.7, 10.0, 10.4, 11.6, 12.5, 14.3, 16.5, 17.1, 17.5. Diffraction peaks of 18.2, 19.2, 19.7, 21.0, 21.7, 23.5, 23.7, 24.4, 25.3, 26.8 and 29.4.
本发明提供了式(I)化合物对甲苯磺酸盐晶型VI的制备方法，式(I)化合物对甲苯磺酸盐在丙酮/乙酸乙酯中打浆转晶得到。The invention provides a preparation method of the p-toluenesulfonate salt form VI of the compound of the formula (I), wherein the compound of the formula (I) is obtained by slurrying and translating the p-toluenesulfonate in acetone/ethyl acetate.
本发明提供了式(I)化合物对甲苯磺酸盐晶型VII。The present invention provides a compound of formula (I) p-toluenesulfonate Form VII.
所述式(I)化合物对甲苯磺酸盐晶型VII的XRPD图谱中包含2θ±0.2°为：5.7、6.9、9.9和17.6的衍射峰；The XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VII comprises 2θ±0.2°: diffraction peaks of 5.7, 6.9, 9.9 and 17.6;
优选的，所述式(I)化合物对甲苯磺酸盐晶型VII的XRPD图谱中包含2θ±0.2°为：5.7、6.9、7.4、8.7、9.9、11.5、12.5、14.6、15.7、17.6、23.6、24.7和26.5的衍射峰。Preferably, the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VII comprises 2θ±0.2°: 5.7, 6.9, 7.4, 8.7, 9.9, 11.5, 12.5, 14.6, 15.7, 17.6, 23.6. , diffraction peaks of 24.7 and 26.5.
本发明提供了式(I)化合物对甲苯磺酸盐晶型VII的制备方法，式(I)化合物与对甲苯磺酸在乙醇中反应得到。The present invention provides a process for the preparation of the p-toluenesulfonate salt form VII of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in ethanol.
本发明提供了式(I)化合物对甲苯磺酸盐晶型VIII。The present invention provides a compound of formula (I) p-toluenesulfonate Form VIII.
所述式(I)化合物对甲苯磺酸盐晶型VIII的XRPD图谱中包含2θ±0.2°为：4.2、5.9、7.2、9.0和25.3的衍射峰；The XRPD pattern of the compound of formula (I) p-toluenesulfonate Form VIII comprises 2θ±0.2°: diffraction peaks of 4.2, 5.9, 7.2, 9.0 and 25.3;
优选的，所述式(I)化合物对甲苯磺酸盐晶型VIII的XRPD图谱中包含2θ±0.2°为：4.2、5.9、7.2、9.0、10.3、11.0、14.3、15.2、16.6、18.9、19.7、19.9、21.0、22.1、23.6、25.3、26.2、29.5和31.1的衍射峰。Preferably, the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VIII comprises 2θ ± 0.2°: 4.2, 5.9, 7.2, 9.0, 10.3, 11.0, 14.3, 15.2, 16.6, 18.9, 19.7 Diffraction peaks of 19.9, 21.0, 22.1, 23.6, 25.3, 26.2, 29.5 and 31.1.
本发明提供了式(I)化合物对甲苯磺酸盐晶型VIII的制备方法，式(I)化合物与对甲苯磺酸在丙酮中反应得到。The present invention provides a process for the preparation of the p-toluenesulfonate salt form VIII of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in acetone.
本发明提供了式(I)化合物对甲苯磺酸盐晶型IX。The present invention provides a crystalline form IX of the compound p-toluenesulfonate of formula (I).
所述式(I)化合物对甲苯磺酸盐晶型IX的XRPD图谱中包含2θ±0.2°为：7.0、7.7、9.4、12.9和15.4的衍射峰；The XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IX comprises 2θ±0.2°: diffraction peaks of 7.0, 7.7, 9.4, 12.9 and 15.4;
优选的，所述式(I)化合物对甲苯磺酸盐晶型IX的XRPD图谱中包含2θ±0.2° 为：7.0、7.7、9.4、10.8、12.2、12.9、13.7、15.4、18.0、20.5、21.9、23.2、26.7和28.0的衍射峰。Preferably, the XRPD pattern of the p-toluenesulfonate salt form IX of the compound of the formula (I) comprises 2θ±0.2°: 7.0, 7.7, 9.4, 10.8, 12.2, 12.9, 13.7, 15.4, 18.0, 20.5, 21.9. , diffraction peaks of 23.2, 26.7 and 28.0.
本发明提供了式(I)化合物对甲苯磺酸盐晶型IX的制备方法，式(I)化合物与对甲苯磺酸在甲醇中反应得到。The present invention provides a process for the preparation of the p-toluenesulfonate salt form IX of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in methanol.
目前尚无文献报道式(I)化合物的可药用盐及其晶型，本发明的盐具有良好的理化性质，尤其在溶解度、稳定性及引湿性方面表现优异，本发明具体优选的盐及其晶型在上述性质方面表现尤为优异。本发明晶型稳定性好、不具有引湿性，溶解度良好，在制剂生产过程中具有良好的适应性，能实现药物良好的溶出行为，确保药物在体内具有良好的生物利用度。相应晶型制备工艺简单，收率高，适合工业化生产。因此，本发明式(I)化合物的盐及晶型非常适合药物制剂应用，具有良好的临床应用前景。·There are currently no reports on the pharmaceutically acceptable salts of the compounds of formula (I) and their crystalline forms. The salts of the present invention have good physicochemical properties, especially in terms of solubility, stability and wettability, and particularly preferred salts of the present invention Its crystal form is particularly excellent in the above properties. The crystal form of the invention has good stability, no hygroscopicity, good solubility, good adaptability in the preparation process, good drug dissolution behavior, and good bioavailability of the drug in the body. The corresponding crystal form preparation process is simple, the yield is high, and it is suitable for industrial production. Therefore, the salt and crystal form of the compound of the formula (I) of the present invention are very suitable for pharmaceutical preparation applications and have good clinical application prospects. ·
附图说明DRAWINGS
图1为式(I)化合物盐酸盐晶型I的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an X-ray powder diffraction pattern of the hydrochloride salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图2为式(I)化合物盐酸盐晶型II的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 2 is an X-ray powder diffraction pattern of the hydrochloride salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图3为式(I)化合物盐酸盐晶型III的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 3 is an X-ray powder diffraction pattern of the hydrochloride salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图4为式(I)化合物盐酸盐晶型IV的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。4 is an X-ray powder diffraction pattern of the hydrochloride salt form IV of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图5为式(I)化合物盐酸盐晶型V的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 5 is an X-ray powder diffraction pattern of the hydrochloride salt form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图6为式(I)化合物硫酸盐晶型I的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 6 is an X-ray powder diffraction pattern of the sulfate form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图7为式(I)化合物硫酸盐晶型II的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 7 is an X-ray powder diffraction pattern of the sulfate form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图8为式(I)化合物硫酸盐晶型III的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 8 is an X-ray powder diffraction pattern of the sulfate form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图9为式(I)化合物硫酸盐晶型IV的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 9 is an X-ray powder diffraction pattern of the sulfate form IV of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图10为式(I)化合物硫酸盐晶型V的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 10 is an X-ray powder diffraction pattern of the sulfate form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图11为式(I)化合物甲磺酸盐晶型I的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 11 is an X-ray powder diffraction pattern of the mesylate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图12为式(I)化合物甲磺酸盐晶型I的DSC图谱；Figure 12 is a DSC chart of the methanesulfonate salt form I of the compound of formula (I);
图13为式(I)化合物甲磺酸盐晶型I的TGA图谱；Figure 13 is a TGA spectrum of the mesylate salt form I of the compound of formula (I);
图14为式(I)化合物甲磺酸盐晶型II的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 14 is an X-ray powder diffraction pattern of the mesylate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图15为式(I)化合物甲磺酸盐晶型III的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 15 is an X-ray powder diffraction pattern of the mesylate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图16为式(I)化合物甲磺酸盐晶型IV的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 16 is an X-ray powder diffraction pattern of the mesylate salt form IV of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图17为式(I)化合物甲磺酸盐晶型V的X射线粉末衍射图，纵轴表示峰强度 (cps)，横轴表示衍射角(2θ[°])。Fig. 17 is an X-ray powder diffraction pattern of the methanesulfonate crystal form V of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2θ [°]).
图18为式(I)化合物甲磺酸盐晶型VI的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 18 is an X-ray powder diffraction pattern of the mesylate salt form VI of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图19为式(I)化合物甲磺酸盐晶型VII的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 19 is an X-ray powder diffraction pattern of the mesylate salt form VII of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2θ [°]).
图20为式(I)化合物甲磺酸盐晶型VIII的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 20 is an X-ray powder diffraction pattern of the mesylate salt form VIII of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2θ [°]).
图21为式(I)化合物甲磺酸盐晶型VIII的DSC图谱；Figure 21 is a DSC chart of the methanesulfonate salt form VIII of the compound of formula (I);
图22为式(I)化合物甲磺酸盐晶型VIII的TGA图谱；Figure 22 is a TGA spectrum of the methanesulfonate salt form VIII of the compound of formula (I);
图23为式(I)化合物苯磺酸盐晶型I的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 23 is an X-ray powder diffraction pattern of the form I of the besylate salt of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2θ [°]).
图24为式(I)化合物苯磺酸盐晶型II的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Fig. 24 is an X-ray powder diffraction pattern of the benzenesulfonate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图25为式(I)化合物苯磺酸盐晶型III的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 25 is an X-ray powder diffraction pattern of the benzenesulfonate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图26为式(I)化合物苯磺酸盐晶型IV的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 26 is an X-ray powder diffraction pattern of the form of the besylate salt of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图27为式(I)化合物苯磺酸盐晶型V的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 27 is an X-ray powder diffraction pattern of the form of the besylate salt form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图28为式(I)化合物苯磺酸盐晶型VI的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 28 is an X-ray powder diffraction pattern of the form of the besylate salt form VI of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图29为式(I)化合物苯磺酸盐晶型VII的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 29 is an X-ray powder diffraction pattern of the benzenesulfonate salt form VII of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图30为式(I)化合物乙磺酸盐晶型I的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 30 is an X-ray powder diffraction pattern of the ethanesulfonate salt form I of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2θ [°]).
图31为式(I)化合物乙磺酸盐晶型II的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 31 is an X-ray powder diffraction pattern of the ethanesulfonate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图32为式(I)化合物乙磺酸盐晶型III的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 32 is an X-ray powder diffraction pattern of the ethanesulfonate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图33为式(I)化合物草酸盐晶型I的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 33 is an X-ray powder diffraction pattern of the oxalate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图34为式(I)化合物草酸盐晶型I的DSC图谱；Figure 34 is a DSC chart of the oxalate salt form I of the compound of formula (I);
图35为式(I)化合物草酸盐晶型I的TGA图谱；Figure 35 is a TGA spectrum of the oxalate salt form I of the compound of formula (I);
图36为式(I)化合物草酸盐晶型II的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 36 is an X-ray powder diffraction pattern of the compound oxalate crystal form II of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图37为式(I)化合物草酸盐晶型II的DSC图谱；Figure 37 is a DSC spectrum of the compound oxalate salt form II of the formula (I);
图38为式(I)化合物草酸盐晶型II的TGA图谱；Figure 38 is a TGA pattern of the oxalate salt form II of the compound of formula (I);
图39为式(I)化合物马来酸盐晶型I的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 39 is an X-ray powder diffraction pattern of the maleate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图40为式(I)化合物马来酸盐晶型I的DSC图谱Figure 40 is a DSC spectrum of the maleate salt form I of the compound of formula (I)
图41为式(I)化合物对甲苯黄酸盐晶型I的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 41 is an X-ray powder diffraction pattern of the compound (I) p-tolylate Form I, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图42为式(I)化合物对甲苯黄酸盐晶型II的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 42 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form II, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图43为式(I)化合物对甲苯黄酸盐晶型III的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 43 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form III, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图44为式(I)化合物对甲苯黄酸盐晶型IV的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 44 is an X-ray powder diffraction pattern of the compound of the formula (I) versus toluene salt form IV, wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2θ [°]).
图45为式(I)化合物对甲苯黄酸盐晶型V的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 45 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form V, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图46为式(I)化合物对甲苯黄酸盐晶型VI的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 46 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form VI, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图47为式(I)化合物对甲苯黄酸盐晶型VII的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 47 is an X-ray powder diffraction pattern of the compound of the formula (I) versus toluene salt crystal form VII, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图48为式(I)化合物对甲苯黄酸盐晶型VIII的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 48 is an X-ray powder diffraction pattern of the compound of the formula (I), p-toluate, Form VIII, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
图49为式(I)化合物对甲苯黄酸盐晶型IX的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。Figure 49 is an X-ray powder diffraction pattern of the compound of the formula (I), p-toluate, Form IX, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2θ [°]).
具体实施方式Detailed ways
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但并不用来限制本发明的范围。The specific embodiments of the present invention are further described in detail below with reference to the drawings and embodiments. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
实施例1：式(I)化合物的制备Example 1: Preparation of a compound of formula (I)
第一步4-(((2-(二甲氧基甲基)-5,6,7,8-四氢-1,8-二氮杂萘-3-基)甲基)氨基)丁烷-1-醇的制备First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol
Figure PCTCN2018112891-appb-000002
Figure PCTCN2018112891-appb-000002
室温下，将2-(二甲氧基甲基)-5,6,7,8-四氢-1,8-二氮杂萘-3-甲醛(1.0g,4.2mmol)，4-氨基丁烷-1-醇(0.45g,5.1mmol)溶于DCE(15mL)，搅拌2小时，然后加入NaBH(OAc) 3(1.35g,6.4mmol)，室温下搅拌过夜。反应液用CH 2Cl 2(100mL)稀释，有机相依次用水(10mL)和饱和食盐水(15mL)洗涤，并用无水硫酸钠干燥，浓缩后柱层析得到化合物4-(((2-(二甲氧基甲基)-5,6,7,8-四氢-1,8-二氮杂萘-3-基)甲基)氨基)丁烷-1-醇(0.9g,69％)。 2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) 3 (1.35g, 6.4mmol), stirred at room temperature overnight. The reaction was diluted with CH 2 Cl 2 (100mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 - (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .
1H NMR(400MHz,CDCl 3)δ7.13(s,1H),5.17(s,1H),4.84(s,1H),3.73(s,2H),3.66-3.49(m,2H),3.42(s,6H),3.40-3.36(m,2H),2.71(t,J＝6.3Hz,2H),2.68-2.56(m,2H),1.95-1.81(m,2H),1.74-1.55(m,4H)； 1 H NMR (400MHz, CDCl 3 ) δ7.13 (s, 1H), 5.17 (s, 1H), 4.84 (s, 1H), 3.73 (s, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);
MS m/z(ESI):310.2[M+H] +. MS m/z (ESI): 310.2 [M+H] + .
第二步3-((2-(二甲氧基甲基)-5,6,7,8-四氢-1,8-二氮杂萘-3-基)甲基)-1,3-噁吖庚环-2-酮的制备The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone
Figure PCTCN2018112891-appb-000003
Figure PCTCN2018112891-appb-000003
冰水浴下，将4-(((2-(二甲氧基甲基)-5,6,7,8-四氢-1,8-二氮杂萘-3-基)甲基)氨基)丁烷-1-醇(0.6g,1.94mmol)溶于DCE(15mL)，然后加入二(三氯甲基)碳酸酯(0.22g,0.76mmol)，缓慢滴加三乙胺(0.78g,7.76mmol)，然后在室温下搅拌3小时。将反应温度升至80℃，在80℃下反应6小时，反应冷却至室温后，用CH 2Cl 2(100mL)稀释，有机相依次用水(10mL)和饱和食盐水(15mL)洗涤，并用无水硫酸钠干燥，浓缩后柱层析得到化合物3-((2-(二甲氧基甲基)-5,6,7,8-四氢-1,8-二氮杂萘-3-基)甲基)-1,3-噁吖庚环-2-酮(0.37g,57％)。 4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).
MS m/z(ESI):336.2[M+H] +. MS m/z (ESI): 336.2 [M+H] + .
第三步苯基7-(二甲氧基甲基)-6-((2-羰基-1,3-噁吖庚环-3-基)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-羧酸酯的制备The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate
Figure PCTCN2018112891-appb-000004
Figure PCTCN2018112891-appb-000004
3-((2-(二甲氧基甲基)-5,6,7,8-四氢-1,8-二氮杂萘-3-基)甲基)-1,3-噁吖庚环-2-酮(670mg,2mmol),碳酸二苯酯(643mg,3mmol)混合于THF(15mL)中，N 2氛围下,冷却至-78℃，滴加LiHMDS的THF(4mL,4mmol)溶液，自然升至室温反应过夜。加入饱和NH 4Cl水溶液(100mL)，乙酸乙酯(100mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析得标题化合物苯基7-(二甲氧基甲基)-6-((3-羰基吗啉代)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-羧酸酯(432mg,47％)。 3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixed in THF (15mL), under N 2 atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .
1H NMR(400MHz,CDCl 3)δ7.56(s,1H),7.38(m,2H),7.21(m,3H),5.22(s,1H),4.77(s,2H),4.16(m,2H),3.95(m,2H),3.39(s,6H),3.25(m,2H),2.84(t,J＝6.5Hz,2H),1.87(m,2H),1.64(m,4H)； 1 H NMR (400MHz, CDCl 3 ) δ7.56 (s, 1H), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (s, 1H), 4.77 (s, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);
MS m/z(ESI):456.2[M+H] +. MS m/z (ESI): 456.2 [M+H] + .
第四步：(R)-N-(5-氰基-4-((1-甲氧基丙烷-2-基)氨基)吡啶-2-基)-7-(二甲氧基甲基)-6-((2-羰基-1,3-噁吖庚环-3-基)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-甲酰胺的合成The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis
Figure PCTCN2018112891-appb-000005
Figure PCTCN2018112891-appb-000005
(R)-6-氨基-4-((1-甲氧基丙烷-2-基)氨基)尼古丁腈(30mg,0.14mmol),苯基7-(二甲氧基甲基)-6-((2-羰基-1,3-噁吖庚环-3-基)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-羧酸酯(60mg,0.13mmol)溶于THF(5mL)中，N 2氛围下冷却至-78℃，滴加LiHMDS的THF(0.3mL,0.3mmol)溶液于反应液中，自然升至室温反应过夜。加入饱和NH 4Cl水溶液(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析得标题化合物(R)-N-(5-氰基-4-((1-甲氧基丙烷-2-基)氨基)吡啶-2-基)-7-(二甲氧基甲基)-6-((2-羰基-1,3-噁吖庚环-3-基)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-甲酰胺(65mg,86％)。 (R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2 atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).
1H NMR(400MHz,CDCl3)δ13.70(s,1H),8.18(s,1H),7.60(s,2H),5.41(s,1H),5.12(d,J＝7.8Hz,1H),4.73(s,2H),4.20-4.11(m,2H),4.06-3.99(m,2H),3.93(s,1H),3.52-3.48(m,7H),3.46-3.42(m,1H),3.39(s,3H),3.26-3.21(m,2H),2.83(t,J＝6.2Hz,2H),2.03-1.95(m,2H),1.91-1.83(m,2H),1.67-1.62(m,2H),1.31(d,J＝6.6Hz,3H)；1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);
MS m/z(ESI):568.3[M+H] +. MS m/z (ESI): 568.3 [M+H] + .
第五步：(R)-N-(5-氰基-4-((1-甲氧基丙烷-2-基)氨基)吡啶-2-基)-7-甲酰基-6-((2-羰基-1,3-噁吖庚环-3-基)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-甲酰胺的合成Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide
Figure PCTCN2018112891-appb-000006
Figure PCTCN2018112891-appb-000006
(R)-N-(5-氰基-4-((1-甲氧基丙烷-2-基)氨基)吡啶-2-基)-7-(二甲氧基甲基)-6-((2-羰基-1,3-噁吖庚环-3-基)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-甲酰胺(65mg,0.12mmol)溶于THF/水(体积比：11/4，4.5mL)中，加入浓HCl(0.45mL,5.4mmol)，室温反应2h。加入饱和NaHCO 3水溶液(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析得标题化合物(R)-N-(5-氰基-4-((1-甲氧基丙烷-2-基)氨基)吡啶-2-基)-7-甲酰基-6-((2-羰基-1,3-噁吖庚环-3-基)甲基)-3,4-二氢-1,8-二氮杂萘-1(2H)-甲酰胺(30mg,51％)。 (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated aqueous NaHCO 3 (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).
1H NMR(400MHz,CDCl 3)δ13.57(s,1H),10.26(s,1H),8.17(s,1H),7.71(s,1H),7.63(s,1H),5.27(s,1H),4.95(s,2H),4.19-4.12(m,2H),4.11-4.04(m,2H), 3.94(s,1H),3.52(m,1H),3.48-3.37(m,4H),3.33-3.28(m,2H),2.93(t,J＝6.3Hz,2H),2.04(m,2H),1.93-1.85(m,2H),1.73(m,2H),1.39-1.28(m,3H)； 1 H NMR (400MHz, CDCl 3 ) δ13.57 (s, 1H), 10.26 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 5.27 (s, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 - 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);
MS m/z(ESI):522.2[M+H] +. MS m/z (ESI): 522.2 [M+H] + .
实施例2：式(I)化合物盐酸盐晶型I的制备Example 2: Preparation of the salt of Form I of the compound of formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙酸乙酯，然后向上述反应器中添加50.0μl盐酸，搅拌6小时，将悬浊液过滤得到固体，即式(I)化合物盐酸盐晶型I。About 300 mg of the compound of the formula (I) was weighed into the reactor, and 10.0 mL of ethyl acetate was added thereto at room temperature, and then 50.0 μl of hydrochloric acid was added to the above reactor, and the mixture was stirred for 6 hours, and the suspension was filtered to obtain a solid, that is, I) Compound hydrochloride salt form I.
实施例3：式(I)化合物盐酸盐晶型II的制备Example 3: Preparation of the salt of Form II of the compound of formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙醇，然后向上述反应器中添加50.0μl盐酸，搅拌6小时，将悬浊液过滤得到固体，即式(I)化合物盐酸盐晶型II。Weigh about 300 mg of the compound of formula (I) into the reactor, add 10.0 mL of ethanol at room temperature, then add 50.0 μl of hydrochloric acid to the above reactor, stir for 6 hours, and filter the suspension to obtain a solid, ie, formula (I) Compound hydrochloride salt form II.
实施例4：式(I)化合物盐酸盐晶型III的制备Example 4: Preparation of the salt of Form III of the compound of formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL二氯甲烷，然后向上述反应器中添加50.0μl盐酸，搅拌6小时，将悬浊液过滤得到固体，即式(I)化合物盐酸盐晶型III。Weigh about 300 mg of the compound of formula (I) into the reactor, add 10.0 mL of dichloromethane at room temperature, then add 50.0 μl of hydrochloric acid to the above reactor, stir for 6 hours, and filter the suspension to obtain a solid, ie, I) Compound hydrochloride salt form III.
实施例5：式(I)化合物盐酸盐晶型IV的制备Example 5: Preparation of the salt of Form IV of the compound of formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙腈，然后向上述反应器中添加50.0μl盐酸，得到澄清液，放置4℃条件下搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物盐酸盐晶型IV。Weigh about 300 mg of the compound of formula (I) into the reactor, add 10.0 mL of acetonitrile at room temperature, then add 50.0 μl of hydrochloric acid to the above reactor to obtain a clear liquid, and stir at 4 ° C for 12 hours to suspend the suspension. Filtration gave a solid, the salt of the compound of formula (I), Form IV.
实施例6：式(I)化合物盐酸盐晶型V的制备Example 6: Preparation of the salt of Form V of the compound of formula (I)
称取约500mg式(I)化合物盐酸盐样品加入反应器中，室温条件下加入10.0mL乙酸乙酯，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物盐酸盐晶型V。Weigh about 500 mg of the hydrochloride salt of the compound of formula (I) into the reactor, add 10.0 mL of ethyl acetate at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the salt of the compound of formula (I) Type V.
实施例7：式(I)化合物硫酸盐晶型I的制备Example 7: Preparation of sulfate form I of the compound of formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙酸乙酯，然后向上述反应器中添加33.0μl硫酸，搅拌6小时，将悬浊液过滤得到固体，即式(I)化合物硫酸盐晶型I。About 300 mg of the compound of the formula (I) was weighed into the reactor, and 10.0 mL of ethyl acetate was added thereto at room temperature, and then 33.0 μl of sulfuric acid was added to the above reactor, and the mixture was stirred for 6 hours, and the suspension was filtered to obtain a solid, that is, I) Compound Sulfate Form I.
实施例8：式(I)化合物硫酸盐晶型II的制备Example 8: Preparation of the sulfate form II of the compound of formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙腈，然后向上述反应器中添加33.0μl硫酸，搅拌6小时，将悬浊液过滤得到固体，即式(I)化合物硫酸盐晶型II。Weigh about 300 mg of the compound of formula (I) into the reactor, add 10.0 mL of acetonitrile at room temperature, then add 33.0 μl of sulfuric acid to the above reactor, stir for 6 hours, and filter the suspension to obtain a solid, ie, formula (I) Compound sulfate form II.
实施例9：式(I)化合物硫酸盐晶型III的制备Example 9: Preparation of sulfate salt form III of compound of formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL丙酮，然后向上述反应器中添加33.0μl硫酸，搅拌2小时，将悬浊液过滤得到固体，即式(I)化合物硫酸盐晶型III。Weigh about 300 mg of the compound of formula (I) into the reactor, add 10.0 mL of acetone at room temperature, then add 33.0 μl of sulfuric acid to the above reactor, stir for 2 hours, and filter the suspension to obtain a solid, ie, formula (I) Compound sulfate form III.
实施例10：式(I)化合物硫酸盐晶型IV的制备Example 10: Preparation of Sulfate Form IV of Compound of Formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL二氯甲烷，然后向上述反应器中添加33.0μl硫酸，搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物硫酸盐晶型IV。Weigh about 300 mg of the compound of formula (I) into the reactor, add 10.0 mL of dichloromethane at room temperature, then add 33.0 μl of sulfuric acid to the above reactor, stir for 12 hours, and filter the suspension to obtain a solid, ie, I) Compound Sulfate Form IV.
实施例11：式(I)化合物硫酸盐晶型V的制备Example 11: Preparation of sulfate form V of compound of formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙腈，然后向上述反应器中添加33.0μl硫酸，搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物硫酸盐晶型V。Weigh about 300 mg of the compound of formula (I) into the reactor, add 10.0 mL of acetonitrile at room temperature, then add 33.0 μl of sulfuric acid to the above reactor, stir for 12 hours, and filter the suspension to obtain a solid, ie, formula (I) Compound sulfate form V.
实施例12：式(I)化合物甲磺酸盐晶型I的制备Example 12: Preparation of the methanesulfonate salt form I of the compound of formula (I)
称取约200mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙腈，然后向上述反应器中添加24.9mg甲磺酸，搅拌6小时，将悬浊液过滤得到固体， 即式(I)化合物甲磺酸盐晶型I。Weigh about 200 mg of the compound of formula (I) into the reactor, add 10.0 mL of acetonitrile at room temperature, then add 24.9 mg of methanesulfonic acid to the above reactor, stir for 6 hours, and filter the suspension to obtain a solid, ie, I) Compound mesylate salt form I.
实施例13：式(I)化合物甲磺酸盐晶型II的制备Example 13: Preparation of the methanesulfonate salt form II of the compound of formula (I)
称取约200mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙醇，然后向上述反应器中添加24.9mg甲磺酸，搅拌6小时，将悬浊液过滤得到固体，即式(I)化合物甲磺酸盐晶型II。Weigh about 200 mg of the compound of formula (I) into the reactor, add 10.0 mL of ethanol at room temperature, then add 24.9 mg of methanesulfonic acid to the above reactor, stir for 6 hours, and filter the suspension to obtain a solid, ie, I) Compound Mesylate Salt Form II.
实施例14：式(I)化合物甲磺酸盐晶型III的制备Example 14: Preparation of Methanesulfonate Form III of Compound of Formula (I)
称取约200mg式(I)化合物甲磺酸盐样品，室温条件下放置湿度92.5％环境中5天，得到式(I)化合物甲磺酸盐晶型III。Approximately 200 mg of the methanesulfonate salt of the compound of the formula (I) was weighed and allowed to stand in an environment of 92.5% humidity for 5 days at room temperature to obtain the methanesulfonate salt form III of the compound of the formula (I).
实施例15：式(I)化合物甲磺酸盐晶型IV的制备Example 15: Preparation of the methanesulfonate salt form IV of the compound of formula (I)
称取约500mg式(I)化合物甲磺酸盐样品加入反应器中，室温条件下加入10.0mL异丁醇，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物甲磺酸盐晶型IV。Weigh about 500 mg of the sample of the compound of formula (I) mesylate into the reactor, add 10.0 mL of isobutanol at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I) methanesulfonic acid Salt crystal form IV.
实施例16：式(I)化合物甲磺酸盐晶型V的制备Example 16: Preparation of Methanesulfonate Form V of Compound of Formula (I)
称取约500mg式(I)化合物甲磺酸盐样品加入反应器中，室温条件下加入10.0mL异丙醇，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物甲磺酸盐晶型V。Weigh about 500 mg of the sample of the compound of formula (I) mesylate into the reactor, add 10.0 mL of isopropanol at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I) methanesulfonic acid Salt crystal form V.
实施例17：式(I)化合物甲磺酸盐晶型VI的制备Example 17: Preparation of the methanesulfonate salt form VI of the compound of formula (I)
称取约500mg式(I)化合物甲磺酸盐样品加入反应器中，室温条件下加入10.0mL甲酸乙酯，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物甲磺酸盐晶型VI。Weigh about 500 mg of the sample of the compound of formula (I) mesylate into the reactor, add 10.0 mL of ethyl formate at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I) methanesulfonic acid Salt crystal form VI.
实施例18：式(I)化合物甲磺酸盐晶型VII的制备Example 18: Preparation of Compound Mesylsulfonate Form VII of Formula (I)
称取约500mg式(I)化合物甲磺酸盐样品加入反应器中，室温条件下加入10.0mL乙酸乙酯，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物甲磺酸盐晶型VII。Weigh about 500 mg of the sample of the compound of formula (I) mesylate into the reactor, add 10.0 mL of ethyl acetate at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I) methanesulfonic acid Salt crystal form VII.
实施例19：式(I)化合物甲磺酸盐晶型VIII的制备Example 19: Preparation of the methanesulfonate salt form VIII of the compound of formula (I)
称取约500mg式(I)化合物甲磺酸盐样品加入反应器中，室温条件下加入10.0mL丙酮，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物甲磺酸盐晶型VIII。Weigh about 500 mg of the sample of the compound of formula (I) mesylate into the reactor, add 10.0 mL of acetone at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the mesylate salt of the compound of formula (I) Type VIII.
实施例20：式(I)化合物苯磺酸盐晶型I的制备Example 20: Preparation of the Form I of the Compound (I) Besylate
称取约200mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙醇，然后向上述反应器中添加50.56mg苯磺酸，搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物苯磺酸盐晶型I。Weigh about 200 mg of the compound of formula (I) into the reactor, add 10.0 mL of ethanol at room temperature, then add 50.56 mg of benzenesulfonic acid to the above reactor, stir for 12 hours, and filter the suspension to obtain a solid, ie, I) Compound besylate salt Form I.
实施例21：式(I)化合物苯磺酸盐晶型II的制备Example 21: Preparation of the Form (II) Compound of the Formula (I)
称取约500mg式(I)化合物苯磺酸盐样品加入反应器中，室温条件下加入10.0mL四氢呋喃，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物苯磺酸盐晶型II。Weigh about 500 mg of the sample of the compound (I) besylate salt into the reactor, add 10.0 mL of tetrahydrofuran at room temperature, stir for 3 days, and filter the suspension to obtain a solid, that is, the compound of the formula (I) besylate crystal Type II.
实施例22：式(I)化合物苯磺酸盐晶型III的制备Example 22: Preparation of the Form (III) Compound of the Formula (I)
称取约500mg式(I)化合物苯磺酸盐样品加入反应器中，室温条件下加入10.0mL二氯甲烷，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物苯磺酸盐晶型III。Weigh about 500 mg of the sample of the compound (I) besylate salt into the reactor, add 10.0 mL of dichloromethane at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I), benzenesulfonic acid Salt crystal form III.
实施例23：式(I)化合物苯磺酸盐晶型IV的制备Example 23: Preparation of the Form (IV) Compound of the Formula (I)
称取约500mg式(I)化合物苯磺酸盐样品加入反应器中，室温条件下加入10.0mL乙腈，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物苯磺酸盐晶型IV。Weigh about 500 mg of the sample of the compound (I) besylate salt into the reactor, add 10.0 mL of acetonitrile at room temperature, stir for 3 days, and filter the suspension to obtain a solid, that is, the compound of the formula (I) besylate crystal Type IV.
实施例24：式(I)化合物苯磺酸盐晶型V的制备Example 24: Preparation of the Form B of the Compound (I) Compound Besylate
称取约500mg式(I)化合物苯磺酸盐样品加入反应器中，室温条件下加入10.0mL75％乙醇水溶液，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物苯磺酸盐晶型V。Weigh about 500 mg of the sample of the compound (I) besylate salt into the reactor, add 10.0 mL of 75% aqueous ethanol solution at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I), benzenesulfonic acid Salt crystal form V.
实施例25：式(I)化合物苯磺酸盐晶型VI的制备Example 25: Preparation of Form B of Compound Benzene Sulfonate of Formula (I)
称取约200mg式(I)化合物加入反应器中，室温条件下加入10.0mL丙酮，然后向上述反应器中添加50.56mg苯磺酸，搅拌12小时，将悬浊液过滤得到固体238mg，即式(I)化合物苯磺酸盐晶型VI。About 200 mg of the compound of the formula (I) was weighed into the reactor, and 10.0 mL of acetone was added thereto at room temperature, and then 50.56 mg of benzenesulfonic acid was added to the above reactor, and the mixture was stirred for 12 hours, and the suspension was filtered to obtain a solid 238 mg. (I) Compound besylate salt form VI.
实施例26：式(I)化合物苯磺酸盐晶型VII的制备Example 26: Preparation of the benzenesulfonate salt form VII of the compound of formula (I)
称取约200mg苯磺酸盐样品，室温条件下放置在湿度92.5％环境中5天，得到式(I)化合物苯磺酸盐晶型VII。A sample of about 200 mg of the besylate salt was weighed and placed in a humidity of 92.5% atmosphere for 5 days at room temperature to obtain a benzenesulfonate salt form VII of the compound of the formula (I).
实施例27：式(I)化合物乙磺酸盐晶型I的制备Example 27: Preparation of Compound I of Ethylsulfonate of Formula (I)
称取约300mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙醇，然后向上述反应器中添加63.34mg乙磺酸，搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物乙磺酸盐晶型I。Weigh about 300 mg of the compound of formula (I) into the reactor, add 10.0 mL of ethanol at room temperature, then add 63.34 mg of ethanesulfonic acid to the above reactor, stir for 12 hours, and filter the suspension to obtain a solid, ie, I) Compound Ethyl sulfonate Form I.
实施例28：式(I)化合物乙磺酸盐晶型II的制备Example 28: Preparation of the compound ethanesulfonate salt form II of the formula (I)
称取约500mg式(I)化合物乙磺酸盐样品加入反应器中，室温条件下加入10.0mL乙酸乙酯，搅拌3天，将悬浊液过滤得到固体，即乙苯磺酸盐晶型II。Weigh about 500 mg of the sample of the compound (I) ethanesulfonate into the reactor, add 10.0 mL of ethyl acetate at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, ethylbenzenesulfonate crystal form II .
实施例29：式(I)化合物乙磺酸盐晶型III的制备Example 29: Preparation of Compound III of Compound (I) Ethylsulfonate Form III
称取约500mg式(I)化合物乙磺酸盐样品加入反应器中，室温条件下加入10.0mL二氯甲烷，搅拌3天，将悬浊液过滤得到固体，即乙苯磺酸盐晶型III。Weigh about 500 mg of the sample of the compound (I) ethanesulfonate into the reactor, add 10.0 mL of dichloromethane at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, ethylbenzenesulfonate crystal form III .
实施例30：式(I)化合物草酸盐晶型I的制备Example 30: Preparation of oxalate salt form I of compound of formula (I)
称取约500mg式(I)化合物加入反应器中，室温条件下加入10.0mL二氯甲烷，然后向上述反应器中添加120mg草酸，搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物草酸盐晶型I。Weigh about 500 mg of the compound of formula (I) into the reactor, add 10.0 mL of dichloromethane at room temperature, then add 120 mg of oxalic acid to the above reactor, stir for 12 hours, and filter the suspension to obtain a solid, ie, formula (I). Compound oxalate crystal form I.
实施例31：式(I)化合物草酸盐晶型II的制备Example 31: Preparation of Compound (I) Oxalate Form II
称取约500mg式(I)化合物草酸盐样品加入反应器中，室温条件下加入10.0mL丙酮，搅拌3天，将悬浊液过滤得到固体，即草酸盐晶型II。About 500 mg of the oxalate salt of the compound of the formula (I) was weighed into the reactor, and 10.0 mL of acetone was added thereto at room temperature, and the mixture was stirred for 3 days, and the suspension was filtered to obtain a solid, i.e., oxalate crystal form II.
实施例32：式(I)化合物马来酸盐晶型I的制备Example 32: Preparation of Compound (I) Compound Maleate Salt Form I
称取1.0g式(I)化合物加入反应器中，加入马来酸1.0g和乙酸乙酯50ml，在室温下搅拌7天，过滤得到式(I)化合物马来酸盐晶型I。1.0 g of the compound of the formula (I) was weighed into the reactor, and 1.0 g of maleic acid and 50 ml of ethyl acetate were added thereto, and the mixture was stirred at room temperature for 7 days, and filtered to obtain the maleic acid salt form I of the compound of the formula (I).
实施例33：式(I)化合物马来酸盐晶型I的制备Example 33: Preparation of Compound (I) Compound Maleate Salt Form I
称取约200mg式(I)化合物加入反应器中，室温条件下加入10.0mL二氯甲烷，然后向上述反应器中添加112mg马来酸，搅拌得到澄清液，缓慢滴加30ml乙酸乙酯，加入10mg马来酸盐晶型I晶种继续搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物马来酸盐晶型I。Weigh about 200 mg of the compound of formula (I) into the reactor, add 10.0 mL of dichloromethane at room temperature, then add 112 mg of maleic acid to the above reactor, stir to obtain a clear liquid, slowly add 30 ml of ethyl acetate, and add The 10 mg maleate crystal form I seed crystals were further stirred for 12 hours, and the suspension was filtered to give a solid, i.e., the compound (I) compound maleate salt form I.
实施例34：式(I)化合物马来酸盐晶型I的制备Example 34: Preparation of Compound (I) Compound Maleate Salt Form I
称取2g式(I)化合物加入到反应器中，室温条件下加入100ml二氯甲烷，加入马来酸1.1g，滴加正庚烷30ml后加入30mg晶型I晶种，继续滴加正庚烷50ml，室温搅拌24h，过滤得到式(I)化合物马来酸盐晶型I。Weigh 2g of the compound of formula (I) into the reactor, add 100ml of dichloromethane at room temperature, add 1.1g of maleic acid, add 30ml of n-heptane, add 30mg of crystal form I, continue to add n-glycan 50 ml of alkane was stirred at room temperature for 24 h and filtered to give the compound of the formula (I) as the maleic acid salt.
实施例35：式(I)化合物对甲苯磺酸盐晶型I的制备Example 35: Preparation of the crystalline form I of the p-toluenesulfonate salt of the compound of formula (I)
称取约200mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙酸乙酯，然后向上述反应器中添加51mg对甲苯磺酸，搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物对甲苯磺酸盐晶型I。About 200 mg of the compound of the formula (I) was weighed into the reactor, and 10.0 mL of ethyl acetate was added thereto at room temperature, and then 51 mg of p-toluenesulfonic acid was added to the above reactor, and the mixture was stirred for 12 hours, and the suspension was filtered to obtain a solid, that is, The compound of formula (I) is p-toluenesulfonate Form I.
实施例36：式(I)化合物对甲苯磺酸盐晶型II的制备Example 36: Preparation of p-toluenesulfonate salt form II of compound of formula (I)
称取约500mg式(I)化合物对甲苯磺酸盐样品加入反应器中，室温条件下加入10.0mL乙醇，搅拌3天，将悬浊液过滤得到固体，即对甲苯磺酸盐晶型II。About 500 mg of the compound of the formula (I) was weighed into the reactor, and 10.0 mL of ethanol was added thereto at room temperature, and the mixture was stirred for 3 days, and the suspension was filtered to obtain a solid, i.e., p-toluenesulfonate crystal form II.
实施例37：式(I)化合物对甲苯磺酸盐晶型III的制备Example 37: Preparation of p-toluenesulfonate salt form III of compound of formula (I)
称取约500mg式(I)化合物对甲苯磺酸盐样品加入反应器中，室温条件下加入10.0mL水，搅拌3天，将悬浊液过滤得到固体，即目标产物对甲苯磺酸盐晶型III。Weigh about 500 mg of the compound of formula (I) to the toluenesulfonate sample and add it to the reactor. Add 10.0 mL of water at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the target product p-toluenesulfonate crystal form. III.
实施例38：式(I)化合物对甲苯磺酸盐晶型IV的制备Example 38: Preparation of p-toluenesulfonate salt form IV of compound of formula (I)
称取约500mg式(I)化合物对甲苯磺酸盐样品加入反应器中，室温条件下加入10.0mL乙酸乙酯，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物对甲苯磺酸盐晶型IV。Weigh about 500 mg of the compound of formula (I) to the toluene sulfonate sample and add it to the reactor. Add 10.0 mL of ethyl acetate at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I) is toluene. Sulfonate crystal form IV.
实施例39：式(I)化合物对甲苯磺酸盐晶型V的制备Example 39: Preparation of p-toluenesulfonate Form V of the compound of formula (I)
称取约500mg式(I)化合物对甲苯磺酸盐样品加入反应器中，室温条件下加入10.0mL二氯甲烷/乙酸乙酯(1:1)混合溶剂，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物对甲苯磺酸盐晶型V。Weigh about 500 mg of the compound of formula (I) to the toluenesulfonate sample and add it to the reactor. Add 10.0 mL of dichloromethane/ethyl acetate (1:1) mixed solvent at room temperature, stir for 3 days, and filter the suspension. A solid, a compound of formula (I), p-toluenesulfonate Form V, is obtained.
实施例40：式(I)化合物对甲苯磺酸盐晶型VI的制备Example 40: Preparation of p-toluenesulfonate salt form VI of compound of formula (I)
称取约500mg式(I)化合物对甲苯磺酸盐样品加入反应器中，室温条件下加入10.0mL丙酮/乙酸乙酯(1:1)混合溶剂，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物对甲苯磺酸盐晶型IV。Weigh about 500 mg of the compound of formula (I) to the toluenesulfonate sample and add it to the reactor. Add 10.0 mL of acetone/ethyl acetate (1:1) mixed solvent at room temperature, stir for 3 days, and filter the suspension to obtain a solid. That is, the compound of formula (I) is p-toluenesulfonate crystal form IV.
实施例41：式(I)化合物对甲苯磺酸盐晶型VII的制备Example 41: Preparation of p-toluenesulfonate salt form VII of compound of formula (I)
称取约200mg式(I)化合物加入反应器中，室温条件下加入10.0mL乙醇，然后向上述反应器中添加51mg对甲苯磺酸，搅拌12小时，将悬浊液过滤得到固体，即式(I)化合物对甲苯磺酸盐晶型VII。Weigh about 200 mg of the compound of formula (I) into the reactor, add 10.0 mL of ethanol at room temperature, then add 51 mg of p-toluenesulfonic acid to the above reactor, stir for 12 hours, and filter the suspension to obtain a solid, ie, I) Compound p-toluenesulfonate Form VII.
实施例41：式(I)化合物对甲苯磺酸盐晶型VIII的制备Example 41: Preparation of p-toluenesulfonate salt form VIII of compound of formula (I)
称取约500mg式(I)化合物对甲苯磺酸盐样品加入反应器中，室温条件下加入10.0mL丙酮，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物对甲苯磺酸盐晶型VIII。Weigh about 500 mg of the compound of formula (I) to the toluenesulfonate sample and add it to the reactor. Add 10.0 mL of acetone at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I) p-toluenesulfonic acid. Salt crystal form VIII.
实施例42：式(I)化合物对甲苯磺酸盐晶型IX的制备Example 42: Preparation of p-toluenesulfonate salt form IX of compound of formula (I)
称取约500mg式(I)化合物对甲苯磺酸盐样品加入反应器中，室温条件下加入10.0mL甲醇，搅拌3天，将悬浊液过滤得到固体，即式(I)化合物对甲苯磺酸盐晶型IX。Weigh about 500 mg of the compound of formula (I) to the toluene sulfonate sample and add it to the reactor. Add 10.0 mL of methanol at room temperature, stir for 3 days, and filter the suspension to obtain a solid, ie, the compound of formula (I) p-toluenesulfonic acid. Salt crystal form IX.
实施例43Example 43
对本发明提供的式(I)化合物草酸盐晶型I和晶型II进行流动性考察，测量休止角，具体结果如下表1。The fluidity of the oxalate crystal form I and the crystal form II of the compound of the formula (I) provided by the present invention was examined, and the angle of repose was measured. The specific results are shown in Table 1 below.
表1Table 1
草酸盐晶型Oxalate crystal form 休止角(°)Angle of repose (°) USP分类USP classification
晶型ICrystal form I 2626 卓越excellence
晶型IIForm II 2929 卓越excellence
实验例44Experimental example 44
将本发明提供的式(I)化合物的甲磺酸盐晶型VIII和马来酸盐晶型I的样品放置在高温40℃和高湿(RH92.5％)条件下，分别于0、1、2、3、6个月取样考察有关物质，具体检测结果如表2。The sample of the methanesulfonate salt form VIII and the maleate salt form I of the compound of the formula (I) provided by the present invention is placed under the conditions of high temperature 40 ° C and high humidity (RH 92.5%) at 0, 1, respectively. At 2, 3, and 6 months, samples were taken to investigate the relevant substances. The specific test results are shown in Table 2.
表2Table 2
Figure PCTCN2018112891-appb-000007
Figure PCTCN2018112891-appb-000007
Figure PCTCN2018112891-appb-000008
Figure PCTCN2018112891-appb-000008
试验例1：酶学实验Test Example 1: Enzymatic experiment
1.FGFR4酶学实验1.FGFR4 enzymatic experiment
本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对FGFR4激酶活性的抑制作用，并得出化合物对FGFR4激酶活性的半数抑制浓度IC 50。 The method used in this experiment a test compound fluorescence resonance energy transfer (TR-FRET) on the inhibition of FGFR4 kinase activity, and compounds derived FGFR4 kinase activity half inhibitory concentration IC 50.
1)在384孔板中加入1～5uL FGFR4酶溶液，酶终浓度为0.1～5nM。1) Add 1 to 5 uL of FGFR4 enzyme solution to a 384-well plate at a final concentration of 0.1 to 5 nM.
2)加入1～5uL梯度稀释好的化合物溶液。2) Add 1 to 5 uL of the gradient diluted compound solution.
3)加入1～5uL底物混合液包含底物多肽终浓度5～50nM和ATP终浓度10～200uM。3) Adding 1 to 5 uL of the substrate mixture comprises a final concentration of the substrate polypeptide of 5 to 50 nM and a final concentration of ATP of 10 to 200 uM.
4)室温孵育0.5～3小时。4) Incubate for 0.5 to 3 hours at room temperature.
5)加入10uL EDTA和含标记抗体的检测液，室温孵育1小时。5) Add 10 uL of EDTA and the labeled antibody-containing assay solution and incubate for 1 hour at room temperature.
6)酶标仪测定各板孔的665nm荧光信号值。6) The 665 nm fluorescence signal value of each well was measured by a microplate reader.
7)通过荧光信号值计算抑制率。7) Calculate the inhibition rate by the fluorescence signal value.
8)根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50，具体实施例酶学活性见表3。 8) The IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations. The enzymatic activities of the specific examples are shown in Table 3.
2.FGFR1酶学实验2.FGFR1 enzymology experiment
本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对FGFR1激酶活性的抑制作用，并得出化合物对FGFR1激酶活性的半数抑制浓度IC 50。 The method used in this experiment a test compound fluorescence resonance energy transfer (TR-FRET) FGFR1 inhibitory effect on kinase activity, and to obtain the compound of the half inhibitory concentration IC 50 of FGFR1 kinase activity.
1)在384孔板中加入1～5uL FGFR1酶溶液，酶终浓度为0.1～5nM。1) Add 1 to 5 uL of FGFR1 enzyme solution to a 384-well plate at a final concentration of 0.1 to 5 nM.
2)加入1～5uL梯度稀释好的化合物溶液。2) Add 1 to 5 uL of the gradient diluted compound solution.
3)加入1～5uL底物混合液包含底物多肽终浓度5～50nM和ATP终浓度10～200uM。3) Adding 1 to 5 uL of the substrate mixture comprises a final concentration of the substrate polypeptide of 5 to 50 nM and a final concentration of ATP of 10 to 200 uM.
4)室温孵育0.5～3小时。4) Incubate for 0.5 to 3 hours at room temperature.
5)加入10uL EDTA和含标记抗体的检测液，室温孵育1小时。5) Add 10 uL of EDTA and the labeled antibody-containing assay solution and incubate for 1 hour at room temperature.
6)酶标仪测定各板孔的665nm荧光信号值。6) The 665 nm fluorescence signal value of each well was measured by a microplate reader.
7)通过荧光信号值计算抑制率。7) Calculate the inhibition rate by the fluorescence signal value.
8)根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50，具体实施例酶学活性见表3。 8) The IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations. The enzymatic activities of the specific examples are shown in Table 3.
表3table 3
化合物编号Compound number FGFR4IC 50(nM) FGFR4IC 50 (nM) FGFR1IC 50(nM) FGFR1IC 50 (nM)
式(I)化合物Compound of formula (I) 0.960.96 >10000>10000
3.Hep 3B细胞增殖抑制实验3. Hep 3B cell proliferation inhibition experiment
本实验采用CellTiter-Glo的方法测试化合物对Hep 3B细胞增殖的抑制作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50。 The method of the present study, the inhibition of a test compound CellTiter-Glo proliferation of Hep 3B cells, derived compounds inhibit cell proliferation and half maximal inhibitory concentration IC 50 activity.
1)在96孔细胞培养板中接种50～100uL的Hep 3B细胞悬液，密度为1～5×10 4细胞/mL，将培养板于培养箱培养16～24小时(37℃,5％CO 2)。 1) Inoculate 50-100 uL of Hep 3B cell suspension in a 96-well cell culture plate at a density of 1 to 5 × 10 4 cells/mL, and incubate the plate in an incubator for 16 to 24 hours (37 ° C, 5% CO). 2 ).
2)向培养板细胞中加入梯度稀释的不同浓度的待测化合物溶液，将培养板在培养箱孵育72小时(37℃,5％CO 2)。 2) Gradiently diluted solutions of different concentrations of the test compound were added to the culture plate cells, and the plates were incubated in an incubator for 72 hours (37 ° C, 5% CO 2 ).
3)每孔加入50～100uL CellTiter-Glo试剂，室温振荡或静置5～30分钟。3) Add 50-100 uL of CellTiter-Glo reagent to each well, shake at room temperature or let stand for 5 to 30 minutes.
4)酶标仪测定各板的化学发光信号值。4) The plate reader measures the chemiluminescence signal values of the plates.
5)通过化学发光信号值计算抑制率。5) Calculate the inhibition rate by the chemiluminescence signal value.
6)根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50，具体实施例细胞活性见表4。 6) The IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations. The cell activity of the specific examples is shown in Table 4.
4.HuH-7细胞增殖抑制实验4.HuH-7 cell proliferation inhibition experiment
本实验采用CellTiter-Glo的方法测试化合物对HuH-7细胞增殖的抑制作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50。 The method of the present study, the inhibition of a test compound on the CellTiter-Glo HuH-7 cell proliferation, and to obtain the compound inhibited cell proliferation half maximal inhibitory concentration IC 50 activity.
1)在96孔细胞培养板中接种50～100uL的HuH-7细胞悬液，密度为1～5×10 4细胞/mL，将培养板于培养箱培养16～24小时(37℃,5％CO 2)。 1) Inoculate 50-100 uL of HuH-7 cell suspension in a 96-well cell culture plate at a density of 1 to 5 × 10 4 cells/mL, and incubate the plate in an incubator for 16 to 24 hours (37 ° C, 5%). CO 2 ).
2)向培养板细胞中加入梯度稀释的不同浓度的待测化合物溶液，将培养板在培养箱孵育72小时(37℃,5％CO 2)。 2) Gradiently diluted solutions of different concentrations of the test compound were added to the culture plate cells, and the plates were incubated in an incubator for 72 hours (37 ° C, 5% CO 2 ).
3)每孔加入50～100uL CellTiter-Glo试剂，室温振荡或静置5～30分钟。3) Add 50-100 uL of CellTiter-Glo reagent to each well, shake at room temperature or let stand for 5 to 30 minutes.
4)酶标仪测定各板的化学发光信号值。4) The plate reader measures the chemiluminescence signal values of the plates.
5)通过化学发光信号值计算抑制率。5) Calculate the inhibition rate by the chemiluminescence signal value.
6)根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50，具体实施例细胞活性见表4。 6) The IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations. The cell activity of the specific examples is shown in Table 4.
5.SK-HEP-1细胞增殖抑制实验5.SK-HEP-1 cell proliferation inhibition experiment
本实验采用CellTiter-Glo的方法测试化合物对SK-HEP-1细胞增殖的抑制作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50。 The method of the present study, the inhibition of a test compound on the CellTiter-Glo SK-HEP-1 cell proliferation, the compounds inhibit cell proliferation and draw half maximal inhibitory concentration IC 50 activity.
1)在96孔细胞培养板中接种50～100uL的SK-HEP-1细胞悬液，密度为1～5×10 4 1) Inoculate 50-100 uL of SK-HEP-1 cell suspension in a 96-well cell culture plate at a density of 1 to 5 × 10 4
细胞/mL，将培养板于培养箱培养16～24小时(37℃,5％CO 2)。 The cells/mL were cultured in an incubator for 16 to 24 hours (37 ° C, 5% CO 2 ).
2)向培养板细胞中加入梯度稀释的不同浓度的待测化合物溶液，将培养板在培养箱孵育72小时(37℃,5％CO 2)。 2) Gradiently diluted solutions of different concentrations of the test compound were added to the culture plate cells, and the plates were incubated in an incubator for 72 hours (37 ° C, 5% CO 2 ).
3)每孔加入50～100uL CellTiter-Glo试剂，室温振荡或静置5～30分钟。3) Add 50-100 uL of CellTiter-Glo reagent to each well, shake at room temperature or let stand for 5 to 30 minutes.
4)酶标仪测定各板的化学发光信号值。4) The plate reader measures the chemiluminescence signal values of the plates.
5)通过化学发光信号值计算抑制率。5) Calculate the inhibition rate by the chemiluminescence signal value.
6)根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50，具体实施例细胞活性见表4。 6) The IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations. The cell activity of the specific examples is shown in Table 4.
表4Table 4
化合物编号Compound number Hep 3B IC 50(nM) Hep 3B IC 50 (nM) HuH-7IC 50(nM) HuH-7IC 50 (nM) SK-HEP-1 IC 50(nM) SK-HEP-1 IC 50 (nM)
式(I)化合物Compound of formula (I) 0.60.6 2.62.6 >10000>10000
6.大鼠的PK分析6. PK analysis of rats
本发明优选实施例的大鼠药物代谢动力学试验采用SD大鼠(上海杰思捷实验动物有限公司)进行。The rat pharmacokinetic test of the preferred embodiment of the present invention was carried out using SD rats (Shanghai Jiesijie Experimental Animal Co., Ltd.).
■给药方式：单次灌胃给药。■ Mode of administration: single oral administration.
■给药剂量：5毫克/10毫升/千克。■ Dosage: 5 mg/10 ml / kg.
■制剂处方：0.5％CMC和1％Tween 80，超声溶解。■ Formulation formulation: 0.5% CMC and 1% Tween 80, sonicated.
■取样点：给药后0.5、1、2、4、6、8和24小时。■Sampling points: 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.
■样品处理：■ Sample processing:
1)静脉采血0.2mL，置于K 2EDTA试管中，室温1000～3000×g离心5～20min分离血浆，于-80℃保存。 1) 0.2 mL of venous blood was collected and placed in a K 2 EDTA test tube. The plasma was separated by centrifugation at 1000 to 3000 × g for 5 to 20 minutes at room temperature, and stored at -80 ° C.
2)血浆样品40uL加入160uL乙腈沉淀,混合后500～2000×g离心5～20分钟。2) The plasma sample was added to 160 uL of acetonitrile precipitate in 40 μL, and mixed for 500 to 2000 × g for 5 to 20 minutes.
3)取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度，LC/MS/MS分析仪器：AB Sciex API 4000。3) Take the supernatant solution 100uL for LC/MS/MS analysis of the concentration of the test compound, LC/MS/MS analytical instrument: AB Sciex API 4000.
■液相分析：■ Liquid phase analysis:
●液相条件：Shimadzu LC-20AD泵●Liquid conditions: Shimadzu LC-20AD pump
●色谱柱：phenomenex Gemiu 5um C18 50×4.6mm●Column column: phenomenex Gemiu 5um C18 50×4.6mm
●移动相：A液为0.1％甲酸水溶液，B液为乙腈● Mobile phase: A solution is 0.1% formic acid aqueous solution, and B solution is acetonitrile.
●流速：0.8mL/min●Flow rate: 0.8mL/min
●洗脱时间：0-3.5分钟，洗脱液如下：● Elution time: 0-3.5 minutes, the eluent is as follows:
时间/分钟Time/minute A液Liquid A B液B liquid
0.010.01 80％80% 20％20%
0.50.5 80％80% 20％20%
1.21.2 10％10% 90％90%
2.62.6 10％10% 90％90%
2.72.7 80％80% 20％20%
3.83.8 80％80% 20％20%
■药代动力学：■Pharmacokinetics:
主要参数用WinNonlin 6.1计算得到，大鼠药代实验结果见下表5：The main parameters were calculated using WinNonlin 6.1. The results of rat pharmacokinetic experiments are shown in Table 5 below:
表5table 5
Figure PCTCN2018112891-appb-000009
Figure PCTCN2018112891-appb-000009
Figure PCTCN2018112891-appb-000010
Figure PCTCN2018112891-appb-000010
7.体内药效试验步骤及结果7. In vivo efficacy test procedures and results
7.1实验目的7.1 Experimental purpose
通过体内药效实验筛选出药效较为明显且毒副作用较小的化合物。The compounds with more obvious effects and less toxic side effects were screened by in vivo pharmacodynamic experiments.
7.2实验主要仪器和试剂7.2 Experimental main instruments and reagents
7.2.1仪器:7.2.1 Instruments:
1、超净工作台(BSC-1300II A2，上海博讯实业有限公司医疗设备厂)1. Ultra-clean workbench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)
2、CO2培养箱(Thermo)2. CO2 incubator (Thermo)
3、离心机(Centrifuge 5720R，Eppendorf)3. Centrifuge (Centrifuge 5720R, Eppendorf)
4、全自动细胞计数仪(Countess II，Life)4, automatic cell counter (Countess II, Life)
5、移液器(10-20uL，Eppendorf)5, pipette (10-20uL, Eppendorf)
6、显微镜(TS100，尼康)6, microscope (TS100, Nikon)
6、游标卡尺(500-196，日本三丰)6, vernier caliper (500-196, Mitutoyo, Japan)
7、细胞培养瓶(T25/T75/T225，Corning)7. Cell culture flask (T25/T75/T225, Corning)
7.2.2试剂7.2.2 Reagents
1、MEM培养基(11095-080，gibico)1, MEM medium (11095-080, gibico)
2、胎牛血清(FBS)(10099-141，gibico)2, fetal bovine serum (FBS) (10099-141, gibico)
3、0.25％胰蛋白酶(25200-056，gibico)3, 0.25% trypsin (25200-056, gibico)
4、青链霉素双抗(SV30010，GE)4. Streptomycin double antibody (SV30010, GE)
5、磷酸盐缓冲液(PBS)(10010-023，gibico)5, phosphate buffer (PBS) (10010-023, gibico)
7.3实验步骤7.3 Experimental steps
7.3.1细胞培养及细胞悬液制备7.3.1 Cell culture and cell suspension preparation
a,从细胞库中取出一株Hep 3B细胞，用MEM培养基(MEM+10％FBS+1％Glu+1％SP)复苏细胞，复苏后的细胞置细胞培养瓶中(在瓶壁标记好细胞种类、日期、培养人名字等)置于CO2培养箱中培养(培养箱温度为37℃，CO2浓度为5％)。a, remove a Hep 3B cell from the cell bank, resuscitate the cells with MEM medium (MEM + 10% FBS + 1% Glu + 1% SP), and resuscitate the cells in a cell culture flask (marked in the bottle wall) The cell type, date, culture name, etc.) were cultured in a CO2 incubator (incubator temperature 37 ° C, CO 2 concentration 5%).
b,待细胞铺满培养瓶底部80-90％后传代，传代后细胞继续置于CO2培养箱中培养。重复该过程直到细胞数满足体内药效需求。b. After the cells are covered with 80-90% of the bottom of the culture flask, they are passaged. After passage, the cells are continuously cultured in a CO2 incubator. This process is repeated until the number of cells meets the in vivo efficacy requirements.
c,收集培养好的细胞，用全自动细胞计数仪计数，根据计数结果用PBS重悬细胞，制成细胞悬液(密度7×107/mL)，置于冰盒中待用。c. The cultured cells were collected, counted by a fully automatic cell counter, and the cells were resuspended in PBS according to the counting results to prepare a cell suspension (density: 7 × 10 7 /mL), which was placed in an ice box for use.
7.3.2细胞接种、量瘤：7.3.2 Cell inoculation, tumor measurement:
a,接种前用一次性大小鼠通用耳标标记裸鼠，并用75％医用酒精消毒接种部位皮肤。a. Nude mice were labeled with a one-time large mouse universal ear tag before inoculation, and the skin of the inoculated site was disinfected with 75% medical alcohol.
b,接种时混匀细胞悬液，用1mL注射器抽取0.1～1mL细胞悬液、排除气泡，然后将注射器置于冰袋上待用。b. Mix the cell suspension at the time of inoculation, extract 0.1 to 1 mL of the cell suspension with a 1 mL syringe, remove air bubbles, and place the syringe on an ice pack for use.
c,依次给试验裸鼠接种(接种部位位于裸鼠右侧背部靠右肩位置皮下接种0.1mL细胞悬液)。c. The test nude mice were inoculated in turn (the inoculation site was placed subcutaneously inoculated with 0.1 mL of cell suspension on the right side of the right side of the nude mouse).
7.3.3荷瘤鼠量瘤、分组、给药7.3.3 Tumor-bearing mice, tumor, group, drug delivery
a,根据肿瘤生长情况，在接种后第14-16天量瘤、并计算肿瘤大小。a, according to tumor growth, tumors were counted on days 14-16 after inoculation, and tumor size was calculated.
肿瘤体积计算：肿瘤体积(mm3)＝长(mm)×宽(mm)×宽(mm)/2Tumor volume calculation: tumor volume (mm3) = length (mm) × width (mm) × width (mm) / 2
b,根据肿瘤大小，采用随机分组的方法进行分组。b, according to the size of the tumor, grouped by random grouping method.
c,根据分组结果，开始给予测试药物(给药方式：口服给药，给药剂量：30mg/kg，给药体积：10mL/kg，给药频率：2次/天，给药周期：14天，溶媒：0.5％CMC/1％吐温80)。c, according to the results of the grouping, the administration of the test drug (administration method: oral administration, administration dose: 30 mg/kg, administration volume: 10 mL/kg, administration frequency: 2 times/day, administration period: 14 days) , solvent: 0.5% CMC / 1% Tween 80).
d,开始给予测试药物后每周二次量瘤、称重。d, the tumor was dosed twice a week after the test drug was administered, and weighed.
e,实验结束后安乐死动物。e. Animals are euthanized after the end of the experiment.
7.4试验数据：7.4 Test data:
分组Grouping 动物数量(只)Number of animals (only) 给药天数(天)Day of administration (days) 抑瘤率Tumor inhibition rate
空白对照Blank control 55 1414 --
式(I)化合物Compound of formula (I) 55 1414 181.67％181.67%
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。The above is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make several improvements and modifications without departing from the technical principles of the present invention. It should also be considered as the scope of protection of the present invention.

Claims (132)

  1. 式(I)化合物的可药用盐，所述可药用盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐、碳酸盐、碳酸氢盐、高氯酸盐、柠檬酸盐、酒石酸盐、富马酸盐、琥珀酸盐、马来酸盐、醋酸盐、苹果酸盐、苯甲酸盐、对甲苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、乙磺酸盐、羟乙基磺酸盐、1-萘磺酸盐、2-萘磺酸盐、樟脑磺酸盐、三氟甲磺酸盐、三氟乙酸盐、乳酸盐、草酸盐、水杨酸盐、苯乙酸盐、扁桃酸盐、甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、草酸盐、羟乙酸盐、羟基马来酸盐、甲基马来酸盐、己二酸盐、肉桂酸盐、抗坏血酸盐、水杨酸盐、2-乙酸基苯甲酸盐、烟酸盐、异烟酸盐、胆酸盐、天冬氨酸盐或谷氨酸盐；a pharmaceutically acceptable salt of a compound of formula (I), which is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, bicarbonate, Perchlorate, citrate, tartrate, fumarate, succinate, maleate, acetate, malate, benzoate, p-toluate, mesylate, Benzene sulfonate, p-toluenesulfonate, ethanesulfonate, isethionate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, camphorsulfonate, trifluoromethanesulfonate, three Fluoroacetate, lactate, oxalate, salicylate, phenylacetate, mandelate, formate, acetate, trifluoroacetate, propionate, oxalate, hydroxy Acetate, hydroxymaleate, methyl maleate, adipate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, nicotinate, isonicotinic acid Salt, cholate, aspartate or glutamate;
    Figure PCTCN2018112891-appb-100001
    Figure PCTCN2018112891-appb-100001
  2. 式(I)化合物可药用盐的晶型。A crystalline form of a pharmaceutically acceptable salt of a compound of formula (I).
  3. 式(I)化合物盐酸盐的晶型I，其XRPD图谱中至少包含有2θ±0.2°为：5.8、9.9、11.0、16.7和25.3的衍射峰。Form I of the hydrochloride salt of the compound of formula (I) has an XRPD pattern containing at least 2θ ± 0.2°: diffraction peaks of 5.8, 9.9, 11.0, 16.7 and 25.3.
  4. 根据权利要求3所述的晶型I，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.8、8.2、9.9、11.0、12.1、12.4、13.0、14.0、16.7、18.5、19.0、22.3、25.3、25.8、26.2和27.7的衍射峰。The crystal form I according to claim 3, wherein the XRPD pattern comprises 2θ±0.2°: 5.8, 8.2, 9.9, 11.0, 12.1, 12.4, 13.0, 14.0, 16.7, 18.5, 19.0, 22.3, Diffraction peaks of 25.3, 25.8, 26.2 and 27.7.
  5. 根据权利要求3所述的晶型I，其粉末X-射线衍射图谱如图1所示。The crystalline form I according to claim 3, which has a powder X-ray diffraction pattern as shown in FIG.
  6. 式(I)化合物盐酸盐的晶型II，其XRPD图谱中至少包含有2θ±0.2°为：6.0、6.5、15.7和23.8的衍射峰。The crystalline form II of the hydrochloride salt of the compound of the formula (I) has at least 2θ±0.2° in the XRPD pattern: diffraction peaks of 6.0, 6.5, 15.7 and 23.8.
  7. 根据权利要求6所述的晶型II，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.0、6.5、8.4、11.7、12.1、13.2、14.6、15.7、16.7、17.7、18.7、19.1、20.0、22.5、23.0、23.8、24.5和25.6的衍射峰。The crystal form II according to claim 6, wherein the XRPD pattern comprises 2θ±0.2°: 6.0, 6.5, 8.4, 11.7, 12.1, 13.2, 14.6, 15.7, 16.7, 17.7, 18.7, 19.1. Diffraction peaks of 20.0, 22.5, 23.0, 23.8, 24.5, and 25.6.
  8. 根据权利要求6所述的晶型II，其粉末X-射线衍射图谱如图2所示。The crystalline form II according to claim 6, wherein the powder X-ray diffraction pattern is as shown in FIG.
  9. 式(I)化合物盐酸盐的晶型III，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.1、7.0、9.2、10.2和21.0的衍射峰。Form III of the hydrochloride salt of the compound of formula (I) is characterized in that it has at least 2θ ± 0.2° in the XRPD pattern: diffraction peaks of 6.1, 7.0, 9.2, 10.2 and 21.0.
  10. 根据权利要求9所述的晶型III，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.1、7.0、9.2、10.2、12.4、14.4、16.4、16.9、18.6、19.5、21.0、24.6、25.6和26.2的衍射峰。The crystal form III according to claim 9, wherein the XRPD pattern comprises 2θ±0.2°: 6.1, 7.0, 9.2, 10.2, 12.4, 14.4, 16.4, 16.9, 18.6, 19.5, 21.0, 24.6, Diffraction peaks of 25.6 and 26.2.
  11. 根据权利要求9所述的式(I)化合物盐酸盐的晶型III，其粉末X-射线衍射图谱如图3所示。Form III of the hydrochloride salt of the compound of formula (I) according to claim 9, the powder X-ray diffraction pattern of which is shown in FIG.
  12. 式(I)化合物盐酸盐的晶型IV，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.1、7.8、9.5、11.9和25.0的衍射峰。Form IV of the hydrochloride salt of the compound of formula (I) is characterized in that it has at least 2θ ± 0.2° in the XRPD pattern: diffraction peaks of 6.1, 7.8, 9.5, 11.9 and 25.0.
  13. 根据权利要求12所述的晶型IV，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.9、6.1、7.8、8.8、9.5、10.0、11.9、12.4、15.5、21.2、23.6、25.0、26.5和32.5的衍射峰。The crystalline form IV according to claim 12, wherein the XRPD pattern comprises 2θ±0.2°: 5.9, 6.1, 7.8, 8.8, 9.5, 10.0, 11.9, 12.4, 15.5, 21.2, 23.6, 25.0, Diffraction peaks of 26.5 and 32.5.
  14. 根据权利要求12所述的式(I)化合物盐酸盐的晶型IV，其粉末X-射线衍射图谱如图4所示。Form IV of the hydrochloride salt of the compound of formula (I) according to claim 12, the powder X-ray diffraction pattern of which is shown in Figure 4.
  15. 式(I)化合物盐酸盐的晶型V，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.5、12.0、13.2、16.5和23.6的衍射峰。The crystalline form V of the hydrochloride salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 6.5, 12.0, 13.2, 16.5 and 23.6.
  16. 根据权利要求15所述的晶型V，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.8、6.5、8.8、11.5、12.0、13.2、14.4、14.8、15.2、16.5、20.3、21.3、23.6、25.3和27.0的衍射峰。The crystal form V according to claim 15, wherein the XRPD pattern comprises 2θ±0.2°: 5.8, 6.5, 8.8, 11.5, 12.0, 13.2, 14.4, 14.8, 15.2, 16.5, 20.3, 21.3, Diffraction peaks of 23.6, 25.3 and 27.0.
  17. 根据权利要求15所述的晶型V，其粉末X-射线衍射图谱如图5所示。The crystalline form V according to claim 15, which has a powder X-ray diffraction pattern as shown in FIG.
  18. 式(I)化合物硫酸盐的晶型I，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.6、6.4、7.6、13.4和27.1的衍射峰。Form I of the sulfate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 5.6, 6.4, 7.6, 13.4 and 27.1.
  19. 根据权利要求18所述的晶型I，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.6、6.4、7.6、11.3、12.1、12.4、13.4、14.1、15.3、18.1、19.0、20.9、21.5、24.5、24.9和27.1的衍射峰。The crystal form I according to claim 18, wherein the XRPD pattern comprises 2θ±0.2°: 5.6, 6.4, 7.6, 11.3, 12.1, 12.4, 13.4, 14.1, 15.3, 18.1, 19.0, 20.9, Diffraction peaks of 21.5, 24.5, 24.9, and 27.1.
  20. 根据权利要求18所述的式(I)化合物硫酸盐的晶型I，其粉末X-射线衍射图谱如图6所示。Crystalline Form I of the sulfate salt of the compound of formula (I) according to claim 18, the powder X-ray diffraction pattern of which is shown in FIG.
  21. 式(I)化合物硫酸盐的晶型II，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.8、6.1、6.5、9.0、13.0和23.9的衍射峰。Form II of the sulfate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 5.8, 6.1, 6.5, 9.0, 13.0 and 23.9.
  22. 根据权利要求21所述的晶型II，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.8、6.1、6.5、7.8、9.0、11.8、13.0、14.6、15.4、16.0、16.6、17.4、18.1、19.8、21.6、22.1、23.0和23.9的衍射峰。The crystal form II according to claim 21, wherein the XRPD pattern comprises 2θ±0.2°: 5.8, 6.1, 6.5, 7.8, 9.0, 11.8, 13.0, 14.6, 15.4, 16.0, 16.6, 17.4, Diffraction peaks of 18.1, 19.8, 21.6, 22.1, 23.0, and 23.9.
  23. 根据权利要求21所述的晶型II，其粉末X-射线衍射图谱如图7所示。The crystalline form II according to claim 21, which has a powder X-ray diffraction pattern as shown in FIG.
  24. 式(I)化合物硫酸盐的晶型III，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.6、7.8、15.5、18.1、25.0和27.1的衍射峰。The crystalline form III of the sulfate of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 6.6, 7.8, 15.5, 18.1, 25.0 and 27.1.
  25. 根据权利要求24所述的晶型III，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.6、7.8、9.5、11.5、12.2、12.6、13.6、14.3、15.5、17.1、18.1、18.7、19.1、19.8、21.1、21.6、23.2、24.6、25.0和27.1的衍射峰。The crystal form III according to claim 24, wherein the XRPD pattern comprises 2θ±0.2°: 6.6, 7.8, 9.5, 11.5, 12.2, 12.6, 13.6, 14.3, 15.5, 17.1, 18.1, 18.7, Diffraction peaks of 19.1, 19.8, 21.1, 21.6, 23.2, 24.6, 25.0 and 27.1.
  26. 根据权利要求24所述的晶型III，其粉末X-射线衍射图谱如图8所示。The crystalline form III according to claim 24, which has a powder X-ray diffraction pattern as shown in FIG.
  27. 式(I)化合物硫酸盐的晶型IV，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.2、6.6、9.8、20.5和23.3的衍射峰。Form IV of the sulfate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 5.2, 6.6, 9.8, 20.5 and 23.3.
  28. 根据权利要求27所述的晶型IV，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.2、6.6、8.7、9.8、11.3、13.4、16.5、20.5、23.3、25.4、26.7和28.8的衍射峰。The crystalline form IV according to claim 27, wherein the XRPD pattern comprises 2θ ± 0.2° of: 5.2, 6.6, 8.7, 9.8, 11.3, 13.4, 16.5, 20.5, 23.3, 25.4, 26.7, and 28.8. Diffraction peaks.
  29. 根据权利要求27所述的晶型IV，其粉末X-射线衍射图谱如图9所示。The crystalline form IV according to claim 27, which has a powder X-ray diffraction pattern as shown in FIG.
  30. 式(I)化合物硫酸盐的晶型V，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.8、6.3、13.5、24.0和24.8的衍射峰。The crystalline form V of the sulfate of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 5.8, 6.3, 13.5, 24.0 and 24.8.
  31. 根据权利要求30所述的晶型V，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.8、6.3、13.5、14.5、14.9、16.8、17.4、18.1、19.4、20.5、20.9、22.8、24.0、24.8、26.7、28.3和31.8的衍射峰。The crystal form V according to claim 30, wherein the XRPD pattern comprises 2θ±0.2°: 5.8, 6.3, 13.5, 14.5, 14.9, 16.8, 17.4, 18.1, 19.4, 20.5, 20.9, 22.8, Diffraction peaks of 24.0, 24.8, 26.7, 28.3 and 31.8.
  32. 根据权利要求30所述的晶型V，其粉末X-射线衍射图谱如图10所示。The crystalline form V according to claim 30, which has a powder X-ray diffraction pattern as shown in FIG.
  33. 式(I)化合物甲磺酸盐的晶型。A crystalline form of the methanesulfonate salt of the compound of formula (I).
  34. 式(I)化合物甲磺酸盐的晶型I，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.2、7.8、9.6、13.8、18.9和25.6的衍射峰。Form I of the methanesulfonate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 6.2, 7.8, 9.6, 13.8, 18.9 and 25.6.
  35. 根据权利要求34所述的晶型I，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.2、7.8、9.6、12.5、13.8、14.6、15.4、16.1、18.9、19.4、20.5、21.0、22.4、23.3、24.0、25.1、25.6、26.6和27.9的衍射峰。The crystal form I according to claim 34, wherein the XRPD pattern comprises 2θ±0.2°: 6.2, 7.8, 9.6, 12.5, 13.8, 14.6, 15.4, 16.1, 18.9, 19.4, 20.5, 21.0, Diffraction peaks of 22.4, 23.3, 24.0, 25.1, 25.6, 26.6 and 27.9.
  36. 根据权利要求34所述的甲磺酸盐晶型I，其粉末X-射线衍射图谱如图11所示。The mesylate salt form I according to claim 34, which has a powder X-ray diffraction pattern as shown in FIG.
  37. 式(I)化合物甲磺酸盐的晶型II，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.5、8.2、13.7、17.3、20.9和25.1的衍射峰。Form II of the mesylate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 7.5, 8.2, 13.7, 17.3, 20.9 and 25.1.
  38. 根据权利要求36所述的甲磺酸盐晶型II，其特征在于其XRPD图谱中包含有2θ±0.2°为：7.5、8.2、11.5、13.7、15.1、17.3、20.0、20.9、23.0、25.1和28.9的衍射峰。The mesylate salt form II according to claim 36, wherein the XRPD pattern comprises 2θ ± 0.2°: 7.5, 8.2, 11.5, 13.7, 15.1, 17.3, 20.0, 20.9, 23.0, 25.1 and A diffraction peak of 28.9.
  39. 根据权利要求37所述的甲磺酸盐晶型II，其粉末X-射线衍射图谱如图14所示。The mesylate salt form II according to claim 37, which has a powder X-ray diffraction pattern as shown in FIG.
  40. 式(I)化合物甲磺酸盐的晶型III，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.2、13.5、16.3、19.5、22.0和24.2的衍射峰。The crystalline form III of the mesylate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 6.2, 13.5, 16.3, 19.5, 22.0 and 24.2.
  41. 根据权利要求40所述的甲磺酸盐晶型III，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.2、6.9、11.1、12.5、13.5、14.7、16.3、17.2、18.4、19.5、20.4、22.0、24.2、24.8和30.4的衍射峰。The mesylate salt form III according to claim 40, wherein the XRPD pattern comprises 2θ ± 0.2°: 6.2, 6.9, 11.1, 12.5, 13.5, 14.7, 16.3, 17.2, 18.4, 19.5, Diffraction peaks of 20.4, 22.0, 24.2, 24.8 and 30.4.
  42. 根据权利要求40所述的甲磺酸盐晶型III，其粉末X-射线衍射图谱如图15所示。The mesylate salt form III according to claim 40, which has a powder X-ray diffraction pattern as shown in FIG.
  43. 式(I)化合物甲磺酸盐的晶型IV，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.1、9.0、11.0、13.6、14.8、22.3和23.8的衍射峰。Form IV of the mesylate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 5.1, 9.0, 11.0, 13.6, 14.8, 22.3 and 23.8.
  44. 根据权利要求43所述的晶型IV，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.1、6.9、9.0、11.0、13.6、14.8、18.4、18.9、20.6、22.3、23.8和25.4的衍射峰。The crystalline form IV according to claim 43, wherein the XRPD pattern comprises 2θ ± 0.2° of: 5.1, 6.9, 9.0, 11.0, 13.6, 14.8, 18.4, 18.9, 20.6, 22.3, 23.8, and 25.4. Diffraction peaks.
  45. 根据权利要求43所述的晶型IV，其粉末X-射线衍射图谱如图16所示。The crystalline form IV according to claim 43, which has a powder X-ray diffraction pattern as shown in FIG.
  46. 式(I)化合物甲磺酸盐的晶型V，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.1、7.9、9.4、15.9、19.2和24.5的衍射峰。Form V of the mesylate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 6.1, 7.9, 9.4, 15.9, 19.2 and 24.5.
  47. 根据权利要求46所述的晶型V，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.1、7.9、9.4、10.1、12.2、12.6、13.3、14.3、15.9、17.2、19.1、21.8、22.8、23.7、24.5、27.3和29.1的衍射峰。The crystal form V according to claim 46, wherein the XRPD pattern comprises 2θ±0.2°: 6.1, 7.9, 9.4, 10.1, 12.2, 12.6, 13.3, 14.3, 15.9, 17.2, 19.1, 21.8, Diffraction peaks of 22.8, 23.7, 24.5, 27.3 and 29.1.
  48. 根据权利要求46所述的晶型V，其粉末X-射线衍射图谱如图17所示。The crystalline form V according to claim 46, which has a powder X-ray diffraction pattern as shown in FIG.
  49. 式(I)化合物甲磺酸盐的晶型VI，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.6、8.6、13.7、17.5、22.1、23.7和28.8的衍射峰。The crystalline form VI of the mesylate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 7.6, 8.6, 13.7, 17.5, 22.1, 23.7 and 28.8.
  50. 根据权利要求49所述的晶型VI，其特征在于其XRPD图谱中包含有2θ±0.2°为：7.6、8.6、11.4、13.7、15.1、17.5、18.5、18.8、20.1、21.1、22.1、23.1、23.7、24.5、25.7和28.8的衍射峰。The crystal form VI according to claim 49, wherein the XRPD pattern comprises 2θ±0.2°: 7.6, 8.6, 11.4, 13.7, 15.1, 17.5, 18.5, 18.8, 20.1, 21.1, 22.1, 23.1, Diffraction peaks of 23.7, 24.5, 25.7, and 28.8.
  51. 根据权利要求49所述的晶型VI，其粉末X-射线衍射图谱如图18所示。The crystalline form VI according to claim 49, which has a powder X-ray diffraction pattern as shown in FIG.
  52. 式(I)化合物甲磺酸盐的晶型VII，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.2、7.1、10.4、14.1和23.3的衍射峰。Form VII of the mesylate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 6.2, 7.1, 10.4, 14.1 and 23.3.
  53. 根据权利要求52所述的晶型VII，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.2、7.1、10.4、12.0、13.2、14.1、16.0、17.2、18.7、23.3、和30.2的衍射峰。The Form VII according to Claim 52, characterized in that the XRPD pattern comprises diffraction of 2θ ± 0.2°: 6.2, 7.1, 10.4, 12.0, 13.2, 14.1, 16.0, 17.2, 18.7, 23.3, and 30.2. peak.
  54. 根据权利要求52所述的晶型VII，其粉末X-射线衍射图谱如图19所示。The Form VII according to Claim 52, which has a powder X-ray diffraction pattern as shown in FIG.
  55. 式(I)化合物甲磺酸盐的晶型VIII，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.9、6.4、13.6、16.9、24.1和25.0的衍射峰。Form VIII of the mesylate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 5.9, 6.4, 13.6, 16.9, 24.1 and 25.0.
  56. 根据权利要求55所述的晶型VIII，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.9、6.4、13.6、14.6、15.1、16.9、17.6、18.2、19.6、20.6、21.0、22.7、24.1、25.0、26.8、28.4和31.9的衍射峰。The crystalline form VIII according to claim 55, wherein the XRPD pattern comprises 2θ ± 0.2°: 5.9, 6.4, 13.6, 14.6, 15.1, 16.9, 17.6, 18.2, 19.6, 20.6, 21.0, 22.7, Diffraction peaks of 24.1, 25.0, 26.8, 28.4 and 31.9.
  57. 根据权利要求55所述的晶型VIII，其粉末X-射线衍射图谱如图20所示。The crystalline form VIII according to claim 55, which has a powder X-ray diffraction pattern as shown in FIG.
  58. 式(I)化合物苯磺酸盐的晶型。The crystalline form of the besylate salt of the compound of formula (I).
  59. 式(I)化合物苯磺酸盐的晶型I，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.4、5.9、7.1、10.4、14.8、17.6和21.9的衍射峰。Form I of the besylate salt of the compound of formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 5.4, 5.9, 7.1, 10.4, 14.8, 17.6 and 21.9.
  60. 根据权利要求59所述的晶型I，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.4、5.9、6.8、7.1、8.3、8.7、10.4、11.7、14.0、14.8、15.1、17.6、20.9、21.9、23.7、24.8和26.6的衍射峰。The crystal form I according to claim 59, wherein the XRPD pattern comprises 2θ±0.2°: 5.4, 5.9, 6.8, 7.1, 8.3, 8.7, 10.4, 11.7, 14.0, 14.8, 15.1, 17.6, Diffraction peaks of 20.9, 21.9, 23.7, 24.8, and 26.6.
  61. 根据权利要求59所述的晶型I，其粉末X-射线衍射图谱如图23所示。The crystalline form I according to claim 59, which has a powder X-ray diffraction pattern as shown in FIG.
  62. 式(I)化合物苯磺酸盐的晶型II，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：4.4、6.0、9.3、11.5、17.5、21.0和26.0的衍射峰。Form II of the besylate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 4.4, 6.0, 9.3, 11.5, 17.5, 21.0 and 26.0.
  63. 根据权利要求62所述的晶型II，其特征在于其XRPD图谱中包含有2θ±0.2°为：4.4、6.0、9.3、11.5、14.8、15.3、17.5、20.0、21.0、21.9、22.7、24.6和26.0的衍射峰。The crystal form II according to claim 62, wherein the XRPD pattern comprises 2θ±0.2°: 4.4, 6.0, 9.3, 11.5, 14.8, 15.3, 17.5, 20.0, 21.0, 21.9, 22.7, 24.6 and A diffraction peak of 26.0.
  64. 根据权利要求62所述的晶型II，其粉末X-射线衍射图谱如图24所示。The crystalline form II according to claim 62, which has a powder X-ray diffraction pattern as shown in FIG.
  65. 式(I)化合物苯磺酸盐的晶型III，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.7、8.3、8.6、17.2、23.2和26.0的衍射峰。The crystalline form III of the besylate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 7.7, 8.3, 8.6, 17.2, 23.2 and 26.0.
  66. 根据权利要求65所述的晶型III，其特征在于其XRPD图谱中包含有2θ±0.2°为：7.7、8.3、8.6、11.6、13.8、14.5、17.2、18.3、18.9、20.8、21.8、23.2和26.0的衍射峰。The crystal form III according to claim 65, wherein the XRPD pattern comprises 2θ ± 0.2°: 7.7, 8.3, 8.6, 11.6, 13.8, 14.5, 17.2, 18.3, 18.9, 20.8, 21.8, 23.2 and A diffraction peak of 26.0.
  67. 根据权利要求65所述的晶型III，其粉末X-射线衍射图谱如图25所示。The crystalline form III according to claim 65, which has a powder X-ray diffraction pattern as shown in FIG.
  68. 式(I)化合物苯磺酸盐的晶型IV，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.7、6.4、13.0、14.4和23.8的衍射峰。Form IV of the besylate salt of the compound of formula (I), characterized in that it has at least 2θ ± 0.2° in the XRPD pattern: diffraction peaks of 5.7, 6.4, 13.0, 14.4 and 23.8.
  69. 根据权利要求68所述的晶型IV，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.7、6.4、12.0、13.0、14.4、15.6、16.5、17.5、18.6、21.0、21.7、23.2、23.8、26.0、26.6和30.0的衍射峰。The crystalline form IV according to claim 68, wherein the XRPD pattern comprises 2θ±0.2°: 5.7, 6.4, 12.0, 13.0, 14.4, 15.6, 16.5, 17.5, 18.6, 21.0, 21.7, 23.2, Diffraction peaks of 23.8, 26.0, 26.6 and 30.0.
  70. 根据权利要求68所述的晶型IV，其粉末X-射线衍射图谱如图26所示。The crystalline form IV according to claim 68, which has a powder X-ray diffraction pattern as shown in FIG.
  71. 式(I)化合物苯磺酸盐的晶型V，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.7、7.5、10.3、14.3和25.1的衍射峰。The crystalline form V of the besylate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 5.7, 7.5, 10.3, 14.3 and 25.1.
  72. 根据权利要求71所述的晶型V，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.7、7.5、10.3、11.0、11.3、11.7、13.8、14.3、16.3、16.6、17.8、18.3、19.0、20.1、23.4、25.1和27.5的衍射峰。The crystal form V according to claim 71, wherein the XRPD pattern comprises 2θ±0.2°: 5.7, 7.5, 10.3, 11.0, 11.3, 11.7, 13.8, 14.3, 16.3, 16.6, 17.8, 18.3, Diffraction peaks of 19.0, 20.1, 23.4, 25.1 and 27.5.
  73. 根据权利要求71所述的晶型V，其粉末X-射线衍射图谱如图27所示。The crystalline form V according to claim 71, which has a powder X-ray diffraction pattern as shown in FIG.
  74. 式(I)化合物苯磺酸盐的晶型VI，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.0、7.4、13.5、18.6、23.6和24.5的衍射峰。Form VI of the besylate salt of the compound of formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 6.0, 7.4, 13.5, 18.6, 23.6 and 24.5.
  75. 根据权利要求84所述的晶型VI，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.0、7.4、11.6、12.2、12.8、13.5、14.8、16.5、17.5、18.6、20.4、21.0、21.6、22.7、23.6、24.5、25.9、26.7和27.5的衍射峰。The crystal form VI according to claim 84, wherein the XRPD pattern comprises 2θ±0.2°: 6.0, 7.4, 11.6, 12.2, 12.8, 13.5, 14.8, 16.5, 17.5, 18.6, 20.4, 21.0, Diffraction peaks of 21.6, 22.7, 23.6, 24.5, 25.9, 26.7 and 27.5.
  76. 根据权利要求74所述的晶型VI，其粉末X-射线衍射图谱如图28所示。The crystalline form VI according to claim 74, which has a powder X-ray diffraction pattern as shown in FIG.
  77. 式(I)化合物苯磺酸盐的晶型VII，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.9、7.1、9.7、15.0、16.4和23.7的衍射峰。Form VII of the besylate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 5.9, 7.1, 9.7, 15.0, 16.4 and 23.7.
  78. 根据权利要求77所述的晶型VII，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.9、7.1、9.7、11.9、12.9、13.4、15.0、16.4、18.3、18.8、20.5、21.2、21.9、22.8和23.7的衍射峰。The crystalline form VII according to claim 77, wherein the XRPD pattern comprises 2θ ± 0.2°: 5.9, 7.1, 9.7, 11.9, 12.9, 13.4, 15.0, 16.4, 18.3, 18.8, 20.5, 2.12. Diffraction peaks of 21.9, 22.8 and 23.7.
  79. 根据权利要求77所述的晶型VII，其粉末X-射线衍射图谱如图29所示。The Form VII according to claim 77, which has a powder X-ray diffraction pattern as shown in FIG.
  80. 式(I)化合物乙磺酸盐的晶型。A crystalline form of the ethanesulfonate salt of the compound of formula (I).
  81. 式(I)化合物乙磺酸盐的晶型I，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.5、8.3和17.9的衍射峰。Form I of the ethanesulfonate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 7.5, 8.3 and 17.9.
  82. 根据权利要求80所述的晶型I，其特征在于其XRPD图谱中包含有2θ±0.2°为：7.5、8.3、10.5、12.9、17.9、23.5和25.0的衍射峰。The crystalline form I according to claim 80, characterized in that the XRPD pattern comprises diffraction peaks of 2θ ± 0.2°: 7.5, 8.3, 10.5, 12.9, 17.9, 23.5 and 25.0.
  83. 根据权利要求80所述的晶型I，其粉末X-射线衍射图谱如图30所示。The crystalline form I according to claim 80, which has a powder X-ray diffraction pattern as shown in FIG.
  84. 式(I)化合物乙磺酸盐的晶型II，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.0、6.6、12.1和24.1的衍射峰。Form II of the ethanesulfonate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 6.0, 6.6, 12.1 and 24.1.
  85. 根据权利要求84所述的晶型II，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.8、6.0、6.6、8.5、12.1、13.3、14.7、15.4、16.3、16.8、17.3、19.1、22.1、23.3和24.1的衍射峰。The crystal form II according to claim 84, wherein the XRPD pattern comprises 2θ±0.2°: 5.8, 6.0, 6.6, 8.5, 12.1, 13.3, 14.7, 15.4, 16.3, 16.8, 17.3, 19.1. Diffraction peaks of 22.1, 23.3 and 24.1.
  86. 根据权利要求84所述的晶型II，其粉末X-射线衍射图谱如图31所示。The crystalline form II according to claim 84, which has a powder X-ray diffraction pattern as shown in FIG.
  87. 式(I)化合物乙磺酸盐的晶型III，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：6.0、7.6、12.2、13.6和18.3的衍射峰。Form III of the ethanesulfonate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 6.0, 7.6, 12.2, 13.6 and 18.3.
  88. 根据权利要求87所述的晶型III，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.0、7.6、9.4、12.2、13.6、14.4、15.2、16.0、17.2、18.4、19.3和20.4的衍射峰。The crystalline form III according to claim 87, wherein the XRPD pattern comprises 2θ ± 0.2° of: 6.0, 7.6, 9.4, 12.2, 13.6, 14.4, 15.2, 15.6, 17.2, 18.4, 19.3, and 20.4. Diffraction peaks.
  89. 根据权利要求87所述的晶型III，其粉末X-射线衍射图谱如图32所示。The crystalline form III according to claim 87, which has a powder X-ray diffraction pattern as shown in FIG.
  90. 式(I)化合物草酸盐的晶型。The crystalline form of the compound oxalate of formula (I).
  91. 式(I)化合物草酸盐的晶型I，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：4.1、6.9、7.9、14.5、19.4、23.8和27.0的衍射峰。Form I of the compound of formula (I) oxalate characterized by having at least 2θ ± 0.2° in the XRPD pattern: diffraction peaks of 4.1, 6.9, 7.9, 14.5, 19.4, 23.8 and 27.0.
  92. 根据权利要求91所述的晶型I，其特征在于其XRPD图谱中包含有2θ±0.2°为：4.1、6.9、7.9、11.7、12.2、13.0、13.9、14.5、15.0、16.4、17.6、19.4、20.3、21.0、23.8、25.5、26.0和27.0的衍射峰。The crystal form I according to claim 91, wherein the XRPD pattern comprises 2θ±0.2°: 4.1, 6.9, 7.9, 11.7, 12.2, 13.0, 13.9, 14.5, 15.0, 16.4, 17.6, 19.4, Diffraction peaks of 20.3, 21.0, 23.8, 25.5, 26.0 and 27.0.
  93. 根据权利要求91所述的晶型I，其粉末X-射线衍射图谱如图33所示。The crystalline form I according to claim 91, which has a powder X-ray diffraction pattern as shown in FIG.
  94. 式(I)化合物草酸盐的晶型II，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：4.0、6.8、7.7、8.1、16.7和23.7的衍射峰。Form II of the compound oxalate of formula (I) characterized in that it has at least 2θ ± 0.2° in the XRPD pattern: diffraction peaks of 4.0, 6.8, 7.7, 8.1, 16.7 and 23.7.
  95. 根据权利要求94所述的晶型II，其特征在于其XRPD图谱中包含有2θ±0.2°为：4.0、6.8、7.7、8.1、14.6、16.7、17.4、17.9、20.9、21.4、22.1、22.7、23.7和27.7的衍射峰。The crystal form II according to claim 94, wherein the XRPD pattern comprises 2θ±0.2°: 4.0, 6.8, 7.7, 8.1, 14.6, 16.7, 17.4, 17.9, 20.9, 21.4, 22.1, 22.7, Diffraction peaks of 23.7 and 27.7.
  96. 根据权利要求94所述的晶型II，其粉末X-射线衍射图谱如图36所示。The crystalline form II according to claim 94, which has a powder X-ray diffraction pattern as shown in FIG.
  97. 式(I)化合物马来酸盐的晶型。The crystalline form of the maleate salt of the compound of formula (I).
  98. 式(I)化合物马来酸盐的晶型I，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.6、8.1、10.8、13.8、23.0和26.3的衍射峰。Form I of the maleate salt of the compound of formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 5.6, 8.1, 10.8, 13.8, 23.0 and 26.3.
  99. 根据权利要求98所述的晶型I，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.6、6.4、8.1、10.8、11.6、12.4、12.9、13.3、13.8、14.7、15.5、16.7、17.4、17.8、18.0、18.6、20.1、21.1、22.6、23.0、23.8、24.8、26.3和28.1的衍 射峰。The crystal form I according to claim 98, wherein the XRPD pattern comprises 2θ±0.2°: 5.6, 6.4, 8.1, 10.8, 11.6, 12.4, 12.9, 13.3, 13.8, 14.7, 15.5, 16.7, Diffraction peaks of 17.4, 17.8, 18.0, 18.6, 20.1, 21.1, 22.6, 23.0, 23.8, 24.8, 26.3 and 28.1.
  100. 根据权利要求98所述的晶型I，其粉末X-射线衍射图谱如图39所示。The crystalline form I according to claim 98, which has a powder X-ray diffraction pattern as shown in FIG.
  101. 式(I)化合物对甲苯磺酸盐的晶型。The crystalline form of the p-toluenesulfonate salt of the compound of formula (I).
  102. 式(I)化合物对甲苯磺酸盐的晶型I，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.6、13.5、15.0、20.6和23.5的衍射峰。Form I of the p-toluenesulfonate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° of diffraction peaks of 7.6, 13.5, 15.0, 20.6 and 23.5.
  103. 根据权利要求102所述的晶型I，其特征在于其XRPD图谱中包含有2θ±0.2°为：7.6、8.5、10.1、11.9、13.0、13.5、15.0、16.5、17.0、17.4、18.4、18.7、20.6、20.9、23.5、24.1、25.7和26.6的衍射峰。The crystal form I according to claim 102, wherein the XRPD pattern comprises 2θ±0.2°: 7.6, 8.5, 10.1, 11.9, 13.0, 13.5, 15.0, 16.5, 17.0, 17.4, 18.4, 18.7, Diffraction peaks of 20.6, 20.9, 23.5, 24.1, 25.7 and 26.6.
  104. 根据权利要求102所述的晶型I，其粉末X-射线衍射图谱如图41所示。The crystalline form I according to claim 102, which has a powder X-ray diffraction pattern as shown in FIG.
  105. 式(I)化合物对甲苯磺酸盐的晶型II，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.5、8.1、13.1、20.7和22.9的衍射峰。The crystalline form II of the p-toluenesulfonate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 7.5, 8.1, 13.1, 20.7 and 22.9.
  106. 根据权利要求101所述的晶型II，其特征在于其XRPD图谱中包含有2θ±0.2°为：7.5、8.1、13.1、13.5、16.5、16.9、17.7、19.9、20.7、21.1、22.9、24.9、25.5和28.7的衍射峰。The crystal form II according to claim 101, wherein the XRPD pattern comprises 2θ±0.2°: 7.5, 8.1, 13.1, 13.5, 16.5, 16.9, 17.7, 19.9, 20.7, 21.1, 22.9, 24.9, Diffraction peaks of 25.5 and 28.7.
  107. 根据权利要求105所述的晶型II，其粉末X-射线衍射图谱如图42所示。The crystalline form II according to claim 105, which has a powder X-ray diffraction pattern as shown in FIG.
  108. 式(I)化合物对甲苯磺酸盐的晶型III，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：8.3、12.8、14.7、16.6和24.3的衍射峰。The crystalline form III of the p-toluenesulfonate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 8.3, 12.8, 14.7, 16.6 and 24.3.
  109. 根据权利要求108所述的晶型III，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.4、6.9、8.3、8.8、9.1、10.5、10.8、11.4、12.1、12.8、14.7、15.5、16.6、17.2、17.8、18.5、18.8、19.3、19.9、20.4、21.1、22.4、23.4、23.9、24.3、25.4、25.8、26.8、27.5、28.4和29.6的衍射峰。The crystal form III according to claim 108, wherein the XRPD pattern comprises 2θ±0.2°: 5.4, 6.9, 8.3, 8.8, 9.1, 10.5, 10.8, 11.4, 12.1, 12.8, 14.7, 15.5, Diffraction peaks of 16.6, 17.2, 17.8, 18.5, 18.8, 19.3, 19.9, 20.4, 21.1, 22.4, 23.4, 23.9, 24.3, 25.4, 25.8, 26.8, 27.5, 28.4 and 29.6.
  110. 根据权利要求108所述的式(I)化合物对甲苯磺酸盐的晶型III，其粉末X-射线衍射图谱如图43所示。Form III of the p-toluenesulfonate salt of the compound of formula (I) according to claim 108, the powder X-ray diffraction pattern of which is shown in Figure 43.
  111. 式(I)化合物对甲苯磺酸盐的晶型IV，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.3、14.4、21.2、23.5和25.3的衍射峰。Form IV of the p-toluenesulfonate salt of the compound of formula (I) is characterized in that it has at least 2θ ± 0.2° in the XRPD pattern: diffraction peaks of 7.3, 14.4, 21.2, 23.5 and 25.3.
  112. 根据权利要求111所述的晶型IV，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.7、7.3、10.1、10.6、11.7、14.4、16.1、16.6、17.2、18.5、18.9、19.9、20.6、21.2、22.3、22.9、23.5、24.4、25.3、25.8、26.9、27.4、28.1、29.2、30.1、31.0、31.6、32.5、33.1、33.6、34.5、35.5、367、38.9和42.7的衍射峰。The crystalline form IV according to claim 111, wherein the XRPD pattern comprises 2θ±0.2°: 5.7, 7.3, 10.1, 10.6, 11.7, 14.4, 16.1, 16.6, 17.2, 18.5, 18.9, 19.9, Diffraction peaks of 20.6, 21.2, 22.3, 22.9, 23.5, 24.4, 25.3, 25.8, 26.9, 27.4, 28.1, 29.2, 30.1, 31.0, 31.6, 32.5, 33.1, 33.6, 34.5, 35.5, 367, 38.9 and 42.7.
  113. 根据权利要求111所述的晶型IV，其粉末X-射线衍射图谱如图44所示。The crystalline form IV according to claim 111, which has a powder X-ray diffraction pattern as shown in FIG.
  114. 式(I)化合物对甲苯磺酸盐的晶型V，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：8.1、10.2、11.0、19.4和24.1的衍射峰。Form V of the p-toluenesulfonate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 8.1, 10.2, 11.0, 19.4 and 24.1.
  115. 根据权利要求114所述的晶型V，其特征在于其XRPD图谱中包含有2θ±0.2°为：8.1、8.5、9.0、10.2、11.0、13.8、14.8、16.6、17.0、17.5、18.3、19.4、20.6、22.1、23.0、24.1、25.8、28.1、30.1和30.7的衍射峰。The crystal form V according to claim 114, wherein the XRPD pattern comprises 2θ±0.2°: 8.1, 8.5, 9.0, 10.2, 11.0, 13.8, 14.8, 16.6, 17.0, 17.5, 18.3, 19.4, Diffraction peaks of 20.6, 22.1, 23.0, 24.1, 25.8, 28.1, 30.1 and 30.7.
  116. 根据权利要求114所述的晶型V，其粉末X-射线衍射图谱如图45所示。The crystalline form V according to claim 114, which has a powder X-ray diffraction pattern as shown in FIG.
  117. 式(I)化合物对甲苯磺酸盐的晶型VI，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.2、12.5、16.5和21.0的衍射峰。Form VI of the p-toluenesulfonate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 7.2, 12.5, 16.5 and 21.0.
  118. 根据权利要求117所述的晶型VI，其特征在于其XRPD图谱中包含有2θ±0.2°为：6.8、7.2、7.7、10.0、10.4、11.6、12.5、14.3、16.5、17.1、17.5、18.2、19.2、19.7、21.0、21.7、23.5、23.7、24.4、25.3、26.8和29.4的衍射峰。The crystal form VI according to claim 117, wherein the XRPD pattern comprises 2θ±0.2°: 6.8, 7.2, 7.7, 10.0, 10.4, 11.6, 12.5, 14.3, 16.5, 17.1, 17.5, 18.2, Diffraction peaks of 19.2, 19.7, 21.0, 21.7, 23.5, 23.7, 24.4, 25.3, 26.8 and 29.4.
  119. 根据权利要求117所述的晶型VI，其粉末X-射线衍射图谱如图46所示。The crystalline form VI according to claim 117, which has a powder X-ray diffraction pattern as shown in FIG.
  120. 式(I)化合物对甲苯磺酸盐的晶型VII，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：5.7、6.9、9.9和17.6的衍射峰。Form VII of the p-toluenesulfonate salt of the compound of the formula (I), characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 5.7, 6.9, 9.9 and 17.6.
  121. 根据权利要求120所述的晶型VII，其特征在于其XRPD图谱中包含有2θ±0.2°为：5.7、6.9、7.4、8.7、9.9、11.5、12.5、14.6、15.7、17.6、23.6、24.7和26.5的衍射峰。The Form VII according to Claim 120, wherein the XRPD pattern comprises 2θ ± 0.2°: 5.7, 6.9, 7.4, 8.7, 9.9, 11.5, 12.5, 14.6, 15.7, 17.6, 23.6, 24.7 and A diffraction peak of 26.5.
  122. 根据权利要求120所述的晶型VII，其粉末X-射线衍射图谱如图47所示。The Form VII according to Claim 120, which has a powder X-ray diffraction pattern as shown in FIG.
  123. 式(I)化合物对甲苯磺酸盐的晶型VIII，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：4.2、5.9、7.2、9.0和25.3的衍射峰。The crystalline form VIII of the p-toluenesulfonate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2° as diffraction peaks of 4.2, 5.9, 7.2, 9.0 and 25.3.
  124. 根据权利要求123所述的晶型VIII，其特征在于其XRPD图谱中包含有2θ±0.2°为：4.2、5.9、7.2、9.0、10.3、11.0、14.3、15.2、16.6、18.9、19.7、19.9、21.0、22.1、23.6、25.3、26.2、29.5和31.1的衍射峰。The crystalline form VIII according to claim 123, wherein the XRPD pattern comprises 2θ±0.2°: 4.2, 5.9, 7.2, 9.0, 10.3, 11.0, 14.3, 15.2, 16.6, 18.9, 19.7, 19.9, Diffraction peaks of 21.0, 22.1, 23.6, 25.3, 26.2, 29.5 and 31.1.
  125. 根据权利要求123所述的晶型VIII，其粉末X-射线衍射图谱如图48所示。The crystalline form VIII according to claim 123, which has a powder X-ray diffraction pattern as shown in FIG.
  126. 式(I)化合物对甲苯磺酸盐的晶型IX，其特征在于其XRPD图谱中至少包含有2θ±0.2°为：7.0、7.7、9.4、12.9和15.4的衍射峰。The crystalline form IX of the p-toluenesulfonate salt of the compound of the formula (I) is characterized in that the XRPD pattern contains at least 2θ ± 0.2°: diffraction peaks of 7.0, 7.7, 9.4, 12.9 and 15.4.
  127. 根据权利要求126所述的晶型IX，其特征在于其XRPD图谱中包含有2θ±0.2°为：7.0、7.7、9.4、10.8、12.2、12.9、13.7、15.4、18.0、20.5、21.9、23.2、26.7和28.0的衍射峰。The crystal form IX according to claim 126, wherein the XRPD pattern comprises 2θ±0.2°: 7.0, 7.7, 9.4, 10.8, 12.2, 12.9, 13.7, 15.4, 18.0, 20.5, 21.9, 23.2, Diffraction peaks of 26.7 and 28.0.
  128. 根据权利要求126所述的晶型IX，其粉末X-射线衍射图谱如图49所示。The crystalline form IX according to claim 126, which has a powder X-ray diffraction pattern as shown in FIG.
  129. 一种药物组合物，其包括治疗有效剂量的权利要求1所述的可药用盐、或权利要求2-128任一所述的式(I)化合物的晶型及可药用的载体。A pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of claim 1, or a crystalline form of a compound of formula (I) according to any of claims 2-128, and a pharmaceutically acceptable carrier.
  130. 权利要求1所述的可药用盐、或2-128任一所述的式(I)化合物晶型，或权利要求129所述的药物组合物在制备FGFR4抑制剂药物中的应用。Use of a pharmaceutically acceptable salt according to claim 1, or a crystalline form of a compound of formula (I) according to any one of 2-128, or a pharmaceutical composition according to claim 129, for the manufacture of a medicament for FGFR4 inhibitor.
  131. 权利要求1所述的可药用盐、或2-128任一所述的式(I)化合物晶型，或权利要求129所述的药物组合物在制备治疗癌症的药物中的应用。Use of a pharmaceutically acceptable salt according to claim 1, or a crystalline form of a compound of formula (I) according to any one of 2-128, or a pharmaceutical composition according to claim 129, for the manufacture of a medicament for the treatment of cancer.
  132. 根据权利要求131所述的应用，其中所述癌症是肝癌、胃癌、前列腺癌、皮肤癌、卵巢癌、肺癌、乳腺癌、结肠癌、胶质瘤或横纹肌肉瘤。The use according to claim 131, wherein the cancer is liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer, glioma or rhabdomyosarcoma.
PCT/CN2018/112891 2017-10-31 2018-10-31 Salt and crystal of fgfr4 inhibitor, preparation method and use thereof WO2019085927A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015059668A1 (en) * 2013-10-25 2015-04-30 Novartis Ag Ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors
WO2016151500A1 (en) * 2015-03-25 2016-09-29 Novartis Ag Particles of n-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2- oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2h)-carboxamide
WO2016151501A1 (en) * 2015-03-25 2016-09-29 Novartis Ag Pharmaceutical combinations
WO2017198149A1 (en) * 2016-05-20 2017-11-23 江苏豪森药业集团有限公司 Fgfr4 inhibitor, preparation method therefor, and applications thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015059668A1 (en) * 2013-10-25 2015-04-30 Novartis Ag Ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors
WO2016151500A1 (en) * 2015-03-25 2016-09-29 Novartis Ag Particles of n-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2- oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2h)-carboxamide
WO2016151501A1 (en) * 2015-03-25 2016-09-29 Novartis Ag Pharmaceutical combinations
WO2017198149A1 (en) * 2016-05-20 2017-11-23 江苏豪森药业集团有限公司 Fgfr4 inhibitor, preparation method therefor, and applications thereof

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