WO2024114793A1 - Salt form and crystal form of ubiquitination-specific protease inhibitor, and preparation method therefor and use thereof - Google Patents

Salt form and crystal form of ubiquitination-specific protease inhibitor, and preparation method therefor and use thereof Download PDF

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Publication number
WO2024114793A1
WO2024114793A1 PCT/CN2023/135850 CN2023135850W WO2024114793A1 WO 2024114793 A1 WO2024114793 A1 WO 2024114793A1 CN 2023135850 W CN2023135850 W CN 2023135850W WO 2024114793 A1 WO2024114793 A1 WO 2024114793A1
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salt form
ray powder
acid
powder diffraction
compound
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PCT/CN2023/135850
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French (fr)
Chinese (zh)
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沈翔
席晓梅
朱建荣
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杭州普济远成生物医药科技有限公司
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Priority to CN202380012864.2A priority Critical patent/CN117916246A/en
Publication of WO2024114793A1 publication Critical patent/WO2024114793A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicine, and in particular to a class of ubiquitination-specific protease inhibitors, salt forms, crystal forms, preparation methods thereof, and applications thereof in anti-tumor drugs.
  • the invention discloses the inhibitory activity of the compound of formula I against USP28 and USP25.
  • the inventors In order to meet the needs of clinical research and marketed drug preparations, the inventors also studied a solid form of the drug that can be easily separated and purified, is suitable for industrial production, and has stable physical and chemical properties.
  • the present invention provides the use of the compound represented by the following formula I and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug in the preparation of a drug for treating cancer:
  • the cancer is selected from leukemia (such as acute myeloid leukemia), liver cancer, colon cancer, ovarian cancer, esophageal cancer, colorectal cancer, pancreatic cancer, lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, lung cancer, breast cancer, gastric cancer, bile duct cancer, kidney cancer, bladder cancer, cervical cancer, prostate cancer, sarcoma;
  • X is CR 5 or N
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 1 or 2;
  • Z is NR 10 , O, S, CR 11 R 12 ; It means it can be a single bond or a double bond;
  • q 1, 2, or 3;
  • R 1 , R 2 , and R 5 may be the same or different, and are independently selected from hydrogen, halogen, amino, and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
  • R 3 is an unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon group
  • R 4 and R 6 may be the same or different and are independently selected from hydrogen, halogen, hydroxyl, amino and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
  • R 7 and R 8 may be the same or different, and are independently selected from hydrogen, halogen, hydroxyl, amino, and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
  • R 9 is selected from hydrogen, halogen, hydroxy, amino and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
  • R 9 is selected from 3-20 membered heterocyclyl or 5-20 membered heteroaryl which is unsubstituted or optionally substituted by one, two or more R 13 ;
  • the "unsubstituted (C 1 -C 12 ) aliphatic hydrocarbon group” is a straight or branched, saturated or unsaturated chain or cyclic hydrocarbon group consisting of 1 to 12 carbon atoms and corresponding hydrogen atoms, and the type of the aliphatic hydrocarbon group can be selected from groups such as alkyl, alkenyl or alkynyl;
  • the "substituted (C 1 -C 12 ) aliphatic hydrocarbon group” is a (C 1 -C 12 ) aliphatic hydrocarbon group containing one, two or more halogen and/or oxygen, sulfur, nitrogen, phosphorus atoms, wherein the halogen, oxygen, sulfur, nitrogen, phosphorus can be on the straight chain or branched chain of the (C 1 -C 12 ) aliphatic hydrocarbon group, and can also be at any position of the straight chain or branched chain;
  • the "(C 1 -C 12 ) aliphatic hydrocarbon group is
  • X is CH or N
  • Z is NH, O, S or CH 2 ;
  • R 1 may be selected from H or a (C 1 -C 6 ) aliphatic hydrocarbon group
  • R 2 may be selected from H or a (C 1 -C 6 ) aliphatic hydrocarbon group, such as H, methyl or ethyl;
  • R 3 may be selected from unsubstituted or substituted (C 1 -C 6 ) aliphatic hydrocarbon groups
  • R3 can be selected from methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl.
  • R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 13 : 3-20 membered heterocyclyl, 5-20 membered heteroaryl.
  • R 9 is selected from a 3-20 membered heterocyclic group or a 5-20 membered heteroaryl group which is unsubstituted or optionally substituted by one, two or more R 13 and contains one, two or more N atoms, and further, is preferably a 3-10 membered heterocyclic group containing only one or two N as heteroatoms.
  • R 9 may be selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 13 :
  • the R 13 may replace the corresponding hydrogen atom on the C atom or N atom of the above group; or two R 13 may replace two hydrogen atoms on the same C atom.
  • the compound of formula I has a structure shown in formula II:
  • R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q are as defined in the above formula I.
  • the compound of formula I is selected from the structures shown below:
  • the pharmaceutically acceptable salt of the compound shown in I is selected from the specific salts described below.
  • it is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
  • the compound is selected from Compound I-85 or Compound I-87 or a pharmaceutically acceptable salt thereof.
  • the compound is selected from a pharmaceutically acceptable salt of compound I-85, such as a methanesulfonate or a fumarate.
  • the compound is selected from the polymorphic forms of compound 1-85 described below.
  • the cancer includes leukemia (such as acute myeloid leukemia), lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, esophageal cancer, lung cancer, breast cancer, liver cancer, gastric cancer, cholangiocarcinoma, pancreatic cancer, colorectal cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, and sarcoma.
  • leukemia such as acute myeloid leukemia
  • lymphoma such as lymphoma
  • glioma such as neuroblastoma
  • nasopharyngeal carcinoma esophageal cancer
  • lung cancer breast cancer
  • liver cancer gastric cancer
  • cholangiocarcinoma pancreatic cancer
  • colorectal cancer renal cancer
  • bladder cancer ovarian cancer
  • cervical cancer cervical cancer
  • prostate cancer prostate cancer
  • sarcoma sarcoma
  • the present invention also provides a polymorph of a compound represented by Formula I or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , X, Z, m, n and q are as defined in Formula I above.
  • the formula I has a structure shown in formula II:
  • R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q are as defined in the above formula I.
  • the compound of formula I is selected from the structures shown below:
  • the present invention also provides a pharmaceutically acceptable salt of the compound represented by Formula I:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , X, Z, m, n, q are as defined in the aforementioned formula I;
  • the pharmaceutically acceptable salt is a salt formed by a compound of formula I and an acid
  • the acid can be selected from an inorganic acid or an organic acid, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectin esters
  • the acid can be selected from hydrochloric acid,
  • the acid can be selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid.
  • the pharmaceutically acceptable salt of the compound shown in I is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
  • the formula I has a structure shown in formula II:
  • R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q are as defined in the above formula I.
  • the compound of formula I is selected from pharmaceutically acceptable salts of the compounds shown below:
  • the pharmaceutically acceptable salt of the compound shown in I is selected from the pharmaceutically acceptable salts of Compound I-85, Compound I-86, Compound I-87, Compound I-88, Compound I-89, Compound I-90, and Compound I-91.
  • the pharmaceutically acceptable salts of these compounds are selected from their hydrochlorides, sulfates, hydrobromides, methanesulfonates, p-toluenesulfonates, phosphates, L-tartrates or fumarates.
  • the present invention also provides the following pharmaceutically acceptable salts of Compound I-87:
  • the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
  • the pharmaceutically acceptable salt of Compound I-87 is the hydrochloride or methanesulfonate of Compound I-87.
  • the present invention also provides the following pharmaceutically acceptable salts of Compound I-85:
  • the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
  • the pharmaceutically acceptable salt of Compound I-85 is the mesylate or fumarate of Compound I-85.
  • the present invention also provides the following polymorphic forms of Compound I-85 or a pharmaceutically acceptable salt thereof:
  • the polymorph is the mesylate salt form I (anhydrate) of compound I-85.
  • the polymorph is the mesylate salt form II (hydrate) of compound I-85.
  • the polymorph is the mesylate salt form III (methanol solvate) of compound I-85.
  • the polymorph is the fumarate salt form I (anhydrate) of compound I-85.
  • the present invention provides a hydrochloride salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 11.128 ⁇ 0.2°, 21.646 ⁇ 0.2°, 22.065 ⁇ 0.2° and 22.893 ⁇ 0.2°.
  • peaks at diffraction angles (2 ⁇ ) of 11.128 ⁇ 0.2°, 18.271 ⁇ 0.2°, 21.646 ⁇ 0.2°, 22.065 ⁇ 0.2°, 22.893 ⁇ 0.2°, and 26.357 ⁇ 0.2° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 11.128 ⁇ 0.2°, 13.020 ⁇ 0.2°, 17.587 ⁇ 0.2°, 18.271 ⁇ 0.2°, 21.646 ⁇ 0.2°, 22.065 ⁇ 0.2°, 22.893 ⁇ 0.2°, 26.357 ⁇ 0.2°, and 27.187 ⁇ 0.2° are also included.
  • the X-ray powder diffraction pattern of the monohydrochloride salt form I has a diffraction angle (2 ⁇ ) as shown in Table 1-1, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the hydrochloride salt form I has an X-ray powder diffraction intensity as shown in Table 1-1.
  • the hydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 1-1.
  • the hydrochloride salt form I has a DSC thermogram with an endothermic peak at a temperature of about 200°C.
  • the hydrochloride salt form I has a DSC graph substantially as shown in Figure 2.
  • the hydrochloride salt form I has a TGA graph substantially as shown in Figure 2.
  • the present invention provides a dihydrochloride salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 6.150 ⁇ 0.2°, 14.095 ⁇ 0.2° and 18.205 ⁇ 0.2°.
  • peaks at diffraction angles (2 ⁇ ) of 4.655 ⁇ 0.2°, 6.150 ⁇ 0.2°, 9.289 ⁇ 0.2°, 12.965 ⁇ 0.2°, 14.095 ⁇ 0.2°, and 18.205 ⁇ 0.2° are also included.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form I has a diffraction angle (2 ⁇ ) as shown in Table 1-2, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the dihydrochloride salt form I has an X-ray powder diffraction intensity as shown in Table 1-2.
  • the dihydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in Figures 1-2.
  • the dihydrochloride salt form I has a DSC thermogram with endothermic peaks at temperatures of about 70.45°C, 145.07°C and 229.64°C.
  • the dihydrochloride salt form I has a DSC graph substantially as shown in FIG3 .
  • the dihydrochloride salt form I has a TGA graph substantially as shown in FIG3 .
  • the present invention provides a sulfate crystalline form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 11.928 ⁇ 0.2°, 14.490 ⁇ 0.2° and 19.321 ⁇ 0.2°.
  • peaks at diffraction angles (2 ⁇ ) of 11.928 ⁇ 0.2°, 14.490 ⁇ 0.2°, 19.321 ⁇ 0.2°, 22.524 ⁇ 0.2°, 23.456 ⁇ 0.2°, and 28.369 ⁇ 0.2° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 9.640 ⁇ 0.2°, 11.928 ⁇ 0.2°, 14.016 ⁇ 0.2°, 14.490 ⁇ 0.2°, 16.433 ⁇ 0.2°, 19.321 ⁇ 0.2°, 22.524 ⁇ 0.2°, 23.456 ⁇ 0.2°, and 28.369 ⁇ 0.2° are also included.
  • the X-ray powder diffraction pattern of the sulfate salt crystalline form I has a diffraction angle (2 ⁇ ) as shown in Table 1-3, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the sulfate salt crystalline form I has an X-ray powder diffraction intensity as shown in Table 1-3.
  • the sulfate salt crystalline form I has a DSC thermogram with endothermic peaks at temperatures of about 87.71°C and 254.89°C.
  • the sulfate salt crystalline form I has a DSC graph substantially as shown in FIG5 .
  • the sulfate salt crystalline form I has a TGA graph substantially as shown in FIG5 .
  • the present invention provides a sulfate crystalline form II of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 11.928 ⁇ 0.2°, 14.490 ⁇ 0.2°, 19.321 ⁇ 0.2° and 22.524 ⁇ 0.2°.
  • peaks at diffraction angles (2 ⁇ ) of 11.928 ⁇ 0.2°, 14.490 ⁇ 0.2°, 16.433 ⁇ 0.2°, 19.321 ⁇ 0.2°, 20.661 ⁇ 0.2°, 22.524 ⁇ 0.2°, and 28.369 ⁇ 0.2° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 9.640 ⁇ 0.2°, 11.928 ⁇ 0.2°, 14.490 ⁇ 0.2°, 16.433 ⁇ 0.2°, 18.625 ⁇ 0.2°, 19.321 ⁇ 0.2°, 20.661 ⁇ 0.2°, 22.524 ⁇ 0.2°, and 28.369 ⁇ 0.2° are also included.
  • the X-ray powder diffraction pattern of the sulfate salt crystalline form II has a diffraction angle (2 ⁇ ) as shown in Table 1-4, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the sulfate salt crystal form II has an X-ray powder diffraction intensity as shown in Table 1-4.
  • the sulfate salt form II has an X-ray powder diffraction pattern substantially as shown in FIG. 4-2 .
  • the sulfate salt crystalline form II has a DSC thermogram with endothermic peaks at temperatures of about 73.33°C and 200.04°C.
  • the sulfate salt form II has a DSC graph substantially as shown in FIG6 .
  • the sulfate salt crystalline form II has a TGA graph substantially as shown in FIG6 .
  • the present invention provides a hydrogen sulfate salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 9.552 ⁇ 0.20°, 14.606 ⁇ 0.20°, 19.544 ⁇ 0.20° and 24.494 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 4.814 ⁇ 0.20°, 9.552 ⁇ 0.20°, 14.606 ⁇ 0.20°, 17.261 ⁇ 0.20°, 19.544 ⁇ 0.20°, and 24.494 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 4.814 ⁇ 0.20°, 9.552 ⁇ 0.20°, 14.398 ⁇ 0.20°, 14.606 ⁇ 0.20°, 17.261 ⁇ 0.20°, 19.544 ⁇ 0.20°, 23.510 ⁇ 0.20°, 24.494 ⁇ 0.20°, and 25.821 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the hydrogen sulfate salt crystalline form I has a diffraction angle (2 ⁇ ) as shown in Tables 1-5, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the bisulfate salt crystalline form I has an X-ray powder diffraction intensity as shown in Table 1-5.
  • the bisulfate salt crystalline form I has an X-ray powder diffraction pattern substantially as shown in Figure 4-3.
  • the hydrogen sulfate salt crystalline form I has a DSC thermogram with an endothermic peak at a temperature of about 227.60°C.
  • the bisulfate salt crystalline form I has a DSC graph substantially as shown in FIG. 7 .
  • the bisulfate salt crystalline form I has a TGA graph substantially as shown in FIG. 7 .
  • the present invention provides a hydrogen sulfate salt form II of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 14.293 ⁇ 0.20°, 17.220 ⁇ 0.20° and 20.621 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 5.534 ⁇ 0.20°, 14.293 ⁇ 0.20°, 16.603 ⁇ 0.20°, 17.220 ⁇ 0.20°, and 20.621 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 5.534 ⁇ 0.20°, 6.296 ⁇ 0.20°, 14.293 ⁇ 0.20°, 16.603 ⁇ 0.20°, 17.220 ⁇ 0.20°, 20.621 ⁇ 0.20°, 22.826 ⁇ 0.20°, and 26.609 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the hydrogen sulfate salt form II has a diffraction angle (2 ⁇ ) as shown in Table 1-6, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the bisulfate salt form II has an X-ray powder diffraction intensity as shown in Table 1-6.
  • the bisulfate salt form II has an X-ray powder diffraction pattern substantially as shown in Figure 4-4.
  • the hydrogen sulfate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 57.18°C and 201.52°C.
  • the bisulfate salt form II has a DSC graph substantially as shown in FIG8 .
  • the bisulfate salt form II has a TGA graph substantially as shown in FIG8 .
  • the present invention provides a hydrobromide salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 15.315 ⁇ 0.20°, 22.092 ⁇ 0.20° and 23.365 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 15.315 ⁇ 0.20°, 19.991 ⁇ 0.20°, 22.092 ⁇ 0.20°, 23.365 ⁇ 0.20°, and 26.373 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 6.059 ⁇ 0.20°, 15.315 ⁇ 0.20°, 19.991 ⁇ 0.20°, 21.673 ⁇ 0.20°, 22.092 ⁇ 0.20°, 23.365 ⁇ 0.20°, 26.373 ⁇ 0.20°, and 28.682 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the monohydrobromide salt form I has a diffraction angle (2 ⁇ ) as shown in Tables 1-7, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the hydrobromide salt form I has an X-ray powder diffraction intensity as shown in Table 1-7.
  • the hydrobromide salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 9-1.
  • the monohydrobromide salt form I has a DSC thermogram with endothermic peaks at temperatures of about 56.68°C, 157.98°C and 250.38°C.
  • the hydrobromide salt form I has a DSC graph substantially as shown in FIG10 .
  • the monohydrobromide salt form I has a TGA graph substantially as shown in Figure 10.
  • the present invention provides a dihydrobromide salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 6.086 ⁇ 0.20°, 14.055 ⁇ 0.20° and 23.929 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 6.086 ⁇ 0.20°, 14.055 ⁇ 0.20°, 17.943 ⁇ 0.20°, 20.805 ⁇ 0.20°, 23.929 ⁇ 0.20°, and 28.342 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 4.681 ⁇ 0.20°, 6.086 ⁇ 0.20°, 14.055 ⁇ 0.20°, 15.539 ⁇ 0.20°, 17.943 ⁇ 0.20°, 20.805 ⁇ 0.20°, 23.929 ⁇ 0.20°, 24.913 ⁇ 0.20°, and 28.342 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the dihydrobromide salt form I has a diffraction angle (2 ⁇ ) as shown in Tables 1-8, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the dihydrobromide salt form I has an X-ray powder diffraction intensity as shown in Table 1-8.
  • the dihydrobromide salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 9-2.
  • the dihydrobromide salt form I has a DSC thermogram with endothermic peaks at temperatures of about 80.50°C and 241.96°C.
  • the dihydrobromide salt form I has a DSC graph substantially as shown in Figure 11.
  • the dihydrobromide salt form I has a TGA graph substantially as shown in Figure 11.
  • the present invention also provides a mesylate crystalline form I of compound I-85, characterized in that the X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 11.995 ⁇ 0.2°, 14.607 ⁇ 0.2°, 19.374 ⁇ 0.2°, 21.027 ⁇ 0.2° and 23.536 ⁇ 0.2°.
  • the mesylate salt form I is characterized in that the X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2 ⁇ ) of 11.995 ⁇ 0.2°, 14.607 ⁇ 0.2°, 16.538 ⁇ 0.2°, 19.374 ⁇ 0.2°, 20.739 ⁇ 0.2°, 21.027 ⁇ 0.2°, 22.577 ⁇ 0.2° and 23.536 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the mesylate salt form I is characterized in that the X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2 ⁇ ) of 11.995 ⁇ 0.2°, 14.095 ⁇ 0.2°, 14.607 ⁇ 0.2°, 15.803 ⁇ 0.2°, 16.538 ⁇ 0.2°, 19.374 ⁇ 0.2°, 20.739 ⁇ 0.2°, 21.027 ⁇ 0.2°, 22.577 ⁇ 0.2° and 23.536 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the mesylate salt form I has a diffraction angle (2 ⁇ ) as shown in Tables 1-9, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the mesylate salt form I has an X-ray powder diffraction intensity as shown in Table 1-9.
  • the mesylate salt Form I has an X-ray powder diffraction pattern substantially as shown in Figure 12.
  • the mesylate salt form I has a DSC thermogram with an endothermic peak at a temperature of about 279.98°C.
  • the mesylate salt Form I has a DSC graph substantially as shown in FIG. 13 .
  • the mesylate salt Form I has a TGA graph substantially as shown in Figure 13.
  • the present invention provides a p-toluenesulfonate crystalline form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 4.970 ⁇ 0.20°, 8.869 ⁇ 0.20° and 18.586 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 4.970 ⁇ 0.20°, 8.869 ⁇ 0.20°, 10.459 ⁇ 0.20°, 14.516 ⁇ 0.20°, and 18.586 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 4.970 ⁇ 0.20°, 8.869 ⁇ 0.20°, 10.459 ⁇ 0.20°, 12.610 ⁇ 0.20°, 14.516 ⁇ 0.20°, 18.586 ⁇ 0.20°, 20.121 ⁇ 0.20°, and 23.391 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I has a diffraction angle (2 ⁇ ) as shown in Tables 1-10, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the p-toluenesulfonate salt form I has an X-ray powder diffraction intensity as shown in Table 1-10.
  • the p-toluenesulfonate salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 14-1.
  • the p-toluenesulfonate salt form I has a DSC thermogram with endothermic peaks at temperatures of about 81.13°C and 153.27°C.
  • the p-toluenesulfonate salt Form I has a DSC graph substantially as shown in Figure 15.
  • the p-toluenesulfonate salt Form I has a TGA graph substantially as shown in Figure 15.
  • the present invention provides a p-toluenesulfonate crystalline form II of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 9.473 ⁇ 0.20°, 15.881 ⁇ 0.20°, 16.721 ⁇ 0.20° and 20.687 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 9.473 ⁇ 0.20°, 15.881 ⁇ 0.20°, 16.721 ⁇ 0.20°, 18.954 ⁇ 0.20°, 20.687 ⁇ 0.20°, and 21.553 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 8.738 ⁇ 0.20°, 9.473 ⁇ 0.20°, 13.727 ⁇ 0.20°, 15.881 ⁇ 0.20°, 16.721 ⁇ 0.20°, 18.954 ⁇ 0.20°, 20.687 ⁇ 0.20°, 21.553 ⁇ 0.20°, and 25.597 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt form II has a diffraction angle (2 ⁇ ) as shown in Table 1-11, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the p-toluenesulfonate salt form II has an X-ray powder diffraction intensity as shown in Table 1-11.
  • the p-toluenesulfonate salt form II has an X-ray powder diffraction pattern substantially as shown in Figure 14-2.
  • the p-toluenesulfonate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 69.82°C, 203.86°C and 225.31°C.
  • the p-toluenesulfonate salt Form II has a DSC graph substantially as shown in FIG. 16 .
  • the p-toluenesulfonate salt Form II has a TGA graph substantially as shown in Figure 16.
  • the present invention provides a p-toluenesulfonate crystalline form III of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 4.641 ⁇ 0.20°, 9.263 ⁇ 0.20° and 17.286 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 4.641 ⁇ 0.20°, 9.263 ⁇ 0.20°, 15.028 ⁇ 0.20°, 17.286 ⁇ 0.20°, and 23.011 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 4.641 ⁇ 0.20°, 6.927 ⁇ 0.20°, 9.263 ⁇ 0.20°, 15.028 ⁇ 0.20°, 17.286 ⁇ 0.20°, 19.388 ⁇ 0.20°, 20.227 ⁇ 0.20°, and 23.011 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt form III has a diffraction angle (2 ⁇ ) as shown in Table 1-12, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the p-toluenesulfonate salt form III has an X-ray powder diffraction intensity as shown in Table 1-12.
  • the p-toluenesulfonate salt form III has an X-ray powder diffraction pattern substantially as shown in Figure 14-3.
  • the p-toluenesulfonate salt form III has a DSC thermogram with endothermic peaks at temperatures of about 144.62°C, 202.96 and 219.07°C.
  • the p-toluenesulfonate salt Form III has a DSC graph substantially as shown in FIG. 17 .
  • the p-toluenesulfonate salt Form III has a TGA graph substantially as shown in Figure 17.
  • the present invention provides a phosphate crystal form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 12.598 ⁇ 0.20°, 18.205 ⁇ 0.20° and 22.722 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 10.223 ⁇ 0.20°, 12.598 ⁇ 0.20°, 18.205 ⁇ 0.20°, 19.058 ⁇ 0.20°, and 22.722 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 10.223 ⁇ 0.20°, 12.598 ⁇ 0.20°, 14.186 ⁇ 0.20°, 18.205 ⁇ 0.20°, 19.058 ⁇ 0.20°, 21.593 ⁇ 0.20°, 22.722 ⁇ 0.20°, and 22.957 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the phosphate crystal form I has a diffraction angle (2 ⁇ ) as shown in Table 1-13, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the phosphate crystal form I has an X-ray powder diffraction intensity as shown in Table 1-13.
  • the phosphate crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 18-1.
  • the phosphate crystal form I has a DSC thermogram with endothermic peaks at temperatures of about 83.01°C, 146.52°C, 175.51 and 242.76°C.
  • the phosphate crystal form I has a DSC graph substantially as shown in Figure 19.
  • the phosphate crystal form I has a TGA graph substantially as shown in Figure 19.
  • the present invention provides a phosphate crystal form II of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 6.913 ⁇ 0.20°, 11.981 ⁇ 0.20° and 18.205 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 6.913 ⁇ 0.20°, 11.981 ⁇ 0.20°, 13.688 ⁇ 0.20°, 17.101 ⁇ 0.20°, and 18.205 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 6.913 ⁇ 0.20°, 9.473 ⁇ 0.20°, 11.981 ⁇ 0.20°, 13.688 ⁇ 0.20°, 15.829 ⁇ 0.20°, 17.101 ⁇ 0.20°, 18.205 ⁇ 0.20°, and 21.317 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the phosphate crystal form II has a diffraction angle (2 ⁇ ) as shown in Table 1-14, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the phosphate crystal form II has an X-ray powder diffraction intensity as shown in Table 1-14.
  • the phosphate crystal form II has an X-ray powder diffraction pattern substantially as shown in Figure 18-2.
  • the phosphate crystal form II has a DSC thermogram with endothermic peaks at temperatures of about 133.16°C and 254.39°C.
  • the phosphate crystal form II has a DSC graph substantially as shown in Figure 20.
  • the phosphate crystal form II has a TGA graph substantially as shown in Figure 20.
  • the present invention provides a tartrate salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 14.305 ⁇ 0.20°, 17.128 ⁇ 0.20° and 22.118 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 5.969 ⁇ 0.20°, 14.305 ⁇ 0.20°, 17.128 ⁇ 0.20°, 20.765 ⁇ 0.20°, and 22.118 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 5.969 ⁇ 0.20°, 7.582 ⁇ 0.20°, 14.305 ⁇ 0.20°, 15.513 ⁇ 0.20°, 17.128 ⁇ 0.20°, 19.885 ⁇ 0.20°, 20.765 ⁇ 0.20°, and 22.118 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the tartrate salt form I has a diffraction angle (2 ⁇ ) as shown in Tables 1-15, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the tartrate salt form I has an X-ray powder diffraction intensity as shown in Table 1-15.
  • the tartrate salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 21.
  • the tartrate salt form I has a DSC thermogram with endothermic peaks at temperatures of about 69.83°C and 199.00°C.
  • the tartrate salt form I has a DSC graph substantially as shown in Figure 22.
  • the tartrate salt form I has a TGA graph substantially as shown in Figure 22.
  • the present invention provides a fumarate crystalline form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2 ⁇ ) of 6.953 ⁇ 0.20°, 15.224 ⁇ 0.20° and 20.267 ⁇ 0.20°.
  • peaks at diffraction angles (2 ⁇ ) of 6.953 ⁇ 0.20°, 15.224 ⁇ 0.20°, 20.267 ⁇ 0.20°, 24.757 ⁇ 0.20°, and 27.067 ⁇ 0.20° are also included.
  • peaks at diffraction angles (2 ⁇ ) of 6.953 ⁇ 0.20°, 10.090 ⁇ 0.20°, 15.224 ⁇ 0.20°, 18.665 ⁇ 0.20°, 20.976 ⁇ 0.20°, 20.267 ⁇ 0.20°, 24.757 ⁇ 0.20°, and 27.067 ⁇ 0.20° are also included.
  • the X-ray powder diffraction pattern of the fumarate salt form I has a diffraction angle (2 ⁇ ) as shown in Table 1-16, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the fumarate salt form I has an X-ray powder diffraction intensity as shown in Table 1-16.
  • the fumarate salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 23.
  • the fumarate salt form I has a DSC thermogram with an endothermic peak at a temperature of about 176.61°C.
  • the fumarate salt form I has a DSC graph substantially as shown in Figure 24.
  • the fumarate salt form I has a TGA graph substantially as shown in Figure 24.
  • the present invention provides a mesylate salt form II of compound I-85, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2 ⁇ ) of 7.832 ⁇ 0.2°, 9.828 ⁇ 0.2°, 12.362 ⁇ 0.2°, 22.852 ⁇ 0.2° and 24.140 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the mesylate salt form II has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2 ⁇ ) of 7.832 ⁇ 0.2°, 9.828 ⁇ 0.2°, 12.362 ⁇ 0.2°, 15.329 ⁇ 0.2°, 16.486 ⁇ 0.2°, 22.852 ⁇ 0.2°, 24.140 ⁇ 0.2° and 26.897 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the mesylate salt form II has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2 ⁇ ) of 7.832 ⁇ 0.2°, 8.251 ⁇ 0.2°, 9.828 ⁇ 0.2°, 12.362 ⁇ 0.2°, 13.805 ⁇ 0.2°, 15.329 ⁇ 0.2°, 16.486 ⁇ 0.2°, 22.852 ⁇ 0.2°, 24.140 ⁇ 0.2° and 26.897 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the mesylate salt form II has a diffraction angle (2 ⁇ ) as shown in Table 1-17, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the mesylate salt form II has an X-ray powder diffraction intensity as shown in Table 1-17.
  • the mesylate salt Form II has an X-ray powder diffraction pattern substantially as shown in Figure 25.
  • the mesylate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 71.31°C, 111.93°C and 273.09°C.
  • the mesylate salt Form II has a DSC graph substantially as shown in Figure 26.
  • the mesylate salt Form II has a TGA graph substantially as shown in Figure 26.
  • the present invention provides a mesylate salt form III of compound I-85, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2 ⁇ ) of 6.939 ⁇ 0.2°, 9.079 ⁇ 0.2°, 17.234 ⁇ 0.2°, 20.030 ⁇ 0.2° and 22.984 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the mesylate salt form III has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2 ⁇ ) of 6.939 ⁇ 0.2°, 9.079 ⁇ 0.2°, 17.234 ⁇ 0.2°, 20.030 ⁇ 0.2°, 22.984 ⁇ 0.2°, 25.058 ⁇ 0.2°, 26.070 ⁇ 0.2° and 27.922 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the mesylate salt form III has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2 ⁇ ) of 6.939 ⁇ 0.2°, 9.079 ⁇ 0.2°, 17.234 ⁇ 0.2°, 20.030 ⁇ 0.2°, 22.315 ⁇ 0.2°, 22.984 ⁇ 0.2°, 23.614 ⁇ 0.2°, 25.058 ⁇ 0.2°, 26.070 ⁇ 0.2° and 27.922 ⁇ 0.2°.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern of the mesylate salt form III has a diffraction angle (2 ⁇ ) as shown in Table 1-18, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the mesylate salt form III has an X-ray powder diffraction intensity as shown in Table 1-18.
  • the mesylate salt Form III has an X-ray powder diffraction pattern substantially as shown in Figure 27.
  • the mesylate salt form III has a DSC thermogram with endothermic peaks at temperatures of about 81.24°C, 167.30°C, 178.52°C and 276.79°C.
  • the mesylate salt Form III has a DSC graph substantially as shown in Figure 28.
  • the mesylate salt Form III has a TGA graph substantially as shown in Figure 28.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound represented by Formula I or a polymorph thereof:
  • the pharmaceutically acceptable salt is as described above.
  • the present invention also provides a pharmaceutical composition comprising at least one of the pharmaceutically acceptable salts of Compound I-85 or Compound I-87 or the crystalline forms as an active ingredient.
  • the pharmaceutical composition further comprises a therapeutically effective amount of a pharmaceutically acceptable salt of the compound I-85 or I-87 or at least one of the crystalline forms and a pharmaceutically acceptable carrier.
  • the carrier in the pharmaceutical composition is "acceptable" in that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated.
  • One or more solubilizing agents may be used as pharmaceutical excipients for delivery of the active compound.
  • the present invention further provides the use of the pharmaceutically acceptable salt of the compound I-85 or at least one of the crystalline forms or the pharmaceutical composition in the preparation of drugs for treating and inhibiting cancer.
  • the present invention further provides the use of the pharmaceutically acceptable salt of the compound I-87 or at least one of the crystalline forms or the pharmaceutical composition in the preparation of drugs for treating and inhibiting cancer.
  • the present invention further provides the use of the pharmaceutically acceptable salt of the compound I-85 and/or compound I-87 or at least one of the crystal forms or the pharmaceutical composition in the preparation of drugs for treating and inhibiting cancer.
  • the cancer includes leukemia (such as acute myeloid leukemia), lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, esophageal cancer, lung cancer, breast cancer, liver cancer, gastric cancer, cholangiocarcinoma, pancreatic cancer, colorectal cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, and sarcoma.
  • leukemia such as acute myeloid leukemia
  • lymphoma such as lymphoma
  • glioma such as neuroblastoma
  • nasopharyngeal carcinoma esophageal cancer
  • lung cancer breast cancer
  • liver cancer gastric cancer
  • cholangiocarcinoma pancreatic cancer
  • colorectal cancer renal cancer
  • bladder cancer ovarian cancer
  • cervical cancer cervical cancer
  • prostate cancer prostate cancer
  • sarcoma sarcoma
  • the present invention also provides a method for treating or preventing cancer, comprising administering to a patient suffering from at least one of the diseases or disorders a pharmaceutically acceptable salt of Compound I-85 or Compound I-87 or at least one of the crystalline forms.
  • the cancer includes leukemia (such as acute myeloid leukemia), lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, esophageal cancer, lung cancer, breast cancer, liver cancer, gastric cancer, cholangiocarcinoma, pancreatic cancer, colorectal cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, and sarcoma.
  • leukemia such as acute myeloid leukemia
  • lymphoma such as lymphoma
  • glioma such as neuroblastoma
  • nasopharyngeal carcinoma esophageal cancer
  • lung cancer breast cancer
  • liver cancer gastric cancer
  • cholangiocarcinoma pancreatic cancer
  • colorectal cancer renal cancer
  • bladder cancer ovarian cancer
  • cervical cancer cervical cancer
  • prostate cancer prostate cancer
  • sarcoma sarcoma
  • the pharmaceutical composition can be in a form suitable for oral administration, such as tablets, lozenges, pastilles, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Oral compositions can be prepared according to any known method for preparing pharmaceutical compositions in the art, and such compositions can contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing.
  • excipients can be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets can be uncoated or can be coated with known techniques that provide sustained-release effects over a long period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract.
  • the active ingredient in the pharmaceutical composition, is mixed with an inert solid diluent or a soft gelatin capsule in which the active ingredient is mixed with a water-soluble carrier or an oily solvent to provide an oral preparation;
  • the aqueous suspension contains the active substance and an excipient suitable for preparing an aqueous suspension for mixing.
  • excipients are suspending agents, dispersants or wetting agents.
  • the aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweeteners;
  • the oil suspension may be prepared by suspending the active ingredient in a vegetable oil or a mineral oil.
  • the oil suspension may contain a thickener.
  • sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions may be preserved by adding antioxidants; dispersible powders and granules suitable for preparing water suspensions may be provided with active ingredients and dispersants or wetting agents, suspending agents or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents may illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added.
  • antioxidants such as ascorbic acid.
  • the pharmaceutical composition can also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil, or a mineral oil or a mixture thereof.
  • a suitable emulsifier can be a naturally occurring phospholipid, and the emulsion can also contain a sweetener, a flavoring agent, a preservative and an antioxidant.
  • Such preparations can also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable water-in-oil microemulsion in which the active ingredient is dissolved in the oil phase.
  • the injection or microemulsion may be injected into the patient's bloodstream by local mass injection.
  • a continuous intravenous drug delivery device may be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.
  • the pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension may be prepared according to known techniques using the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations may also be The aseptic injection solution or suspension can be prepared in a parenterally acceptable nontoxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • the compounds of the present invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will dissolve in the rectum to release the drug.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound of formula (I) or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.
  • the present invention provides a class of ubiquitination-specific protease inhibitors with higher activity, which have good anti-cancer effects.
  • the present invention also provides salt forms and crystal forms of compound I-85 and compound I-87 and preparation methods thereof, which have good stability, can meet the needs of clinical drug preparation development, and have very important clinical application value.
  • Figure 23 is the XRPD pattern of compound I-85 fumarate salt Form I.
  • FIG29 Comparison of the inhibitory effects of compound I-58 and compound I-85 mesylate salts on the growth of solid tumor cells.
  • FIG30 shows the concentration required for 50% (IC 50 ) inhibition of the growth of 59 tumor cell lines from different tissues by the mesylate salt of compound I-85.
  • FIG31 shows the concentration of compound I-1 required to inhibit the growth of tumor cell lines from different tissues by 50% (IC 50 ).
  • FIG32 Compound I-1 induces apoptosis of tumor cells.
  • FIG. 33 Compound I-1 induces tumor cell cycle arrest at G1 (MDAH2774), G2 (HCT116) or S (SMMC7721).
  • FIG34 Compound I-85 mesylate and compound I-1 reduce the expression levels of c-MYC, LSD1, and Tankyrase (TNKS) proteins in tumor cells.
  • FIG35 Compound I-85 mesylate (PBSS1113) inhibits the growth of human esophageal cancer in mice (* represents p value less than 0.05).
  • FIG36 Compound I-85 mesylate (PBSS1113) inhibits the growth of human liver cancer in mice (** represents p value less than 0.01).
  • FIG37 Compound I-85 mesylate (PBSS1113) inhibits the growth of human colorectal cancer in mice (**** represents p value less than 0.0001).
  • FIG38 Compound I-85 mesylate (PBSS1113) inhibits the growth of human pancreatic cancer in mice.
  • FIG39 Compound I-85 mesylate (PBSS1113) inhibits the growth of human lymphoma in mice (* represents p value less than 0.05, ** represents p value less than 0.01, **** represents p value less than 0.0001).
  • FIG40 Compound I-85 mesylate (PBSS1113) inhibits the growth of human neuroblastoma in mice.
  • FIG41 Compound I-85 mesylate (PBSS1113) and Compound I-87 inhibit the growth of mouse breast cancer in mice (** represents p value less than 0.01, *** represents p value less than 0.001, **** represents p value less than 0.0001).
  • FIG42 Compound I-87 inhibits the growth of human pancreatic cancer in mice (*** represents p value less than 0.001, **** represents p value less than 0.0001).
  • FIG43 Compound I-87 inhibits the growth of human colorectal cancer in mice (** represents p value less than 0.01, *** represents p value less than 0.001).
  • FIG44 Compound I-87 inhibits the growth of mouse breast cancer in mice (** represents p value less than 0.01).
  • FIG45 Compound I-87 inhibits the growth of mouse melanoma in mice (** represents p value less than 0.01).
  • FIG46 Compound I-87 inhibits the growth of mouse colorectal cancer in mice (** represents p value less than 0.01).
  • FIG48 shows the growth inhibitory effect of compound I-85 on 29 AML cell lines.
  • FIG49 Compound I-85 treatment can lead to apoptosis of AML cells.
  • FIG50 shows the effect of compound I-85 (PBSS1113) on AML mouse model, with doxorubicin as a positive control.
  • halogen refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I may be described as “halogen" in the present specification.
  • aliphatic hydrocarbon group includes saturated or unsaturated, linear or branched chain or cyclic hydrocarbon groups.
  • the type of the aliphatic hydrocarbon group can be selected from alkyl, alkenyl, alkynyl, etc.
  • the number of carbon atoms of the aliphatic hydrocarbon group is preferably 1 to 12, and can also be 1 to 10, and a further preferred range is 1 to 6.
  • substituents may include groups such as hydroxyl, halogen, cyano and amino, for example, the aliphatic hydrocarbon group may contain one, two or more halogens, which means that one, two or more hydrogen atoms of the aliphatic hydrocarbon group may be replaced by an equal number of halogens. If the hydrocarbon group contains more than one carbon, then those carbons do not necessarily have to be connected to each other. For example, at least two of the carbons may be connected via a suitable element or group. That is, the aliphatic group may optionally contain one, two or more heteroatoms (or be interpreted as optionally heteroatoms inserted into the aliphatic group, optionally C—C bonds and C—H bonds).
  • heteroatoms are obvious to those skilled in the art and include, for example, sulfur, nitrogen, oxygen, phosphorus and silicon.
  • the heteroatom-containing aliphatic group may be selected from the following groups: (C 1 -C 6 ) aliphatic oxy, (C 1 -C 6 ) aliphatic mercapto, halogenated (C 1 -C 6 ) aliphatic, halogenated (C 1 -C 6 ) aliphatic oxy, halogenated (C 1 -C 6 ) aliphatic thio, (C 1 -C 6 ) aliphatic oxy (C 1 -C 6 ) aliphatic, (C 1 -C 6 ) aliphatic mercapto (C 1 -C 6 ) aliphatic, N-(C 1 -C 3 ) aliphatic amino (C 1 -C 6 ) aliphatic, N,N-di-(C 1 -C 3 ) aliphatic amino (
  • 3-20 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably a “3-10 membered heterocyclyl".
  • 3-10 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present).
  • the heterocyclyl may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl.
  • a 4-membered ring such as azetidinyl, oxetanyl
  • a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyr
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing the nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or, it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • the 3-20-membered heterocyclic group may be further selected from the following groups:
  • heterocyclic or heteroaryl includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridyl or pyridinylene includes pyridine-2-yl, pyridine-2-ylene, pyridine-3-yl, pyridine-3-ylene, pyridine-4-ylene and pyridine-4-ylene;
  • thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene.
  • any method for preparing the compounds of the invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This may be accomplished by conventional protecting groups, such as those described in textbooks or reference books in the art.
  • the protecting groups may be removed at a convenient subsequent stage using methods known in the art.
  • other reagents may be used for the deprotection step, including but not limited to Pd/C, Pd(OH) 2 , PdCl 2 , Pd(OAc) 2 /Et 3 SiH, Raney nickel, appropriately selected acids, appropriately selected bases, fluorides, and the like.
  • the target compound can be isolated according to known methods, for example by extraction, filtration, column chromatography, FCC or preparative HPLC.
  • the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms.
  • these compounds may exist in racemic form or in optically active form.
  • the compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis.
  • diastereomers are prepared from the mixture by reaction with optically active resolution agents.
  • suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in the R and S forms.
  • Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolution agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel).
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane.
  • the "pharmaceutically acceptable salts” include not only salts formed at one of the salt-forming sites of the compounds of the present invention, but also salts formed at 2, 3 or all of the salt-forming sites. For this reason, the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid or the cation of the base required for salt formation in the "pharmaceutically acceptable salt” may vary within a wide range, for example, it may be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
  • the compounds of the present invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms may exist in (R) or (S) configurations, with only one asymmetric center resulting in a racemic mixture and multiple asymmetric centers resulting in a diastereomeric mixture.
  • asymmetry may also exist due to hindered rotation around a particular bond, such as the central bond connecting two substituted aromatic rings of a particular compound.
  • the substituents may also exist in cis or trans isomeric forms.
  • the compounds of the present invention also include all possible stereoisomers thereof, in the form of a single stereoisomer or any mixture of any proportion of said stereoisomers (e.g., R-isomers or S-isomers, or E-isomers or Z-isomers).
  • the separation of a single stereoisomer (e.g., a single enantiomer or a single diastereomer) of a compound of the present invention can be achieved by any suitable prior art method (e.g., chromatography, in particular, e.g., chiral chromatography).
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule.
  • the keto form predominates; while in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but one or more atoms are replaced by atoms having atomic masses or mass numbers different from the atomic masses or mass numbers usually occurring in nature.
  • isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F and Cl, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • Compounds of the present invention, prodrugs thereof, or pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention, for example compounds incorporating radioactive isotopes (such as 3 H and 14 C) can be used for drug and/or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon 14 (i.e., 14 C) isotopes are particularly preferred due to ease of preparation and detectability.
  • substitution with heavier isotopes may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability, and therefore may be preferred in certain circumstances.
  • the compounds of the invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium.
  • the presence of hydrogen in a substituent without the term deuterium or tritium being separately listed does not exclude deuterium or tritium, but may also contain deuterium or tritium.
  • an effective amount refers to an amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below).
  • the therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition to be treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art.
  • the specific dosage will vary depending on the following factors: the specific compound selected, the dosage regimen relied on, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • excipient types include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.
  • Examples of typical pharmaceutically acceptable carriers suitable for the above-mentioned preparations are: sugars, such as lactose, sucrose, mannitol and sorbitol; starches, such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinyl pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; fatty alcohols; and cereal hydrolyzed solids and other non-toxic compatible fillers, binders,
  • solvate refers to those forms of the compounds of the present invention, which form complexes in a solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination is with water. In the present invention, preferred solvates are hydrates. Further, pharmaceutically acceptable solvates (hydrates) of compounds of formula I of the present invention refer to cocrystals and inclusion compounds formed by compound I with one or more molecules of water or other solvents in stoichiometry. Solvents that can be used for solvates include, but are not limited to, water, methanol, ethanol, ethylene glycol and acetic acid.
  • prodrug or “drug precursor” refers to a compound that is converted in vivo into a compound represented by the aforementioned general formula or specific compound. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues.
  • the prodrug of the present invention can be an ester.
  • esters that can be used as prodrugs in the present invention are phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group or a carboxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent.
  • the mesylate salts of I-85 described in the test examples are all mesylate crystal form I of compound I-85.
  • the solid morphology of the solid obtained in the experiment was analyzed using an X-ray powder diffractometer PANalytical Empyrean equipped with a PIXcel 1D detector.
  • the sample scan range was from 3°2 ⁇ to 40°2 ⁇ , with a step size of 0.013°2 ⁇ .
  • the light tube voltage and current were 45KV and 40mA, respectively.
  • Thermal analysis of the samples was performed using a Discovery DSC 250 (TA Instruments, US). ⁇ 2 mg of the sample was weighed and placed in a DSC sample pan and pierced. The sample was equilibrated at 25°C and then heated to 300°C at a rate of 10°C/min.
  • the samples were subjected to thermogravimetric analysis using a TGA 55 (TA Instruments, US).
  • TGA 55 TA Instruments, US.
  • the samples were placed in a peeled closed aluminum sample pan, and after the sample mass was automatically weighed in the TGA heating furnace, the samples were heated to 300°C at a rate of 10°C/min (no balance program was set, and the sample pan was covered and perforated).
  • the samples were subjected to moisture adsorption/desorption tests using a moisture adsorption analyzer from Vsorp (ProUmid GmbH & Co. KG, Germany). The samples were placed in a peeled sample pan and the changes in sample mass with humidity at 25°C were recorded.
  • the instrument used for PLM analysis is Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).
  • the instrument used for HPLC analysis was Agilent HPLC 1260 series.
  • the HPLC method used for solubility and stability tests is shown in Table 4.
  • A2 (1.9 g, 7.42 mmol) and anhydrous THF (32 mL) were added to the reaction flask (100 mL), cooled to 0 ° C, and borane tetrahydrofuran solution (1M, 37.1 mL, 37.1 mmol) was added dropwise under nitrogen protection. After the addition was complete, the ice bath was removed, NaBH 4 (0.28 g, 7.42 mmol) was added, and the reaction was refluxed for 18 hours. The reaction solution was cooled to room temperature, 1N hydrochloric acid was slowly added dropwise to adjust the pH to 1-2, and the temperature was raised to 70 ° C for 1.5 hours.
  • reaction solution was cooled to room temperature, extracted with ether (60 mL ⁇ 2), and the aqueous solution was adjusted to pH ⁇ 10 with 1N sodium hydroxide solution.
  • Ethyl acetate 60 mL ⁇ 3 was extracted, the extracts were combined, washed with saturated NaCl solution (60 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain ( ⁇ )-7-bromo-benzodihydropyran-3-amine (light brown solid 1.51 g, 89%).
  • A6 (180 mg, 0.5 mmol), B4 (175 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol) and EDCI (115 mg, 0.6 mmol) were added to a reaction bottle (10 mL), and then anhydrous DMF (2.5 mL) and DIEA (262 ⁇ L, 1.5 mmol) were added.
  • the reaction mixture was reacted at room temperature overnight under the protection of N 2.
  • Water (10 mL) was added to the reaction solution, and it was extracted with DCM (10 mL ⁇ 3). The extracts were combined, washed with saturated NaCl solution (15 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to obtain a crude product.
  • EtOH was recrystallized several times to obtain tert-butyl 3-methyl-7-trifluoroacetylaminothieno[2,3-b]pyrazine-6-carboxylate (light yellow solid 70.06 g, yield 83%).
  • A6 (16.30 g, 51 mmol), DCM (300 mL), DIPEA (17.0 g, 131 mmol), HOBt (8.65 g, 64 mmol), EDCI (12.52 g, 65 mmol) and C2 (15.20 g, 42 mmol) were added to a reaction bottle (500 mL) and reacted at room temperature overnight. Water (150 mL) was added, and the layers were separated by extraction. The aqueous phase was extracted once with DCM (150 mL), and the organic phases were combined, washed once with water (150 mL), dried over anhydrous Na 2 SO 4 , and spin-dried to obtain a dark green liquid.
  • I-87 free base 11.58 g, 25 mmol
  • EtOH 120 mL
  • concentrated hydrochloric acid 3.3 mL
  • the mixture was reacted for 2 h, filtered, rinsed with a small amount of EtOH, and dried in vacuo to obtain I-87 hydrochloride (yellow solid 11.07 g, yield 85%).
  • p-toluenesulfonic acid crystal form I (hydrate of p-toluenesulfonate of compound I-85), p-toluenesulfonic acid crystal form II (acetone solvate of p-toluenesulfonate of compound I-85), and p-toluenesulfonic acid crystal form III (ethyl acetate solvate of p-toluenesulfonate of compound I-85) were prepared.
  • the characterization data are shown in Figures 14-1 to 17.
  • the solubility of the three in FaSSIF and FeSSIF bio-related media is relatively low, so HPLC method is used for detection.
  • About 15 mg of I-85 free base, mesylate crystal form I and fumarate crystal form I were weighed and added to 5 mL of bio-related medium to form a suspension, which was shaken at 100 rpm in a shaker at 37 ° C. After 0.5 h, 2 h and 24 h, 1 mL of the suspension was filtered and diluted to the corresponding multiples for HPLC analysis and pH test, and the remaining filter cake was subjected to XRPD analysis.
  • the crystal forms of the two salts are also almost converted into amorphous substances in FaSSIF and FeSSIF media for 0.5 hours, and the XRPD spectrum is similar to that of the free base in FeSSIF medium for 0.5 hours.
  • the residual solid of the mesylate salt in FeSSIF medium for 24 hours was subjected to nuclear magnetic resonance analysis, and it was found that the sample was dissociated, indicating that this low-crystallinity substance is a free base.
  • Tables 10-11 The relevant characterization results are summarized in Tables 10-11.
  • the stability results show that the mesylate salt Form I is physically and chemically stable at 60°C/closed cup and 40°C/75% RH.
  • the free base is chemically stable at 60°C/closed cup and 40°C/75% RH, and the crystallinity is improved.
  • the fumarate salt Form I is chemically unstable after being placed at 60°C/closed cup and 40°C/75% RH for one week (the purity decreases by ⁇ 0.4% and ⁇ 3%, respectively).
  • the fumarate salt Form I is not as chemically stable as the mesylate salt Form I and the free base.
  • Form I was used as the starting material, and the corresponding experimental results are summarized in Table 17.
  • Form I was converted into Form II ( aw ⁇ 0.92) under the condition of an alcohol-water ratio of 3/7, but remained stable under the condition of an alcohol-water ratio of 1/1 ( aw ⁇ 0.87).
  • Test Example 4 In vitro tumor cell growth inhibitory activity test of compound I-85 mesylate (number: CT1113 or PBSS1113) and compound I-87 hydrochloride
  • the active test compounds used in the present invention are as follows:
  • Test Example 4-1 Comparison of the inhibitory effects of Compound I-58, Compound I-85 methanesulfonate and Compound I-87 hydrochloride on tumor cell growth
  • HCT116 colonal cancer cells were placed in 96-well plates (3x10 3 cells/well), culture medium (DMEM+10% FBS+1% penicillin-streptomycin) and compounds were added to a final concentration of 0, 50nM, 100nM, 200nM, 500nM or 1000nM, and cultured in a carbon dioxide cell culture incubator (37°C, 5% CO 2 ). After 72 hours of culture, the number of live cells was determined by the MTS method, with the number of cells without compound (only the same amount of compound solvent DMSO) being 1. The results are shown in Table 21 and Figure 29 (growth curve).
  • compound I-58 has no obvious inhibitory activity on the growth of HepG2 and HCT116, while compound I-85 mesylate and compound I-87 hydrochloride significantly inhibited the growth of HCT116 at a concentration of 100nM and above.
  • Compound I-85 mesylate and compound I-87 hydrochloride have significantly better inhibitory activity on tumor cell growth than compound I-58.
  • Test Example 4-2 Growth inhibition effects of compound I-85 methanesulfonate, compound I-87 (hydrochloride) and compound I-1 (hydrochloride) on tumor cell lines of different tissue origins
  • IC 50 concentrations required for 50% inhibition of the growth of each cell line by compound I-85 mesylate (CT1113) ( FIG. 29 ), compound I-87 hydrochloride ( FIG. 30 ), and I-1 hydrochloride (CT1073) ( FIG. 31 ) were calculated.
  • the IC 50 values are shown in Table 22 below:
  • Test Example 4-3 Inhibitory effect of compound I-1 (hydrochloride, CT1073) on tumor cell growth
  • Tumor cell lines MDA-MB-231, LN-18, HT-1080, MDAH2774, HCT116 and SMMC7721 were cultured in DMEM + 10% FBS + 1% penicillin-streptomycin, with or without 500 nM CT1073, and T47D and CNE1 were cultured in another medium (RPMI-1640 + 10% FBS + 1% penicillin-streptomycin medium, with or without 500 nM CT1073). They were placed in a carbon dioxide cell culture incubator (37°C, 5% CO2 ) for different time periods before testing.
  • Compound I-1 (CT1073) caused MDA-MB-231, T47D, CNE1, LN-18, and HT-1080 cells to enter apoptosis ( FIG. 32 ), while MDAH2774, SMMC7721, and HCT116 were blocked in the G1, S, and G2/M phases, respectively ( FIG. 33 ).
  • This test example shows that the inhibitory effect of compound I-1 on tumor cell growth may be due to cell apoptosis or cell cycle arrest.
  • Test Example 4-4 Effects of Compound I-85 Methanesulfonate (CT1113) and Compound I-1 Hydrochloride (CT1073) on the Expression Levels of c-MYC, LSD1, and Tankyrase (TNKS) Proteins in Tumor Cells
  • Tumor cell lines HCT116, HCG27 and SMMC7721 were cultured in culture medium (DMEM + 10% FBS + 1% penicillin-streptomycin), and DMSO (control group), 500nM CT1073 (experimental group 1) or 500nM CT1113 (experimental group 2) were added respectively. After 24 hours of treatment, samples were collected and subjected to Western blotting detection.
  • Test Example 5 Test of the inhibition of tumor growth by compound I-85 mesylate (numbered: CT1113 or PBSS1113) and compound I-87 hydrochloride in various human tumor mouse transplant models
  • compound I-85 mesylate and compound I-87 hydrochloride were dissolved in 40% (2-hydroxypropyl)- ⁇ -cyclodextrin to make a 50 mg/mL stock solution, which was diluted with water when used.
  • the vehicle control was 40% cyclodextrin as the stock solution and diluted in the same manner.
  • Test Example 5-1 Anti-cancer effect of compound I-85 mesylate (PBSS1113) on a human esophageal cancer mouse model (human KYSE-150 cell line transplanted tumor).
  • mice Human esophageal cancer cells KYSE-150 in the logarithmic growth phase were collected and resuspended in PBS, and 100 ⁇ l of 1 ⁇ 10 6 cells were implanted subcutaneously in BALB/c-nude mice.
  • the tumor grew to 50-100 mm 3
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 methanesulfonate (PBSS1113) (experimental group) respectively, with a dosage of 15 mg/kg, and the administration method was oral administration, the frequency of administration was three times a day, and the duration of administration was 15 days.
  • the experimental results showed that after 15 days of drug administration, the growth of transplanted tumors of the human KYSE-150 cell line was significantly inhibited, and the tumor growth inhibition rate was 61.4%.
  • Test Example 5-2 Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human liver cancer mouse model (human HepG2 and HuH6 cell line transplanted tumors).
  • mice Human liver cancer cells HepG2 or HuH6 in the logarithmic growth phase were collected and resuspended in PBS, mixed with matrix gel at a ratio of 3:1, and 100 ⁇ l of 1x10 7 cells were implanted subcutaneously in BALB/c-nude mice.
  • the tumor grew to about 100 mm 3
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 mesylate (PBSS1113) (experimental group) at a dose of 20 mg/kg.
  • the administration method was oral administration, the frequency of administration was twice a day, and the duration of administration was 22 days and 16 days respectively.
  • the experimental results showed that after 22 days and 16 days of drug treatment, respectively, the growth of transplanted tumors of human HepG2 and HuH6 liver cancer cell lines was significantly inhibited, with growth inhibition rates of 73.4% and 70.4%, respectively.
  • Test Example 5-3 Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human colorectal cancer mouse model (human colorectal cancer PDX transplant tumor).
  • PDX patient-derived xenograft
  • CoY1607 and CoY0495 were taken and divided into 1mm x 1mm tumor blocks, washed twice with PBS, and then transplanted subcutaneously into BALB/c-nude mice.
  • the tumor grew to about 100mm3
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 mesylate (PBSS1113) (experimental group) respectively.
  • the dosage was 20mg/kg, and the administration method was oral administration.
  • the frequency of administration was twice a day.
  • the duration of administration of PDX CoY1607 was 15 days, and the duration of administration of PDX CoY0495 was 12 days.
  • Test Example 5-4 Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human pancreatic cancer mouse model (human pancreatic cancer cell line SW1990 transplanted tumor).
  • mice Human pancreatic cancer cells SW1990 in the logarithmic growth phase were collected and resuspended in PBS, mixed with matrix gel at a ratio of 3:1, and 100 ⁇ l of 5x10 6 cells were implanted subcutaneously in BALB/c-nude mice.
  • the tumor grew to about 50-100 mm 3
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 mesylate (PBSS1113) (experimental group) respectively, with a dose of 20 mg/kg, and the administration method was oral administration, the frequency of administration was twice a day, and the duration of administration was 20 days.
  • the experimental results showed that after 20 days of drug administration, the growth of transplanted tumors of the human pancreatic cancer cell line SW1990 was significantly inhibited, with a growth inhibition rate of 45.9%.
  • Test Example 5-5 Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human Burritt's lymphoma mouse model (human Burritt's lymphoma cell line Raji transplant tumor).
  • Human Burritt lymphoma cell line (Raji cells carrying Luciferase, Raji-Luc) in the logarithmic growth phase was collected and resuspended in PBS, and 200 ⁇ l of a total of 8x10 4 cells were injected into the tail vein of NSG mice.
  • the tumor proliferation was monitored using a luciferase imaging system.
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 methyl (compound I-85 methyl) respectively.
  • Sulfonate (PBSS1113) (experimental group)
  • the dosage was 20 mg/kg
  • the administration method was oral administration
  • the administration frequency was twice a day
  • the administration duration was 18 days.
  • the experimental results showed that after 18 days of drug administration, the growth of human Burritt's lymphoma cell line Raji transplanted tumors was significantly inhibited, with a growth inhibition rate of 66.1%.
  • Test Example 5-6 Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human neuroblastoma mouse model (human neuroblastoma cell line SK-N-BE(2) transplanted tumor).
  • mice A well-growing human neuroblastoma SK-N-BE(2) xenograft tumor was taken and divided into 1mm x 1mm tumor pieces, washed twice with PBS, and then transplanted subcutaneously into BALB/c-nude mice.
  • the tumor grew to about 50-100mm3
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 methanesulfonate (PBSS1113) (experimental group 1 and experimental group 2), respectively, with a dose of 15 and 20 mg/kg, respectively, by oral administration, with a frequency of twice a day and a duration of 18 days.
  • Test Example 5-7 Anti-tumor effects of Compound I-85 mesylate and Compound I-87 hydrochloride on mouse breast cancer model (mouse breast cancer cell line EMT6 transplanted tumor).
  • mice The mouse breast cancer cell line EMT6 in the logarithmic growth phase was collected and resuspended in PBS, and fully mixed with matrix gel at a ratio of 3:1. 100 ⁇ l of a total of 3x10 5 cells were implanted subcutaneously in female C57BL/6 mice. When the tumor grew to about 50-100 mm 3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group), compound I-85 mesylate (PBSS1113) (dosage of 20 mg/kg, administration by gavage, administration frequency twice a day, administration duration of 18 days) and compound I-87 hydrochloride (dosage of 50 mg/kg, administration by gavage, administration frequency twice a day, administration duration of 18 days).
  • control group cyclodextrin solvent
  • PBSS1113 compound I-85 mesylate
  • compound I-87 hydrochloride dosage of 50 mg/kg, administration by gavage, administration frequency twice a day, administration duration of 18 days.
  • Test Example 5-8 Anti-tumor effect of compound I-87 hydrochloride on a human pancreatic cancer mouse model (human pancreatic cancer cell line SW1990 transplanted tumor).
  • mice Human pancreatic cancer cells SW1990 in the logarithmic growth phase were collected and resuspended in PBS, mixed with matrix gel at a ratio of 3:1, and 100 ⁇ l of 5x10 6 cells were implanted subcutaneously in BALB/c-nude.
  • the tumor grew to about 50-100 mm 3
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group), compound I-87 hydrochloride (dosage of 50 mg/kg, administration by gavage, administration frequency of twice a day, administration duration of 38 days) and gemcitabine (dosage of 100 mg/kg, administration by gavage, administration frequency of once every three days, administration duration of 38 days).
  • Test Example 5-9 Anti-tumor effect of compound I-87 hydrochloride on a human colorectal cancer mouse model (human colorectal cancer PDX transplant tumor).
  • a well-growing human colorectal cancer PDX (patient-derived xenograft, CoY1607 strain) was taken and divided into 1.5mm x1.5mm tumor pieces, washed twice with PBS, and then transplanted subcutaneously into BALB/c-nude mice.
  • the tumor grew to about 100mm3 , the mice were randomly divided into two groups and given cyclodextrin solvent, compound I-87 hydrochloride (dosage of 50mg/kg, administration by gavage, frequency of administration twice a day, duration of administration for 28 days) and irinotecan (dosage of 20mg/kg, administration by intraperitoneal injection, frequency of administration once a week, duration of administration for 28 days).
  • Test Example 5-10 Anti-tumor effect of compound I-87 hydrochloride on mouse breast cancer model (mouse breast cancer cell line 4T1 transplanted tumor).
  • Mouse breast cancer cell line 4T1 in the logarithmic growth phase was collected and resuspended in PBS, and fully mixed with matrix gel at a ratio of 3:1.
  • 100 ⁇ l of 1x10 6 cells were implanted subcutaneously in BALB/c mice.
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-87 hydrochloride (experimental group) respectively.
  • the dosage was 50 mg/kg, and the administration method was oral administration.
  • the frequency of administration was twice a day, and the duration of administration was 15 days.
  • Test Example 5-11 Anti-tumor effect of compound I-87 hydrochloride on mouse melanoma model (mouse melanoma cell line B16 transplanted tumor).
  • mice Take a well-growing mouse melanoma (a tumor produced by implanting a melanoma cell line B16 in a C57BL/6 mouse) and divide it into 1.5mm x 1.5mm tumor pieces, wash it twice with PBS, and implant it subcutaneously in a C57BL/6 mouse.
  • the tumor grows to about 50-100mm3
  • the mice are randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-87 hydrochloride (experimental group) respectively, with a dose of 50mg/kg, and the administration method is oral administration, the frequency of administration is twice a day, and the duration of administration is 10 days.
  • Test Example 5-12 Anti-tumor effect of compound I-87 hydrochloride on mouse colorectal cancer model (mouse colorectal cancer cell line MC38 transplanted tumor).
  • Mouse colorectal cancer cell line MC38 in the logarithmic growth phase was collected and resuspended in PBS, mixed with matrix gel at a ratio of 3:1, and 100 ⁇ l of 2x10 5 cells were implanted subcutaneously in C57BL/6 mice.
  • the tumor grew to about 50-100 mm 3
  • the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-87 hydrochloride (experimental group) at a dose of 50 mg/kg, by oral administration, twice a day, and for 10 days.
  • Test Example 6 Activity test of compound I-85 methanesulfonate (number: PBSS1113) on the growth inhibition of acute myeloid leukemia cells
  • Test Example 6-1 Comparison of the growth inhibitory effects of compound I-58 and compound I-85 mesylate on acute myeloid leukemia (AML) cell lines.
  • AML cell lines Molm-13, MV4-11, and OCI-AML2 were placed in 6 cm culture dishes (5x104 cells/ml, 6 ml/dish), and culture medium (MOLM13 and MV4-11: IMDM+10% FBS+1% penicillin-streptomycin; OCI-AML2: RPMI-1640+10% FBS+1% penicillin-streptomycin) and compounds were added to final concentrations of 0, 50 nM, 100 nM, 200 nM, or 500 nM, and cultured in a carbon dioxide cell culture incubator (37°C, 5% CO2). After 72 hours of culture, the number of live cells was determined by the MTS method, and the number of cells without adding compounds (only adding the same amount of compound solvent DMSO) was taken as 1. The results are shown in Table 23 below and Figure 47 (growth curve).
  • Test Example 6-2 Growth inhibitory effect of compound I-85 mesylate on 29 AML cell lines.
  • the number of metabolically active cells was determined by quantitatively measuring ATP after cell lysis and luciferase-catalyzed beetle luciferase to produce luminescent signal molecules, and the concentration of compound I-85 mesylate (PBSS1113) required for 50% inhibition (IC 50 ) of the growth of each cell line was calculated (Table 25 below and Figure 48 ).
  • Test Example 6-3 Compound I-85 mesylate causes apoptosis of AML cells.
  • OCI-AML3 AML cells (OCI-AML3) were cultured with different concentrations of compound I-85 mesylate (PBSS1113) for 6 days and then cell apoptosis was determined by flow cytometry (Figure 49)
  • Test Example 6-4 Antitumor activity of compound I-85 mesylate in human AML animal model.
  • PBSS1113 (two doses: 15 and 20 mg/kg body weight, bid) was administered by gavage; doxorubicin (doxorubincin, dissolved in normal saline, 1 mg/kg body weight, 2 days on and 5 days off) was administered by intravenous injection.
  • doxorubicin doxorubincin, dissolved in normal saline, 1 mg/kg body weight, 2 days on and 5 days off
  • Tumor growth was represented by Luc activity.
  • Compound I-85 mesylate salt achieved 57.5% and 87.8% inhibition rates at two doses, 15 and 20 mg/kg, respectively (see Table 26 below and Figure 50).
  • Table 26 Note: a. Mean ⁇ standard error; b. Compared with the solvent control group.
  • Test Example 6 show that compound I-85 mesylate has a strong growth inhibitory effect on different types of acute myeloid leukemia cells and can cause cell apoptosis. In animal models, compound I-85 mesylate has a significant effect and a dose-effect relationship. At 20 mg/kg, the tumor inhibition effect is better than that of the positive control drug doxorubicin.

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Abstract

The present invention relates to the use of a compound as represented by formula (I) and a racemate, stereoisomer, tautomer, isotopic label, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof in the preparation of an antitumor drug. Provided in the present invention are a polymorph of the compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the polymorph, a method for preparing the polymorph, and the pharmaceutical use of the polymorph. The structure of formula (I) is as follows:

Description

泛素化特异性蛋白酶抑制剂盐型、晶型及其制备方法与应用Ubiquitination-specific protease inhibitor salt form, crystal form, preparation method and application thereof
本发明要求享有于2022年12月01日向中国国家知识产权局提交的，专利申请号为2022115391958，名称为“泛素化特异性蛋白酶抑制剂盐型、晶型及其制备方法与应用”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本发明中。The present invention claims the priority of a prior application filed with the State Intellectual Property Office of China on December 1, 2022, with patent application number 2022115391958, entitled "Ubiquitination-specific protease inhibitor salt form, crystal form, preparation method and application thereof". The entire text of the prior application is incorporated into the present invention by reference.
技术领域Technical Field
本发明涉及药物领域，具体地，本发明涉及一类泛素化特异性蛋白酶抑制剂的盐型、晶型及其制备方法与在抗肿瘤药物中的应用。The present invention relates to the field of medicine, and in particular to a class of ubiquitination-specific protease inhibitors, salt forms, crystal forms, preparation methods thereof, and applications thereof in anti-tumor drugs.
背景技术Background technique
发明人于2020年5月8日提交了申请号为PCT/CN/2020/089284的PCT专利申请，其全文引入本文作为参考。在该发明中，发明人研究了一类泛素化特异性蛋白酶抑制剂及其制备方法和应用。该申请涉及如下通式化合物：
The inventor submitted a PCT patent application with application number PCT/CN/2020/089284 on May 8, 2020, the entire text of which is incorporated herein by reference. In the invention, the inventor studied a class of ubiquitination-specific protease inhibitors and their preparation methods and applications. The application involves the following general formula compounds:
该发明公开了式I化合物对USP28和USP25的抑制活性。The invention discloses the inhibitory activity of the compound of formula I against USP28 and USP25.
在上述发明的基础上，发明人经过深入研究，发现上述式I中的部分化合物对于肿瘤(尤其是白血病等)具有优异的抑制活性，因而完成本发明。On the basis of the above invention, the inventors conducted in-depth research and found that some compounds in the above formula I have excellent inhibitory activity against tumors (especially leukemia, etc.), thus completing the present invention.
为满足临床研究以及上市药物制剂需要，发明人还研究一种能够方便分离纯化，适合工业化生产，具有稳定的物理化学性质的药物固体形态。In order to meet the needs of clinical research and marketed drug preparations, the inventors also studied a solid form of the drug that can be easily separated and purified, is suitable for industrial production, and has stable physical and chemical properties.
发明内容Summary of the invention
为改善现有技术存在的问题，本发明提供下式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药在制备治疗癌症药物中的应用：In order to improve the problems existing in the prior art, the present invention provides the use of the compound represented by the following formula I and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug in the preparation of a drug for treating cancer:
优选地，所述癌症选自白血病(如急性髓系白血病)、肝癌、结肠癌、卵巢癌、食道癌、结直肠癌、胰腺癌、淋巴瘤、胶质瘤、神经母细胞瘤、鼻咽癌、肺癌、乳腺癌、胃癌、胆管癌、肾癌、膀胱癌、宫颈癌、前列腺癌、肉瘤；
Preferably, the cancer is selected from leukemia (such as acute myeloid leukemia), liver cancer, colon cancer, ovarian cancer, esophageal cancer, colorectal cancer, pancreatic cancer, lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, lung cancer, breast cancer, gastric cancer, bile duct cancer, kidney cancer, bladder cancer, cervical cancer, prostate cancer, sarcoma;
其中：in:
X为CR5或N；X is CR 5 or N;
m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
n为1或2；n is 1 or 2;
Z为NR10、O、S、CR11R12；表示可以为单键或双键；Z is NR 10 , O, S, CR 11 R 12 ; It means it can be a single bond or a double bond;
q为1、2或3；q is 1, 2, or 3;
R1、R2、R5可以相同也可以不同，彼此独立地选自氢、卤素、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基；R 1 , R 2 , and R 5 may be the same or different, and are independently selected from hydrogen, halogen, amino, and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
R3为无取代或取代的(C1-C12)脂肪烃基；R 3 is an unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon group;
每一个R4和R6可以相同也可以不同，彼此独立地选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基； Each of R 4 and R 6 may be the same or different and are independently selected from hydrogen, halogen, hydroxyl, amino and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
R7和R8可以相同也可以不同，彼此独立地选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基；R 7 and R 8 may be the same or different, and are independently selected from hydrogen, halogen, hydroxyl, amino, and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
R9选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基；R 9 is selected from hydrogen, halogen, hydroxy, amino and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
或者，R9选自无取代或任选地被一个、两个或更多个R13所取代的3-20元杂环基或5-20元杂芳基；Alternatively, R 9 is selected from 3-20 membered heterocyclyl or 5-20 membered heteroaryl which is unsubstituted or optionally substituted by one, two or more R 13 ;
R10选自氢、无取代或取代的(C1-C12)脂肪烃基；R 10 is selected from hydrogen, unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon group;
R11、R12和R13选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基。R 11 , R 12 and R 13 are selected from hydrogen, halogen, hydroxy, amino and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups.
根据本发明的实施方案，所述“无取代的(C1-C12)脂肪烃基”为由1～12碳原子和相应的氢原子组成的直链或支链、饱和或不饱和的链状或环状烃基，所述脂肪烃基的类型可选自烷基、烯基或炔基等基团；所述“取代的(C1-C12)脂肪烃基”为包含一个、两个或更多个卤素和/或氧、硫、氮、磷原子的(C1-C12)脂肪烃基”，其中卤素、氧、硫、氮、磷可以在(C1-C12)脂肪烃基的直链或支链上，还可以在直链或支链的任何一个位置上；所述的“(C1-C12)脂肪烃基”优选可以为“(C1-C10)脂肪烃基”、“(C1-C8)脂肪烃基”和“(C1-C6)脂肪烃基”。例如可选自以下基团：(C1-C6)脂肪烃基、(C1-C6)脂肪烃基氧基、N-(C1-C6)脂肪烃基胺基、N,N-二-(C1-C3)脂肪烃基胺基、(C1-C6)脂肪烃基巯基、卤代(C1-C6)脂肪烃基、卤代(C1-C6)脂肪烃基氧基、(单或二-N取代)卤代(C1-C6)脂肪烃基胺基、卤代(C1-C6)脂肪烃基巯基、(C1-C6)脂肪烃基氧基(C1-C6)脂肪烃基、(C1-C6)脂肪烃基巯基(C1-C6)脂肪烃基、N-(C1-C6)脂肪烃基氨基(C1-C6)脂肪烃基、N,N-二-(C1-C3)脂肪烃基氨基(C1-C6)脂肪烃基。更具体的，可以为甲基、乙基、丙基、异丙基、环丙基，甲氧基甲基、乙氧基甲基、丙氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基，N-甲基胺甲基、N-甲基胺乙基、N-乙基胺乙基、N,N-二甲基胺甲基、N,N-二甲基胺乙基、N,N-二乙基胺乙基。According to an embodiment of the present invention, the "unsubstituted (C 1 -C 12 ) aliphatic hydrocarbon group" is a straight or branched, saturated or unsaturated chain or cyclic hydrocarbon group consisting of 1 to 12 carbon atoms and corresponding hydrogen atoms, and the type of the aliphatic hydrocarbon group can be selected from groups such as alkyl, alkenyl or alkynyl; the "substituted (C 1 -C 12 ) aliphatic hydrocarbon group" is a (C 1 -C 12 ) aliphatic hydrocarbon group containing one, two or more halogen and/or oxygen, sulfur, nitrogen, phosphorus atoms, wherein the halogen, oxygen, sulfur, nitrogen, phosphorus can be on the straight chain or branched chain of the (C 1 -C 12 ) aliphatic hydrocarbon group, and can also be at any position of the straight chain or branched chain; the "(C 1 -C 12 ) aliphatic hydrocarbon group" can preferably be a "(C 1 -C 10 ) aliphatic hydrocarbon group", "(C 1 -C 8 ) aliphatic hydrocarbon group" and "(C 1 -C 6 ) aliphatic hydrocarbon group". For example, it can be selected from the following groups: (C 1 -C 12 ) aliphatic hydrocarbon group; 6 ) aliphatic hydrocarbon group, (C 1 -C 6 ) aliphatic hydrocarbon group oxy group, N-(C 1 -C 6 ) aliphatic hydrocarbon group amino group, N,N-di-(C 1 -C 3 ) aliphatic hydrocarbon group amino group, (C 1 -C 6 ) aliphatic hydrocarbon group mercapto group, halogenated (C 1 -C 6 ) aliphatic hydrocarbon group, halogenated (C 1 -C 6 ) aliphatic hydrocarbon group oxy group, (mono- or di-N-substituted) halogenated (C 1 -C 6 ) aliphatic hydrocarbon group amino group, halogenated (C 1 -C 6 ) aliphatic hydrocarbon group mercapto group, (C 1 -C 6 ) aliphatic hydrocarbon group oxy group (C 1 -C 6 ) aliphatic hydrocarbon group, (C 1 -C 6 ) aliphatic hydrocarbon group mercapto group (C 1 -C 6 ) aliphatic hydrocarbon group, N-(C 1 -C 6 ) aliphatic hydrocarbon group amino group (C 1 -C 6 ) aliphatic hydrocarbon group, N,N-di-(C 1 -C 3) aliphatic hydrocarbon group More specifically, it can be methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl , propoxyethyl , methoxypropyl , ethoxypropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl.
根据本发明的实施方案，X为CH或N；According to an embodiment of the present invention, X is CH or N;
根据本发明的实施方案，Z为NH、O、S或CH2；According to an embodiment of the present invention, Z is NH, O, S or CH 2 ;
根据本发明的实施方案，R1可选自H或(C1-C6)脂肪烃基；According to an embodiment of the present invention, R 1 may be selected from H or a (C 1 -C 6 ) aliphatic hydrocarbon group;
根据本发明的实施方案，R2可选自H或(C1-C6)脂肪烃基，例如H、甲基或乙基；According to an embodiment of the present invention, R 2 may be selected from H or a (C 1 -C 6 ) aliphatic hydrocarbon group, such as H, methyl or ethyl;
根据本发明的实施方案，R3可选自无取代或取代的(C1-C6)脂肪烃基；According to an embodiment of the present invention, R 3 may be selected from unsubstituted or substituted (C 1 -C 6 ) aliphatic hydrocarbon groups;
根据本发明的实施方案，R3可选自甲基、乙基、丙基、丁基、甲氧基甲基，乙氧基甲基，丙氧基甲基，甲氧基乙基，乙氧基乙基，丙氧基乙基，甲氧基丙基，乙氧基丙基，丙氧基丙基，N-甲基胺甲基，N-甲基胺乙基，N-乙基胺乙基，N,N-二甲基胺甲基，N,N-二甲基胺乙基，N,N-二乙基胺乙基。According to an embodiment of the present invention, R3 can be selected from methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl.
根据本发明的实施方案，R9选自无取代或任选地被一个、两个或更多个R13所取代的下列基团：3-20元杂环基、5-20元杂芳基。According to an embodiment of the present invention, R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 13 : 3-20 membered heterocyclyl, 5-20 membered heteroaryl.
根据本发明的实施方案，R9选自无取代或任选地被一个、两个或更多个R13所取代的，含有一个、两个或更多个N原子的3-20元杂环基或5-20元杂芳基，进一步的，优选为仅含有一个或两个N作为杂原子的3-10元杂环基。According to an embodiment of the present invention, R 9 is selected from a 3-20 membered heterocyclic group or a 5-20 membered heteroaryl group which is unsubstituted or optionally substituted by one, two or more R 13 and contains one, two or more N atoms, and further, is preferably a 3-10 membered heterocyclic group containing only one or two N as heteroatoms.
根据本发明的实施方案，R9可选自无取代或任选地被一个、两个或更多个R13所取代的以下基团：
According to an embodiment of the present invention, R 9 may be selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 13 :
根据本发明的实施方案，所述R13可以在上述基团的C原子上或者N原子上取代相应的氢原子；也可以是两个R13取代相同C原子上的两个氢原子。According to an embodiment of the present invention, the R 13 may replace the corresponding hydrogen atom on the C atom or N atom of the above group; or two R 13 may replace two hydrogen atoms on the same C atom.
根据本发明的实施方案，式I所述化合物具有式II所示的结构：
According to an embodiment of the present invention, the compound of formula I has a structure shown in formula II:
所述式II中，R1、R2、R3、R6、R9，X、Z、q的定义如前述式I中所定义。In the formula II, R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q are as defined in the above formula I.
根据本发明的实施方案，式I所述化合物选自如下所示的结构：

According to an embodiment of the present invention, the compound of formula I is selected from the structures shown below:

根据本发明，所述I所示的化合物药学上可接受的盐选自下文所述的具体的盐。优选选自盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐。According to the present invention, the pharmaceutically acceptable salt of the compound shown in I is selected from the specific salts described below. Preferably, it is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
根据本发明，所述化合物选自化合物I-85或者化合物I-87或其药学上可接受的盐。According to the present invention, the compound is selected from Compound I-85 or Compound I-87 or a pharmaceutically acceptable salt thereof.
根据本发明，所述化合物选自化合物I-85药学上可接受的盐，如甲磺酸盐或者富马酸盐。According to the present invention, the compound is selected from a pharmaceutically acceptable salt of compound I-85, such as a methanesulfonate or a fumarate.
根据本发明，所述化合物选自下文所述的化合物I-85的多晶型。According to the present invention, the compound is selected from the polymorphic forms of compound 1-85 described below.
根据本发明的技术方案，所述癌症包括白血病(Leukemia，如急性髓系白血病)、淋巴瘤(lymphoma)、胶质瘤(Glioma)、神经母细胞瘤(Neuroblastoma)、鼻咽癌(Nasopharyngeal carcinoma)、食道癌(Esophageal cancer)、肺癌(Lung cancer)、乳腺癌(Breast cancer)、肝癌(Liver cancer)、胃癌(Gastric cancer)、胆管癌(Cholangiocarcinoma)、胰腺癌(Pancreatic cancer)、结直肠癌(Colorectal cancer)、肾癌(Renal carcinoma)、膀胱癌(Bladder cancer)、卵巢癌(Ovarian cancer)、宫颈癌(Cervical cancer)、前列腺癌(Prostate cancer)、以及肉瘤(Sarcoma)。According to the technical solution of the present invention, the cancer includes leukemia (such as acute myeloid leukemia), lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, esophageal cancer, lung cancer, breast cancer, liver cancer, gastric cancer, cholangiocarcinoma, pancreatic cancer, colorectal cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, and sarcoma.
本发明还提供式I所示的化合物或其药学上可接受的盐的多晶型物：
The present invention also provides a polymorph of a compound represented by Formula I or a pharmaceutically acceptable salt thereof:
其中，R1、R2、R3、R4、R6、R7、R8、R9，X、Z、m、n、q的定义如前述式I中所述。wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , X, Z, m, n and q are as defined in Formula I above.
根据本发明的实施方案，所述式I具有式II所示的结构：
According to an embodiment of the present invention, the formula I has a structure shown in formula II:
所述式II中，R1、R2、R3、R6、R9，X、Z、q的定义如前述式I中所定义。In the formula II, R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q are as defined in the above formula I.
根据本发明的实施方案，式I所述化合物选自如下所示的结构：

According to an embodiment of the present invention, the compound of formula I is selected from the structures shown below:

本发明还提供式I所示的化合物药学上可接受的盐：
The present invention also provides a pharmaceutically acceptable salt of the compound represented by Formula I:
其中，R1、R2、R3、R4、R6、R7、R8、R9，X、Z、m、n、q的定义如前述式I中所述；wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , X, Z, m, n, q are as defined in the aforementioned formula I;
其中，所述药学上可接受的盐为式I化合物与酸形成的盐，所述酸可以选自无机酸或有机酸，例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸，甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、L-酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。作为实例，所述酸可以选自盐酸、氢溴酸、硫酸、磷酸、硝酸、甲磺酸、对甲苯磺酸、富马酸、马来酸、柠檬酸、L-酒石酸、草酸、甲酸、乙酸、三氟乙酸、月桂酸、苯甲酸和苯磺酸中的一种。Wherein, the pharmaceutically acceptable salt is a salt formed by a compound of formula I and an acid, and the acid can be selected from an inorganic acid or an organic acid, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectin esters The acid can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid. As an example, the acid can be selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid.
根据本发明的实施方案，所述I所示的化合物药学上可接受的盐选自盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐。According to an embodiment of the present invention, the pharmaceutically acceptable salt of the compound shown in I is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
根据本发明的实施方案，所述式I具有式II所示的结构：
According to an embodiment of the present invention, the formula I has a structure shown in formula II:
所述式II中，R1、R2、R3、R6、R9，X、Z、q的定义如前述式I中所定义。In the formula II, R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q are as defined in the above formula I.
根据本发明的实施方案，所述式I所述化合物选自如下所示的化合物药学上可接受的盐：
According to an embodiment of the present invention, the compound of formula I is selected from pharmaceutically acceptable salts of the compounds shown below:
根据本发明的实施方案，所述I所示的化合物药学上可接受的盐选自化合物Ⅰ-85、化合物Ⅰ-86、化合物Ⅰ-87、化合物Ⅰ-88、化合物I-89、化合物Ⅰ-90、化合物Ⅰ-91的药学上可接受的盐，进一步地，这些化合物药学上可接受的盐选自其盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐。According to an embodiment of the present invention, the pharmaceutically acceptable salt of the compound shown in I is selected from the pharmaceutically acceptable salts of Compound I-85, Compound I-86, Compound I-87, Compound I-88, Compound I-89, Compound I-90, and Compound I-91. Further, the pharmaceutically acceptable salts of these compounds are selected from their hydrochlorides, sulfates, hydrobromides, methanesulfonates, p-toluenesulfonates, phosphates, L-tartrates or fumarates.
本发明还提供如下化合物Ⅰ-87药学上可接受的盐：
The present invention also provides the following pharmaceutically acceptable salts of Compound I-87:
其中，所述药学上可接受的盐选自盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐。Wherein, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
根据本发明的实施方案，所述化合物Ⅰ-87药学上可接受的盐为化合物Ⅰ-87的盐酸盐或甲磺酸盐。According to an embodiment of the present invention, the pharmaceutically acceptable salt of Compound Ⅰ-87 is the hydrochloride or methanesulfonate of Compound Ⅰ-87.
本发明还提供如下化合物Ⅰ-85药学上可接受的盐，
The present invention also provides the following pharmaceutically acceptable salts of Compound Ⅰ-85:
其中，所述药学上可接受的盐选自盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐。Wherein, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
根据本发明的实施方案，所述化合物Ⅰ-85药学上可接受的盐为化合物Ⅰ-85的甲磺酸盐或富马酸盐。According to an embodiment of the present invention, the pharmaceutically acceptable salt of Compound I-85 is the mesylate or fumarate of Compound I-85.
本发明还提供如下化合物Ⅰ-85或其药学上可接受的盐的多晶型，
The present invention also provides the following polymorphic forms of Compound I-85 or a pharmaceutically acceptable salt thereof:
根据本发明的实施方案，所述多晶型为化合物I-85的甲磺酸盐晶型I(无水物)。According to an embodiment of the present invention, the polymorph is the mesylate salt form I (anhydrate) of compound I-85.
根据本发明的实施方案，所述多晶型为化合物I-85的甲磺酸盐晶型II(水合物)。According to an embodiment of the present invention, the polymorph is the mesylate salt form II (hydrate) of compound I-85.
根据本发明的实施方案，所述多晶型为化合物I-85的甲磺酸盐晶型III(甲醇溶剂化物)。According to an embodiment of the present invention, the polymorph is the mesylate salt form III (methanol solvate) of compound I-85.
根据本发明的实施方案，所述多晶型为化合物Ⅰ-85的富马酸盐晶型I(无水物)。According to an embodiment of the present invention, the polymorph is the fumarate salt form I (anhydrate) of compound I-85.
本发明提供了化合物Ⅰ-85的一盐酸盐晶型I，其X-射线粉末衍射图包括位于11.128±0.2°、21.646±0.2°、22.065±0.2°和22.893±0.2°的衍射角(2θ)处的峰。The present invention provides a hydrochloride salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 11.128±0.2°, 21.646±0.2°, 22.065±0.2° and 22.893±0.2°.
优选还包括位于11.128±0.2°、18.271±0.2°、21.646±0.2°、22.065±0.2°、22.893±0.2°和26.357±0.2°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 11.128±0.2°, 18.271±0.2°, 21.646±0.2°, 22.065±0.2°, 22.893±0.2°, and 26.357±0.2° are also included.
更优选还包括位于11.128±0.2°、13.020±0.2°、17.587±0.2°、18.271±0.2°、21.646±0.2°、22.065±0.2°、22.893±0.2°、26.357±0.2°和27.187±0.2°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 11.128±0.2°, 13.020±0.2°, 17.587±0.2°, 18.271±0.2°, 21.646±0.2°, 22.065±0.2°, 22.893±0.2°, 26.357±0.2°, and 27.187±0.2° are also included.
优选地，所述一盐酸盐晶型I的X-射线粉末衍射图具有如表1-1所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the monohydrochloride salt form I has a diffraction angle (2θ) as shown in Table 1-1, wherein the error range of the 2θ angle is ±0.20°:
表1-1

Table 1-1

优选地，所述一盐酸盐晶型I具有如表1-1所示的X-射线粉末衍射强度。Preferably, the hydrochloride salt form I has an X-ray powder diffraction intensity as shown in Table 1-1.
优选地，所述一盐酸盐晶型I具有基本如图1-1所示的X射线粉末衍射图。Preferably, the hydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 1-1.
优选地，所述一盐酸盐晶型I在约200℃的温度处具有吸热峰的DSC热谱图。Preferably, the hydrochloride salt form I has a DSC thermogram with an endothermic peak at a temperature of about 200°C.
优选地，所述一盐酸盐晶型I具有基本如图2所示的DSC图。Preferably, the hydrochloride salt form I has a DSC graph substantially as shown in Figure 2.
优选地，所述一盐酸盐晶型I具有基本如图2所示的TGA图。Preferably, the hydrochloride salt form I has a TGA graph substantially as shown in Figure 2.
本发明提供了化合物Ⅰ-85的二盐酸盐晶型I，其X-射线粉末衍射图包括位于6.150±0.2°、14.095±0.2°和18.205±0.2°的衍射角(2θ)处的峰。The present invention provides a dihydrochloride salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 6.150±0.2°, 14.095±0.2° and 18.205±0.2°.
优选还包括位于4.655±0.2°、6.150±0.2°、9.289±0.2°、12.965±0.2°、14.095±0.2°和18.205±0.2°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 4.655±0.2°, 6.150±0.2°, 9.289±0.2°, 12.965±0.2°, 14.095±0.2°, and 18.205±0.2° are also included.
更优选还包括位于4.655±0.2°、6.150±0.2°、8.003±0.2°、9.289±0.2°、12.965±0.2°、14.095±0.2°、16.169±0.2°、18.205±0.2°、19.413±0.2°、23.942±0.2°和27.621±0.2°的衍射角(2θ)处的峰。More preferably, it also includes peaks at diffraction angles (2θ) of 4.655±0.2°, 6.150±0.2°, 8.003±0.2°, 9.289±0.2°, 12.965±0.2°, 14.095±0.2°, 16.169±0.2°, 18.205±0.2°, 19.413±0.2°, 23.942±0.2° and 27.621±0.2°.
优选地，所述二盐酸盐晶型I的X-射线粉末衍射图具有如表1-2所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the dihydrochloride salt form I has a diffraction angle (2θ) as shown in Table 1-2, wherein the error range of the 2θ angle is ±0.20°:
表1-2
Table 1-2
优选地，所述二盐酸盐晶型I具有如表1-2所示的X-射线粉末衍射强度。Preferably, the dihydrochloride salt form I has an X-ray powder diffraction intensity as shown in Table 1-2.
优选地，所述二盐酸盐晶型I具有基本如图1-2所示的X射线粉末衍射图。 Preferably, the dihydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in Figures 1-2.
优选地，所述二盐酸盐晶型I在约70.45℃、145.07℃和229.64℃的温度处具有吸热峰的DSC热谱图。Preferably, the dihydrochloride salt form I has a DSC thermogram with endothermic peaks at temperatures of about 70.45°C, 145.07°C and 229.64°C.
优选地，所述二盐酸盐晶型I具有基本如图3所示的DSC图。Preferably, the dihydrochloride salt form I has a DSC graph substantially as shown in FIG3 .
优选地，所述二盐酸盐晶型I具有基本如图3所示的TGA图。Preferably, the dihydrochloride salt form I has a TGA graph substantially as shown in FIG3 .
本发明提供了化合物Ⅰ-85的硫酸盐晶型I，其X-射线粉末衍射图包括位于11.928±0.2°、14.490±0.2°和19.321±0.2°的衍射角(2θ)处的峰。The present invention provides a sulfate crystalline form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 11.928±0.2°, 14.490±0.2° and 19.321±0.2°.
优选还包括位于11.928±0.2°、14.490±0.2°、19.321±0.2°、22.524±0.2°、23.456±0.2°和28.369±0.2°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 11.928±0.2°, 14.490±0.2°, 19.321±0.2°, 22.524±0.2°, 23.456±0.2°, and 28.369±0.2° are also included.
更优选还包括位于9.640±0.2°、11.928±0.2°、14.016±0.2°、14.490±0.2°、16.433±0.2°、19.321±0.2°、22.524±0.2°、23.456±0.2°和28.369±0.2°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 9.640±0.2°, 11.928±0.2°, 14.016±0.2°, 14.490±0.2°, 16.433±0.2°, 19.321±0.2°, 22.524±0.2°, 23.456±0.2°, and 28.369±0.2° are also included.
优选地，所述硫酸盐晶型I的X-射线粉末衍射图具有如表1-3所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the sulfate salt crystalline form I has a diffraction angle (2θ) as shown in Table 1-3, wherein the error range of the 2θ angle is ±0.20°:
表1-3
Table 1-3
优选地，所述硫酸盐晶型I具有如表1-3所示的X-射线粉末衍射强度。Preferably, the sulfate salt crystalline form I has an X-ray powder diffraction intensity as shown in Table 1-3.
优选地，所述硫酸盐晶型I具有基本如图4-1所示的X射线粉末衍射图。Preferably, the sulfate salt crystalline form I has an X-ray powder diffraction pattern substantially as shown in Figure 4-1.
优选地，所述硫酸盐晶型I在约87.71℃和254.89℃的温度处具有吸热峰的DSC热谱图。Preferably, the sulfate salt crystalline form I has a DSC thermogram with endothermic peaks at temperatures of about 87.71°C and 254.89°C.
优选地，所述硫酸盐晶型I具有基本如图5所示的DSC图。Preferably, the sulfate salt crystalline form I has a DSC graph substantially as shown in FIG5 .
优选地，所述硫酸盐晶型I具有基本如图5所示的TGA图。Preferably, the sulfate salt crystalline form I has a TGA graph substantially as shown in FIG5 .
本发明提供了化合物Ⅰ-85的硫酸盐晶型II，其X-射线粉末衍射图包括位于11.928±0.2°、14.490±0.2°、19.321±0.2°和22.524±0.2°的衍射角(2θ)处的峰。The present invention provides a sulfate crystalline form II of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 11.928±0.2°, 14.490±0.2°, 19.321±0.2° and 22.524±0.2°.
优选还包括位于11.928±0.2°、14.490±0.2°、16.433±0.2°、19.321±0.2°、20.661±0.2°、22.524±0.2°和28.369±0.2°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 11.928±0.2°, 14.490±0.2°, 16.433±0.2°, 19.321±0.2°, 20.661±0.2°, 22.524±0.2°, and 28.369±0.2° are also included.
更优选还包括位于9.640±0.2°、11.928±0.2°、14.490±0.2°、16.433±0.2°、18.625±0.2°、19.321±0.2°、20.661±0.2°、22.524±0.2°和28.369±0.2°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 9.640±0.2°, 11.928±0.2°, 14.490±0.2°, 16.433±0.2°, 18.625±0.2°, 19.321±0.2°, 20.661±0.2°, 22.524±0.2°, and 28.369±0.2° are also included.
优选地，所述硫酸盐晶型II的X-射线粉末衍射图具有如表1-4所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the sulfate salt crystalline form II has a diffraction angle (2θ) as shown in Table 1-4, wherein the error range of the 2θ angle is ±0.20°:
表1-4

Table 1-4

优选地，所述硫酸盐晶型II具有如表1-4所示的X-射线粉末衍射强度。Preferably, the sulfate salt crystal form II has an X-ray powder diffraction intensity as shown in Table 1-4.
优选地，所述硫酸盐晶型II具有基本如图4-2所示的X射线粉末衍射图。Preferably, the sulfate salt form II has an X-ray powder diffraction pattern substantially as shown in FIG. 4-2 .
优选地，所述硫酸盐晶型II在约73.33℃和200.04℃的温度处具有吸热峰的DSC热谱图。Preferably, the sulfate salt crystalline form II has a DSC thermogram with endothermic peaks at temperatures of about 73.33°C and 200.04°C.
优选地，所述硫酸盐晶型II具有基本如图6所示的DSC图。Preferably, the sulfate salt form II has a DSC graph substantially as shown in FIG6 .
优选地，所述硫酸盐晶型II具有基本如图6所示的TGA图。Preferably, the sulfate salt crystalline form II has a TGA graph substantially as shown in FIG6 .
本发明提供了化合物Ⅰ-85的硫酸氢盐晶型I，其X-射线粉末衍射图包括位于9.552±0.20°、14.606±0.20°19.544±0.20°和24.494±0.20°的衍射角(2θ)处的峰。The present invention provides a hydrogen sulfate salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.552±0.20°, 14.606±0.20°, 19.544±0.20° and 24.494±0.20°.
优选还包括位于4.814±0.20°、9.552±0.20°、14.606±0.20°、17.261±0.20°、19.544±0.20°和24.494±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 4.814±0.20°, 9.552±0.20°, 14.606±0.20°, 17.261±0.20°, 19.544±0.20°, and 24.494±0.20° are also included.
更优选还包括位于4.814±0.20°、9.552±0.20°、14.398±0.20°、14.606±0.20°、17.261±0.20°、19.544±0.20°、23.510±0.20°、24.494±0.20°和25.821±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 4.814±0.20°, 9.552±0.20°, 14.398±0.20°, 14.606±0.20°, 17.261±0.20°, 19.544±0.20°, 23.510±0.20°, 24.494±0.20°, and 25.821±0.20° are also included.
优选地，所述硫酸氢盐晶型I的X-射线粉末衍射图具有如表1-5所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the hydrogen sulfate salt crystalline form I has a diffraction angle (2θ) as shown in Tables 1-5, wherein the error range of the 2θ angle is ±0.20°:
表1-5

Table 1-5

优选地，所述硫酸氢盐晶型I具有如表1-5所示的X-射线粉末衍射强度。Preferably, the bisulfate salt crystalline form I has an X-ray powder diffraction intensity as shown in Table 1-5.
优选地，所述硫酸氢盐晶型I具有基本如图4-3所示的X射线粉末衍射图。Preferably, the bisulfate salt crystalline form I has an X-ray powder diffraction pattern substantially as shown in Figure 4-3.
优选地，所述硫酸氢盐晶型I在约227.60℃的温度处具有吸热峰的DSC热谱图。Preferably, the hydrogen sulfate salt crystalline form I has a DSC thermogram with an endothermic peak at a temperature of about 227.60°C.
优选地，所述硫酸氢盐晶型I具有基本如图7所示的DSC图。Preferably, the bisulfate salt crystalline form I has a DSC graph substantially as shown in FIG. 7 .
优选地，所述硫酸氢盐晶型I具有基本如图7所示的TGA图。Preferably, the bisulfate salt crystalline form I has a TGA graph substantially as shown in FIG. 7 .
本发明提供了化合物Ⅰ-85的硫酸氢盐晶型II，其X-射线粉末衍射图包括位于14.293±0.20°、17.220±0.20°和20.621±0.20°的衍射角(2θ)处的峰。The present invention provides a hydrogen sulfate salt form II of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 14.293±0.20°, 17.220±0.20° and 20.621±0.20°.
优选还包括位于5.534±0.20°、14.293±0.20°、16.603±0.20°、17.220±0.20°和20.621±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 5.534±0.20°, 14.293±0.20°, 16.603±0.20°, 17.220±0.20°, and 20.621±0.20° are also included.
更优选还包括位于5.534±0.20°、6.296±0.20°、14.293±0.20°、16.603±0.20°、17.220±0.20°、20.621±0.20°、22.826±0.20°和26.609±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 5.534±0.20°, 6.296±0.20°, 14.293±0.20°, 16.603±0.20°, 17.220±0.20°, 20.621±0.20°, 22.826±0.20°, and 26.609±0.20° are also included.
优选地，所述硫酸氢盐晶型II的X-射线粉末衍射图具有如表1-6所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the hydrogen sulfate salt form II has a diffraction angle (2θ) as shown in Table 1-6, wherein the error range of the 2θ angle is ±0.20°:
表1-6
Table 1-6
优选地，所述硫酸氢盐晶型II具有如表1-6所示的X-射线粉末衍射强度。Preferably, the bisulfate salt form II has an X-ray powder diffraction intensity as shown in Table 1-6.
优选地，所述硫酸氢盐晶型II具有基本如图4-4所示的X射线粉末衍射图。Preferably, the bisulfate salt form II has an X-ray powder diffraction pattern substantially as shown in Figure 4-4.
优选地，所述硫酸氢盐晶型II在约57.18℃和201.52℃的温度处具有吸热峰的DSC热谱图。Preferably, the hydrogen sulfate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 57.18°C and 201.52°C.
优选地，所述硫酸氢盐晶型II具有基本如图8所示的DSC图。Preferably, the bisulfate salt form II has a DSC graph substantially as shown in FIG8 .
优选地，所述硫酸氢盐晶型II具有基本如图8所示的TGA图。Preferably, the bisulfate salt form II has a TGA graph substantially as shown in FIG8 .
本发明提供了化合物Ⅰ-85的一氢溴酸盐晶型I，其X-射线粉末衍射图包括位于15.315±0.20°、22.092±0.20°和23.365±0.20°的衍射角(2θ)处的峰。The present invention provides a hydrobromide salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 15.315±0.20°, 22.092±0.20° and 23.365±0.20°.
优选还包括位于15.315±0.20°、19.991±0.20°、22.092±0.20°、23.365±0.20°和26.373±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 15.315±0.20°, 19.991±0.20°, 22.092±0.20°, 23.365±0.20°, and 26.373±0.20° are also included.
更优选还包括位于6.059±0.20°、15.315±0.20°、19.991±0.20°、21.673±0.20°、22.092±0.20°、23.365±0.20°、26.373±0.20°和28.682±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 6.059±0.20°, 15.315±0.20°, 19.991±0.20°, 21.673±0.20°, 22.092±0.20°, 23.365±0.20°, 26.373±0.20°, and 28.682±0.20° are also included.
优选地，所述一氢溴酸盐晶型I的X-射线粉末衍射图具有如表1-7所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the monohydrobromide salt form I has a diffraction angle (2θ) as shown in Tables 1-7, wherein the error range of the 2θ angle is ±0.20°:
表1-7

Table 1-7

优选地，所述一氢溴酸盐晶型I具有如表1-7所示的X-射线粉末衍射强度。Preferably, the hydrobromide salt form I has an X-ray powder diffraction intensity as shown in Table 1-7.
优选地，所述一氢溴酸盐晶型I具有基本如图9-1所示的X射线粉末衍射图。Preferably, the hydrobromide salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 9-1.
优选地，所述一氢溴酸盐晶型I在约56.68℃、157.98℃和250.38℃的温度处具有吸热峰的DSC热谱图。Preferably, the monohydrobromide salt form I has a DSC thermogram with endothermic peaks at temperatures of about 56.68°C, 157.98°C and 250.38°C.
优选地，所述一氢溴酸盐晶型I具有基本如图10所示的DSC图。Preferably, the hydrobromide salt form I has a DSC graph substantially as shown in FIG10 .
优选地，所述一氢溴酸盐晶型I具有基本如图10所示的TGA图。Preferably, the monohydrobromide salt form I has a TGA graph substantially as shown in Figure 10.
本发明提供了化合物Ⅰ-85的二氢溴酸盐晶型I，其X-射线粉末衍射图包括位于6.086±0.20°、14.055±0.20°和23.929±0.20°的衍射角(2θ)处的峰。The present invention provides a dihydrobromide salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 6.086±0.20°, 14.055±0.20° and 23.929±0.20°.
优选还包括位于6.086±0.20°、14.055±0.20°、17.943±0.20°、20.805±0.20°、23.929±0.20°和28.342±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 6.086±0.20°, 14.055±0.20°, 17.943±0.20°, 20.805±0.20°, 23.929±0.20°, and 28.342±0.20° are also included.
更优选还包括位于4.681±0.20°、6.086±0.20°、14.055±0.20°、15.539±0.20°、17.943±0.20°、20.805±0.20°、23.929±0.20°、24.913±0.20°和28.342±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 4.681±0.20°, 6.086±0.20°, 14.055±0.20°, 15.539±0.20°, 17.943±0.20°, 20.805±0.20°, 23.929±0.20°, 24.913±0.20°, and 28.342±0.20° are also included.
优选地，所述二氢溴酸盐晶型I的X-射线粉末衍射图具有如表1-8所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the dihydrobromide salt form I has a diffraction angle (2θ) as shown in Tables 1-8, wherein the error range of the 2θ angle is ±0.20°:
表1-8

Table 1-8

优选地，所述二氢溴酸盐晶型I具有如表1-8所示的X-射线粉末衍射强度。Preferably, the dihydrobromide salt form I has an X-ray powder diffraction intensity as shown in Table 1-8.
优选地，所述二氢溴酸盐晶型I具有基本如图9-2所示的X射线粉末衍射图。Preferably, the dihydrobromide salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 9-2.
优选地，所述二氢溴酸盐晶型I在约80.50℃和241.96℃的温度处具有吸热峰的DSC热谱图。Preferably, the dihydrobromide salt form I has a DSC thermogram with endothermic peaks at temperatures of about 80.50°C and 241.96°C.
优选地，所述二氢溴酸盐晶型I具有基本如图11所示的DSC图。Preferably, the dihydrobromide salt form I has a DSC graph substantially as shown in Figure 11.
优选地，所述二氢溴酸盐晶型I具有基本如图11所示的TGA图。Preferably, the dihydrobromide salt form I has a TGA graph substantially as shown in Figure 11.
本发明还提供了化合物Ⅰ-85的甲磺酸盐晶型I，其特征在于，X-射线粉末衍射图包括位于11.995±0.2°、14.607±0.2°、19.374±0.2°、21.027±0.2°和23.536±0.2°的衍射角(2θ)处的峰。The present invention also provides a mesylate crystalline form I of compound Ⅰ-85, characterized in that the X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 11.995±0.2°, 14.607±0.2°, 19.374±0.2°, 21.027±0.2° and 23.536±0.2°.
优选地，所述甲磺酸盐晶型I，其特征在于，X-射线粉末衍射图(XRPD)包括位于11.995±0.2°、14.607±0.2°、16.538±0.2°、19.374±0.2°、20.739±0.2°、21.027±0.2°、22.577±0.2°和23.536±0.2°的衍射角(2θ)处的峰。Preferably, the mesylate salt form I is characterized in that the X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 11.995±0.2°, 14.607±0.2°, 16.538±0.2°, 19.374±0.2°, 20.739±0.2°, 21.027±0.2°, 22.577±0.2° and 23.536±0.2°.
优选地，所述甲磺酸盐晶型I，其特征在于，X-射线粉末衍射图(XRPD)包括位于11.995±0.2°、14.095±0.2°、14.607±0.2°、15.803±0.2°、16.538±0.2°、19.374±0.2°、20.739±0.2°、21.027±0.2°、22.577±0.2°和23.536±0.2°的衍射角(2θ)处的峰。Preferably, the mesylate salt form I is characterized in that the X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 11.995±0.2°, 14.095±0.2°, 14.607±0.2°, 15.803±0.2°, 16.538±0.2°, 19.374±0.2°, 20.739±0.2°, 21.027±0.2°, 22.577±0.2° and 23.536±0.2°.
优选地，所述甲磺酸盐晶型I的X-射线粉末衍射图具有如表1-9所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the mesylate salt form I has a diffraction angle (2θ) as shown in Tables 1-9, wherein the error range of the 2θ angle is ±0.20°:
表1-9
Table 1-9
优选地，所述甲磺酸盐晶型I具有如表1-9所示的X-射线粉末衍射强度。Preferably, the mesylate salt form I has an X-ray powder diffraction intensity as shown in Table 1-9.
优选地，所述甲磺酸盐晶型I具有基本如图12所示的X射线粉末衍射图。Preferably, the mesylate salt Form I has an X-ray powder diffraction pattern substantially as shown in Figure 12.
优选地，所述甲磺酸盐晶型I在约279.98℃的温度处具有吸热峰的DSC热谱图。Preferably, the mesylate salt form I has a DSC thermogram with an endothermic peak at a temperature of about 279.98°C.
优选地，所述甲磺酸盐晶型I具有基本如图13所示的DSC图。Preferably, the mesylate salt Form I has a DSC graph substantially as shown in FIG. 13 .
优选地，所述甲磺酸盐晶型I具有基本如图13所示的TGA图。Preferably, the mesylate salt Form I has a TGA graph substantially as shown in Figure 13.
本发明提供了化合物Ⅰ-85的对甲苯磺酸盐晶型I，其X-射线粉末衍射图包括位于4.970±0.20°、8.869±0.20°和18.586±0.20°的衍射角(2θ)处的峰。 The present invention provides a p-toluenesulfonate crystalline form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 4.970±0.20°, 8.869±0.20° and 18.586±0.20°.
优选还包括位于4.970±0.20°、8.869±0.20°、10.459±0.20°、14.516±0.20°和18.586±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 4.970±0.20°, 8.869±0.20°, 10.459±0.20°, 14.516±0.20°, and 18.586±0.20° are also included.
更优选还包括位于4.970±0.20°、8.869±0.20°、10.459±0.20°、12.610±0.20°、14.516±0.20°、18.586±0.20°、20.121±0.20°和23.391±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 4.970±0.20°, 8.869±0.20°, 10.459±0.20°, 12.610±0.20°, 14.516±0.20°, 18.586±0.20°, 20.121±0.20°, and 23.391±0.20° are also included.
优选地，所述对甲苯磺酸盐晶型I的X-射线粉末衍射图具有如表1-10所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I has a diffraction angle (2θ) as shown in Tables 1-10, wherein the error range of the 2θ angle is ±0.20°:
表1-10
Table 1-10
优选地，所述对甲苯磺酸盐晶型I具有如表1-10所示的X-射线粉末衍射强度。Preferably, the p-toluenesulfonate salt form I has an X-ray powder diffraction intensity as shown in Table 1-10.
优选地，所述对甲苯磺酸盐晶型I具有基本如图14-1所示的X射线粉末衍射图。Preferably, the p-toluenesulfonate salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 14-1.
优选地，所述对甲苯磺酸盐晶型I在约81.13℃和153.27℃的温度处具有吸热峰的DSC热谱图。Preferably, the p-toluenesulfonate salt form I has a DSC thermogram with endothermic peaks at temperatures of about 81.13°C and 153.27°C.
优选地，所述对甲苯磺酸盐晶型I具有基本如图15所示的DSC图。Preferably, the p-toluenesulfonate salt Form I has a DSC graph substantially as shown in Figure 15.
优选地，所述对甲苯磺酸盐晶型I具有基本如图15所示的TGA图。Preferably, the p-toluenesulfonate salt Form I has a TGA graph substantially as shown in Figure 15.
本发明提供了化合物Ⅰ-85的对甲苯磺酸盐晶型II，其X-射线粉末衍射图包括位于9.473±0.20°、15.881±0.20°、16.721±0.20°和20.687±0.20°的衍射角(2θ)处的峰。The present invention provides a p-toluenesulfonate crystalline form II of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.473±0.20°, 15.881±0.20°, 16.721±0.20° and 20.687±0.20°.
优选还包括位于9.473±0.20°、15.881±0.20°、16.721±0.20°、18.954±0.20°、20.687±0.20°和21.553±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 9.473±0.20°, 15.881±0.20°, 16.721±0.20°, 18.954±0.20°, 20.687±0.20°, and 21.553±0.20° are also included.
更优选还包括位于8.738±0.20°、9.473±0.20°、13.727±0.20°、15.881±0.20°、16.721±0.20°、18.954±0.20°、20.687±0.20°、21.553±0.20°和25.597±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 8.738±0.20°, 9.473±0.20°, 13.727±0.20°, 15.881±0.20°, 16.721±0.20°, 18.954±0.20°, 20.687±0.20°, 21.553±0.20°, and 25.597±0.20° are also included.
优选地，所述对甲苯磺酸盐晶型II的X-射线粉末衍射图具有如表1-11所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form II has a diffraction angle (2θ) as shown in Table 1-11, wherein the error range of the 2θ angle is ±0.20°:
表1-11

Table 1-11

优选地，所述对甲苯磺酸盐晶型II具有如表1-11所示的X-射线粉末衍射强度。Preferably, the p-toluenesulfonate salt form II has an X-ray powder diffraction intensity as shown in Table 1-11.
优选地，所述对甲苯磺酸盐晶型II具有基本如图14-2所示的X射线粉末衍射图。Preferably, the p-toluenesulfonate salt form II has an X-ray powder diffraction pattern substantially as shown in Figure 14-2.
优选地，所述对甲苯磺酸盐晶型II在约69.82℃、203.86℃和225.31℃的温度处具有吸热峰的DSC热谱图。Preferably, the p-toluenesulfonate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 69.82°C, 203.86°C and 225.31°C.
优选地，所述对甲苯磺酸盐晶型II具有基本如图16所示的DSC图。Preferably, the p-toluenesulfonate salt Form II has a DSC graph substantially as shown in FIG. 16 .
优选地，所述对甲苯磺酸盐晶型II具有基本如图16所示的TGA图。Preferably, the p-toluenesulfonate salt Form II has a TGA graph substantially as shown in Figure 16.
本发明提供了化合物Ⅰ-85的对甲苯磺酸盐晶型III，其X-射线粉末衍射图包括位于4.641±0.20°、9.263±0.20°和17.286±0.20°的衍射角(2θ)处的峰。The present invention provides a p-toluenesulfonate crystalline form III of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 4.641±0.20°, 9.263±0.20° and 17.286±0.20°.
优选还包括位于4.641±0.20°、9.263±0.20°、15.028±0.20°、17.286±0.20°和23.011±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 4.641±0.20°, 9.263±0.20°, 15.028±0.20°, 17.286±0.20°, and 23.011±0.20° are also included.
更优选还包括位于4.641±0.20°、6.927±0.20°、9.263±0.20°、15.028±0.20°、17.286±0.20°、19.388±0.20°、20.227±0.20°和23.011±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 4.641±0.20°, 6.927±0.20°, 9.263±0.20°, 15.028±0.20°, 17.286±0.20°, 19.388±0.20°, 20.227±0.20°, and 23.011±0.20° are also included.
优选地，所述对甲苯磺酸盐晶型III的X-射线粉末衍射图具有如表1-12所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form III has a diffraction angle (2θ) as shown in Table 1-12, wherein the error range of the 2θ angle is ±0.20°:
表1-12
Table 1-12
优选地，所述对甲苯磺酸盐晶型III具有如表1-12所示的X-射线粉末衍射强度。Preferably, the p-toluenesulfonate salt form III has an X-ray powder diffraction intensity as shown in Table 1-12.
优选地，所述对甲苯磺酸盐晶型III具有基本如图14-3所示的X射线粉末衍射图。Preferably, the p-toluenesulfonate salt form III has an X-ray powder diffraction pattern substantially as shown in Figure 14-3.
优选地，所述对甲苯磺酸盐晶型III在约144.62℃、202.96和219.07℃的温度处具有吸热峰的DSC热谱图。 Preferably, the p-toluenesulfonate salt form III has a DSC thermogram with endothermic peaks at temperatures of about 144.62°C, 202.96 and 219.07°C.
优选地，所述对甲苯磺酸盐晶型III具有基本如图17所示的DSC图。Preferably, the p-toluenesulfonate salt Form III has a DSC graph substantially as shown in FIG. 17 .
优选地，所述对甲苯磺酸盐晶型III具有基本如图17所示的TGA图。Preferably, the p-toluenesulfonate salt Form III has a TGA graph substantially as shown in Figure 17.
本发明提供了化合物Ⅰ-85的磷酸盐晶型I，其X-射线粉末衍射图包括位于12.598±0.20°、18.205±0.20°和22.722±0.20°的衍射角(2θ)处的峰。The present invention provides a phosphate crystal form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 12.598±0.20°, 18.205±0.20° and 22.722±0.20°.
优选还包括位于10.223±0.20°、12.598±0.20°、18.205±0.20°、19.058±0.20°和22.722±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 10.223±0.20°, 12.598±0.20°, 18.205±0.20°, 19.058±0.20°, and 22.722±0.20° are also included.
更优选还包括位于10.223±0.20°、12.598±0.20°、14.186±0.20°、18.205±0.20°、19.058±0.20°、21.593±0.20°、22.722±0.20°和22.957±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 10.223±0.20°, 12.598±0.20°, 14.186±0.20°, 18.205±0.20°, 19.058±0.20°, 21.593±0.20°, 22.722±0.20°, and 22.957±0.20° are also included.
优选地，所述磷酸盐晶型I的X-射线粉末衍射图具有如表1-13所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the phosphate crystal form I has a diffraction angle (2θ) as shown in Table 1-13, wherein the error range of the 2θ angle is ±0.20°:
表1-13
Table 1-13
优选地，所述磷酸盐晶型I具有如表1-13所示的X-射线粉末衍射强度。Preferably, the phosphate crystal form I has an X-ray powder diffraction intensity as shown in Table 1-13.
优选地，所述磷酸盐晶型I具有基本如图18-1所示的X射线粉末衍射图。Preferably, the phosphate crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 18-1.
优选地，所述磷酸盐晶型I在约83.01℃、146.52℃、175.51和242.76℃的温度处具有吸热峰的DSC热谱图。Preferably, the phosphate crystal form I has a DSC thermogram with endothermic peaks at temperatures of about 83.01°C, 146.52°C, 175.51 and 242.76°C.
优选地，所述磷酸盐晶型I具有基本如图19所示的DSC图。Preferably, the phosphate crystal form I has a DSC graph substantially as shown in Figure 19.
优选地，所述磷酸盐晶型I具有基本如图19所示的TGA图。Preferably, the phosphate crystal form I has a TGA graph substantially as shown in Figure 19.
本发明提供了化合物Ⅰ-85的磷酸盐晶型II，其X-射线粉末衍射图包括位于6.913±0.20°、11.981±0.20°和18.205±0.20°的衍射角(2θ)处的峰。The present invention provides a phosphate crystal form II of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 6.913±0.20°, 11.981±0.20° and 18.205±0.20°.
优选还包括位于6.913±0.20°、11.981±0.20°、13.688±0.20°、17.101±0.20°和18.205±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 6.913±0.20°, 11.981±0.20°, 13.688±0.20°, 17.101±0.20°, and 18.205±0.20° are also included.
更优选还包括位于6.913±0.20°、9.473±0.20°、11.981±0.20°、13.688±0.20°、15.829±0.20°、17.101±0.20°、18.205±0.20°和21.317±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 6.913±0.20°, 9.473±0.20°, 11.981±0.20°, 13.688±0.20°, 15.829±0.20°, 17.101±0.20°, 18.205±0.20°, and 21.317±0.20° are also included.
优选地，所述磷酸盐晶型II的X-射线粉末衍射图具有如表1-14所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the phosphate crystal form II has a diffraction angle (2θ) as shown in Table 1-14, wherein the error range of the 2θ angle is ±0.20°:
表1-14

Table 1-14

优选地，所述磷酸盐晶型II具有如表1-14所示的X-射线粉末衍射强度。Preferably, the phosphate crystal form II has an X-ray powder diffraction intensity as shown in Table 1-14.
优选地，所述磷酸盐晶型II具有基本如图18-2所示的X射线粉末衍射图。Preferably, the phosphate crystal form II has an X-ray powder diffraction pattern substantially as shown in Figure 18-2.
优选地，所述磷酸盐晶型II在约133.16℃和254.39℃的温度处具有吸热峰的DSC热谱图。Preferably, the phosphate crystal form II has a DSC thermogram with endothermic peaks at temperatures of about 133.16°C and 254.39°C.
优选地，所述磷酸盐晶型II具有基本如图20所示的DSC图。Preferably, the phosphate crystal form II has a DSC graph substantially as shown in Figure 20.
优选地，所述磷酸盐晶型II具有基本如图20所示的TGA图。Preferably, the phosphate crystal form II has a TGA graph substantially as shown in Figure 20.
本发明提供了化合物Ⅰ-85的酒石酸盐晶型I，其X-射线粉末衍射图包括位于14.305±0.20°、17.128±0.20°和22.118±0.20°的衍射角(2θ)处的峰。The present invention provides a tartrate salt form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 14.305±0.20°, 17.128±0.20° and 22.118±0.20°.
优选还包括位于5.969±0.20°、14.305±0.20°、17.128±0.20°、20.765±0.20°和22.118±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 5.969±0.20°, 14.305±0.20°, 17.128±0.20°, 20.765±0.20°, and 22.118±0.20° are also included.
更优选还包括位于5.969±0.20°、7.582±0.20°、14.305±0.20°、15.513±0.20°、17.128±0.20°、19.885±0.20°、20.765±0.20°和22.118±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 5.969±0.20°, 7.582±0.20°, 14.305±0.20°, 15.513±0.20°, 17.128±0.20°, 19.885±0.20°, 20.765±0.20°, and 22.118±0.20° are also included.
优选地，所述酒石酸盐晶型I的X-射线粉末衍射图具有如表1-15所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the tartrate salt form I has a diffraction angle (2θ) as shown in Tables 1-15, wherein the error range of the 2θ angle is ±0.20°:
表1-15
Table 1-15
优选地，所述酒石酸盐晶型I具有如表1-15所示的X-射线粉末衍射强度。Preferably, the tartrate salt form I has an X-ray powder diffraction intensity as shown in Table 1-15.
优选地，所述酒石酸盐晶型I具有基本如图21所示的X射线粉末衍射图。Preferably, the tartrate salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 21.
优选地，所述酒石酸盐晶型I在约69.83℃和199.00℃的温度处具有吸热峰的DSC热谱图。Preferably, the tartrate salt form I has a DSC thermogram with endothermic peaks at temperatures of about 69.83°C and 199.00°C.
优选地，所述酒石酸盐晶型I具有基本如图22所示的DSC图。Preferably, the tartrate salt form I has a DSC graph substantially as shown in Figure 22.
优选地，所述酒石酸盐晶型I具有基本如图22所示的TGA图。 Preferably, the tartrate salt form I has a TGA graph substantially as shown in Figure 22.
本发明提供了化合物Ⅰ-85的富马酸盐晶型I，其X-射线粉末衍射图包括位于6.953±0.20°、15.224±0.20°和20.267±0.20°的衍射角(2θ)处的峰。The present invention provides a fumarate crystalline form I of compound I-85, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 6.953±0.20°, 15.224±0.20° and 20.267±0.20°.
优选还包括位于6.953±0.20°、15.224±0.20°、20.267±0.20°、24.757±0.20°和27.067±0.20°的衍射角(2θ)处的峰。Preferably, peaks at diffraction angles (2θ) of 6.953±0.20°, 15.224±0.20°, 20.267±0.20°, 24.757±0.20°, and 27.067±0.20° are also included.
更优选还包括位于6.953±0.20°、10.090±0.20°、15.224±0.20°、18.665±0.20°、20.976±0.20°、20.267±0.20°、24.757±0.20°和27.067±0.20°的衍射角(2θ)处的峰。More preferably, peaks at diffraction angles (2θ) of 6.953±0.20°, 10.090±0.20°, 15.224±0.20°, 18.665±0.20°, 20.976±0.20°, 20.267±0.20°, 24.757±0.20°, and 27.067±0.20° are also included.
优选地，所述富马酸盐晶型I的X-射线粉末衍射图具有如表1-16所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the fumarate salt form I has a diffraction angle (2θ) as shown in Table 1-16, wherein the error range of the 2θ angle is ±0.20°:
表1-16
Table 1-16
优选地，所述富马酸盐晶型I具有如表1-16所示的X-射线粉末衍射强度。Preferably, the fumarate salt form I has an X-ray powder diffraction intensity as shown in Table 1-16.
优选地，所述富马酸盐晶型I具有基本如图23所示的X射线粉末衍射图。Preferably, the fumarate salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 23.
优选地，所述富马酸盐晶型I在约176.61℃的温度处具有吸热峰的DSC热谱图。Preferably, the fumarate salt form I has a DSC thermogram with an endothermic peak at a temperature of about 176.61°C.
优选地，所述富马酸盐晶型I具有基本如图24所示的DSC图。Preferably, the fumarate salt form I has a DSC graph substantially as shown in Figure 24.
优选地，所述富马酸盐晶型I具有基本如图24所示的TGA图。Preferably, the fumarate salt form I has a TGA graph substantially as shown in Figure 24.
本发明提供了化合物Ⅰ-85的甲磺酸盐晶型II，其X-射线粉末衍射图(XRPD)包括位于7.832±0.2°、9.828±0.2°、12.362±0.2°、22.852±0.2°和24.140±0.2°的衍射角(2θ)处的峰。The present invention provides a mesylate salt form II of compound I-85, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 7.832±0.2°, 9.828±0.2°, 12.362±0.2°, 22.852±0.2° and 24.140±0.2°.
优选地，所述甲磺酸盐晶型II，其X-射线粉末衍射图(XRPD)包括位于7.832±0.2°、9.828±0.2°、12.362±0.2°、15.329±0.2°、16.486±0.2°、22.852±0.2°、24.140±0.2°和26.897±0.2°的衍射角(2θ)处的峰。Preferably, the mesylate salt form II has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 7.832±0.2°, 9.828±0.2°, 12.362±0.2°, 15.329±0.2°, 16.486±0.2°, 22.852±0.2°, 24.140±0.2° and 26.897±0.2°.
优选地，所述甲磺酸盐晶型II，其X-射线粉末衍射图(XRPD)包括位于7.832±0.2°、8.251±0.2°、9.828±0.2°、12.362±0.2°、13.805±0.2°、15.329±0.2°、16.486±0.2°、22.852±0.2°、24.140±0.2°和26.897±0.2°的衍射角(2θ)处的峰。Preferably, the mesylate salt form II has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 7.832±0.2°, 8.251±0.2°, 9.828±0.2°, 12.362±0.2°, 13.805±0.2°, 15.329±0.2°, 16.486±0.2°, 22.852±0.2°, 24.140±0.2° and 26.897±0.2°.
优选地，所述甲磺酸盐晶型II的X-射线粉末衍射图具有如表1-17所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the mesylate salt form II has a diffraction angle (2θ) as shown in Table 1-17, wherein the error range of the 2θ angle is ±0.20°:
表1-17

Table 1-17

优选地，所述甲磺酸盐晶型II具有如表1-17所示的X-射线粉末衍射强度。Preferably, the mesylate salt form II has an X-ray powder diffraction intensity as shown in Table 1-17.
优选地，所述甲磺酸盐晶型II具有基本如图25所示的X射线粉末衍射图。Preferably, the mesylate salt Form II has an X-ray powder diffraction pattern substantially as shown in Figure 25.
优选地，所述甲磺酸盐晶型II在约71.31℃、111.93℃和273.09℃的温度处具有吸热峰的DSC热谱图。Preferably, the mesylate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 71.31°C, 111.93°C and 273.09°C.
优选地，所述甲磺酸盐晶型II具有基本如图26所示的DSC图。Preferably, the mesylate salt Form II has a DSC graph substantially as shown in Figure 26.
优选地，所述甲磺酸盐晶型II具有基本如图26所示的TGA图。Preferably, the mesylate salt Form II has a TGA graph substantially as shown in Figure 26.
本发明提供了化合物Ⅰ-85的甲磺酸盐晶型III，其X-射线粉末衍射图(XRPD)包括位于6.939±0.2°、9.079±0.2°、17.234±0.2°、20.030±0.2°和22.984±0.2°的衍射角(2θ)处的峰。The present invention provides a mesylate salt form III of compound I-85, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 6.939±0.2°, 9.079±0.2°, 17.234±0.2°, 20.030±0.2° and 22.984±0.2°.
优选地，所述甲磺酸盐晶型III，其X-射线粉末衍射图(XRPD)包括位于6.939±0.2°、9.079±0.2°、17.234±0.2°、20.030±0.2°、22.984±0.2°、25.058±0.2°、26.070±0.2°和27.922±0.2°的衍射角(2θ)处的峰。Preferably, the mesylate salt form III has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 6.939±0.2°, 9.079±0.2°, 17.234±0.2°, 20.030±0.2°, 22.984±0.2°, 25.058±0.2°, 26.070±0.2° and 27.922±0.2°.
优选地，所述甲磺酸盐晶型III，其X-射线粉末衍射图(XRPD)包括位于6.939±0.2°、9.079±0.2°、17.234±0.2°、20.030±0.2°、22.315±0.2°、22.984±0.2°、23.614±0.2°、25.058±0.2°、26.070±0.2°和27.922±0.2°的衍射角(2θ)处的峰。Preferably, the mesylate salt form III has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 6.939±0.2°, 9.079±0.2°, 17.234±0.2°, 20.030±0.2°, 22.315±0.2°, 22.984±0.2°, 23.614±0.2°, 25.058±0.2°, 26.070±0.2° and 27.922±0.2°.
优选地，所述甲磺酸盐晶型III的X-射线粉末衍射图具有如表1-18所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the mesylate salt form III has a diffraction angle (2θ) as shown in Table 1-18, wherein the error range of the 2θ angle is ±0.20°:
表1-18
Table 1-18
优选地，所述甲磺酸盐晶型III具有如表1-18所示的X-射线粉末衍射强度。Preferably, the mesylate salt form III has an X-ray powder diffraction intensity as shown in Table 1-18.
优选地，所述甲磺酸盐晶型III具有基本如图27所示的X射线粉末衍射图。Preferably, the mesylate salt Form III has an X-ray powder diffraction pattern substantially as shown in Figure 27.
优选地，所述甲磺酸盐晶型III在约81.24℃、167.30℃、178.52℃和276.79℃的温度处具有吸热峰的DSC热谱图。Preferably, the mesylate salt form III has a DSC thermogram with endothermic peaks at temperatures of about 81.24°C, 167.30°C, 178.52°C and 276.79°C.
优选地，所述甲磺酸盐晶型III具有基本如图28所示的DSC图。Preferably, the mesylate salt Form III has a DSC graph substantially as shown in Figure 28.
优选地，所述甲磺酸盐晶型III具有基本如图28所示的TGA图。Preferably, the mesylate salt Form III has a TGA graph substantially as shown in Figure 28.
本发明还提供了一种药物组合物，其包含式I所示的化合物药学上可接受的盐或其多晶型：
The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound represented by Formula I or a polymorph thereof:
其中，所述药学上可接受的盐如上所述。 Wherein, the pharmaceutically acceptable salt is as described above.
本发明还提供了一种药物组合物，其包含化合物I-85或化合物I-87的药学上可接受的盐或所述晶型中的至少一种作为活性成分。The present invention also provides a pharmaceutical composition comprising at least one of the pharmaceutically acceptable salts of Compound I-85 or Compound I-87 or the crystalline forms as an active ingredient.
根据本发明的实施方案，所述的药物组合物进一步包含治疗有效量的所述化合物I-85或I-87的药学上可接受的盐或所述晶型中的至少一种和药学上可接受的载体。According to an embodiment of the present invention, the pharmaceutical composition further comprises a therapeutically effective amount of a pharmaceutically acceptable salt of the compound I-85 or I-87 or at least one of the crystalline forms and a pharmaceutically acceptable carrier.
所述药物组合物中的载体为“可接受的”，其可与组合物的活性成分相容(并且优选地，能够稳定活性成分)并且对被治疗的受试者不是有害的。可以使用一种或多种增溶剂作为药物赋形剂用于递送活性化合物。The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated. One or more solubilizing agents may be used as pharmaceutical excipients for delivery of the active compound.
本发明进一步提供所述化合物I-85的药学上可接受的盐或所述晶型中的至少一种或所述药物组合物在制备用于治疗与抑制癌症的药物中的用途。The present invention further provides the use of the pharmaceutically acceptable salt of the compound I-85 or at least one of the crystalline forms or the pharmaceutical composition in the preparation of drugs for treating and inhibiting cancer.
本发明进一步提供所述化合物I-87的药学上可接受的盐或所述晶型中的至少一种或所述药物组合物在制备用于治疗与抑制癌症的药物中的用途。The present invention further provides the use of the pharmaceutically acceptable salt of the compound I-87 or at least one of the crystalline forms or the pharmaceutical composition in the preparation of drugs for treating and inhibiting cancer.
本发明进一步提供所述化合物I-85和/或化合物I-87的药学上可接受的盐或所述晶型中的至少一种或所述药物组合物在制备用于治疗与抑制癌症的药物中的用途。The present invention further provides the use of the pharmaceutically acceptable salt of the compound I-85 and/or compound I-87 or at least one of the crystal forms or the pharmaceutical composition in the preparation of drugs for treating and inhibiting cancer.
根据本发明，所述癌症包括白血病(Leukemia，如急性髓系白血病)、淋巴瘤(lymphoma)、胶质瘤(Glioma)、神经母细胞瘤(Neuroblastoma)、鼻咽癌(Nasopharyngeal carcinoma)、食道癌(Esophageal cancer)、肺癌(Lung cancer)、乳腺癌(Breast cancer)、肝癌(Liver cancer)、胃癌(Gastric cancer)、胆管癌(Cholangiocarcinoma)、胰腺癌(Pancreatic cancer)、结直肠癌(Colorectal cancer)、肾癌(Renal carcinoma)、膀胱癌(Bladder cancer)、卵巢癌(Ovarian cancer)、宫颈癌(Cervical cancer)、前列腺癌(Prostate cancer)、以及肉瘤(Sarcoma)。According to the present invention, the cancer includes leukemia (such as acute myeloid leukemia), lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, esophageal cancer, lung cancer, breast cancer, liver cancer, gastric cancer, cholangiocarcinoma, pancreatic cancer, colorectal cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, and sarcoma.
本发明还提供一种治疗或预防癌症的方法，所述方法包括向患有所述疾病或障碍中的至少一种的患者给予化合物I-85或化合物I-87的药学上可接受的盐或所述晶型中的至少一种。The present invention also provides a method for treating or preventing cancer, comprising administering to a patient suffering from at least one of the diseases or disorders a pharmaceutically acceptable salt of Compound I-85 or Compound I-87 or at least one of the crystalline forms.
根据本发明的实施方案，所述癌症包括白血病(Leukemia，如急性髓系白血病)、淋巴瘤(lymphoma)、胶质瘤(Glioma)、神经母细胞瘤(Neuroblastoma)、鼻咽癌(Nasopharyngeal carcinoma)、食道癌(Esophageal cancer)、肺癌(Lung cancer)、乳腺癌(Breast cancer)、肝癌(Liver cancer)、胃癌(Gastric cancer)、胆管癌(Cholangiocarcinoma)、胰腺癌(Pancreatic cancer)、结直肠癌(Colorectal cancer)、肾癌(Renal carcinoma)、膀胱癌(Bladder cancer)、卵巢癌(Ovarian cancer)、宫颈癌(Cervical cancer)、前列腺癌(Prostate cancer)、以及肉瘤(Sarcoma)。According to an embodiment of the present invention, the cancer includes leukemia (such as acute myeloid leukemia), lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, esophageal cancer, lung cancer, breast cancer, liver cancer, gastric cancer, cholangiocarcinoma, pancreatic cancer, colorectal cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, and sarcoma.
根据本发明的实施方案，所述药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，造粒剂、崩解剂，粘合剂，和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。According to an embodiment of the present invention, the pharmaceutical composition can be in a form suitable for oral administration, such as tablets, lozenges, pastilles, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any known method for preparing pharmaceutical compositions in the art, and such compositions can contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets can be uncoated or can be coated with known techniques that provide sustained-release effects over a long period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract.
根据本发明的实施方案，所述药物组合物中，活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂；水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂；油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物；通过加入水可使适用于制备水混悬的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。According to an embodiment of the present invention, in the pharmaceutical composition, the active ingredient is mixed with an inert solid diluent or a soft gelatin capsule in which the active ingredient is mixed with a water-soluble carrier or an oily solvent to provide an oral preparation; the aqueous suspension contains the active substance and an excipient suitable for preparing an aqueous suspension for mixing. Such excipients are suspending agents, dispersants or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweeteners; the oil suspension may be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants; dispersible powders and granules suitable for preparing water suspensions may be provided with active ingredients and dispersants or wetting agents, suspending agents or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents may illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions may be preserved by adding antioxidants such as ascorbic acid.
根据本发明的实施方案，所述药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。According to an embodiment of the present invention, the pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, or a mineral oil or a mixture thereof. A suitable emulsifier can be a naturally occurring phospholipid, and the emulsion can also contain a sweetener, a flavoring agent, a preservative and an antioxidant. Such preparations can also contain a demulcent, a preservative, a coloring agent and an antioxidant.
根据本发明的实施方案，所述药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。According to an embodiment of the present invention, the pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable water-in-oil microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.
根据本发明的实施方案，所述药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可 以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。According to an embodiment of the present invention, the pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension may be prepared according to known techniques using the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations may also be The aseptic injection solution or suspension can be prepared in a parenterally acceptable nontoxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.
根据本发明的实施方案，可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。According to an embodiment of the present invention, the compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will dissolve in the rectum to release the drug.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound of formula (I) or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.
本发明的有益效果：Beneficial effects of the present invention:
本发明提供了一类具有更高活性的泛素化特异性蛋白酶抑制剂，具有较好的抗癌症疾病的作用。本发明还提供了化合物I-85和化合物I-87的盐型和晶型及其制备方法，稳定性好，能够满足临床药物制剂开发需要，具有非常重要的临床应用价值。The present invention provides a class of ubiquitination-specific protease inhibitors with higher activity, which have good anti-cancer effects. The present invention also provides salt forms and crystal forms of compound I-85 and compound I-87 and preparation methods thereof, which have good stability, can meet the needs of clinical drug preparation development, and have very important clinical application value.
附图说明：Description of the drawings:
图1-1化合物I-85一盐酸盐晶型I的XRPD图谱。Figure 1-1 XRPD spectrum of compound I-85 hydrochloride salt form I.
图1-2化合物I-85二盐酸盐晶型I的XRPD图谱。Figure 1-2 XRPD spectrum of compound I-85 dihydrochloride salt form I.
图2化合物I-85一盐酸盐晶型I的DSC和TGA图谱。Figure 2 DSC and TGA spectra of compound I-85 hydrochloride salt form I.
图3化合物I-85二盐酸盐晶型I盐酸盐的DSC和TGA图谱。Figure 3 DSC and TGA spectra of compound I-85 dihydrochloride form I hydrochloride.
图4-1化合物I-85硫酸盐晶型I的XRPD图谱。Figure 4-1 XRPD spectrum of compound I-85 sulfate salt form I.
图4-2化合物I-85硫酸盐晶型II的XRPD图谱。Figure 4-2 XRPD spectrum of compound I-85 sulfate salt form II.
图4-3化合物I-85硫酸氢盐晶型I的XRPD图谱。Figure 4-3 XRPD spectrum of compound I-85 hydrogen sulfate salt form I.
图4-4化合物I-85硫酸氢盐晶型II的XRPD图谱。Figure 4-4 XRPD spectrum of compound I-85 hydrogen sulfate salt form II.
图5化合物I-85硫酸盐晶型I的TGA和DSC图谱。Figure 5 TGA and DSC spectra of compound I-85 sulfate salt form I.
图6化合物I-85硫酸盐晶型II的TGA和DSC图谱。Figure 6 TGA and DSC spectra of compound I-85 sulfate salt form II.
图7化合物I-85硫酸氢盐晶型I的TGA和DSC图谱。Figure 7 TGA and DSC spectra of compound I-85 hydrogen sulfate salt form I.
图8化合物I-85硫酸氢盐晶型II的TGA和DSC图谱。Figure 8 TGA and DSC spectra of compound I-85 hydrogen sulfate salt form II.
图9-1化合物I-85一氢溴酸盐晶型I的XRPD图谱。Figure 9-1 XRPD spectrum of compound I-85 hydrobromide salt form I.
图9-2化合物I-85二氢溴酸盐晶型I的XRPD图谱。Figure 9-2 XRPD spectrum of compound I-85 dihydrobromide salt form I.
图10化合物I-85一氢溴酸盐晶型I的DSC和TGA图谱。Figure 10 DSC and TGA spectra of compound I-85 hydrobromide salt form I.
图11化合物I-85二氢溴酸盐晶型I的DSC和TGA图谱。Figure 11 DSC and TGA spectra of compound I-85 dihydrobromide salt form I.
图12化合物I-85甲磺酸盐晶型I的XRPD图谱。Figure 12 XRPD spectrum of compound I-85 mesylate salt Form I.
图13化合物I-85甲磺酸盐晶型I的DSC和TGA图谱。Figure 13 DSC and TGA spectra of compound I-85 mesylate salt form I.
图14-1化合物I-85对甲苯磺酸盐晶型I的XRPD图谱。Figure 14-1 XRPD spectrum of compound I-85 p-toluenesulfonate salt form I.
图14-2化合物I-85对甲苯磺酸盐晶型II的XRPD图谱。Figure 14-2 XRPD spectrum of compound I-85 p-toluenesulfonate salt form II.
图14-3化合物I-85对甲苯磺酸盐晶型III的XRPD图谱。Figure 14-3 XRPD spectrum of compound I-85 p-toluenesulfonate salt form III.
图15化合物I-85对甲苯磺酸盐晶型I的DSC和TGA图。Figure 15 DSC and TGA charts of compound I-85 p-toluenesulfonate salt Form I.
图16化合物I-85对甲苯磺酸盐晶型II的DSC和TGA图。Figure 16 DSC and TGA charts of compound I-85 p-toluenesulfonate form II.
图17化合物I-85对甲苯磺酸盐晶型III的DSC和TGA图。Figure 17 DSC and TGA charts of compound I-85 p-toluenesulfonate form III.
图18-1化合物I-85磷酸盐晶型I的XRPD图谱。Figure 18-1 XRPD spectrum of compound I-85 phosphate salt form I.
图18-2化合物I-85磷酸盐晶型II的XRPD图谱。Figure 18-2 XRPD spectrum of compound I-85 phosphate salt form II.
图19化合物I-85磷酸盐晶型I的DSC和TGA图谱。Figure 19 DSC and TGA spectra of compound I-85 phosphate salt form I.
图20化合物I-85磷酸盐晶型II的DSC和TGA图谱。Figure 20 DSC and TGA spectra of compound I-85 phosphate salt form II.
图21化合物I-85酒石酸盐晶型I的XRPD图谱。Figure 21 XRPD spectrum of compound I-85 tartrate salt form I.
图22化合物I-85酒石酸盐晶型I的DSC和TGA图谱。Figure 22 DSC and TGA spectra of compound I-85 tartrate salt form I.
图23化合物I-85富马酸盐晶型I的XRPD图。Figure 23 is the XRPD pattern of compound I-85 fumarate salt Form I.
图24化合物I-85富马酸盐晶型I的DSC和TGA图。Figure 24 DSC and TGA charts of compound I-85 fumarate salt Form I.
图25化合物I-85甲磺酸盐晶型II的XRPD图谱。Figure 25 XRPD spectrum of compound I-85 mesylate salt Form II.
图26化合物I-85甲磺酸盐晶型II的TGA和DSC图谱。Figure 26 TGA and DSC spectra of compound I-85 mesylate salt form II.
图27化合物I-85甲磺酸盐晶型III的XRPD图谱。Figure 27 XRPD spectrum of compound I-85 mesylate salt Form III.
图28化合物I-85甲磺酸盐晶型III的TGA和DSC图谱。Figure 28 TGA and DSC spectra of compound I-85 mesylate salt Form III.
图29化合物I-58与化合物I-85甲磺酸盐对实体肿瘤细胞生长抑制作用的比较。FIG29 Comparison of the inhibitory effects of compound I-58 and compound I-85 mesylate salts on the growth of solid tumor cells.
图30化合物I-85甲磺酸盐对59株不同组织来源的肿瘤细胞系的生长抑制50％(IC50)所需浓度。 FIG30 shows the concentration required for 50% (IC 50 ) inhibition of the growth of 59 tumor cell lines from different tissues by the mesylate salt of compound I-85.
图31化合物I-1对不同组织来源的肿瘤细胞系的生长抑制50％(IC50)所需浓度。FIG31 shows the concentration of compound I-1 required to inhibit the growth of tumor cell lines from different tissues by 50% (IC 50 ).
图32化合物I-1诱导肿瘤细胞凋亡。FIG32 Compound I-1 induces apoptosis of tumor cells.
图33化合物I-1诱导肿瘤细胞周期阻滞在G1(MDAH2774)、G2(HCT116)或S(SMMC7721)。FIG. 33 Compound I-1 induces tumor cell cycle arrest at G1 (MDAH2774), G2 (HCT116) or S (SMMC7721).
图34化合物I-85甲磺酸盐和化合物I-1降低肿瘤细胞内c-MYC、LSD1、Tankyrase(TNKS)蛋白表达水平。FIG34 Compound I-85 mesylate and compound I-1 reduce the expression levels of c-MYC, LSD1, and Tankyrase (TNKS) proteins in tumor cells.
图35化合物I-85甲磺酸盐(PBSS1113)抑制人食管癌在小鼠体内的生长(*代表p值小于0.05)。FIG35 Compound I-85 mesylate (PBSS1113) inhibits the growth of human esophageal cancer in mice (* represents p value less than 0.05).
图36化合物I-85甲磺酸盐(PBSS1113)抑制人肝癌在小鼠体内的生长(**代表p值小于0.01)。FIG36 Compound I-85 mesylate (PBSS1113) inhibits the growth of human liver cancer in mice (** represents p value less than 0.01).
图37化合物I-85甲磺酸盐(PBSS1113)抑制人结直肠癌在小鼠体内的生长(****代表p值小于0.0001)。FIG37 Compound I-85 mesylate (PBSS1113) inhibits the growth of human colorectal cancer in mice (**** represents p value less than 0.0001).
图38化合物I-85甲磺酸盐(PBSS1113)抑制人胰腺癌在小鼠体内的生长。FIG38 Compound I-85 mesylate (PBSS1113) inhibits the growth of human pancreatic cancer in mice.
图39化合物I-85甲磺酸盐(PBSS1113)抑制人淋巴瘤在小鼠体内的生长(*代表p值小于0.05，**代表p值小于0.01，****代表p值小于0.0001)。FIG39 Compound I-85 mesylate (PBSS1113) inhibits the growth of human lymphoma in mice (* represents p value less than 0.05, ** represents p value less than 0.01, **** represents p value less than 0.0001).
图40化合物I-85甲磺酸盐(PBSS1113)抑制人神经母细胞瘤小鼠体内的生长。FIG40 Compound I-85 mesylate (PBSS1113) inhibits the growth of human neuroblastoma in mice.
图41化合物I-85甲磺酸盐(PBSS1113)及化合物I-87抑制小鼠乳腺癌在小鼠体内的生长(**代表p值小于0.01，***代表p值小于0.001，****代表p值小于0.0001)。FIG41 Compound I-85 mesylate (PBSS1113) and Compound I-87 inhibit the growth of mouse breast cancer in mice (** represents p value less than 0.01, *** represents p value less than 0.001, **** represents p value less than 0.0001).
图42化合物I-87抑制人胰腺癌在小鼠体内的生长(***代表p值小于0.001，****代表p值小于0.0001)。FIG42 Compound I-87 inhibits the growth of human pancreatic cancer in mice (*** represents p value less than 0.001, **** represents p value less than 0.0001).
图43化合物I-87抑制人结直肠癌在小鼠体内的生长(**代表p值小于0.01，***代表p值小于0.001)。FIG43 Compound I-87 inhibits the growth of human colorectal cancer in mice (** represents p value less than 0.01, *** represents p value less than 0.001).
图44化合物I-87抑制小鼠乳腺癌在小鼠体内的生长(**代表p值小于0.01)。FIG44 Compound I-87 inhibits the growth of mouse breast cancer in mice (** represents p value less than 0.01).
图45化合物I-87抑制小鼠黑色素瘤在小鼠体内的生长(**代表p值小于0.01)。FIG45 Compound I-87 inhibits the growth of mouse melanoma in mice (** represents p value less than 0.01).
图46化合物I-87抑制小鼠结直肠癌在小鼠体内的生长(**代表p值小于0.01)。FIG46 Compound I-87 inhibits the growth of mouse colorectal cancer in mice (** represents p value less than 0.01).
图47化合物I-58与化合物I-85甲磺酸盐对AML细胞肿瘤细胞生长抑制作用的比较。Figure 47 Comparison of the inhibitory effects of compound I-58 and compound I-85 mesylate salts on the growth of AML tumor cells.
图48化合物I-85对29株AML细胞系生长抑制作用。FIG48 shows the growth inhibitory effect of compound I-85 on 29 AML cell lines.
图49化合物I-85处理可导致AML细胞凋亡。FIG49 Compound I-85 treatment can lead to apoptosis of AML cells.
图50化合物I-85(PBSS1113)在AML小鼠模型上的效果，阿霉素为阳性对照。FIG50 shows the effect of compound I-85 (PBSS1113) on AML mouse model, with doxorubicin as a positive control.
术语解释：Terminology explanation:
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combinations and combinations shall fall within the scope of the description of this application.
本申请说明书和权利要求书记载的数值范围，当该数值范围被定义为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。“更多个”表示三个或三个以上。When the numerical range described in the specification and claims of this application is defined as an "integer", it should be understood that the two endpoints of the range and each integer in the range are recorded. For example, "an integer from 0 to 6" should be understood as recording each integer of 0, 1, 2, 3, 4, 5 and 6. "More" means three or more.
术语“卤素”指F、Cl、Br和I。换言之，F、Cl、Br和I在本说明书中可描述为“卤素”。The term "halogen" refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I may be described as "halogen" in the present specification.
术语“脂肪烃基”包括饱和或不饱和，直链或支链的链状或环状烃基，所述脂肪烃基的类型可选自烷基、烯基、炔基等，所述脂肪烃基的碳原子数优选为1～12，还可以为1～10，进一步的优选范围为1～6，具体可包括但不限于如下基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基、1-己炔基、环丙基、环丁基、环戊基和环己基；所述脂肪烃基可任选包括一个或多个其它适宜的取代基。上述取代基的实例可以包括羟基、卤素、氰基和氨基等基团，例如所述脂肪烃基可以包含一个、两个或更多个卤素，即意味着脂肪烃基的一个、两个或更多个氢原子可以被同等数量的卤素所取代。如果所述烃基含有超过一个碳，那么那些碳不必必须彼此连接。例如，其中至少两个碳可以经适宜的元素或者基团进行连接。也就是说，所述脂肪烃基基团可以任选地包含一个、两个或更多个杂原子(或解释为任选地杂原子插入至脂肪烃基中任选地C-C键和C-H键)。适宜的杂原子对于本领域熟练技术人员而言是显而易见的，并且包括例如硫、氮、氧、磷和硅。所述包含杂原子的脂肪烃基基团可选自以下基团：(C1-C6)脂肪烃基氧基、(C1-C6)脂肪烃基巯基，卤代(C1-C6)脂肪烃基，卤代(C1-C6)脂肪烃基氧基、卤代(C1-C6)脂肪烃基硫基、(C1-C6)脂肪烃基氧基(C1-C6)脂肪烃基、(C1-C6)脂肪烃基巯基(C1-C6)脂肪烃基、N-(C1-C3)脂肪烃基胺基(C1-C6)脂肪烃基、N,N-二-(C1-C3)脂肪烃基胺基(C1-C6)脂肪烃基，例如可以为甲氧基甲基，乙氧基甲基、丙氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基、N-甲基胺甲基、N-甲基胺乙基、N-乙基胺乙基、N,N-二甲基胺甲基、N,N-二甲基胺乙基、N,N-二乙基胺乙基；其他基团中所含“脂肪烃基”部分同上述解释。 The term "aliphatic hydrocarbon group" includes saturated or unsaturated, linear or branched chain or cyclic hydrocarbon groups. The type of the aliphatic hydrocarbon group can be selected from alkyl, alkenyl, alkynyl, etc. The number of carbon atoms of the aliphatic hydrocarbon group is preferably 1 to 12, and can also be 1 to 10, and a further preferred range is 1 to 6. Specifically, it may include but is not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1- Methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the aliphatic hydrocarbon group may optionally include one or more other suitable substituents. Examples of the above-mentioned substituents may include groups such as hydroxyl, halogen, cyano and amino, for example, the aliphatic hydrocarbon group may contain one, two or more halogens, which means that one, two or more hydrogen atoms of the aliphatic hydrocarbon group may be replaced by an equal number of halogens. If the hydrocarbon group contains more than one carbon, then those carbons do not necessarily have to be connected to each other. For example, at least two of the carbons may be connected via a suitable element or group. That is, the aliphatic group may optionally contain one, two or more heteroatoms (or be interpreted as optionally heteroatoms inserted into the aliphatic group, optionally C—C bonds and C—H bonds). Suitable heteroatoms are obvious to those skilled in the art and include, for example, sulfur, nitrogen, oxygen, phosphorus and silicon. The heteroatom-containing aliphatic group may be selected from the following groups: (C 1 -C 6 ) aliphatic oxy, (C 1 -C 6 ) aliphatic mercapto, halogenated (C 1 -C 6 ) aliphatic, halogenated (C 1 -C 6 ) aliphatic oxy, halogenated (C 1 -C 6 ) aliphatic thio, (C 1 -C 6 ) aliphatic oxy (C 1 -C 6 ) aliphatic, (C 1 -C 6 ) aliphatic mercapto (C 1 -C 6 ) aliphatic, N-(C 1 -C 3 ) aliphatic amino (C 1 -C 6 ) aliphatic, N,N-di-(C 1 -C 3 ) aliphatic amino (C 1 -C 6 ) aliphatic hydrocarbon group, for example, may be methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl; the "aliphatic hydrocarbon group" contained in other groups is the same as explained above.
术语“3-20元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个独立选自N、O和S的杂原子，优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。所述3-20元杂环基可以进一步选自如下基团：
The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably a "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or, it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. According to the present invention, the heterocyclic group is non-aromatic. The 3-20-membered heterocyclic group may be further selected from the following groups:
除非另有说明，杂环基或杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。Unless otherwise indicated, heterocyclic or heteroaryl includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, pyridyl or pyridinylene includes pyridine-2-yl, pyridine-2-ylene, pyridine-3-yl, pyridine-3-ylene, pyridine-4-ylene and pyridine-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene.
在任何用于制备本发明化合物的方法中，可能必需和/或期望保护任何有关分子上的敏感或反应性基团。这可通过常规的保护基来实现，如本领域教科书或工具书描述的保护基。可使用本领域已知的方法在方便的后续阶段移除保护基团。本领域技术人员将认识到，取决于具体的保护基团，可将其他试剂用于该去保护步骤，包括但不限于Pd/C、Pd(OH)2、PdCl2、Pd(OAc)2/Et3SiH、雷尼镍、适当选择的酸、适当选择的碱、氟化物等等。In any method for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This may be accomplished by conventional protecting groups, such as those described in textbooks or reference books in the art. The protecting groups may be removed at a convenient subsequent stage using methods known in the art. Those skilled in the art will recognize that, depending on the specific protecting group, other reagents may be used for the deprotection step, including but not limited to Pd/C, Pd(OH) 2 , PdCl 2 , Pd(OAc) 2 /Et 3 SiH, Raney nickel, appropriately selected acids, appropriately selected bases, fluorides, and the like.
可以根据已知的方法，例如通过萃取、过滤、柱层析、FCC或制备型HPLC来分离目标化合物。The target compound can be isolated according to known methods, for example by extraction, filtration, column chromatography, FCC or preparative HPLC.
根据其分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。According to their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic form or in optically active form. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with optically active resolution agents. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in the R and S forms. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolution agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
本领域技术人员将理解，由于氮需要具有可用的孤对电子用于被氧化为氧化物，因此并非所有的含氮杂环都可以形成N-氧化物；本领域技术人员将识别能够形成N-氧化物的含氮杂环。本领域技术人员还将认识到叔胺能够形成N-氧化物。制备杂环和叔胺的N-氧化物的合成方法对于本领域技术人员而言是熟知的，所述合成方法包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基氢过氧化物如叔丁基氢过氧化物、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷氧化杂环和叔胺。这些制备N-氧化物的方法已在文献中广泛地描述和综述。Those skilled in the art will appreciate that, since nitrogen needs to have an available lone pair of electrons for being oxidized to oxides, not all nitrogen-containing heterocycles can form N-oxides; those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. The synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature.
由于本发明的化合物可存在多个成盐位点，所述“药学上可接受的盐”不仅包括本发明化合物其中1个成盐位点上形成的盐，而且还包括其中2、3或全部成盐位点上形成的盐。为此，所述“药学上可接受的盐”中式(I)化合物与成盐所需的酸的根离子(阴离子)或碱的阳离子摩尔比可以在较大的范围内变化，例如可以是4:1～1:4，如3:1、2:1、1:1、1:2、1:3等。Since the compounds of the present invention may have multiple salt-forming sites, the "pharmaceutically acceptable salts" include not only salts formed at one of the salt-forming sites of the compounds of the present invention, but also salts formed at 2, 3 or all of the salt-forming sites. For this reason, the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid or the cation of the base required for salt formation in the "pharmaceutically acceptable salt" may vary within a wide range, for example, it may be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
根据不同取代基的位置和性质，本发明的化合物还可以包含一个或多个不对称中心。不对称碳原子可以(R)或(S)构型存在，仅有一个不对称中心时，产生外消旋混合物，含有多个不对称中心时，得到非对映异构体混合物。在某些情况下，由于围绕特定键的旋转受阻还可能存在不对称性，例如该中心键连接特定化合物的两个被取代的芳族环。并且，取代基还可以顺式或反式异构的形式存在。Depending on the position and properties of the different substituents, the compounds of the present invention may also contain one or more asymmetric centers. Asymmetric carbon atoms may exist in (R) or (S) configurations, with only one asymmetric center resulting in a racemic mixture and multiple asymmetric centers resulting in a diastereomeric mixture. In some cases, asymmetry may also exist due to hindered rotation around a particular bond, such as the central bond connecting two substituted aromatic rings of a particular compound. Furthermore, the substituents may also exist in cis or trans isomeric forms.
本发明化合物还包括其各自所有可能的立体异构体，其是单一立体异构体或所述立体异构体(例如R-异构体或S-异构体，或者E-异构体或Z-异构体)的任意比例的任意混合物的形式。可通过任意适合的现有技术方法(例如色谱法，特别是例如手性色谱法)实现本发明的化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离。 The compounds of the present invention also include all possible stereoisomers thereof, in the form of a single stereoisomer or any mixture of any proportion of said stereoisomers (e.g., R-isomers or S-isomers, or E-isomers or Z-isomers). The separation of a single stereoisomer (e.g., a single enantiomer or a single diastereomer) of a compound of the present invention can be achieved by any suitable prior art method (e.g., chromatography, in particular, e.g., chiral chromatography).
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
在本发明中，所涉及的化合物亦包括经同位素标记的化合物，所述经同位素标记的化合物与式I中所示的那些相同，但是其中一或多个原子被原子质量或质量数不同于通常天然存在的原子质量或质量数的原子替代。可掺入本发明的化合物的同位素的实例包括H、C、N、O、S、F及Cl的同位素，分别诸如2H、3H、13C、11C、14C、15N、18O、17O、32P、35S、18F及36Cl。含有上述同位素和/或其他原子的其他同位素的本发明的化合物、其前药、或者所述化合物或所述前药的药学上可接受的盐在本发明的范围内。本发明的某些经同位素标记的化合物，例如掺入放射性同位素(诸如3H和14C)的化合物可用于药物和/或底物组织分布测定。氚(即3H)和碳14(即14C)同位素因易于制备和可检测性而成为特别优选的。再者，以较重的同位素(诸如氘，即2H)替代可提供源自更高的代谢稳定性的某些治疗优势(例如增加的体内半衰期或减少的剂量需求)，并因此可在某些情况下是优选的。如权利要求所请求保护的本发明化合物可特别地限定以氘或氚替代。此外，取代基中出现的氢未单独列明术语氘或氚并不表示排除氘或氚，而是同样也可以包含氘或氚。In the present invention, the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but one or more atoms are replaced by atoms having atomic masses or mass numbers different from the atomic masses or mass numbers usually occurring in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F and Cl, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F and 36 Cl, respectively. Compounds of the present invention, prodrugs thereof, or pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example compounds incorporating radioactive isotopes (such as 3 H and 14 C) can be used for drug and/or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon 14 (i.e., 14 C) isotopes are particularly preferred due to ease of preparation and detectability. Furthermore, substitution with heavier isotopes (such as deuterium, i.e., 2 H) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability, and therefore may be preferred in certain circumstances. The compounds of the invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. In addition, the presence of hydrogen in a substituent without the term deuterium or tritium being separately listed does not exclude deuterium or tritium, but may also contain deuterium or tritium.
术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述化合物的量。治疗有效量可以取决于以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定化合物、所依据的给药方案、是否与其它化合物组合给药、给药的时间安排、所给药的组织和所承载的物理递送系统。The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition to be treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific compound selected, the dosage regimen relied on, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried.
术语“辅料”是指可药用惰性成分。赋形剂种类的实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的药学上可接受的载体的实例为：糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；硬脂酸；植物油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和负离子表面活性剂；乙二醇聚合物；脂肪醇类；和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of excipient types include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion. Examples of typical pharmaceutically acceptable carriers suitable for the above-mentioned preparations are: sugars, such as lactose, sucrose, mannitol and sorbitol; starches, such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinyl pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; fatty alcohols; and cereal hydrolyzed solids and other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants and other excipients commonly used in pharmaceutical preparations.
术语“溶剂化物”是本发明的化合物的那些形式，其以固体或液体的状态通过与溶剂分子的配位作用形成配合物。水合物是溶剂化物的特定形式，其中配位作用是与水进行。在本发明中，优选的溶剂化物是水合物。进一步的，本发明通式I化合物的药学上可接受的溶剂化物(水合物)是指化合物I与化学计量学的一个或多个分子的水或其他溶剂形成的共晶和包合物。可用于溶剂化物的溶剂包括但不限于：水、甲醇、乙醇、乙二醇和醋酸。The term "solvate" refers to those forms of the compounds of the present invention, which form complexes in a solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination is with water. In the present invention, preferred solvates are hydrates. Further, pharmaceutically acceptable solvates (hydrates) of compounds of formula I of the present invention refer to cocrystals and inclusion compounds formed by compound I with one or more molecules of water or other solvents in stoichiometry. Solvents that can be used for solvates include, but are not limited to, water, methanol, ethanol, ethylene glycol and acetic acid.
术语“前药”或称为“药物前体”，代表化合物在体内转化为前述通式或具体化合物所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前药可以是酯，在本发明中酯可以作为前药的有苯酯类，脂肪族(C1-C24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基或羧基，即可以将其酰化得到前体药物形式的化合物。其他的前药形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。The term "prodrug" or "drug precursor" refers to a compound that is converted in vivo into a compound represented by the aforementioned general formula or specific compound. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug of the present invention can be an ester. Among the esters that can be used as prodrugs in the present invention are phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group or a carboxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
本发明所述式(I)所示化合物的制备方法参考专利文献WO2020/224652A1。The preparation method of the compound represented by formula (I) described in the present invention refers to patent document WO2020/224652A1.
测试例中所述的I-85的甲磺酸盐均为化合物I-85的甲磺酸盐晶型I。The mesylate salts of I-85 described in the test examples are all mesylate crystal form I of compound I-85.
实施例中使用的各种分析方法如下：The various analytical methods used in the examples are as follows:
X射线粉末衍射(XRPD)X-ray powder diffraction (XRPD)
利用配备了PIXcel1D检测器的X射线粉末衍射仪PANalytical Empyrean对实验中所得到的固体进行固体形态分析。样品扫描范围从3°2θ到40°2θ，步长为0.013°2θ。光管电压和电流分别为45KV和40mA。 The solid morphology of the solid obtained in the experiment was analyzed using an X-ray powder diffractometer PANalytical Empyrean equipped with a PIXcel 1D detector. The sample scan range was from 3°2θ to 40°2θ, with a step size of 0.013°2θ. The light tube voltage and current were 45KV and 40mA, respectively.
示差扫描量热分析(DSC)Differential Scanning Calorimetry (DSC)
利用Discovery DSC 250(TA Instruments,US)对样品进行了热分析。称取～2mg样品置于DSC样品盘中并扎孔。将样品在25℃平衡后以10℃/min的速率加热至300℃。Thermal analysis of the samples was performed using a Discovery DSC 250 (TA Instruments, US). ~2 mg of the sample was weighed and placed in a DSC sample pan and pierced. The sample was equilibrated at 25°C and then heated to 300°C at a rate of 10°C/min.
热重分析(TGA)Thermogravimetric analysis (TGA)
利用TGA 55(TA Instruments,US)对样品进行了热重分析。将样品置于已去皮的闭口铝制样品盘中，样品质量在TGA加热炉内自动称量后，将样品以10℃/min的速率加热至300℃(未设置平衡程序，样品盘加盖打孔)。The samples were subjected to thermogravimetric analysis using a TGA 55 (TA Instruments, US). The samples were placed in a peeled closed aluminum sample pan, and after the sample mass was automatically weighed in the TGA heating furnace, the samples were heated to 300°C at a rate of 10°C/min (no balance program was set, and the sample pan was covered and perforated).
动态水分吸附脱附分析(DVS)Dynamic Water Sorption and Desorption Analysis (DVS)
利用Vsorp(ProUmid GmbH & Co.KG,Germany)水分吸附分析仪对样品进行水分吸附/脱附测试。将样品置于去皮后的样品盘中，并记录25℃下样品质量随湿度的变化。The samples were subjected to moisture adsorption/desorption tests using a moisture adsorption analyzer from Vsorp (ProUmid GmbH & Co. KG, Germany). The samples were placed in a peeled sample pan and the changes in sample mass with humidity at 25°C were recorded.
偏光显微镜分析(PLM)Polarized light microscopy (PLM)
PLM分析采用的仪器为Polarizing Microscope ECLIPSE LV100POL(Nikon,JPN)。The instrument used for PLM analysis is Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).
1H-NMR分析(1H-NMR) 1 H-NMR analysis ( 1 H-NMR)
固体样品的结构经1H-NMR确认。1H-NMR分析采用的仪器是配备有Sample Xpress 60自动进样系统的Bruker AVANCE III HD 300/400。The structure of the solid sample was confirmed by 1 H-NMR. 1 H-NMR analysis was performed using a Bruker AVANCE III HD 300/400 equipped with a Sample Xpress 60 autosampler.
高效液相色谱(HPLC)High Performance Liquid Chromatography (HPLC)
HPLC分析采用的仪器为Agilent HPLC 1260 series。溶解度和稳定性试验所用的HPLC方法如表4所示。
The instrument used for HPLC analysis was Agilent HPLC 1260 series. The HPLC method used for solubility and stability tests is shown in Table 4.
制备例1、化合物Ⅰ-85(游离碱)的制备Preparation Example 1. Preparation of Compound I-85 (free base)
化合物I-85游离碱的制备路线:
Preparation route of compound I-85 free base:
具体操作如下：
The specific operations are as follows:
向反应瓶(100mL)中加入4-溴-2-羟基苯甲醛A1(3.02g,15mmol)、二正丁胺盐酸盐(1.24g,7.5mmol)、2-硝基乙醇(2.73g,30mmol)和乙酸戊酯(15mL)。氮气保护，加热回流，分水器除水。反应8小时后冷却至室温，过滤，深色固体用乙酸乙酯洗涤，滤液减压浓缩。硅胶柱层析(100g，200-300目，PE/EtOAc＝20:1洗脱)，浓缩，干燥得A2(黄色固体1.92g,50％)。ESI-MS:255.7/257.7[M+H]+；1H NMR(600MHz,CDCl3)δ7.74(br s,1H),7.16(dd,J＝8.1,1.8Hz,1H),7.11(d,J＝8.1Hz,1H),7.10(d,J＝1.8Hz,1H),5.25(d,J＝1.0Hz,2H)。
Add 4-bromo-2-hydroxybenzaldehyde A1 (3.02 g, 15 mmol), di-n-butylamine hydrochloride (1.24 g, 7.5 mmol), 2-nitroethanol (2.73 g, 30 mmol) and amyl acetate (15 mL) to a reaction bottle (100 mL). Protect with nitrogen, heat to reflux, and remove water with a water separator. After reacting for 8 hours, cool to room temperature, filter, wash the dark solid with ethyl acetate, and concentrate the filtrate under reduced pressure. Silica gel column chromatography (100 g, 200-300 mesh, PE/EtOAc=20:1 elution), concentrate, and dry to obtain A2 (yellow solid 1.92 g, 50%). ESI-MS: 255.7/257.7 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 ) δ 7.74 (br s, 1H), 7.16 (dd, J=8.1, 1.8 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.10 (d, J=1.8 Hz, 1H), 5.25 (d, J=1.0 Hz, 2H).
向反应瓶(100mL)中加入A2(1.9g，7.42mmol)和无水THF(32mL)，冷却至0℃，氮气保护下滴加硼烷四氢呋喃溶液(1M，37.1mL,37.1mmol)。滴加完后，移除冰浴，加入NaBH4(0.28g,7.42mmol)，回流反应18小时。反应液冷却至室温，缓慢滴加1N盐酸调pH 1～2，升温至70℃反应1.5小时。反应液冷却至室温，乙醚(60mL×2)萃取，水溶液加1N氢氧化钠溶液调pH～10。乙酸乙酯(60mL×3)萃取，合并萃取液，饱和NaCl溶液(60mL×2)洗，无水硫酸钠干燥，过滤，浓缩，干燥得(±)-7-溴-苯并二氢吡喃-3-胺(淡棕色固体1.51g,89％)。ESI-MS:227.7/229.7[M+H]+；1H NMR(600MHz,CDCl3)δ6.99(d,J＝2.0Hz,1H),6.98(dd,J＝8.0,2.0Hz,1H),6.90(d,J＝8.0Hz,1H),4.12(ddd,J＝10.6,2.9,1.6Hz,1H),3.80(ddd,J＝10.6,7.1,1.0Hz,1H),3.35(tdd,J＝7.1,5.1,2.9Hz,1H),2.98(dd,J＝16.1,5.1Hz,1H),2.51(dd,J＝16.1,7.1Hz,1H)。A2 (1.9 g, 7.42 mmol) and anhydrous THF (32 mL) were added to the reaction flask (100 mL), cooled to 0 ° C, and borane tetrahydrofuran solution (1M, 37.1 mL, 37.1 mmol) was added dropwise under nitrogen protection. After the addition was complete, the ice bath was removed, NaBH 4 (0.28 g, 7.42 mmol) was added, and the reaction was refluxed for 18 hours. The reaction solution was cooled to room temperature, 1N hydrochloric acid was slowly added dropwise to adjust the pH to 1-2, and the temperature was raised to 70 ° C for 1.5 hours. The reaction solution was cooled to room temperature, extracted with ether (60 mL × 2), and the aqueous solution was adjusted to pH ~ 10 with 1N sodium hydroxide solution. Ethyl acetate (60 mL × 3) was extracted, the extracts were combined, washed with saturated NaCl solution (60 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain (±)-7-bromo-benzodihydropyran-3-amine (light brown solid 1.51 g, 89%). ESI-MS: 227.7/229.7 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 ) δ 6.99 (d, J=2.0 Hz, 1H), 6.98 (dd, J=8.0, 2.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.12 (ddd, J=10.6, 2.9, 1.6 Hz, 1H), 3.80 (ddd, J=10.6, 7.1, 1.0 Hz, 1H), 3.35 (tdd, J=7.1, 5.1, 2.9 Hz, 1H), 2.98 (dd, J=16.1, 5.1 Hz, 1H), 2.51 (dd, J=16.1, 7.1 Hz, 1H).
化合物A3的拆分Resolution of compound A3
方法Ι：手性柱拆分Method I: Chiral column separation
(±)7-溴-苯并二氢吡喃-3-胺(742mg)溶于1.5mL Hexane-EtOH(1:1)，Daicel IA(5μm,10×250mm)，流动相：Hexane/EtOH/DEA＝70:30:0.2，流速：2.5mL/min，柱温：25℃，检测波长：254nm，进样量25μL。得(R)-7-溴-苯并二氢吡喃-3-胺A3(白色固体323mg,tR1＝14.0min,[α]25 D＝-100.2(c 0.2,MeOH))和(S)-7-溴-苯并二氢吡喃-3-胺(白色固体306mg,tR2＝16.7min,[α]25 D＝100.0(c 0.2,MeOH))。(±)7-Bromo-chroman-3-amine (742 mg) was dissolved in 1.5 mL Hexane-EtOH (1:1), Daicel IA (5 μm, 10×250 mm), mobile phase: Hexane/EtOH/DEA=70:30:0.2, flow rate: 2.5 mL/min, column temperature: 25°C, detection wavelength: 254 nm, injection volume 25 μL. (R)-7-Bromo-chroman-3-amine A3 (white solid 323 mg, t R1 ＝14.0 min, [α] 25 D ＝-100.2 (c 0.2, MeOH)) and (S)-7-Bromo-chroman-3-amine (white solid 306 mg, t R2 ＝16.7 min, [α] 25 D ＝100.0 (c 0.2, MeOH)) were obtained.
方法ΙΙ：手性酸拆分Method II: Chiral Acid Resolution
向反应瓶(500mL)中加入(±)-7-溴-苯并二氢吡喃-3-胺(8.20g,36.0mmol)、S-(+)-2-苯丙酸(5.41g,36.0mmol)和MeOH(360mL)，加热回流。待固体全部溶解后，室温下静置结晶，大量针状晶体析出。抽滤，MeOH(50mL)洗涤，干燥得(R)-(-)-7-溴-苯并二氢吡喃-3-胺-S-(+)-2-苯丙酸盐(白色晶体4.49g)，多次重结晶得(R)-(-)-7-溴-苯并二氢吡喃-3-胺-S-(+)-2-苯丙酸盐(3.09g)。向反应瓶(100mL)中加入(R)-(-)-7-溴-苯并二氢吡喃-3-胺-S-(+)-2-苯丙酸盐(3.09g)、水(30mL)和EtOAc(30mL)，搅拌下滴加18％HCl溶液调pH～1，分出EtOAc层，水相用EtOAc(30mL×2)萃取回收S-(+)-2-苯丙酸。水相用CHCl3(30mL)萃除残留EtOAc后，用10N氢氧化钠溶液调pH～10，CHCl3(30mL×3)萃取，CHCl3层用饱和NaCl溶液(30mL×2)洗涤，无水Na2SO4干燥，减压浓缩，干燥得(R)-(-)-7-溴-苯并二氢吡喃-3-胺A3(白色固体1.85g,99.1％ee)。详细拆分流程如下：
Add (±)-7-bromo-benzodihydropyran-3-amine (8.20 g, 36.0 mmol), S-(+)-2-phenylpropionic acid (5.41 g, 36.0 mmol) and MeOH (360 mL) to a reaction bottle (500 mL) and heat to reflux. After all the solids are dissolved, stand at room temperature for crystallization, and a large number of needle-shaped crystals are precipitated. Filter by suction, wash with MeOH (50 mL), and dry to obtain (R)-(-)-7-bromo-benzodihydropyran-3-amine-S-(+)-2-phenylpropionic acid salt (white crystals 4.49 g), which is recrystallized multiple times to obtain (R)-(-)-7-bromo-benzodihydropyran-3-amine-S-(+)-2-phenylpropionic acid salt (3.09 g). Add (R)-(-)-7-bromo-benzodihydropyran-3-amine-S-(+)-2-phenylpropionic acid salt (3.09 g), water (30 mL) and EtOAc (30 mL) to a reaction bottle (100 mL), add 18% HCl solution dropwise to adjust the pH to 1 under stirring, separate the EtOAc layer, and extract the aqueous phase with EtOAc (30 mL×2) to recover S-(+)-2-phenylpropionic acid. After the aqueous phase is extracted with CHCl 3 (30 mL) to remove the residual EtOAc, adjust the pH to 10 with 10N sodium hydroxide solution, extract with CHCl 3 (30 mL×3), wash the CHCl 3 layer with saturated NaCl solution (30 mL×2), dry over anhydrous Na 2 SO 4 , and concentrate under reduced pressure to obtain (R)-(-)-7-bromo-benzodihydropyran-3-amine A3 (white solid 1.85 g, 99.1% ee). The detailed separation process is as follows:
向反应瓶(100mL)中加入A3(1.82g,8mmol)、K2CO3(6.36g,46mmol)、KI(133mg,0.8mmol)和MeCN(25mL)，升温至80℃，30min内滴加氯苄(3.04g,24mmol)/MeCN(7mL)。滴加完毕，80℃继续反应4h。反应液冷却至室温，加入水(40mL)，用DCM(40mL×3)萃取，合并萃取液，饱和NaCl溶液(40mL×2)洗，无水Na2SO4干燥，减压浓缩得粗品。硅胶柱层析(100g，200-300目，PE/EtOAc＝50:1洗脱)，得A4(白色固体3.11g,95％)。Rf＝0.68(PE/EtOAc＝19:1)；ESI-MS:407.8/409.8[M+H]+；1H NMR(600MHz,CDCl3)δ7.37(d,J＝7.2Hz,4H),7.31(dd,J＝7.7,7.4Hz,4H),7.23(tt,J＝7.3,1.4Hz,2H),6.96(dd,J＝8.1,1.9Hz,1H),6.93(d,J＝1.9Hz,1H),6.90(d,J＝8.1Hz,1H),4.32(ddd,J＝10.5,3.6,1.9Hz,1H),3.96(t,J＝10.1Hz,1H),3.76(d,J＝14.1Hz,2H),3.74(d,J＝14.1Hz,2H),3.24(tdd,J＝9.8,5.7,3.6Hz,1H),2.93(dd,J＝16.1,10.1Hz,1H),2.87(ddd,J＝16.1,5.7,1.2Hz,1H).
A3 (1.82 g, 8 mmol), K 2 CO 3 (6.36 g, 46 mmol), KI (133 mg, 0.8 mmol) and MeCN (25 mL) were added to a reaction flask (100 mL), the temperature was raised to 80°C, and benzyl chloride (3.04 g, 24 mmol)/MeCN (7 mL) was added dropwise within 30 min. After the addition was complete, the reaction was continued at 80°C for 4 h. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with DCM (40 mL × 3). The extracts were combined, washed with saturated NaCl solution (40 mL × 2), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (100 g, 200-300 mesh, PE/EtOAc = 50:1 elution) gave A4 (white solid 3.11 g, 95%). R f =0.68 (PE/EtOAc=19:1); ESI-MS: 407.8/409.8 [M+H] + ; 1 H NMR (600 MHz, CDCl3) δ7.37 (d, J=7.2 Hz, 4H), 7.31 (dd, J=7.7, 7.4 Hz, 4H), 7.23 (tt, J=7.3, 1.4 Hz, 2H), 6.96 (dd, J=8.1, 1.9 Hz, 1H), 6.93 (d, J=1.9 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 4.32 (ddd, J=10. 5,3.6,1.9 Hz,1H),3.96 (t, J = 10.1 Hz,1H),3.76 (d, J = 14.1 Hz,2H),3.74 (d, J = 14.1 Hz,2H),3.24 (tdd, J = 9.8,5.7,3.6 Hz,1H),2.93 (dd, J = 16.1,10.1 Hz,1H),2.87 (ddd, J = 16.1,5.7,1.2 Hz,1H).
向反应瓶(10mL)中加入A4(318mg,1.0mmol)、8-Boc-3,8-二氮杂双环[3.2.1]辛烷(234mg,1.1mmol)、Pd(OAc)2(22mg,0.1mmol)、Xphos(48mg,0.1mmol)和Cs2CO3(652mg,2.0mmol)，N2保护下加入PhMe(5mL)。升温至100℃反应过夜。反应液冷却至室温，加入水(10mL)，用DCM(10mL×3)萃取，合并萃取液，饱和NaCl溶液(15mL×2)洗，无水Na2SO4干燥，减压浓缩得粗品。硅胶柱层析(20g，200-300目，DCM/MeOH＝100:1洗脱)，得A5(浅黄色胶状物450mg,100％)。Rf＝0.24(DCM/MeOH＝100:1)；ESI-MS:540.4[M+H]+；1H NMR(600MHz,CDCl3)δ7.37(d,J＝7.6Hz,4H),7.30(t,J＝7.5Hz,4H),7.22(t,J＝7.3Hz,2H),6.93(d,J＝8.5Hz,1H),6.38(dd,J＝8.5,2.4Hz,1H),6.23(d,J＝2.4Hz,1H),4.42–4.20(m,3H),3.94(t,J＝10.1Hz,1H),3.76(d,J＝14.7Hz,2H),3.73(d,J＝14.7Hz,2H),3.31(td,J＝11.4,1.9Hz,2H),3.27–3.20(m,1H),2.92(dd,J＝15.5,10.5Hz,2H),2.84(dd,J＝15.5,5.3Hz,1H),1.96–1.88(m,2H),1.85–1.77(m,2H),,1.46(s,9H).
A4 (318 mg, 1.0 mmol), 8-Boc-3,8-diazabicyclo[3.2.1]octane (234 mg, 1.1 mmol), Pd(OAc) 2 (22 mg, 0.1 mmol), Xphos (48 mg, 0.1 mmol) and Cs 2 CO 3 (652 mg, 2.0 mmol) were added to a reaction flask (10 mL). PhMe (5 mL) was added under N 2 protection. The temperature was raised to 100°C and the reaction was continued overnight. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with DCM (10 mL×3). The extracts were combined, washed with saturated NaCl solution (15 mL×2), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (20 g, 200-300 mesh, DCM/MeOH=100:1 elution) gave A5 (450 mg, 100%) as a light yellow jelly. R f =0.24 (DCM/MeOH=100:1); ESI-MS: 540.4 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 ) δ7.37 (d, J=7.6 Hz, 4H), 7.30 (t, J=7.5 Hz, 4H), 7.22 (t, J=7.3 Hz, 2H), 6.93 (d, J=8.5 Hz, 1H), 6.38 (dd, J=8.5, 2.4 Hz, 1H), 6.23 (d, J=2.4 Hz, 1H), 4.42-4.20 (m, 3H), 3.94 (t, J=10.1 Hz, 1H), 3.76 (d, J= 14.7 Hz, 2H), 3.73 (d, J = 14.7 Hz, 2H), 3.31 (td, J = 11.4, 1.9 Hz, 2H), 3.27–3.20 (m, 1H), 2.92 (dd, J = 15.5, 10.5 Hz, 2H), 2.84 (dd, J = 15.5, 5.3 Hz, 1H), 1.96–1.88 (m, 2H), 1.85–1.77 (m, 2H),, 1.46 (s, 9H).
向反应瓶(10mL)中加入A5(450mg,1.0mmol)、甲酸铵(1.26g,20mmol)和Pd(OH)2-C(71mg,0.1mmol,含15％Pd)，N2保护下加入MeOH(5mL)，升温至50℃反应过夜。反应液冷却至室温，过滤，减压浓缩得粗品。硅胶柱层析(30g，200-300目，DCM/MeOH＝25:1–9:1洗脱)，得A6(浅黄色胶状物450mg,100％)。Rf＝0.52(DCM/MeOH＝9:1)；ESI-MS:360.2[M+H]+。
A5 (450 mg, 1.0 mmol), ammonium formate (1.26 g, 20 mmol) and Pd(OH) 2 -C (71 mg, 0.1 mmol, containing 15% Pd) were added to a reaction bottle (10 mL). MeOH (5 mL) was added under N 2 protection and the temperature was raised to 50°C for overnight reaction. The reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (30 g, 200-300 mesh, DCM/MeOH=25:1–9:1 elution) gave A6 (450 mg, 100% light yellow jelly). R f =0.52 (DCM/MeOH=9:1); ESI-MS:360.2[M+H] + .
向反应瓶(500mL)中加入KSAc(57.11g,0.50mol)和干燥DMF(250mL)，室温搅拌下，30min内滴加溴代乙酸叔丁酯B1。继续室温反应1h后，反应液80℃减压除DMF。浓缩液冷至室温，加入水(150mL)，DCM(150mL×2)萃取，合并萃取液，饱和NaCl溶液(100mL×3)洗，无水Na2SO4干燥。抽滤，减压浓缩得B2(橙红色液体95.09g,100％)。Rf＝0.53(PE/EA＝9:1)；1H NMR(600MHz,CDCl3)δ3.61(s,2H),2.37(s,3H),1.45(s,9H)。
Add KSAc (57.11 g, 0.50 mol) and dry DMF (250 mL) to a reaction flask (500 mL). Stir at room temperature and then dropwise add tert-butyl bromoacetate B1 within 30 min. Continue to react at room temperature for 1 h, and then remove DMF at 80 °C under reduced pressure. The concentrated solution is cooled to room temperature, and water (150 mL) is added. DCM (150 mL × 2) is extracted, and the combined extracts are washed with saturated NaCl solution (100 mL × 3), and dried over anhydrous Na 2 SO 4. Filter and concentrate under reduced pressure to obtain B2 (orange-red liquid 95.09 g, 100%). R f = 0.53 (PE/EA = 9:1); 1 H NMR (600 MHz, CDCl 3 ) δ 3.61 (s, 2H), 2.37 (s, 3H), 1.45 (s, 9H).
向反应瓶(250mL)中加入2-氯-3-氰基-6-甲基吡啶(7.63g,50mmol)、B2(10.46g,55mmol)和干燥DMF(100mL)，冰浴冷却至0℃，分3批加入NaOMe(3.24g,60mmol)/45min。加完后回温至室温反应1h。搅拌下，反应液缓慢倾入水(1.2L)中，大量黄色固体析出。抽滤，水洗至滤液中性。粗品经甲醇重结晶，得B3(黄色晶体10.80g,82％)。Rf＝0.36(PE/Acetone＝17:3)；ESI-MS:265.0[M+H]+；1H NMR(600MHz,CDCl3)δ7.77(d,J＝8.3Hz,1H),7.13(d,J＝8.3Hz,1H),5.79(s,2H),2.66(s,3H),1.59(s,9H)。
Add 2-chloro-3-cyano-6-methylpyridine (7.63 g, 50 mmol), B2 (10.46 g, 55 mmol) and dry DMF (100 mL) to the reaction bottle (250 mL), cool to 0 ° C in an ice bath, and add NaOMe (3.24 g, 60 mmol) in 3 batches/45 min. After adding, return to room temperature and react for 1 h. Under stirring, the reaction solution is slowly poured into water (1.2 L), and a large amount of yellow solid precipitates. Filter and wash with water until the filtrate is neutral. The crude product is recrystallized from methanol to obtain B3 (yellow crystals 10.80 g, 82%). R f =0.36 (PE/Acetone=17:3); ESI-MS: 265.0 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 ) δ7.77 (d, J=8.3 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 5.79 (s, 2H), 2.66 (s, 3H), 1.59 (s, 9H).
向反应瓶(250mL)中加入B3(7.93g,30mmol)、NaHCO3(5.04g,60mmol)和DCM(60mL)。室温下滴加三氟乙酸酐(7.56g,36mmol)/15min，室温反应30min。搅拌下向反应液中加入冰水(30mL)，分出DCM层，水溶液用DCM(30mL×2)萃取，合并萃取液，饱和NaCl溶液(40mL×2)洗，无水Na2SO4干燥。减压浓缩得3-三氟乙酰氨基-6-甲基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯(黄色固体10.80g，收率100％)。Rf＝0.57(PE/EtOAc＝17:3)；ESI-MS:361.0[M+H]+；359.1[M-H]-；1H NMR(600MHz,CDCl3)δ11.14(s,1H),8.46(d,J＝8.6Hz,1H),7.23(d,J＝8.6Hz,1H),2.69(s,3H),1.63(s,9H)。Add B3 (7.93 g, 30 mmol), NaHCO 3 (5.04 g, 60 mmol) and DCM (60 mL) to a reaction flask (250 mL). Add trifluoroacetic anhydride (7.56 g, 36 mmol) dropwise at room temperature for 15 min and react at room temperature for 30 min. Add ice water (30 mL) to the reaction solution under stirring, separate the DCM layer, extract the aqueous solution with DCM (30 mL × 2), combine the extracts, wash with saturated NaCl solution (40 mL × 2), and dry over anhydrous Na 2 SO 4. Concentrate under reduced pressure to obtain tert-butyl 3-trifluoroacetylamino-6-methylthieno[2,3-b]pyridine-2-carboxylate (yellow solid 10.80 g, yield 100%). R f =0.57 (PE/EtOAc=17:3); ESI-MS: 361.0 [M+H] + ; 359.1 [MH] − ; 1 H NMR (600 MHz, CDCl 3 ) δ11.14 (s, 1H), 8.46 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 2.69 (s, 3H), 1.63 (s, 9H).
向反应瓶(250mL)中加入3-三氟乙酰氨基-6-甲基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯(10.80g,30mmol)和干燥DMF(90mL)，室温搅拌使固体全溶。降温至0℃，加入NaH(60％油分散，1.26g,31.5mmol)，大量H2产生，0℃下继续反应30min后，滴加MeI(5.11g,36mmol)/30min。滴加完毕，撤除冰浴，回温至室温继续反应1h。反应液滴加HOAc调pH～7，加入水(150mL)，DCM(100mL×3)萃取，合并萃取液，饱和NaCl溶液(100mL×2)洗，无水Na2SO4干燥，减压浓缩，EtOH多次重结晶，得3-N-甲基-N-三氟乙酰-氨基-6-甲基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯(白色晶体9.89g,收率88％)。Rf＝0.35(PE/EtOAc＝17:3)；ESI-MS:375.1[M+H]+；1H NMR(500MHz,CDCl3)δ7.83(d,J＝8.3Hz,1H),7.30(d,J＝8.3Hz,1H),3.36(s,3H),2.72(s,3H),1.57(s,9H)。Add tert-butyl 3-trifluoroacetylamino-6-methylthieno[2,3-b]pyridine-2-carboxylate (10.80 g, 30 mmol) and dry DMF (90 mL) to the reaction bottle (250 mL), stir at room temperature to dissolve the solid. Cool to 0°C, add NaH (60% oil dispersion, 1.26 g, 31.5 mmol), a large amount of H 2 is generated, continue to react at 0°C for 30 min, then add MeI (5.11 g, 36 mmol)/30 min. After the addition is complete, remove the ice bath, return to room temperature and continue to react for 1 h. HOAc was added dropwise to the reaction solution to adjust the pH to 7, water (150 mL) was added, and DCM (100 mL×3) was used for extraction. The extracts were combined, washed with saturated NaCl solution (100 mL×2), dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and recrystallized from EtOH several times to obtain tert-butyl 3-N-methyl-N-trifluoroacetyl-amino-6-methylthieno[2,3-b]pyridine-2-carboxylate (white crystals, 9.89 g, yield 88%). R f ＝0.35 (PE/EtOAc＝17:3); ESI-MS: 375.1[M+H] + ； 1 H NMR (500 MHz, CDCl 3 )δ7.83(d, J＝8.3 Hz, 1H), 7.30(d, J＝8.3 Hz, 1H), 3.36(s, 3H), 2.72(s, 3H), 1.57(s, 9H).
向反应瓶(100mL)中加入3-N-甲基-N-三氟乙酰-氨基-6-甲基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯(3.00g,8mmol)、DCM(20mL)和三氟乙酸(10mL)，40℃过夜反应。减压蒸除DCM和三氟乙酸，过硅胶短柱得B4(黄色泡沫状固体2.55g,收率100％)。Rf＝0.30(CHCl3/MeOH＝4:1)；ESI-MS:317.1[M-H]-；1H NMR(600MHz,DMSO-d6)δ14.23(br s,1H),8.32(d,J＝8.3Hz,1H),7.50(d,J＝8.3Hz,1H),3.30(s,3H),2.65(s,3H)。
3-N-methyl-N-trifluoroacetyl-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid tert-butyl ester (3.00 g, 8 mmol), DCM (20 mL) and trifluoroacetic acid (10 mL) were added to a reaction bottle (100 mL) and reacted at 40°C overnight. DCM and trifluoroacetic acid were evaporated under reduced pressure, and B4 (yellow foamy solid 2.55 g, yield 100%) was obtained by passing through a silica gel short column. R f = 0.30 (CHCl 3 /MeOH = 4:1); ESI-MS: 317.1 [MH] - ; 1 H NMR (600 MHz, DMSO-d6) δ 14.23 (br s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 3.30 (s, 3H), 2.65 (s, 3H).
向反应瓶(10mL)中加入A6(180mg,0.5mmol)、B4(175mg,0.55mmol)、HOBt(74mg,0.55mmol)和EDCI(115mg,0.6mmol)，再加入无水DMF(2.5mL)和DIEA(262μL,1.5mmol)，N2保护下室温反应过夜。反应液加入水(10mL)，用DCM(10mL×3)萃取，合并萃取液，饱和NaCl溶液(15mL×2)洗，无水Na2SO4干燥，减压浓缩得粗品。硅胶柱层析(20g，200-300目，DCM/MeOH＝200:1洗脱)，得A7(黄色胶状物330mg,100％)。Rf＝0.41(DCM/MeOH＝100:1)；ESI-MS:660.4[M+H]+。A6 (180 mg, 0.5 mmol), B4 (175 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol) and EDCI (115 mg, 0.6 mmol) were added to a reaction bottle (10 mL), and then anhydrous DMF (2.5 mL) and DIEA (262 μL, 1.5 mmol) were added. The reaction mixture was reacted at room temperature overnight under the protection of N 2. Water (10 mL) was added to the reaction solution, and it was extracted with DCM (10 mL×3). The extracts were combined, washed with saturated NaCl solution (15 mL×2), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (20 g, 200-300 mesh, DCM/MeOH=200:1 elution) gave A7 (yellow gum 330 mg, 100%). R f =0.41 (DCM/MeOH=100:1); ESI-MS: 660.4 [M+H] + .
化合物I-85
Compound I-85
向反应瓶(10mL)中加入A7(330mg,0.5mmol)、DCM(2mL)和TFA(743μL,20mmol)，室温下反应过夜。减压蒸除溶剂，得红棕色胶状物。用MeOH(4mL)溶解胶状物。搅拌下用10N氢氧化钠溶液调pH～10，继续搅拌15min后，反应液加入水(20mL)，用DCM(10mL×3)萃取，合并萃取液，饱和NaCl溶液(15mL×2)洗，无水Na2SO4干燥，过滤，减压浓缩得黄色胶状物。硅胶柱层析(20g，200-300目，DCM/MeOH＝19:1洗脱)，得到化合物I-85(黄色固体170mg,收率73％)。Rf＝0.24(DCM/MeOH＝19:1)。ESI-MS:464.3[M+H]+.1H NMR(500MHz,CDCl3)δ8.25(d,J＝8.5Hz,1H),7.97(q,J＝5.7Hz,1H),7.08(d,J＝8.5Hz,1H),6.91(d,J＝8.5Hz,1H),6.41(dd,J＝8.5,2.5Hz,1H),6.30(d,J＝2.5Hz,1H),5.77(d,J＝7.7Hz,1H),4.55(m,1H),4.19(dd,J＝10.8,2.1Hz,1H),4.14(ddd,J＝10.8,4.8,1.6Hz,1H),3.62(s,2H),3.39(ddd,J＝11.0,5.9,2.4Hz,2H),3.29(d,J＝5.7Hz,3H),3.09(dd,J＝16.2,5.4Hz,1H),2.87(dd,J＝11.0,1.9Hz,2H),2.77(dd,J＝16.2,4.7Hz,1H),2.63(s,3H),1.85(m,2H),1.80(m,2H). A7 (330 mg, 0.5 mmol), DCM (2 mL) and TFA (743 μL, 20 mmol) were added to the reaction bottle (10 mL) and reacted at room temperature overnight. The solvent was evaporated under reduced pressure to obtain a reddish brown colloid. The colloid was dissolved with MeOH (4 mL). The pH was adjusted to 10 with 10N sodium hydroxide solution under stirring. After stirring for 15 min, water (20 mL) was added to the reaction solution, extracted with DCM (10 mL × 3), the extracts were combined, washed with saturated NaCl solution (15 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a yellow colloid. Silica gel column chromatography (20 g, 200-300 mesh, DCM/MeOH = 19:1 elution) gave compound I-85 (yellow solid 170 mg, yield 73%). R f = 0.24 (DCM/MeOH = 19:1). ESI-MS: 464.3 [M+H] + . 1 H NMR (500 MHz, CDCl 3 ) δ8.25 (d, J=8.5 Hz, 1H), 7.97 (q, J=5.7 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.41 (dd, J=8.5, 2.5 Hz, 1H), 6.30 (d, J=2.5 Hz, 1H), 5.77 (d, J=7.7 Hz, 1H), 4.55 (m, 1H), 4.19 (dd, J=10.8, 2.1 Hz, 1H), 4.14 (ddd, J= 10.8,4.8,1.6 Hz,1H),3.62 (s,2H),3.39 (ddd,J＝11.0,5.9,2.4 Hz,2H),3.29 (d,J＝5.7 Hz,3H),3.09 (dd,J＝16.2,5.4 Hz,1H),2.87 (dd,J＝11.0,1.9 Hz,2H),2.77 (dd,J＝16.2,4.7 Hz,1H),2.63 (s,3H),1.85 (m,2H),1.80 (m,2H).
制备例2、化合物Ⅰ-87(游离碱及盐酸盐)的制备Preparation Example 2: Preparation of Compound I-87 (free base and hydrochloride)
化合物I-87游离碱及盐酸盐的制备路线:
Preparation route of compound I-87 free base and hydrochloride:
具体操作如下：The specific operations are as follows:
A6及B2合成过程同I-85
The synthesis process of A6 and B2 is the same as I-85
向反应瓶(500mL)中加入3-氯-5-甲基吡嗪-2-甲腈(37.78g，246mmol)、B2(56.89g，299mmol)和无水乙醇(200mL)，升温回流反应3h。搅拌下，反应液趁热倾入水中(1.2L)，大量棕黄色固体析出。抽滤，水洗至滤液中性。真空加热干燥，得C1(土黄色固体61.80g，收率94％)。Rf＝0.39(PE/Acetone＝17:3)；ESI-MS:265.9[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),6.89(br s,2H),2.62(s,3H),1.53(s,9H).
3-Chloro-5-methylpyrazine-2-carbonitrile (37.78 g, 246 mmol), B2 (56.89 g, 299 mmol) and anhydrous ethanol (200 mL) were added to the reaction bottle (500 mL), and the temperature was raised to reflux for reaction for 3 h. Under stirring, the reaction solution was poured into water (1.2 L) while hot, and a large amount of brown-yellow solid precipitated. Filtered and washed with water until the filtrate was neutral. Vacuum heating and drying gave C1 (61.80 g of khaki solid, yield 94%). R f = 0.39 (PE/Acetone = 17:3); ESI-MS: 265.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 6.89 (br s, 2H), 2.62 (s, 3H), 1.53 (s, 9H).
向反应瓶(1L)中加入C1(61.80g,233mmol)、NaHCO3(40.75g,485mmol)和DCM(310mL)，室温搅拌下滴加三氟乙酸酐(50mL,360mmol)，滴加完毕，室温下继续反应30min。反应完毕，向反应液中缓慢滴加水至无气体产生，分出DCM层，水相用DCM萃取，合并有机相，饱和NaCl溶液洗一次，无水Na2SO4干燥，减压浓缩至干。EtOH多次重结晶，得3-甲基-7-三氟乙酰氨基噻吩并[2,3-b]吡嗪-6-甲酸叔丁酯(浅黄色固体70.06g,收率83％)。Rf＝0.42(PE/EA＝3:1)；ESI-MS:262.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.84(s,1H),2.71(s,3H),1.57(s,9H).C1 (61.80 g, 233 mmol), NaHCO 3 (40.75 g, 485 mmol) and DCM (310 mL) were added to the reaction bottle (1 L), and trifluoroacetic anhydride (50 mL, 360 mmol) was added dropwise under stirring at room temperature. After the addition was completed, the reaction was continued at room temperature for 30 min. After the reaction was completed, water was slowly added dropwise to the reaction solution until no gas was generated, the DCM layer was separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed once with saturated NaCl solution, dried over anhydrous Na 2 SO 4 , and concentrated to dryness under reduced pressure. EtOH was recrystallized several times to obtain tert-butyl 3-methyl-7-trifluoroacetylaminothieno[2,3-b]pyrazine-6-carboxylate (light yellow solid 70.06 g, yield 83%). R f =0.42 (PE/EA=3:1); ESI-MS: 262.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ11.84 (s, 1H), 8.84 (s, 1H), 2.71 (s, 3H), 1.57 (s, 9H).
向反应瓶(1L)中加入3-甲基-7-三氟乙酰氨基噻吩并[2,3-b]吡嗪-6-甲酸叔丁酯(70.06g,194mmol)、K2CO3(41.22g,298mmol)和干燥THF(420mL)，加入TsOMe(47.92g,257mmol),60℃反应4h。反应液冷却后直接过滤，DCM洗不溶物，滤液减压浓缩至干，得墨绿色液体。粗品中加入EtOH和PE多次重结晶，得3-甲基-7-(N-甲基-N-三氟乙酰基)氨基噻吩并[2,3-b]吡嗪-6-甲酸叔丁酯(类白色固体64.0g，收率88％)。Rf＝0.34(PE/Acetone＝17:3)。ESI-MS:398.1[M+Na]+；1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),3.38(s,3H),2.74(s,3H),1.56(s,9H). Add tert-butyl 3-methyl-7-trifluoroacetylaminothieno[2,3-b]pyrazine-6-carboxylate (70.06 g, 194 mmol), K 2 CO 3 (41.22 g, 298 mmol) and dry THF (420 mL) to a reaction flask (1 L), add TsOMe (47.92 g, 257 mmol), and react at 60°C for 4 h. After the reaction solution is cooled, filter it directly, wash the insoluble matter with DCM, and concentrate the filtrate to dryness under reduced pressure to obtain a dark green liquid. Add EtOH and PE to the crude product for multiple recrystallization to obtain tert-butyl 3-methyl-7-(N-methyl-N-trifluoroacetyl)aminothieno[2,3-b]pyrazine-6-carboxylate (off-white solid 64.0 g, yield 88%). R f = 0.34 (PE/Acetone = 17:3). ESI-MS: 398.1 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 3.38 (s, 3H), 2.74 (s, 3H), 1.56 (s, 9H).
向反应瓶(500mL)中加入3-甲基-7-(N-甲基-N-三氟乙酰基)氨基噻吩并[2,3-b]吡嗪-6-甲酸叔丁酯(59.0g,157mmol)、DCM(590mL)，冰浴冷却，加入三氟乙酸(236mL)，升温至35℃，反应过夜。反应液减压浓缩至干，得棕色油状物。加入PE，室温打浆，过滤，滤饼真空干燥，得C2(类白色固体50.20g，收率100％)。Rf＝0.30(CHCl3/MeOH＝4:1)。ESI-MS:319.9[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),3.34(s,3H),2.72(s,3H).
Add tert-butyl 3-methyl-7-(N-methyl-N-trifluoroacetyl)aminothieno[2,3-b]pyrazine-6-carboxylate (59.0 g, 157 mmol) and DCM (590 mL) to a reaction bottle (500 mL), cool in an ice bath, add trifluoroacetic acid (236 mL), raise the temperature to 35°C, and react overnight. The reaction solution is concentrated to dryness under reduced pressure to obtain a brown oil. Add PE, slurry at room temperature, filter, and vacuum dry the filter cake to obtain C2 (off-white solid 50.20 g, yield 100%). R f = 0.30 (CHCl 3 /MeOH = 4:1). ESI-MS: 319.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 3.34 (s, 3H), 2.72 (s, 3H).
向反应瓶(500mL)中加入A6(16.30g，51mmol)、DCM(300mL)、DIPEA(17.0g，131mmol)、HOBt(8.65g，64mmol)、EDCI(12.52g，65mmol)和C2(15.20g，42mmol)，室温反应过夜。加入水(150mL)，萃取分层，水相用DCM(150mL)萃取一次，合并有机相，用水(150mL)洗涤一次，无水Na2SO4干燥，旋干得墨绿色液体。硅胶柱层析(200g，200-300目，PE:EA＝6:1→4:1→2:1梯度洗脱)，得C3(黄色泡沫状固体22.38g，收率80％)。Rf＝0.18(PE/EA＝2:1)；1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.70(d,J＝7.5Hz,1H),6.92(d,J＝8.6Hz,1H),6.46(dd,J＝8.6,2.4Hz,1H),6.27(d,J＝2.4Hz,1H),4.41–4.27m,1H),4.21(s,2H),4.13(dd,J＝10.5,3.5Hz,1H),3.87(dd,J＝10.5,8.6Hz,1H),3.48–3.38(m,2H),3.34(s,3H),2.94(d,J＝16.1,5.5Hz,1H),2.81(d,J＝16.1,8.8Hz,1H),2.77–2.67(m,5H),1.90–1.80(m,2H),1.79–1.69(m,2H),1.42(s,9H).
A6 (16.30 g, 51 mmol), DCM (300 mL), DIPEA (17.0 g, 131 mmol), HOBt (8.65 g, 64 mmol), EDCI (12.52 g, 65 mmol) and C2 (15.20 g, 42 mmol) were added to a reaction bottle (500 mL) and reacted at room temperature overnight. Water (150 mL) was added, and the layers were separated by extraction. The aqueous phase was extracted once with DCM (150 mL), and the organic phases were combined, washed once with water (150 mL), dried over anhydrous Na 2 SO 4 , and spin-dried to obtain a dark green liquid. Silica gel column chromatography (200 g, 200-300 mesh, PE:EA=6:1→4:1→2:1 gradient elution) was performed to obtain C3 (yellow foamy solid 22.38 g, yield 80%). R f =0.18 (PE/EA=2:1); 1 H NMR (400 MHz, DMSO-d6) δ8.85 (s, 1H), 8.70 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.46 (dd, J = 8.6, 2.4 Hz, 1H), 6.27 (d, J = 2.4 Hz, 1H), 4.41–4.27 m, 1H), 4.21 (s, 2H), 4.13 (dd, J = 10.5, 3.5 Hz, 1H ),3.87(dd,J＝10.5,8.6Hz,1H),3.48–3.38(m,2H),3.34(s,3H),2.94(d,J＝16.1,5.5Hz,1H),2.81(d,J＝16.1,8.8Hz,1H),2.77–2.67(m,5H),1.90–1.80(m,2H),1.79–1.69(m,2H),1.42(s,9H).
向反应瓶(500mL)中加入酰胺C3(22.38g，34mmol)、THF(180mL)、氢氧化钠溶液(NaOH(5.85g，146mmol)、水45mL)，室温下反应2h。反应结束后，加入DCM和水萃取分层，有机相用无水Na2SO4干燥，过滤，减压浓缩至干，得到黄色脱Tfa产物。加入ACN(230mL)、4M盐酸乙醇溶液(95mL)，反应过夜，析出大量固体。反应液中缓慢加入饱和K2CO3溶液至无气泡产生。加入DCM萃取分层，有机相用无水Na2SO4干燥，过滤，浓缩至干。硅胶柱层析(100g，200-300目，DCM/MeOH＝20:1→10:1梯度洗脱)，得到I-87游离碱(黄色固体11.58g，收率＝73％)。Rf＝0.16(DCM/MeOH＝10:1)。ESI-MS:465.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.00(q,J＝5.5Hz,1H),7.79(d,J＝7.5Hz,1H),6.89(d,J＝8.5Hz,1H),6.39(dd,J＝8.5,2.5Hz,1H),6.19(d,J＝2.5Hz,1H),4.33–4.23(m,1H),4.15(dd,J＝10.2,3.6Hz,1H),3.80(t,J＝9.9Hz,1H),3.57(s,2H),3.39(d,J＝5.5Hz,3H),3.38–3.29(m,2H),2.88–2.82(m,2H),2.76–2.69(m,2H),2.63(s,3H),1.70(s,4H).Add amide C3 (22.38 g, 34 mmol), THF (180 mL), sodium hydroxide solution (NaOH (5.85 g, 146 mmol), water 45 mL) to a reaction flask (500 mL) and react at room temperature for 2 h. After the reaction is completed, add DCM and water to extract and separate the layers. The organic phase is dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness under reduced pressure to obtain a yellow Tfa-free product. Add ACN (230 mL) and 4M hydrochloric acid ethanol solution (95 mL) and react overnight to precipitate a large amount of solid. Saturated K 2 CO 3 solution is slowly added to the reaction solution until no bubbles are generated. Add DCM to extract and separate the layers. The organic phase is dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness. Silica gel column chromatography (100 g, 200-300 mesh, DCM/MeOH=20:1→10:1 gradient elution) gives I-87 free base (yellow solid 11.58 g, yield = 73%). Rf = 0.16 (DCM/MeOH = 10:1). ESI-MS: 465.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.00 (q, J = 5.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.39 (dd, J = 8.5, 2.5 Hz, 1H), 6.19 (d, J = 2.5 Hz, 1H), 4.33–4.23 (m, 1H ),4.15(dd,J＝10.2,3.6Hz,1H),3.80(t,J＝9.9Hz,1H),3.57(s,2H),3.39(d,J＝5.5Hz,3H),3.38–3.29(m,2H),2.88–2.82(m,2H),2.76–2.69(m,2H),2.63(s,3H),1.70(s,4H).
向反应瓶(250mL)中加入I-87游离碱(11.58g，25mmol)、EtOH(120mL)，室温搅拌下加入浓盐酸(3.3mL)，反应2h，过滤，用少量EtOH淋洗，真空干燥得到I-87盐酸盐(黄色固体11.07g，收率85％)。ESI-MS:465.2[M+H]+；1H NMR(800MHz,DMSO-d6)δ9.56(d,J＝9.5Hz,1H),9.51(d,J＝9.5Hz,1H),8.62(s,1H),7.99(br s,1H),7.83(d,J＝7.5Hz,1H),6.95(d,J＝8.5Hz,1H),6.48(dd,J＝8.5,2.3Hz,1H),6.31(d,J＝2.3Hz,1H),4.32–4.26(m,1H),4.17(ddd,J＝10.1,3.6,1.5Hz,1H),4.09(s,2H),3.84(t,J＝9.9Hz,1H),3.54(t,J＝10.7Hz,2H),3.39(s,3H),3.08(d,J＝11.8Hz,2H),2.90(dd,J＝15.6,9.8Hz,2H),2.86(dd,J＝15.6,6.0Hz,2H),2.62(s,3H),2.01–1.95(m,2H),1.93–1.87(m,2H).I-87 free base (11.58 g, 25 mmol) and EtOH (120 mL) were added to a reaction bottle (250 mL), and concentrated hydrochloric acid (3.3 mL) was added under stirring at room temperature. The mixture was reacted for 2 h, filtered, rinsed with a small amount of EtOH, and dried in vacuo to obtain I-87 hydrochloride (yellow solid 11.07 g, yield 85%). ESI-MS: 465.2 [M+H] + ; 1 H NMR (800 MHz, DMSO-d6) δ 9.56 (d, J = 9.5 Hz, 1H), 9.51 (d, J = 9.5 Hz, 1H), 8.62 (s, 1H), 7.99 (br s, 1H), 7.83 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.48 (dd, J = 8.5, 2.3 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 4.32–4.26 (m, 1H), 4.17 (ddd, J = 10.1, 3.6, 1.5 Hz, 1H), 4.09 (s, 2H), 3.84 (t, J = 9.9 Hz, 1H), 3.54 (t, J = 10.7 Hz, 2H), 3.39 (s, 3H), 3.08 (d, J = 11.8 Hz, 2H), 2.90 (dd, J = 15.6, 9.8 Hz, 2H), 2.86 (dd, J = 15.6, 6.0 Hz, 2H), 2.62 (s, 3H), 2.01–1.95 (m, 2H), 1.93–1.87 (m, 2H).
实施例1、化合物Ⅰ-85盐酸盐及其晶型的制备Example 1. Preparation of Compound I-85 Hydrochloride and Its Crystalline Forms
称取约50mg的化合物Ⅰ-85悬浮于对应溶剂中，加入1M的盐酸甲醇溶液后，室温搅拌约20小时。过滤收集样品，于40℃真空干燥>4小时，具体信息及结果汇总于表1，制备得到一盐酸盐晶型I(化合物Ⅰ-85一盐酸盐的水合物)和二盐酸盐晶型I(化合物Ⅰ-85二盐酸盐的水合物)，表征数据见图1-1至图3。About 50 mg of compound I-85 was weighed and suspended in the corresponding solvent, and 1M hydrochloric acid methanol solution was added and stirred at room temperature for about 20 hours. The sample was collected by filtration and vacuum dried at 40°C for >4 hours. The specific information and results are summarized in Table 1. Monohydrochloride crystal form I (hydrate of compound I-85 monohydrochloride) and dihydrochloride crystal form I (hydrate of compound I-85 dihydrochloride) were prepared. The characterization data are shown in Figures 1-1 to 3.
表1盐酸盐的制备

Table 1 Preparation of hydrochloride

实施例2、化合物Ⅰ-85硫酸盐或硫酸氢盐及其晶型的制备Example 2. Preparation of Compound I-85 Sulfate or Hydrogen Sulfate and Its Crystalline Forms
称取约50mg的化合物Ⅰ-85悬浮于对应溶剂中，加入1M的硫酸甲醇溶液后，室温搅拌约20小时。过滤收集样品，于40℃真空干燥>4小时，具体信息及结果汇总于表2，制备得到硫酸盐晶型I(化合物Ⅰ-85硫酸盐的水合物甲醇溶剂化物)、硫酸盐晶型II(化合物Ⅰ-85硫酸盐的水合物乙酸乙酯溶剂化物)、硫酸氢盐晶型I(化合物Ⅰ-85硫酸氢盐无水物1)、硫酸氢盐晶型II(化合物Ⅰ-85硫酸氢盐无水物2)，表征数据见图4-1至图8。About 50 mg of compound I-85 was weighed and suspended in the corresponding solvent, and a 1M sulfuric acid methanol solution was added, and stirred at room temperature for about 20 hours. The sample was collected by filtration and vacuum dried at 40°C for >4 hours. The specific information and results are summarized in Table 2. Sulfate crystal form I (hydrate methanol solvate of compound I-85 sulfate), sulfate crystal form II (hydrate ethyl acetate solvate of compound I-85 sulfate), hydrogen sulfate crystal form I (compound I-85 hydrogen sulfate anhydrous 1), and hydrogen sulfate crystal form II (compound I-85 hydrogen sulfate anhydrous 2) were prepared. The characterization data are shown in Figures 4-1 to 8.
表2
Table 2
实施例3、化合物Ⅰ-85氢溴酸盐及其晶型的制备Example 3. Preparation of Compound I-85 Hydrobromide and Its Crystalline Form
称取约50mg的化合物Ⅰ-85悬浮于对应溶剂中，加入1M的氢溴酸甲醇溶液后，室温搅拌约20小时。过滤收集样品，于40℃真空干燥约17小时，具体信息及结果汇总于表3，制备得到一氢溴酸晶型I(化合物Ⅰ-85一氢溴酸盐的水合物)、二氢溴酸晶型I(化合物Ⅰ-85二氢溴酸盐的水合物)，表征数据见图9-1至图11。About 50 mg of compound I-85 was weighed and suspended in the corresponding solvent, and 1M methanol solution of hydrobromic acid was added, and stirred at room temperature for about 20 hours. The sample was collected by filtration and vacuum dried at 40°C for about 17 hours. The specific information and results are summarized in Table 3. Monohydrobromic acid form I (hydrate of monohydrobromide of compound I-85) and dihydrobromic acid form I (hydrate of dihydrobromide of compound I-85) were prepared. The characterization data are shown in Figures 9-1 to 11.
表3
table 3
实施例4、化合物Ⅰ-85甲磺酸盐及其晶型的制备Example 4. Preparation of Compound I-85 Methanesulfonate and Its Crystalline Form
称取约50mg的化合物Ⅰ-85悬浮于对应溶剂中，加入1M的甲磺酸甲醇溶液后，室温搅拌约17小时。过滤收集样品，于40℃真空干燥约4小时，具体信息及结果汇总于表4，制备得到磺酸盐晶型I(化合物Ⅰ-85一甲磺酸盐无水物)，表征数据见图12和图13。About 50 mg of compound I-85 was weighed and suspended in the corresponding solvent, and 1M methanesulfonic acid methanol solution was added, and stirred at room temperature for about 17 hours. The sample was collected by filtration and vacuum dried at 40°C for about 4 hours. The specific information and results are summarized in Table 4 to prepare sulfonate salt form I (compound I-85 monomethanesulfonate anhydrous), and the characterization data are shown in Figures 12 and 13.
表4
Table 4
实施例5、化合物Ⅰ-85对甲苯磺酸盐及其晶型的制备Example 5. Preparation of Compound I-85 p-toluenesulfonate and its crystalline form
称取约50mg的化合物Ⅰ-85悬浮于对应溶剂中，加入1M的对甲苯磺酸甲醇溶液后，室温搅拌约17小时。过滤收集样品，于40℃真空干燥约4小时，具体信息及结果汇总于表5，制备得到对甲苯磺酸晶型I(化合物Ⅰ-85对甲苯磺酸盐的水合物)、对甲苯磺酸晶型II(化合物Ⅰ-85对甲苯磺酸盐的丙酮溶剂化物)、对甲苯磺酸晶型III(化合物Ⅰ-85对甲苯磺酸盐的乙酸乙酯溶剂化物)，表征数据见图14-1至图17。About 50 mg of compound I-85 was weighed and suspended in the corresponding solvent, and 1M p-toluenesulfonic acid methanol solution was added, and stirred at room temperature for about 17 hours. The sample was collected by filtration and vacuum dried at 40°C for about 4 hours. The specific information and results are summarized in Table 5. p-toluenesulfonic acid crystal form I (hydrate of p-toluenesulfonate of compound I-85), p-toluenesulfonic acid crystal form II (acetone solvate of p-toluenesulfonate of compound I-85), and p-toluenesulfonic acid crystal form III (ethyl acetate solvate of p-toluenesulfonate of compound I-85) were prepared. The characterization data are shown in Figures 14-1 to 17.
表5

table 5

实施例6、化合物Ⅰ-85磷酸盐及其晶型的制备Example 6. Preparation of Compound I-85 Phosphate and Its Crystalline Form
称取约50mg的化合物Ⅰ-85悬浮于对应溶剂中，加入1M的磷酸甲醇溶液后，室温搅拌约20小时。过滤收集样品，于40℃真空干燥约17小时，具体信息及结果汇总于表6，制备得到磷酸盐晶型I(化合物Ⅰ-85磷酸盐的水合物)、磷酸盐晶型II(化合物Ⅰ-85磷酸盐的水合物丙酮溶剂化合物)，表征数据见图18-1至图20。About 50 mg of compound I-85 was weighed and suspended in the corresponding solvent, and 1M phosphoric acid methanol solution was added and stirred at room temperature for about 20 hours. The sample was collected by filtration and vacuum dried at 40°C for about 17 hours. The specific information and results are summarized in Table 6. Phosphate crystal form I (hydrate of compound I-85 phosphate) and phosphate crystal form II (hydrate of compound I-85 phosphate in acetone solvent) were prepared. The characterization data are shown in Figures 18-1 to 20.
表6
Table 6
实施例7、化合物Ⅰ-85酒石酸盐及其晶型的制备Example 7. Preparation of Compound I-85 Tartrate and Its Crystalline Forms
称取约50mg的化合物Ⅰ-85悬浮于对应溶剂中，加入1M的酒石酸甲醇溶液后，室温搅拌约20小时。过滤收集样品，于40℃真空干燥约17小时。具体信息及结果汇总于表7，制备得到酒石酸盐晶型I(化合物Ⅰ-85半酒石酸盐的水合物)，表征数据见图21和图22。About 50 mg of compound I-85 was weighed and suspended in the corresponding solvent, and 1M tartaric acid methanol solution was added and stirred at room temperature for about 20 hours. The sample was collected by filtration and vacuum dried at 40°C for about 17 hours. The specific information and results are summarized in Table 7, and the tartrate salt form I (hydrate of compound I-85 hemi-tartrate) was prepared, and the characterization data are shown in Figures 21 and 22.
表7
Table 7
实施例8、化合物Ⅰ-85富马酸盐及其晶型的制备Example 8. Preparation of Compound I-85 Fumarate and Its Crystalline Form
称取约50mg的化合物Ⅰ-85悬浮于对应溶剂中，加入富马酸后，室温搅拌约17小时。过滤收集样品，于40℃真空干燥约4小时。具体信息及结果汇总于表8，制备得到富马酸晶型I(化合物Ⅰ-85一富马酸盐无水物)，表征数据见图23和图24。About 50 mg of compound I-85 was weighed and suspended in the corresponding solvent, and fumaric acid was added and stirred at room temperature for about 17 hours. The sample was collected by filtration and vacuum dried at 40°C for about 4 hours. The specific information and results are summarized in Table 8, and fumaric acid crystal form I (compound I-85-fumarate anhydrous) was prepared, and the characterization data are shown in Figures 23 and 24.
表8
Table 8
化合物I-85的游离碱和实施例1-8中得到晶型的信息汇总如下：The information of the free base of compound I-85 and the crystalline forms obtained in Examples 1-8 are summarized as follows:
表9化合物I-85的游离碱和晶体盐的信息汇总

Table 9 Summary of information on the free base and crystalline salt of compound I-85

(a)基于TGA失重和核磁溶残计算含水量；(a) Calculate water content based on TGA weight loss and NMR residual;
(b)通过1H-NMR确定有机盐酸碱比例。(b) Determination of the organic hydrochloric acid-base ratio by 1 H-NMR.
测试例1、溶解度测试Test Example 1: Solubility Test
对I-85的甲磺酸盐晶型I、富马酸盐晶型I和游离碱进行了生物相关介质中的溶解度实验。由于I-85的甲磺酸盐晶型I、富马酸盐晶型I和游离碱在SGF中的溶解度较大，故在室温下采用目视法对两种盐的晶型和游离碱进行了溶解度粗测。具体方法为：称取一定量固体，缓慢逐步加入SGF介质，加入过程辅助搅拌或超声，直至无固体残留，依据体积计算粗溶解度。Solubility experiments were conducted on the mesylate form I, fumarate form I and free base of I-85 in biologically relevant media. Since the solubility of the mesylate form I, fumarate form I and free base of I-85 in SGF is relatively large, the solubility of the two salt forms and free base was roughly measured by visual method at room temperature. The specific method is: weigh a certain amount of solid, slowly and gradually add SGF medium, assist with stirring or ultrasound during the addition process, until no solid remains, and calculate the rough solubility based on volume.
三者在FaSSIF和FeSSIF生物相关介质中的溶解度较小，故采用HPLC方法检测。分别称取约15mg I-85的游离碱、甲磺酸盐晶型I和富马酸盐晶型I样品加入到5mL生物相关介质形成悬浮液，在37℃摇床中以100rpm转速下振荡，在0.5h，2h和24h下，取1mL悬浮液过滤，并稀释相应倍数进行HPLC分析和PH测试，剩余滤饼进行XRPD分析。The solubility of the three in FaSSIF and FeSSIF bio-related media is relatively low, so HPLC method is used for detection. About 15 mg of I-85 free base, mesylate crystal form I and fumarate crystal form I were weighed and added to 5 mL of bio-related medium to form a suspension, which was shaken at 100 rpm in a shaker at 37 ° C. After 0.5 h, 2 h and 24 h, 1 mL of the suspension was filtered and diluted to the corresponding multiples for HPLC analysis and pH test, and the remaining filter cake was subjected to XRPD analysis.
三者在SGF中都具有良好的溶解度(>2mg/mL)，特别是甲磺酸盐最佳(>10mg/mL)。另外由于Ksp影响，化合物会以一盐酸盐晶型I的形式从SGF介质中析出。相比FaSSIF介质，三者在FeSSIF介质中的溶解度更好(0.4-0.6mg/mL vs 0.1mg/mL)。游离碱在FaSSIF介质中24小时晶型不变，在FeSSIF介质中0.5小时几乎转为无定型物，结晶度低。两种盐的晶型在FaSSIF和FeSSIF介质中0.5小时也几乎转为无定型物，XRPD图谱与游离碱在FeSSIF介质中0.5小时相似。此外，将甲磺酸盐在FeSSIF介质中24小时的残留固体进行核磁分析，发现样品解离，表明此低结晶度物质为游离碱。相关表征结果汇总于表10-11。All three have good solubility in SGF (>2mg/mL), especially the mesylate salt is the best (>10mg/mL). In addition, due to the influence of Ksp, the compound will precipitate from the SGF medium in the form of a hydrochloride crystal form I. Compared with FaSSIF medium, the solubility of the three in FeSSIF medium is better (0.4-0.6mg/mL vs 0.1mg/mL). The free base has unchanged crystal form in FaSSIF medium for 24 hours, and almost turns into an amorphous substance in FeSSIF medium for 0.5 hours, with low crystallinity. The crystal forms of the two salts are also almost converted into amorphous substances in FaSSIF and FeSSIF media for 0.5 hours, and the XRPD spectrum is similar to that of the free base in FeSSIF medium for 0.5 hours. In addition, the residual solid of the mesylate salt in FeSSIF medium for 24 hours was subjected to nuclear magnetic resonance analysis, and it was found that the sample was dissociated, indicating that this low-crystallinity substance is a free base. The relevant characterization results are summarized in Tables 10-11.
表10.SGF介质中的溶解度结果
Table 10. Solubility results in SGF medium
表11.FaSSIF和FeSSIF介质中的溶解度结果
Table 11. Solubility results in FaSSIF and FeSSIF media
测试例2、稳定性测试Test Example 2: Stability Test
在60℃/闭口和40℃/75％RH两种条件下对I-85的甲磺酸盐晶型I、富马酸盐晶型I和游离碱进行一周稳定性测试。相关表征结果汇总于表12。The stability of I-85 mesylate salt form I, fumarate salt form I and free base was tested for one week at 60°C/closed cup and 40°C/75% RH. The relevant characterization results are summarized in Table 12.
稳定性结果显示甲磺酸盐晶型I在60℃/闭口和40℃/75％RH两种条件下物理和化学稳定。游离碱在60℃/闭口和40℃/75％RH两种条件下化学稳定，结晶度有提高。富马酸盐晶型I在60℃/闭口和40℃/75％RH两种条件下放置一周后化学不稳定(纯度分别下降～0.4％和～3％)。富马酸盐晶型I在化学稳定性上不如甲磺酸盐晶型I和游离碱。The stability results show that the mesylate salt Form I is physically and chemically stable at 60°C/closed cup and 40°C/75% RH. The free base is chemically stable at 60°C/closed cup and 40°C/75% RH, and the crystallinity is improved. The fumarate salt Form I is chemically unstable after being placed at 60°C/closed cup and 40°C/75% RH for one week (the purity decreases by ～0.4% and ～3%, respectively). The fumarate salt Form I is not as chemically stable as the mesylate salt Form I and the free base.
表12.稳定性评估结果
Table 12. Stability evaluation results
实施例9、化合物Ⅰ-85甲磺酸盐晶型I的制备1Example 9. Preparation of Compound I-85 Methanesulfonate Form I
称取4g化合物Ⅰ-85游离碱室温悬浮于25mL甲醇，然后加入8.63mL的1M甲磺酸甲醇溶液进行成盐。反应后加入甲磺酸盐晶型I晶种(100mg)。室温搅拌18小时后，过滤收集固体并在40℃真空烘箱中干燥4小时。共制备得到约3.9g甲磺酸盐晶型I，熔点约279℃。HPLC分析纯度约～99.8％(220nm)。DVS数据显示样品轻微吸湿，在0％RH-90％RH范围内增重～1.1％，晶型在测试前后未转变。Weigh 4 g of compound Ⅰ-85 free base and suspend it in 25 mL of methanol at room temperature, then add 8.63 mL of 1 M methanesulfonic acid methanol solution to form salt. After the reaction, add mesylate crystal form I seed (100 mg). After stirring at room temperature for 18 hours, filter and collect the solid and dry it in a vacuum oven at 40°C for 4 hours. A total of about 3.9 g of mesylate crystal form I was prepared, with a melting point of about 279°C. HPLC analysis purity is about ~99.8% (220nm). DVS data show that the sample is slightly hygroscopic, with a weight gain of ~1.1% in the range of 0% RH-90% RH, and the crystal form does not change before and after the test.
实施例10、化合物Ⅰ-85甲磺酸盐晶型I的制备2Example 10. Preparation of Compound I-85 Methanesulfonate Form I
称取适量的Ⅰ-85甲磺酸盐晶型I于洁净小瓶，加入相应良溶剂形成悬浮液。过滤得到饱和清液。室温下将反溶剂缓慢添加至溶清液中进行反溶剂沉淀(正加法)。其次将溶清液缓慢添加至反溶剂中进行反溶剂沉淀(反加法)。收集沉淀析出的固体样品并进行XRPD表征。良溶剂药液浓度约100mg/mL，相关结果汇总于表13-14。在二甲亚砜为良溶剂的其他体系中都得到了晶型I。其他体系未析出沉淀。Weigh an appropriate amount of Ⅰ-85 mesylate salt form I into a clean vial and add the corresponding good solvent to form a suspension. Filter to obtain a saturated clear solution. Slowly add the antisolvent to the clear solution at room temperature for antisolvent precipitation (positive addition method). Secondly, slowly add the clear solution to the antisolvent for antisolvent precipitation (negative addition method). Collect the precipitated solid samples and characterize them by XRPD. The concentration of the good solvent solution is about 100 mg/mL, and the relevant results are summarized in Tables 13-14. Form I was obtained in other systems with dimethyl sulfoxide as the good solvent. No precipitate was precipitated in other systems.
表13.反溶剂沉淀正加结果
Table 13. Antisolvent precipitation positive addition results
表14.反溶剂沉淀反加结果
Table 14. Anti-solvent precipitation back addition results
实施例11、化合物Ⅰ-85甲磺酸盐晶型I和晶型II的制备Example 11. Preparation of Compound I-85 Methanesulfonate Form I and Form II
称取约20mgⅠ-85甲磺酸盐晶型I于洁净小瓶，加入相应溶剂形成悬浮液，于室温下悬浮搅拌4天，相关结果汇总于表15。在有机溶剂体系中都得到了甲磺酸盐晶型I，而在水体系中得到了甲磺酸盐晶型II(图25和图26)。About 20 mg of I-85 mesylate salt form I was weighed into a clean vial, and the corresponding solvent was added to form a suspension, which was suspended and stirred at room temperature for 4 days. The relevant results are summarized in Table 15. Mesylate salt form I was obtained in the organic solvent system, and mesylate salt form II was obtained in the water system (Figures 25 and 26).
表15.室温悬浮搅拌结果

Table 15. Room temperature suspension stirring results

本次实验将Ⅰ-85甲磺酸盐晶型I在对应溶剂中50℃悬浮搅拌4天，相关结果汇总于表11。所有实验中都得到了甲磺酸盐晶型I。In this experiment, the mesylate crystal form I of Ⅰ-85 was suspended and stirred in the corresponding solvent at 50°C for 4 days, and the relevant results are summarized in Table 11. The mesylate crystal form I was obtained in all experiments.
表11、50℃悬浮搅拌结果
Table 11, 50℃ suspension stirring results
在不同水含量的乙醇溶液中进行，室温条件悬浮搅拌3天。晶型I为起始原料，相应的实验结果汇总于表17。晶型I在醇水比3/7条件下转化为晶型II(aw≈0.92)，但在醇水比1/1条件下保持晶型稳定(aw≈0.87)。The reaction was carried out in ethanol solutions with different water contents and suspended and stirred at room temperature for 3 days. Form I was used as the starting material, and the corresponding experimental results are summarized in Table 17. Form I was converted into Form II ( aw ≈0.92) under the condition of an alcohol-water ratio of 3/7, but remained stable under the condition of an alcohol-water ratio of 1/1 ( aw ≈0.87).
表17、不同水含量乙醇溶液中悬浮搅拌结果
Table 17. Suspension stirring results in ethanol solutions with different water contents
实施例12、化合物Ⅰ-85甲磺酸盐无定形、晶型I和晶型II的制备Example 12. Preparation of amorphous, crystalline form I and crystalline form II of compound I-85 methanesulfonate
称取约20mgⅠ-85甲磺酸盐晶型I于洁净小瓶，加入相应溶剂形成悬浮液，滤液用于单一溶剂室温挥发结晶(缓慢挥发)或在氮气吹拂下挥发结晶(快速挥发)。结果汇总于表18。在甲醇和水体系中的快速挥发实验得到了无定型样品。在甲醇和水体系的缓慢挥发实验分别得到了晶型I和晶型II。Weigh about 20 mg of Ⅰ-85 mesylate salt form I into a clean vial, add the corresponding solvent to form a suspension, and use the filtrate for single solvent room temperature evaporation crystallization (slow evaporation) or evaporation crystallization under nitrogen purge (fast evaporation). The results are summarized in Table 18. The fast evaporation experiment in methanol and water system obtained an amorphous sample. The slow evaporation experiment in methanol and water system obtained form I and form II, respectively.
表18.挥发实验结果

Table 18. Volatilization test results

实施例13、化合物Ⅰ-85甲磺酸盐晶型III的制备Example 13. Preparation of Compound I-85 Methanesulfonate Form III
称取适量的Ⅰ-85甲磺酸盐晶型I于洁净小瓶，加入相应溶剂加热下得到溶清液。过滤得到饱和溶液，将其置于一定条件下冷却结晶。若让其在水/油浴中自然冷却至室温或4℃，则为缓慢冷却。若直接将热饱和溶液置于4℃则为快速冷却。实验结果见表19。在乙醇体系冷却结晶未得到固体。在甲醇体系中缓慢和快速冷却结晶得到了晶型III(图27)。晶型III在170℃之前约有8.8％的失重(图28)。核磁分析检测到样品约含有8.8％的甲醇(～1.6当量的甲醇)。因此，晶型III是甲醇溶剂化物。Weigh an appropriate amount of Ⅰ-85 mesylate salt form I into a clean vial, add the corresponding solvent and heat to obtain a clear solution. Filter to obtain a saturated solution, and place it under certain conditions to cool and crystallize. If it is allowed to cool naturally to room temperature or 4°C in a water/oil bath, it is slow cooling. If the hot saturated solution is directly placed at 4°C, it is rapid cooling. The experimental results are shown in Table 19. No solid was obtained by cooling and crystallizing in the ethanol system. Slow and rapid cooling and crystallization in the methanol system gave form III (Figure 27). Form III has a weight loss of about 8.8% before 170°C (Figure 28). Nuclear magnetic resonance analysis detected that the sample contained approximately 8.8% methanol (~1.6 equivalents of methanol). Therefore, form III is a methanol solvate.
表19.冷却结晶结果
Table 19. Cooling crystallization results
测试例3、固态稳定性实验Test Example 3: Solid-state stability experiment
通过不同的加速条件(60℃/闭口和40℃/75％RH)对I-85的甲磺酸盐晶型I放置7天所得到的结果。结果显示甲磺酸盐晶型I在稳定性实验中晶型和HPLC化学纯度不变(表20)。因此，甲磺酸盐晶型I在60℃/闭口和40℃/75％RH两种条件下物理和化学稳定。The results obtained by placing the mesylate salt form I of I-85 for 7 days under different accelerated conditions (60°C/closed cup and 40°C/75%RH). The results show that the crystal form and HPLC chemical purity of the mesylate salt form I remain unchanged in the stability experiment (Table 20). Therefore, the mesylate salt form I is physically and chemically stable under both 60°C/closed cup and 40°C/75%RH conditions.
表20
Table 20
测试例4、化合物I-85甲磺酸盐(编号为：CT1113或PBSS1113)及化合物I-87盐酸盐对体外(in vitro)肿瘤细胞生长抑制活性测试Test Example 4: In vitro tumor cell growth inhibitory activity test of compound I-85 mesylate (number: CT1113 or PBSS1113) and compound I-87 hydrochloride
用于本发明的活性测试化合物如下所示：The active test compounds used in the present invention are as follows:
其中具体试验中使用化合物I-85的甲磺酸盐，化合物I-87的盐酸盐，化合物I-1的盐酸盐，以及化合物I-58。化合物I-85、I-87、I-58和I-1具有如下结构：
The specific test used the mesylate of compound I-85, the hydrochloride of compound I-87, the hydrochloride of compound I-1, and compound I-58. Compounds I-85, I-87, I-58 and I-1 have the following structures:
测试例4-1：化合物I-58、化合物I-85甲磺酸盐与化合物I-87盐酸盐对肿瘤细胞生长抑制作用的比较Test Example 4-1: Comparison of the inhibitory effects of Compound I-58, Compound I-85 methanesulfonate and Compound I-87 hydrochloride on tumor cell growth
HCT116(结直肠癌)细胞，置96孔板(3x103细胞/孔)，加入培养液(DMEM+10％FBS+1％青-链霉素)以及化合物至0、50nM、100nM、200nM、500nM或1000nM终浓度，置于二氧化碳细胞培养箱(37℃，5％CO2)中培养培养72小时后，用MTS法测定活细胞数量，以不加化合物(只加同样量的化合物溶剂DMSO)的细胞数为1，结果如下表21及图29(生长曲线)所示。可见化合物I-58抑制HepG2与HCT116生长活性不明显，而化合物I-85甲磺酸盐及化合物I-87盐酸盐在浓度100nM及以上显著抑制了HCT116的生长。化合物I-85甲磺酸盐及化合物I-87盐酸盐对肿瘤细胞生长的抑制活性显著优于化合物I-58。HCT116 (colorectal cancer) cells were placed in 96-well plates (3x10 3 cells/well), culture medium (DMEM+10% FBS+1% penicillin-streptomycin) and compounds were added to a final concentration of 0, 50nM, 100nM, 200nM, 500nM or 1000nM, and cultured in a carbon dioxide cell culture incubator (37°C, 5% CO 2 ). After 72 hours of culture, the number of live cells was determined by the MTS method, with the number of cells without compound (only the same amount of compound solvent DMSO) being 1. The results are shown in Table 21 and Figure 29 (growth curve). It can be seen that compound I-58 has no obvious inhibitory activity on the growth of HepG2 and HCT116, while compound I-85 mesylate and compound I-87 hydrochloride significantly inhibited the growth of HCT116 at a concentration of 100nM and above. Compound I-85 mesylate and compound I-87 hydrochloride have significantly better inhibitory activity on tumor cell growth than compound I-58.
表21

Table 21

测试例4-2：化合物I-85甲磺酸盐、化合物I-87(盐酸盐)和化合物I-1(盐酸盐)对不同组织来源的肿瘤细胞系的生长抑制作用Test Example 4-2: Growth inhibition effects of compound I-85 methanesulfonate, compound I-87 (hydrochloride) and compound I-1 (hydrochloride) on tumor cell lines of different tissue origins
不同组织来源的肿瘤细胞系，用测试例4-1同样的方法培养及测试，计算获得化合物I-85甲磺酸盐(CT1113)(图29)、化合物I-87盐酸盐(图30)和I-1盐酸盐(CT1073)(图31)对各细胞系生长50％抑制(IC50)所需浓度。IC50值如下表22所示：Tumor cell lines from different tissues were cultured and tested in the same manner as in Test Example 4-1, and the concentrations required for 50% inhibition (IC 50 ) of the growth of each cell line by compound I-85 mesylate (CT1113) ( FIG. 29 ), compound I-87 hydrochloride ( FIG. 30 ), and I-1 hydrochloride (CT1073) ( FIG. 31 ) were calculated. The IC 50 values are shown in Table 22 below:
表22


注：n.d.代表未测(not determined)。Table 22


Note: nd stands for not determined.
结果显示化合物I-85甲磺酸盐和化合物I-87对不同组织来源的人肿瘤细胞系均有良好的生长抑制作用，展现出广谱抗肿瘤活性。The results showed that compound I-85 mesylate and compound I-87 had good growth inhibitory effects on human tumor cell lines from different tissues, exhibiting broad-spectrum anti-tumor activity.
测试例4-3：化合物I-1(盐酸盐，CT1073)对肿瘤细胞的生长抑制作用Test Example 4-3: Inhibitory effect of compound I-1 (hydrochloride, CT1073) on tumor cell growth
肿瘤细胞系MDA-MB-231、LN-18、HT-1080、MDAH2774、HCT116和SMMC7721使用培养液(DMEM+10％FBS+1％青-链霉素，加减500nM CT1073)，T47D和CNE1使用另一种培养液(RPMI-1640+10％FBS+1％青-链霉素培养基，加减500nM CT1073)，置于二氧化碳细胞培养箱(37℃，5％CO2)中培养不同时间后测试。Tumor cell lines MDA-MB-231, LN-18, HT-1080, MDAH2774, HCT116 and SMMC7721 were cultured in DMEM + 10% FBS + 1% penicillin-streptomycin, with or without 500 nM CT1073, and T47D and CNE1 were cultured in another medium (RPMI-1640 + 10% FBS + 1% penicillin-streptomycin medium, with or without 500 nM CT1073). They were placed in a carbon dioxide cell culture incubator (37°C, 5% CO2 ) for different time periods before testing.
化合物I-1(CT1073)引起MDA-MB-231、T47D、CNE1、LN-18和HT-1080细胞进入凋亡(图32)，而MDAH2774、SMMC7721、HCT116则分别阻滞在G1、S、和G2/M期(图33)。Compound I-1 (CT1073) caused MDA-MB-231, T47D, CNE1, LN-18, and HT-1080 cells to enter apoptosis ( FIG. 32 ), while MDAH2774, SMMC7721, and HCT116 were blocked in the G1, S, and G2/M phases, respectively ( FIG. 33 ).
该测试例表明化合物I-1对肿瘤细胞的生长抑制作用或源于细胞凋亡，或源于细胞周期阻滞。This test example shows that the inhibitory effect of compound I-1 on tumor cell growth may be due to cell apoptosis or cell cycle arrest.
测试例4-4：化合物I-85甲磺酸盐(CT1113)和化合物I-1盐酸盐(CT1073)对肿瘤细胞内c-MYC、LSD1、Tankyrase(TNKS)蛋白表达水平的影响 Test Example 4-4: Effects of Compound I-85 Methanesulfonate (CT1113) and Compound I-1 Hydrochloride (CT1073) on the Expression Levels of c-MYC, LSD1, and Tankyrase (TNKS) Proteins in Tumor Cells
肿瘤细胞系HCT116，HCG27和SMMC7721使用培养液(DMEM+10％FBS+1％青-链霉素)培养，并分别加入DMSO(对照组)、500nM CT1073(实验组1)或500nM CT1113(实验组2)，处理24小时后，收取样品，进行Western blotting检测。Tumor cell lines HCT116, HCG27 and SMMC7721 were cultured in culture medium (DMEM + 10% FBS + 1% penicillin-streptomycin), and DMSO (control group), 500nM CT1073 (experimental group 1) or 500nM CT1113 (experimental group 2) were added respectively. After 24 hours of treatment, samples were collected and subjected to Western blotting detection.
实验结果(图34)显示，化合物I-85甲磺酸盐(CT1113)比化合物I-1盐酸盐(CT1073)具有更好的降低c-MYC和LSD1的蛋白水平，以及Tankyrase(TNKS)的蛋白水平的效果。c-MYC、LSD1和Tankyrase均与肿瘤发生发展相关。The experimental results (Figure 34) show that compound I-85 mesylate (CT1113) has a better effect of reducing the protein levels of c-MYC and LSD1, as well as the protein level of Tankyrase (TNKS) than compound I-1 hydrochloride (CT1073). c-MYC, LSD1 and Tankyrase are all related to the occurrence and development of tumors.
测试例5、化合物I-85甲磺酸盐(编号为：CT1113或PBSS1113)及化合物I-87盐酸盐在各种人肿瘤小鼠移植模型上抑制肿瘤生长的测试Test Example 5: Test of the inhibition of tumor growth by compound I-85 mesylate (numbered: CT1113 or PBSS1113) and compound I-87 hydrochloride in various human tumor mouse transplant models
以下所有测试中，化合物I-85甲磺酸盐及化合物I-87盐酸盐均溶于40％(2-羟丙基)-β-环糊精配成50mg/mL母液，用时用水稀释。对照(vehicle control)为40％环糊精作为母液同样稀释。In all the following tests, compound I-85 mesylate and compound I-87 hydrochloride were dissolved in 40% (2-hydroxypropyl)-β-cyclodextrin to make a 50 mg/mL stock solution, which was diluted with water when used. The vehicle control was 40% cyclodextrin as the stock solution and diluted in the same manner.
测试例5-1：化合物I-85甲磺酸盐(PBSS1113)在人食管癌小鼠模型(人KYSE-150细胞系移植瘤)上的抑癌作用。Test Example 5-1: Anti-cancer effect of compound I-85 mesylate (PBSS1113) on a human esophageal cancer mouse model (human KYSE-150 cell line transplanted tumor).
收取处于对数生长期的人食管癌细胞KYSE-150并重悬于PBS中，将100μl共计1x106个细胞种植于BALB/c-nude小鼠皮下。待肿瘤长至50～100mm3，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-85甲磺酸盐(PBSS1113)(实验组)，给药剂量为15mg/kg，给药方式为灌胃给药，给药频率为一天三次，给药时长为15天。Human esophageal cancer cells KYSE-150 in the logarithmic growth phase were collected and resuspended in PBS, and 100 μl of 1×10 6 cells were implanted subcutaneously in BALB/c-nude mice. When the tumor grew to 50-100 mm 3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 methanesulfonate (PBSS1113) (experimental group) respectively, with a dosage of 15 mg/kg, and the administration method was oral administration, the frequency of administration was three times a day, and the duration of administration was 15 days.
实验结果(图35)显示，经过15天的给药处理，人KYSE-150细胞系移植瘤生长明显被抑制，肿瘤生长抑制率为61.4％。The experimental results ( FIG. 35 ) showed that after 15 days of drug administration, the growth of transplanted tumors of the human KYSE-150 cell line was significantly inhibited, and the tumor growth inhibition rate was 61.4%.
测试例5-2：化合物I-85甲磺酸盐(PBSS1113)在人肝癌小鼠模型(人HepG2和HuH6细胞系移植瘤)上的抑癌作用。Test Example 5-2: Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human liver cancer mouse model (human HepG2 and HuH6 cell line transplanted tumors).
收取处于对数生长期的人肝癌细胞HepG2或HuH6并重悬于PBS中，按照3:1的比例与基质胶充分混合，将100μl共计1x107个细胞种植于BALB/c-nude小鼠皮下。待肿瘤长至100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-85甲磺酸盐(PBSS1113)(实验组)，给药剂量为20mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长分别为22天和16天。Human liver cancer cells HepG2 or HuH6 in the logarithmic growth phase were collected and resuspended in PBS, mixed with matrix gel at a ratio of 3:1, and 100 μl of 1x10 7 cells were implanted subcutaneously in BALB/c-nude mice. When the tumor grew to about 100 mm 3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 mesylate (PBSS1113) (experimental group) at a dose of 20 mg/kg. The administration method was oral administration, the frequency of administration was twice a day, and the duration of administration was 22 days and 16 days respectively.
实验结果(图36)表明，分别经过22天和16天的给药处理，人HepG2和HuH6肝癌细胞系移植瘤生长皆受到明显抑制，生长抑制率分别为73.4％和70.4％。The experimental results ( FIG. 36 ) showed that after 22 days and 16 days of drug treatment, respectively, the growth of transplanted tumors of human HepG2 and HuH6 liver cancer cell lines was significantly inhibited, with growth inhibition rates of 73.4% and 70.4%, respectively.
测试例5-3：化合物I-85甲磺酸盐(PBSS1113)在人结直肠癌小鼠模型(人结直肠癌PDX移植瘤)上的抑癌作用。Test Example 5-3: Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human colorectal cancer mouse model (human colorectal cancer PDX transplant tumor).
取生长状态良好的的两株人结直肠癌PDX(patient-derived xenograft)，CoY1607和CoY0495，将其分成1mm x 1mm的肿瘤块，用PBS清洗两次，然后分别移植于BALB/c-nude小鼠皮下。待肿瘤长至100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-85甲磺酸盐(PBSS1113)(实验组)，给药剂量为20mg/kg，给药方式为灌胃给药，给药频率为一天两次，PDX CoY1607给药时长为15天，PDX CoY0495给药时长为12天。Two well-growing human colorectal cancer PDX (patient-derived xenograft), CoY1607 and CoY0495, were taken and divided into 1mm x 1mm tumor blocks, washed twice with PBS, and then transplanted subcutaneously into BALB/c-nude mice. When the tumor grew to about 100mm3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 mesylate (PBSS1113) (experimental group) respectively. The dosage was 20mg/kg, and the administration method was oral administration. The frequency of administration was twice a day. The duration of administration of PDX CoY1607 was 15 days, and the duration of administration of PDX CoY0495 was 12 days.
实验结果(图37)表明，分别经过15天和12天的给药处理，人结直肠癌PDX CoY1607和CoY0495生长皆受到明显抑制，生长抑制率分别为62.9％和70.8％。The experimental results (Figure 37) showed that after 15 and 12 days of drug treatment, respectively, the growth of human colorectal cancer PDX CoY1607 and CoY0495 were significantly inhibited, with growth inhibition rates of 62.9% and 70.8%, respectively.
测试例5-4：化合物I-85甲磺酸盐(PBSS1113)在人胰腺癌小鼠模型(人胰腺癌细胞系SW1990移植瘤)上的抑癌作用。Test Example 5-4: Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human pancreatic cancer mouse model (human pancreatic cancer cell line SW1990 transplanted tumor).
收取处于对数生长期的人胰腺癌细胞SW1990并重悬于PBS中，按照3:1的比例与基质胶充分混合，将100μl共计5x106个细胞种植于BALB/c-nude小鼠皮下。待肿瘤长至50～100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-85甲磺酸盐(PBSS1113)(实验组)，给药剂量为20mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为20天。Human pancreatic cancer cells SW1990 in the logarithmic growth phase were collected and resuspended in PBS, mixed with matrix gel at a ratio of 3:1, and 100 μl of 5x10 6 cells were implanted subcutaneously in BALB/c-nude mice. When the tumor grew to about 50-100 mm 3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 mesylate (PBSS1113) (experimental group) respectively, with a dose of 20 mg/kg, and the administration method was oral administration, the frequency of administration was twice a day, and the duration of administration was 20 days.
实验结果(图38)表明，经过20天的给药处理，人胰腺癌细胞系SW1990移植瘤生长受到明显抑制，生长抑制率为45.9％。The experimental results ( FIG. 38 ) showed that after 20 days of drug administration, the growth of transplanted tumors of the human pancreatic cancer cell line SW1990 was significantly inhibited, with a growth inhibition rate of 45.9%.
测试例5-5：化合物I-85甲磺酸盐(PBSS1113)在人Burritt淋巴瘤小鼠模型(人Burritt淋巴瘤细胞系Raji移植瘤)上的抑癌作用。Test Example 5-5: Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human Burritt's lymphoma mouse model (human Burritt's lymphoma cell line Raji transplant tumor).
收取处于对数生长期的人Burritt淋巴瘤细胞系(携带Luciferase的Raji细胞，Raji-Luc)并重悬于PBS中，将200μl共计8x104个细胞尾静脉注射进入NSG小鼠体内。应用荧光素酶成像系统监测肿瘤增殖，待肿瘤负荷至106左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-85甲 磺酸盐(PBSS1113)(实验组)，给药剂量为20mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为18天。Human Burritt lymphoma cell line (Raji cells carrying Luciferase, Raji-Luc) in the logarithmic growth phase was collected and resuspended in PBS, and 200 μl of a total of 8x10 4 cells were injected into the tail vein of NSG mice. The tumor proliferation was monitored using a luciferase imaging system. When the tumor load reached about 10 6 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 methyl (compound I-85 methyl) respectively. Sulfonate (PBSS1113) (experimental group), the dosage was 20 mg/kg, the administration method was oral administration, the administration frequency was twice a day, and the administration duration was 18 days.
实验结果(图39)表明，经过18天的给药处理，人Burritt淋巴瘤细胞系Raji移植瘤生长受到明显抑制，生长抑制率为66.1％。The experimental results ( FIG. 39 ) showed that after 18 days of drug administration, the growth of human Burritt's lymphoma cell line Raji transplanted tumors was significantly inhibited, with a growth inhibition rate of 66.1%.
测试例5-6：化合物I-85甲磺酸盐(PBSS1113)在人神经母细胞瘤小鼠模型(人神经母细胞瘤细胞系SK-N-BE(2)移植瘤)上的抑癌作用。Test Example 5-6: Anti-tumor effect of compound I-85 mesylate (PBSS1113) on a human neuroblastoma mouse model (human neuroblastoma cell line SK-N-BE(2) transplanted tumor).
取生长状态良好的人神经母细胞瘤SK-N-BE(2)异种移植瘤，将其分成1mm x 1mm的肿瘤块，用PBS清洗两次，然后移植于BALB/c-nude小鼠皮下。待肿瘤长至50～100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-85甲磺酸盐(PBSS1113)(实验组1和实验组2)，给药剂量分别为15和20mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为18天。A well-growing human neuroblastoma SK-N-BE(2) xenograft tumor was taken and divided into 1mm x 1mm tumor pieces, washed twice with PBS, and then transplanted subcutaneously into BALB/c-nude mice. When the tumor grew to about 50-100mm3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-85 methanesulfonate (PBSS1113) (experimental group 1 and experimental group 2), respectively, with a dose of 15 and 20 mg/kg, respectively, by oral administration, with a frequency of twice a day and a duration of 18 days.
实验结果(图40)显示经过18天的给药处理，化合物I-85甲磺酸盐15和20mg/kg两种剂量皆能明显抑制人神经母细胞瘤细胞系SK-N-BE(2)移植瘤的生长，生长抑制率分别为57.9％和78.4％。The experimental results ( FIG. 40 ) showed that after 18 days of administration, both 15 and 20 mg/kg doses of compound I-85 mesylate could significantly inhibit the growth of human neuroblastoma cell line SK-N-BE(2) transplanted tumors, with growth inhibition rates of 57.9% and 78.4%, respectively.
测试例5-7：化合物I-85甲磺酸盐及化合物I-87盐酸盐在小鼠乳腺癌模型(小鼠乳腺癌细胞系EMT6移植瘤)上的抑癌作用。Test Example 5-7: Anti-tumor effects of Compound I-85 mesylate and Compound I-87 hydrochloride on mouse breast cancer model (mouse breast cancer cell line EMT6 transplanted tumor).
收取生长对数生长期小鼠乳腺癌细胞系EMT6并重悬于PBS中，按照3:1的比例与基质胶充分混合，将100μl共计3x105个细胞种植于雌性C57BL/6小鼠皮下。待肿瘤长至50～100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)、化合物I-85甲磺酸盐(PBSS1113)(给药剂量为20mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为18天)及化合物I-87盐酸盐(给药剂量为50mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为18天)。The mouse breast cancer cell line EMT6 in the logarithmic growth phase was collected and resuspended in PBS, and fully mixed with matrix gel at a ratio of 3:1. 100 μl of a total of 3x10 5 cells were implanted subcutaneously in female C57BL/6 mice. When the tumor grew to about 50-100 mm 3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group), compound I-85 mesylate (PBSS1113) (dosage of 20 mg/kg, administration by gavage, administration frequency twice a day, administration duration of 18 days) and compound I-87 hydrochloride (dosage of 50 mg/kg, administration by gavage, administration frequency twice a day, administration duration of 18 days).
实验结果(图41)显示经过18天的给药处理，化合物I-85甲磺酸盐及化合物I-87盐酸盐皆能明显抑制小鼠乳腺癌细胞系EMT6移植瘤的生长，生长抑制率分别为54.6％(I-8520mg/kg)、61.4％(I-85，25mg/kg)和71％(I-87)。The experimental results (Figure 41) show that after 18 days of administration, both compound I-85 methanesulfonate and compound I-87 hydrochloride can significantly inhibit the growth of mouse breast cancer cell line EMT6 transplanted tumors, with growth inhibition rates of 54.6% (I-85 20 mg/kg), 61.4% (I-85, 25 mg/kg) and 71% (I-87), respectively.
测试例5-8：化合物I-87盐酸盐在人胰腺癌小鼠模型(人胰腺癌细胞系SW1990移植瘤)上的抑癌作用。Test Example 5-8: Anti-tumor effect of compound I-87 hydrochloride on a human pancreatic cancer mouse model (human pancreatic cancer cell line SW1990 transplanted tumor).
收取处于对数生长期的人胰腺癌细胞SW1990并重悬于PBS中，按照3:1的比例与基质胶充分混合，将100μl共计5x106个细胞种植于BALB/c-nude皮下。待肿瘤长至50～100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)、化合物I-87盐酸盐(给药剂量为50mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为38天)和吉西他滨(给药剂量为100mg/kg，给药方式为灌胃给药，给药频率为三天一次，给药时长为38天)。Human pancreatic cancer cells SW1990 in the logarithmic growth phase were collected and resuspended in PBS, mixed with matrix gel at a ratio of 3:1, and 100 μl of 5x10 6 cells were implanted subcutaneously in BALB/c-nude. When the tumor grew to about 50-100 mm 3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group), compound I-87 hydrochloride (dosage of 50 mg/kg, administration by gavage, administration frequency of twice a day, administration duration of 38 days) and gemcitabine (dosage of 100 mg/kg, administration by gavage, administration frequency of once every three days, administration duration of 38 days).
实验结果(图42)显示经过38天的给药处理，化合物I-87盐酸盐能明显抑制人胰腺癌细胞系SW1990移植瘤的生长，生长抑制率为47.2％，与化疗药物吉西他滨51.3％的抑制率相仿。The experimental results ( FIG. 42 ) showed that after 38 days of administration, compound I-87 hydrochloride could significantly inhibit the growth of human pancreatic cancer cell line SW1990 transplanted tumors, with a growth inhibition rate of 47.2%, which was similar to the 51.3% inhibition rate of the chemotherapy drug gemcitabine.
测试例5-9：化合物I-87盐酸盐在人结直肠癌小鼠模型(人结直肠癌PDX移植瘤)上的抑癌作用。Test Example 5-9: Anti-tumor effect of compound I-87 hydrochloride on a human colorectal cancer mouse model (human colorectal cancer PDX transplant tumor).
取生长状态良好的的人结直肠癌PDX(patient-derived xenograft,CoY1607株)将其分成1.5mm x1.5mm的肿瘤块，用PBS清洗两次，然后分别移植于BALB/c-nude小鼠皮下。待肿瘤长至100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂、化合物I-87盐酸盐(给药剂量为50mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为28天)和伊立替康(给药剂量为20mg/kg，给药方式为腹腔注射，给药频率为一周一次，给药时长为28天)。A well-growing human colorectal cancer PDX (patient-derived xenograft, CoY1607 strain) was taken and divided into 1.5mm x1.5mm tumor pieces, washed twice with PBS, and then transplanted subcutaneously into BALB/c-nude mice. When the tumor grew to about 100mm3 , the mice were randomly divided into two groups and given cyclodextrin solvent, compound I-87 hydrochloride (dosage of 50mg/kg, administration by gavage, frequency of administration twice a day, duration of administration for 28 days) and irinotecan (dosage of 20mg/kg, administration by intraperitoneal injection, frequency of administration once a week, duration of administration for 28 days).
实验结果(图43)显示经过28天的给药处理，化合物I-87盐酸盐能明显抑制人结直肠癌PDX移植瘤的生长，生长抑制率为57.4％，与化疗药物伊立替康61.7％的抑制率相仿。The experimental results ( FIG. 43 ) showed that after 28 days of administration, compound I-87 hydrochloride could significantly inhibit the growth of human colorectal cancer PDX transplanted tumors, with a growth inhibition rate of 57.4%, which is similar to the 61.7% inhibition rate of the chemotherapy drug irinotecan.
测试例5-10：化合物I-87盐酸盐在小鼠乳腺癌模型(小鼠乳腺癌细胞系4T1移植瘤)上的抑癌作用。Test Example 5-10: Anti-tumor effect of compound I-87 hydrochloride on mouse breast cancer model (mouse breast cancer cell line 4T1 transplanted tumor).
收取处于对数生长期的小鼠乳腺癌细胞系4T1并重悬于PBS中，按照3:1的比例与基质胶充分混合，将100μl共计1x106个细胞种植于BALB/c小鼠皮下。待肿瘤长至50～100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-87盐酸盐(实验组)，给药剂量为50mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为15天。Mouse breast cancer cell line 4T1 in the logarithmic growth phase was collected and resuspended in PBS, and fully mixed with matrix gel at a ratio of 3:1. 100 μl of 1x10 6 cells were implanted subcutaneously in BALB/c mice. When the tumor grew to about 50-100 mm 3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-87 hydrochloride (experimental group) respectively. The dosage was 50 mg/kg, and the administration method was oral administration. The frequency of administration was twice a day, and the duration of administration was 15 days.
实验结果(图44)显示经过15天的给药处理，化合物I-87盐酸盐能明显抑制小鼠乳腺癌细胞系4T1移植瘤的生长，生长抑制率为38％。 The experimental results ( FIG. 44 ) showed that after 15 days of administration, compound I-87 hydrochloride could significantly inhibit the growth of mouse breast cancer cell line 4T1 transplanted tumors, with a growth inhibition rate of 38%.
测试例5-11：化合物I-87盐酸盐在在小鼠黑色素瘤模型(小鼠黑色素瘤细胞系B16移植瘤)上的抑癌作用。Test Example 5-11: Anti-tumor effect of compound I-87 hydrochloride on mouse melanoma model (mouse melanoma cell line B16 transplanted tumor).
取生长状态良好的小鼠黑色素瘤(来自黑色素瘤细胞系B16种植于C57BL/6小鼠后产生的肿瘤)将其分成1.5mm x 1.5mm的肿瘤块，用PBS清洗两次，种植于C57BL/6小鼠皮下。待肿瘤长至50～100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-87盐酸盐(实验组)，给药剂量为50mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为10天。Take a well-growing mouse melanoma (a tumor produced by implanting a melanoma cell line B16 in a C57BL/6 mouse) and divide it into 1.5mm x 1.5mm tumor pieces, wash it twice with PBS, and implant it subcutaneously in a C57BL/6 mouse. When the tumor grows to about 50-100mm3 , the mice are randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-87 hydrochloride (experimental group) respectively, with a dose of 50mg/kg, and the administration method is oral administration, the frequency of administration is twice a day, and the duration of administration is 10 days.
实验结果(图45)显示经过10天的给药处理，化合物I-87盐酸盐能明显抑制小鼠B16黑色素瘤的生长，生长抑制率分56.3％。The experimental results ( FIG. 45 ) showed that after 10 days of administration, compound I-87 hydrochloride could significantly inhibit the growth of mouse B16 melanoma, with a growth inhibition rate of 56.3%.
测试例5-12：化合物I-87盐酸盐在在小鼠结直肠癌模型(小鼠结直肠癌细胞系MC38移植瘤)上的抑癌作用。Test Example 5-12: Anti-tumor effect of compound I-87 hydrochloride on mouse colorectal cancer model (mouse colorectal cancer cell line MC38 transplanted tumor).
收取处于对数生长期的小鼠结直肠癌细胞系MC38并重悬于PBS中，按照3:1的比例与基质胶充分混合，将100μl共计2x105个细胞种植于C57BL/6小鼠皮下。待肿瘤长至50～100mm3左右，将小鼠随机分成两组，分别给予环糊精溶剂(对照组)及化合物I-87盐酸盐(实验组)，给药剂量为50mg/kg，给药方式为灌胃给药，给药频率为一天两次，给药时长为10天。Mouse colorectal cancer cell line MC38 in the logarithmic growth phase was collected and resuspended in PBS, mixed with matrix gel at a ratio of 3:1, and 100 μl of 2x10 5 cells were implanted subcutaneously in C57BL/6 mice. When the tumor grew to about 50-100 mm 3 , the mice were randomly divided into two groups and given cyclodextrin solvent (control group) and compound I-87 hydrochloride (experimental group) at a dose of 50 mg/kg, by oral administration, twice a day, and for 10 days.
实验结果(图46)显示经过10天的给药处理，化合物I-87盐酸盐能明显抑制小鼠结直肠癌细胞系MC38移植瘤的生长，生长抑制率72.3％。The experimental results ( FIG. 46 ) showed that after 10 days of administration, compound I-87 hydrochloride could significantly inhibit the growth of mouse colorectal cancer cell line MC38 transplanted tumors, with a growth inhibition rate of 72.3%.
上述测试例结果显示，化合物I-85甲磺酸盐及化合物I-87盐酸盐对移植于小鼠的各种人类肿瘤及小鼠肿瘤具有优良的生长抑制作用，显示了这两个化合物作为广谱抗肿瘤药物的巨大潜力。The above test results show that compound I-85 mesylate and compound I-87 hydrochloride have excellent growth inhibitory effects on various human tumors and mouse tumors transplanted into mice, demonstrating the great potential of these two compounds as broad-spectrum anti-tumor drugs.
测试例6、化合物I-85甲磺酸盐(编号为：PBSS1113)对急性髓系白血病细胞生长抑制的活性测试Test Example 6: Activity test of compound I-85 methanesulfonate (number: PBSS1113) on the growth inhibition of acute myeloid leukemia cells
测试例6-1：化合物I-58与化合物I-85甲磺酸盐对急性髓系白血病(AML，acute myeloid leukemia)细胞系生长抑制作用的比较。Test Example 6-1: Comparison of the growth inhibitory effects of compound I-58 and compound I-85 mesylate on acute myeloid leukemia (AML) cell lines.
三株AML细胞系，Molm-13、MV4-11、OCI-AML2，置6cm培养皿(5x104细胞/ml，6ml/皿)，加入培养液(MOLM13和MV4-11：IMDM+10％FBS+1％青-链霉素；OCI-AML2：RPMI-1640+10％FBS+1％青-链霉素)以及化合物至0、50nM、100nM、200nM、或500nM终浓度，置于二氧化碳细胞培养箱(37℃，5％CO2)中培养培养72小时后，用MTS法测定活细胞数量，以不加化合物(只加同样量的化合物溶剂DMSO)的细胞数为1，结果如下表23及图47(生长曲线)所示。Three AML cell lines, Molm-13, MV4-11, and OCI-AML2, were placed in 6 cm culture dishes (5x104 cells/ml, 6 ml/dish), and culture medium (MOLM13 and MV4-11: IMDM+10% FBS+1% penicillin-streptomycin; OCI-AML2: RPMI-1640+10% FBS+1% penicillin-streptomycin) and compounds were added to final concentrations of 0, 50 nM, 100 nM, 200 nM, or 500 nM, and cultured in a carbon dioxide cell culture incubator (37°C, 5% CO2). After 72 hours of culture, the number of live cells was determined by the MTS method, and the number of cells without adding compounds (only adding the same amount of compound solvent DMSO) was taken as 1. The results are shown in Table 23 below and Figure 47 (growth curve).
表23
Table 23
结果显示，化合物I-85甲磺酸盐对AML细胞生长抑制活性优于化合物I-58。The results showed that the mesylate salt of compound I-85 had better inhibitory activity on AML cell growth than compound I-58.
测试例6-2：化合物I-85甲磺酸盐对29株AML细胞系的生长抑制作用。Test Example 6-2: Growth inhibitory effect of compound I-85 mesylate on 29 AML cell lines.
29株AML细胞系，置96孔板(2x103细胞/孔)，加不同浓度化合物，在所需培养基(下表24)中培养72小时。29 AML cell lines were placed in 96-well plates (2x10 3 cells/well), and different concentrations of compounds were added and cultured in the required culture medium (Table 24 below) for 72 hours.
表24

Table 24

培养结束后，在Mg2+、ATP和分子氧存在下，通过定量测量细胞裂解后的ATP和荧光素酶催化甲虫荧光素酶产生发光信号分子来确定代谢活性细胞的数量，计算获得化合物I-85甲磺酸盐(PBSS1113)对各细胞系生长50％抑制(IC50)所需浓度(下表25及图48)。After the culture, in the presence of Mg 2+ , ATP and molecular oxygen, the number of metabolically active cells was determined by quantitatively measuring ATP after cell lysis and luciferase-catalyzed beetle luciferase to produce luminescent signal molecules, and the concentration of compound I-85 mesylate (PBSS1113) required for 50% inhibition (IC 50 ) of the growth of each cell line was calculated (Table 25 below and Figure 48 ).
表25

Table 25

测试例6-3：化合物I-85甲磺酸盐导致AML细胞凋亡。Test Example 6-3: Compound I-85 mesylate causes apoptosis of AML cells.
AML细胞(OCI-AML3)经不同浓度化合物I-85甲磺酸盐(PBSS1113)培养6天后用细胞流式方法测定细胞凋亡(图49)AML cells (OCI-AML3) were cultured with different concentrations of compound I-85 mesylate (PBSS1113) for 6 days and then cell apoptosis was determined by flow cytometry (Figure 49)
测试例6-4：化合物I-85甲磺酸盐在人AML动物模型上的抑瘤活性。Test Example 6-4: Antitumor activity of compound I-85 mesylate in human AML animal model.
收取处于对数生长期的人AML细胞Moml-13-Luc(表达Luciferase的Molm-13 AML细胞)并重悬于PBS中，经尾静脉注射(1x107细胞，200 l)接种到免疫缺陷(NSG)小鼠体内。肿瘤细胞接种后第10天，根据动物体重和肿瘤部位光学信号强度，将动物随机分为4组，每组10只，分别给予药物处理14天。PBSS1113(两个剂量：15和20mg/kg体重，bid)灌胃给药；阿霉素(doxorubincin，溶于生理盐水，1mg/kg体重，给2天停5天)，静脉注射给药。Human AML cells Moml-13-Luc (Molm-13 AML cells expressing Luciferase) in the logarithmic growth phase were collected and resuspended in PBS, and inoculated into immunodeficient (NSG) mice via tail vein injection (1x10 7 cells, 200 l). On the 10th day after tumor cell inoculation, the animals were randomly divided into 4 groups, 10 in each group, according to the animal weight and the optical signal intensity of the tumor site, and treated with drugs for 14 days. PBSS1113 (two doses: 15 and 20 mg/kg body weight, bid) was administered by gavage; doxorubicin (doxorubincin, dissolved in normal saline, 1 mg/kg body weight, 2 days on and 5 days off) was administered by intravenous injection.
肿瘤生长以Luc活性为代表。化合物I-85甲磺酸盐两个剂量，15和20mg/kg，分别达到57.5％和87.8％的抑制率(见下表26及图50)。Tumor growth was represented by Luc activity. Compound I-85 mesylate salt achieved 57.5% and 87.8% inhibition rates at two doses, 15 and 20 mg/kg, respectively (see Table 26 below and Figure 50).
表26

注：a.均数±标准误；b.与溶剂对照组比较。Table 26

Note: a. Mean ± standard error; b. Compared with the solvent control group.
测试例6的结果表明，化合物I-85甲磺酸盐对不同种类的急性髓系白血病细胞均有很强的生长抑制作用，可导致细胞凋亡。在动物模型上，化合物I-85甲磺酸盐效果明显，存在剂量-效应关系，在20mg/kg时肿瘤抑制效果优于阳性对照药物阿霉素。The results of Test Example 6 show that compound I-85 mesylate has a strong growth inhibitory effect on different types of acute myeloid leukemia cells and can cause cell apoptosis. In animal models, compound I-85 mesylate has a significant effect and a dose-effect relationship. At 20 mg/kg, the tumor inhibition effect is better than that of the positive control drug doxorubicin.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims (10)

  1. 式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药在制备治疗癌症的药物中的应用：Use of the compound represented by Formula I and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug in the preparation of a drug for treating cancer:
    优选地，所述式I所示的化合物的多晶型物或药学上可接受的盐在制备治疗癌症的药物中的应用；Preferably, the use of the polymorph or pharmaceutically acceptable salt of the compound represented by Formula I in the preparation of a drug for treating cancer;
    优选地，所述癌症包括白血病(如急性髓系白血病)、肝癌、结肠癌、卵巢癌、食道癌、结直肠癌、胰腺癌、淋巴瘤、胶质瘤、神经母细胞瘤、鼻咽癌、肺癌、乳腺癌、胃癌、胆管癌、肾癌、膀胱癌、宫颈癌、前列腺癌、肉瘤；
    Preferably, the cancer includes leukemia (such as acute myeloid leukemia), liver cancer, colon cancer, ovarian cancer, esophageal cancer, colorectal cancer, pancreatic cancer, lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, lung cancer, breast cancer, gastric cancer, bile duct cancer, kidney cancer, bladder cancer, cervical cancer, prostate cancer, sarcoma;
    其中：in:
    X为CR5或N；X is CR 5 or N;
    m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
    n为1或2；n is 1 or 2;
    Z为NR10、O、S、CR11R12；表示可以为单键或双键；Z is NR 10 , O, S, CR 11 R 12 ; It means it can be a single bond or a double bond;
    q为1、2或3；q is 1, 2, or 3;
    R1、R2、R5可以相同也可以不同，彼此独立地选自氢、卤素、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基；R 1 , R 2 , and R 5 may be the same or different, and are independently selected from hydrogen, halogen, amino, and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
    R3为无取代或取代的(C1-C12)脂肪烃基；R 3 is an unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon group;
    每一个R4和R6可以相同也可以不同，彼此独立地选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基；Each of R 4 and R 6 may be the same or different and are independently selected from hydrogen, halogen, hydroxyl, amino and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
    R7和R8可以相同也可以不同，彼此独立地选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基；R 7 and R 8 may be the same or different, and are independently selected from hydrogen, halogen, hydroxyl, amino, and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
    R9选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基；R 9 is selected from hydrogen, halogen, hydroxy, amino and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups;
    或者，R9选自无取代或任选地被一个、两个或更多个R13所取代的3-20元杂环基或5-20元杂芳基；Alternatively, R 9 is selected from 3-20 membered heterocyclyl or 5-20 membered heteroaryl which is unsubstituted or optionally substituted by one, two or more R 13 ;
    R10选自氢、无取代或取代的(C1-C12)脂肪烃基；R 10 is selected from hydrogen, unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon group;
    R11、R12和R13选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基。R 11 , R 12 and R 13 are selected from hydrogen, halogen, hydroxy, amino and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups.
    优选地，所述癌症包括白血病(如急性髓系白血病)、肝癌、结肠癌、卵巢癌、食道癌、结直肠癌、胰腺癌。Preferably, the cancer includes leukemia (such as acute myeloid leukemia), liver cancer, colon cancer, ovarian cancer, esophageal cancer, colorectal cancer, pancreatic cancer.
  2. 根据权利要求1所述的应用，其特征在于，X为CH或N；The use according to claim 1, characterized in that X is CH or N;
    优选地，Z为NH、O、S或CH2；Preferably, Z is NH, O, S or CH 2 ;
    优选地，R1可选自H或(C1-C6)脂肪烃基；Preferably, R 1 can be selected from H or (C 1 -C 6 ) aliphatic hydrocarbon group;
    优选地，R2可选自H或(C1-C6)脂肪烃基，例如H、甲基或乙基；Preferably, R 2 can be selected from H or (C 1 -C 6 ) aliphatic hydrocarbon groups, such as H, methyl or ethyl;
    优选地，R3可选自无取代或取代的(C1-C6)脂肪烃基；Preferably, R 3 can be selected from unsubstituted or substituted (C 1 -C 6 ) aliphatic hydrocarbon groups;
    优选地，R3可选自甲基、乙基、丙基、丁基、甲氧基甲基，乙氧基甲基，丙氧基甲基，甲氧基乙基，乙氧基乙基，丙氧基乙基，甲氧基丙基，乙氧基丙基，丙氧基丙基，N-甲基胺甲基，N-甲基胺乙基，N-乙基胺乙基，N,N-二甲基胺甲基，N,N-二甲基胺乙基，N,N-二乙基胺乙基；Preferably, R3 can be selected from methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl;
    优选地，R9选自无取代或任选地被一个、两个或更多个R13所取代的下列基团：3-20元杂环基、5-20元杂芳基；Preferably, R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 13 : 3-20 membered heterocyclyl, 5-20 membered heteroaryl;
    优选地，R9选自无取代或任选地被一个、两个或更多个R13所取代的，含有一个、两个或更多个N原子的3-20元杂环基或5-20元杂芳基，进一步的，优选为仅含有一个或两个N作为杂原子的3-10元杂环基；Preferably, R 9 is selected from a 3-20 membered heterocyclic group or a 5-20 membered heteroaryl group which is unsubstituted or optionally substituted by one, two or more R 13 and contains one, two or more N atoms, and further preferably is a 3-10 membered heterocyclic group containing only one or two N atoms as heteroatoms;
    优选地，R9可选自无取代或任选地被一个、两个或更多个R13所取代的以下基团：
    Preferably, R 9 can be selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 13 :
  3. 根据权利要求1或2所述的应用，其特征在于，式I所述化合物具有式II所示的结构：
    The use according to claim 1 or 2, characterized in that the compound of formula I has a structure shown in formula II:
    所述式II中，R1、R2、R3、R6、R9，X、Z、q的定义如前述式I中所定义。In the formula II, R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q are as defined in the above formula I.
  4. 根据权利要求1-3任一项所述的应用，其特征在于，式I所述化合物选自如下所示的结构：
    The use according to any one of claims 1 to 3, characterized in that the compound of formula I is selected from the following structures:
    优选地，所述I所示的化合物药学上可接受的盐选自下文所述的具体的盐。优选选自盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐。Preferably, the pharmaceutically acceptable salt of the compound shown in I is selected from the specific salts described below, preferably selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate.
    优选地，所述化合物选自化合物I-85或者化合物I-87或其药学上可接受的盐。Preferably, the compound is selected from Compound I-85 or Compound I-87 or a pharmaceutically acceptable salt thereof.
    优选地，所述化合物选自化合物I-85药学上可接受的盐，如甲磺酸盐或者富马酸盐。Preferably, the compound is selected from a pharmaceutically acceptable salt of Compound I-85, such as a mesylate or a fumarate.
    优选地，所述化合物选自化合物I-85的多晶型。Preferably, the compound is selected from the polymorphic forms of compound 1-85.
  5. 式I所示的化合物或其药学上可接受的盐的多晶型物：
    The polymorph of the compound represented by Formula I or its pharmaceutically acceptable salt:
    其中，R1、R2、R3、R4、R6、R7、R8、R9，X、Z、m、n、q具有权利要求1-4中任一项所述的定义；Wherein, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , X, Z, m, n, q have the definitions as defined in any one of claims 1 to 4;
    优选地，所述式I具有式II所示的结构：
    Preferably, the formula I has the structure shown in formula II:
    所述式II中，R1、R2、R3、R6、R9，X、Z、q具有权利要求1-4中任一项所述的定义；In the formula II, R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q have the definitions as defined in any one of claims 1 to 4;
    优选地，式I所述化合物选自如下所示的结构：
    Preferably, the compound of formula I is selected from the following structures:
  6. 式I所示的化合物药学上可接受的盐：
    Pharmaceutically acceptable salts of the compound represented by formula I:
    其中，R1、R2、R3、R4、R6、R7、R8、R9，X、Z、m、n、q具有权利要求1-4中任一项所述的定义；Wherein, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , X, Z, m, n, q have the definitions as defined in any one of claims 1 to 4;
    其中，所述药学上可接受的盐为式I化合物与酸形成的盐，所述酸可以选自无机酸或有机酸，例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸，甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、L-酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸；作为实例，所述酸可以选自盐酸、氢溴酸、硫酸、磷酸、硝酸、甲磺酸、对甲苯磺酸、富马酸、马来酸、柠檬酸、L-酒石酸、草酸、甲酸、乙酸、三氟乙酸、月桂酸、苯甲酸和苯磺酸中的一种；Wherein, the pharmaceutically acceptable salt is a salt formed by a compound of formula I and an acid, and the acid can be selected from an inorganic acid or an organic acid, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid , dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid; as an example, the acid may be selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid;
    优选地，所述I所示的化合物药学上可接受的盐选自盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐；Preferably, the pharmaceutically acceptable salt of the compound shown in I is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate;
    优选地，所述式I具有式II所示的结构：
    Preferably, the formula I has the structure shown in formula II:
    所述式II中，R1、R2、R3、R6、R9，X、Z、q具有权利要求1-4中任一项所述的定义；In the formula II, R 1 , R 2 , R 3 , R 6 , R 9 , X, Z, and q have the definitions as defined in any one of claims 1 to 4;
    优选地，所述式I所述化合物选自如下所示的化合物药学上可接受的盐：
    Preferably, the compound of formula I is selected from pharmaceutically acceptable salts of the compounds shown below:
    优选地，所述式I所示的化合物药学上可接受的盐选自化合物Ⅰ-85、化合物Ⅰ-86、化合物Ⅰ-87、化合物Ⅰ-88、化合物I-89、化合物Ⅰ-90、化合物Ⅰ-91的药学上可接受的盐，进一步地，这些化合物药学上可接受的盐选自其盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐。Preferably, the pharmaceutically acceptable salt of the compound represented by Formula I is selected from the pharmaceutically acceptable salts of Compound I-85, Compound I-86, Compound I-87, Compound I-88, Compound I-89, Compound I-90, and Compound I-91. Furthermore, the pharmaceutically acceptable salts of these compounds are selected from their hydrochlorides, sulfates, hydrobromides, methanesulfonates, p-toluenesulfonates, phosphates, L-tartrates or fumarates.
  7. 化合物Ⅰ-85或化合物Ⅰ-87的药学上可接受的盐或其多晶型：A pharmaceutically acceptable salt or polymorph thereof of Compound I-85 or Compound I-87:
    优选地，化合物Ⅰ-85药学上可接受的盐，
    Preferably, the pharmaceutically acceptable salt of Compound I-85 is
    其中，所述药学上可接受的盐选自盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐；Wherein, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate;
    优选地，所述化合物Ⅰ-85药学上可接受的盐为化合物Ⅰ-85的甲磺酸盐或富马酸盐；Preferably, the pharmaceutically acceptable salt of Compound I-85 is the mesylate or fumarate of Compound I-85;
    优选地，化合物Ⅰ-85或其药学上可接受的盐的多晶型，
    Preferably, the polymorphic form of Compound I-85 or a pharmaceutically acceptable salt thereof,
    优选地，所述多晶型为化合物I-85的甲磺酸盐晶型I(无水物)；Preferably, the polymorph is the mesylate salt form I (anhydrate) of compound I-85;
    优选地，所述多晶型为化合物I-85的甲磺酸盐晶型II(水合物)；Preferably, the polymorph is the mesylate salt form II (hydrate) of compound I-85;
    优选地，所述多晶型为化合物I-85的甲磺酸盐晶型III(甲醇溶剂化物)；Preferably, the polymorph is the mesylate salt form III (methanol solvate) of compound I-85;
    优选地，所述多晶型为化合物Ⅰ-85的富马酸盐晶型I(无水物)；Preferably, the polymorph is the fumarate salt form I (anhydrate) of compound I-85;
    优选地，化合物Ⅰ-87药学上可接受的盐：
    Preferably, the pharmaceutically acceptable salt of compound I-87 is:
    其中，所述药学上可接受的盐选自盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、磷酸盐、L-酒石酸盐或富马酸盐；Wherein, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, p-toluenesulfonate, phosphate, L-tartrate or fumarate;
    优选地，所述化合物Ⅰ-87药学上可接受的盐为化合物Ⅰ-87的盐酸盐或甲磺酸盐。Preferably, the pharmaceutically acceptable salt of Compound Ⅰ-87 is the hydrochloride or methanesulfonate of Compound Ⅰ-87.
  8. 化合物Ⅰ-85的药学上可接受的盐或其多晶型，可以选自如下晶型：The pharmaceutically acceptable salt of compound I-85 or its polymorphic form can be selected from the following crystalline forms:
    优选地，化合物Ⅰ-85的一盐酸盐晶型I，其X-射线粉末衍射图包括位于11.128±0.2°、21.646±0.2°、22.065±0.2°和22.893±0.2°的衍射角(2θ)处的峰；Preferably, the monohydrochloride form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 11.128±0.2°, 21.646±0.2°, 22.065±0.2° and 22.893±0.2°;
    优选地，所述一盐酸盐晶型I，其X-射线粉末衍射图包括位于11.128±0.2°、18.271±0.2°、21.646±0.2°、22.065±0.2°、22.893±0.2°和26.357±0.2°的衍射角(2θ)处的峰；Preferably, the monohydrochloride crystalline form I has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 11.128±0.2°, 18.271±0.2°, 21.646±0.2°, 22.065±0.2°, 22.893±0.2° and 26.357±0.2°;
    优选地，所述一盐酸盐晶型I，其X-射线粉末衍射图包括位于11.128±0.2°、13.020±0.2°、17.587±0.2°、18.271±0.2°、21.646±0.2°、22.065±0.2°、22.893±0.2°、26.357±0.2°和27.187±0.2°的衍射角(2θ)处的峰；Preferably, the monohydrochloride crystalline form I has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 11.128±0.2°, 13.020±0.2°, 17.587±0.2°, 18.271±0.2°, 21.646±0.2°, 22.065±0.2°, 22.893±0.2°, 26.357±0.2° and 27.187±0.2°;
    优选地，所述一盐酸盐晶型I的X-射线粉末衍射图具有如表1-1所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the monohydrochloride salt form I has a diffraction angle (2θ) as shown in Table 1-1, wherein the error range of the 2θ angle is ±0.20°:
    表1-1
    Table 1-1
    优选地，所述一盐酸盐晶型I具有如表1-1所示的X-射线粉末衍射强度；Preferably, the hydrochloride salt form I has an X-ray powder diffraction intensity as shown in Table 1-1;
    优选地，所述一盐酸盐晶型I具有基本如图1-1所示的X射线粉末衍射图；Preferably, the hydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in FIG1-1;
    优选地，所述一盐酸盐晶型I在约200℃的温度处具有吸热峰的DSC热谱图；Preferably, the hydrochloride salt form I has a DSC thermogram with an endothermic peak at a temperature of about 200° C.;
    优选地，所述一盐酸盐晶型I具有基本如图2所示的DSC图；Preferably, the hydrochloride salt form I has a DSC graph substantially as shown in FIG2 ;
    优选地，所述一盐酸盐晶型I具有基本如图2所示的TGA图； Preferably, the hydrochloride salt form I has a TGA graph substantially as shown in FIG2 ;
    优选地，化合物Ⅰ-85的二盐酸盐晶型I，其X-射线粉末衍射图包括位于6.150±0.2°、14.095±0.2°和18.205±0.2°的衍射角(2θ)处的峰；Preferably, the dihydrochloride salt form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.150±0.2°, 14.095±0.2° and 18.205±0.2°;
    优选地，所述二盐酸盐晶型I的X-射线粉末衍射图还包括位于4.655±0.2°、6.150±0.2°、9.289±0.2°、12.965±0.2°、14.095±0.2°和18.205±0.2°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the dihydrochloride salt form I further includes peaks at diffraction angles (2θ) of 4.655±0.2°, 6.150±0.2°, 9.289±0.2°, 12.965±0.2°, 14.095±0.2° and 18.205±0.2°;
    优选地，所述二盐酸盐晶型I的X-射线粉末衍射图还包括位于4.655±0.2°、6.150±0.2°、8.003±0.2°、9.289±0.2°、12.965±0.2°、14.095±0.2°、16.169±0.2°、18.205±0.2°、19.413±0.2°、23.942±0.2°和27.621±0.2°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the dihydrochloride salt form I further includes peaks at diffraction angles (2θ) of 4.655±0.2°, 6.150±0.2°, 8.003±0.2°, 9.289±0.2°, 12.965±0.2°, 14.095±0.2°, 16.169±0.2°, 18.205±0.2°, 19.413±0.2°, 23.942±0.2° and 27.621±0.2°;
    优选地，所述二盐酸盐晶型I的X-射线粉末衍射图具有如表1-2所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the dihydrochloride salt form I has a diffraction angle (2θ) as shown in Table 1-2, wherein the error range of the 2θ angle is ±0.20°:
    表1-2
    Table 1-2
    优选地，所述二盐酸盐晶型I具有如表1-2所示的X-射线粉末衍射强度；Preferably, the dihydrochloride salt form I has an X-ray powder diffraction intensity as shown in Table 1-2;
    优选地，所述二盐酸盐晶型I具有基本如图1-2所示的X射线粉末衍射图；Preferably, the dihydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in Figures 1-2;
    优选地，所述二盐酸盐晶型I在约70.45℃、145.07℃和229.64℃的温度处具有吸热峰的DSC热谱图；Preferably, the dihydrochloride salt form I has a DSC thermogram with endothermic peaks at temperatures of about 70.45°C, 145.07°C and 229.64°C;
    优选地，所述二盐酸盐晶型I具有基本如图3所示的DSC图；Preferably, the dihydrochloride salt form I has a DSC graph substantially as shown in FIG3 ;
    优选地，所述二盐酸盐晶型I具有基本如图3所示的TGA图；Preferably, the dihydrochloride salt form I has a TGA graph substantially as shown in Figure 3;
    优选地，化合物Ⅰ-85的硫酸盐晶型I，其X-射线粉末衍射图包括位于11.928±0.2°、14.490±0.2°和19.321±0.2°的衍射角(2θ)处的峰；Preferably, the sulfate salt form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 11.928±0.2°, 14.490±0.2° and 19.321±0.2°;
    优选地，所述硫酸盐晶型I的X-射线粉末衍射图还包括位于11.928±0.2°、14.490±0.2°、19.321±0.2°、22.524±0.2°、23.456±0.2°和28.369±0.2°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the sulfate salt crystalline form I further includes peaks at diffraction angles (2θ) of 11.928±0.2°, 14.490±0.2°, 19.321±0.2°, 22.524±0.2°, 23.456±0.2° and 28.369±0.2°;
    优选地，所述硫酸盐晶型I的X-射线粉末衍射图还包括位于9.640±0.2°、11.928±0.2°、14.016±0.2°、14.490±0.2°、16.433±0.2°、19.321±0.2°、22.524±0.2°、23.456±0.2°和28.369±0.2°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the sulfate salt crystalline form I further includes peaks at diffraction angles (2θ) of 9.640±0.2°, 11.928±0.2°, 14.016±0.2°, 14.490±0.2°, 16.433±0.2°, 19.321±0.2°, 22.524±0.2°, 23.456±0.2° and 28.369±0.2°;
    优选地，所述硫酸盐晶型I的X-射线粉末衍射图具有如表1-3所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the sulfate salt crystalline form I has a diffraction angle (2θ) as shown in Table 1-3, wherein the error range of the 2θ angle is ±0.20°:
    表1-3

    Table 1-3

    优选地，所述硫酸盐晶型I具有如表1-3所示的X-射线粉末衍射强度；Preferably, the sulfate crystal form I has an X-ray powder diffraction intensity as shown in Table 1-3;
    优选地，所述硫酸盐晶型I具有基本如图4-1所示的X射线粉末衍射图；Preferably, the sulfate salt crystalline form I has an X-ray powder diffraction pattern substantially as shown in FIG4-1;
    优选地，所述硫酸盐晶型I在约87.71℃和254.89℃的温度处具有吸热峰的DSC热谱图；Preferably, the sulfate salt crystalline form I has a DSC thermogram with endothermic peaks at temperatures of about 87.71° C. and 254.89° C.;
    优选地，所述硫酸盐晶型I具有基本如图5所示的DSC图；Preferably, the sulfate salt crystalline form I has a DSC graph substantially as shown in FIG5 ;
    优选地，所述硫酸盐晶型I具有基本如图5所示的TGA图；Preferably, the sulfate salt crystalline form I has a TGA graph substantially as shown in FIG5 ;
    优选地，化合物Ⅰ-85的硫酸盐晶型II，其X-射线粉末衍射图包括位于11.928±0.2°、14.490±0.2°、19.321±0.2°和22.524±0.2°的衍射角(2θ)处的峰；Preferably, the sulfate salt form II of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 11.928±0.2°, 14.490±0.2°, 19.321±0.2° and 22.524±0.2°;
    优选地，所述硫酸盐晶型II的X-射线粉末衍射图还包括位于11.928±0.2°、14.490±0.2°、16.433±0.2°、19.321±0.2°、20.661±0.2°、22.524±0.2°和28.369±0.2°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the sulfate salt crystalline form II further includes peaks at diffraction angles (2θ) of 11.928±0.2°, 14.490±0.2°, 16.433±0.2°, 19.321±0.2°, 20.661±0.2°, 22.524±0.2° and 28.369±0.2°;
    优选地，所述硫酸盐晶型II的X-射线粉末衍射图还包括位于9.640±0.2°、11.928±0.2°、14.490±0.2°、16.433±0.2°、18.625±0.2°、19.321±0.2°、20.661±0.2°、22.524±0.2°和28.369±0.2°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the sulfate salt crystalline form II further includes peaks at diffraction angles (2θ) of 9.640±0.2°, 11.928±0.2°, 14.490±0.2°, 16.433±0.2°, 18.625±0.2°, 19.321±0.2°, 20.661±0.2°, 22.524±0.2° and 28.369±0.2°;
    优选地，所述硫酸盐晶型II的X-射线粉末衍射图具有如表1-4所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the sulfate salt crystalline form II has a diffraction angle (2θ) as shown in Table 1-4, wherein the error range of the 2θ angle is ±0.20°:
    表1-4

    Table 1-4

    优选地，所述硫酸盐晶型II具有如表1-4所示的X-射线粉末衍射强度；Preferably, the sulfate salt crystal form II has an X-ray powder diffraction intensity as shown in Table 1-4;
    优选地，所述硫酸盐晶型II具有基本如图4-2所示的X射线粉末衍射图；Preferably, the sulfate salt form II has an X-ray powder diffraction pattern substantially as shown in FIG4-2;
    优选地，所述硫酸盐晶型II在约73.33℃和200.04℃的温度处具有吸热峰的DSC热谱图；Preferably, the sulfate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 73.33°C and 200.04°C;
    优选地，所述硫酸盐晶型II具有基本如图6所示的DSC图；Preferably, the sulfate salt crystalline form II has a DSC graph substantially as shown in FIG6 ;
    优选地，所述硫酸盐晶型II具有基本如图6所示的TGA图；Preferably, the sulfate salt form II has a TGA graph substantially as shown in FIG6 ;
    优选地，化合物Ⅰ-85的硫酸氢盐晶型I，其X-射线粉末衍射图包括位于9.552±0.20°、14.606±0.20°19.544±0.20°和24.494±0.20°的衍射角(2θ)处的峰；Preferably, the hydrogen sulfate salt form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 9.552±0.20°, 14.606±0.20°, 19.544±0.20°, and 24.494±0.20°;
    优选地，所述硫酸氢盐晶型I的X-射线粉末衍射图还包括位于4.814±0.20°、9.552±0.20°、14.606±0.20°、17.261±0.20°、19.544±0.20°和24.494±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the hydrogen sulfate salt form I further includes peaks at diffraction angles (2θ) of 4.814±0.20°, 9.552±0.20°, 14.606±0.20°, 17.261±0.20°, 19.544±0.20° and 24.494±0.20°;
    优选地，所述硫酸氢盐晶型I的X-射线粉末衍射图还包括位于4.814±0.20°、9.552±0.20°、14.398±0.20°、14.606±0.20°、17.261±0.20°、19.544±0.20°、23.510±0.20°、24.494±0.20°和25.821±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the hydrogen sulfate salt form I further includes peaks at diffraction angles (2θ) of 4.814±0.20°, 9.552±0.20°, 14.398±0.20°, 14.606±0.20°, 17.261±0.20°, 19.544±0.20°, 23.510±0.20°, 24.494±0.20° and 25.821±0.20°;
    优选地，所述硫酸氢盐晶型I的X-射线粉末衍射图具有如表1-5所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the hydrogen sulfate salt crystalline form I has a diffraction angle (2θ) as shown in Tables 1-5, wherein the error range of the 2θ angle is ±0.20°:
    表1-5
    Table 1-5
    优选地，所述硫酸氢盐晶型I具有如表1-5所示的X-射线粉末衍射强度；Preferably, the hydrogen sulfate salt crystalline form I has an X-ray powder diffraction intensity as shown in Table 1-5;
    优选地，所述硫酸氢盐晶型I具有基本如图4-3所示的X射线粉末衍射图；Preferably, the bisulfate salt form I has an X-ray powder diffraction pattern substantially as shown in FIG. 4-3 ;
    优选地，所述硫酸氢盐晶型I在约227.60℃的温度处具有吸热峰的DSC热谱图；Preferably, the bisulfate salt crystalline form I has a DSC thermogram with an endothermic peak at a temperature of about 227.60°C;
    优选地，所述硫酸氢盐晶型I具有基本如图7所示的DSC图；Preferably, the bisulfate salt form I has a DSC graph substantially as shown in FIG7 ;
    优选地，所述硫酸氢盐晶型I具有基本如图7所示的TGA图；Preferably, the bisulfate salt form I has a TGA graph substantially as shown in FIG7 ;
    优选地，化合物Ⅰ-85的硫酸氢盐晶型II，其X-射线粉末衍射图包括位于14.293±0.20°、17.220±0.20°和20.621±0.20°的衍射角(2θ)处的峰； Preferably, the hydrogen sulfate salt form II of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 14.293±0.20°, 17.220±0.20° and 20.621±0.20°;
    优选地，所述硫酸氢盐晶型II的X-射线粉末衍射图还包括位于5.534±0.20°、14.293±0.20°、16.603±0.20°、17.220±0.20°和20.621±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the hydrogen sulfate salt form II further includes peaks at diffraction angles (2θ) of 5.534±0.20°, 14.293±0.20°, 16.603±0.20°, 17.220±0.20° and 20.621±0.20°;
    优选地，所述硫酸氢盐晶型II的X-射线粉末衍射图还包括位于5.534±0.20°、6.296±0.20°、14.293±0.20°、16.603±0.20°、17.220±0.20°、20.621±0.20°、22.826±0.20°和26.609±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the hydrogen sulfate salt form II further includes peaks at diffraction angles (2θ) of 5.534±0.20°, 6.296±0.20°, 14.293±0.20°, 16.603±0.20°, 17.220±0.20°, 20.621±0.20°, 22.826±0.20° and 26.609±0.20°;
    优选地，所述硫酸氢盐晶型II的X-射线粉末衍射图具有如表1-6所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the hydrogen sulfate salt form II has a diffraction angle (2θ) as shown in Table 1-6, wherein the error range of the 2θ angle is ±0.20°:
    表1-6
    Table 1-6
    优选地，所述硫酸氢盐晶型II具有如表1-6所示的X-射线粉末衍射强度；Preferably, the hydrogen sulfate salt form II has an X-ray powder diffraction intensity as shown in Table 1-6;
    优选地，所述硫酸氢盐晶型II具有基本如图4-4所示的X射线粉末衍射图；Preferably, the bisulfate salt Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 4-4 ;
    优选地，所述硫酸氢盐晶型II在约57.18℃和201.52℃的温度处具有吸热峰的DSC热谱图；Preferably, the bisulfate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 57.18° C. and 201.52° C.;
    优选地，所述硫酸氢盐晶型II具有基本如图8所示的DSC图；Preferably, the bisulfate salt form II has a DSC graph substantially as shown in FIG8 ;
    优选地，所述硫酸氢盐晶型II具有基本如图8所示的TGA图；Preferably, the bisulfate salt Form II has a TGA graph substantially as shown in FIG8 ;
    优选地，化合物Ⅰ-85的一氢溴酸盐晶型I，其X-射线粉末衍射图包括位于15.315±0.20°、22.092±0.20°和23.365±0.20°的衍射角(2θ)处的峰；Preferably, the monohydrobromide salt form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 15.315±0.20°, 22.092±0.20° and 23.365±0.20°;
    优选地，所述一氢溴酸盐晶型I的X-射线粉末衍射图还包括位于15.315±0.20°、19.991±0.20°、22.092±0.20°、23.365±0.20°和26.373±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the monohydrobromide salt form I further includes peaks at diffraction angles (2θ) of 15.315±0.20°, 19.991±0.20°, 22.092±0.20°, 23.365±0.20° and 26.373±0.20°;
    优选地，所述一氢溴酸盐晶型I的X-射线粉末衍射图还包括位于6.059±0.20°、15.315±0.20°、19.991±0.20°、21.673±0.20°、22.092±0.20°、23.365±0.20°、26.373±0.20°和28.682±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the monohydrobromide salt form I further includes peaks at diffraction angles (2θ) of 6.059±0.20°, 15.315±0.20°, 19.991±0.20°, 21.673±0.20°, 22.092±0.20°, 23.365±0.20°, 26.373±0.20° and 28.682±0.20°;
    优选地，所述一氢溴酸盐晶型I的X-射线粉末衍射图具有如表1-7所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the monohydrobromide salt form I has a diffraction angle (2θ) as shown in Tables 1-7, wherein the error range of the 2θ angle is ±0.20°:
    表1-7

    Table 1-7

    优选地，所述一氢溴酸盐晶型I具有如表1-7所示的X-射线粉末衍射强度；Preferably, the hydrobromide salt form I has an X-ray powder diffraction intensity as shown in Table 1-7;
    优选地，所述一氢溴酸盐晶型I具有基本如图9-1所示的X射线粉末衍射图；Preferably, the hydrobromide salt form I has an X-ray powder diffraction pattern substantially as shown in FIG9-1;
    优选地，所述一氢溴酸盐晶型I在约56.68℃、157.98℃和250.38℃的温度处具有吸热峰的DSC热谱图；Preferably, the monohydrobromide salt form I has a DSC thermogram with endothermic peaks at temperatures of about 56.68°C, 157.98°C and 250.38°C;
    优选地，所述一氢溴酸盐晶型I具有基本如图10所示的DSC图；Preferably, the hydrobromide salt form I has a DSC graph substantially as shown in Figure 10;
    优选地，所述一氢溴酸盐晶型I具有基本如图10所示的TGA图；Preferably, the hydrobromide salt form I has a TGA graph substantially as shown in Figure 10;
    优选地，化合物Ⅰ-85的二氢溴酸盐晶型I，其X-射线粉末衍射图包括位于6.086±0.20°、14.055±0.20°和23.929±0.20°的衍射角(2θ)处的峰；Preferably, the dihydrobromide salt form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.086±0.20°, 14.055±0.20° and 23.929±0.20°;
    优选地，所述二氢溴酸盐晶型I的X-射线粉末衍射图还包括位于6.086±0.20°、14.055±0.20°、17.943±0.20°、20.805±0.20°、23.929±0.20°和28.342±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the dihydrobromide salt form I further includes peaks at diffraction angles (2θ) of 6.086±0.20°, 14.055±0.20°, 17.943±0.20°, 20.805±0.20°, 23.929±0.20° and 28.342±0.20°;
    优选地，所述二氢溴酸盐晶型I的X-射线粉末衍射图还包括位于4.681±0.20°、6.086±0.20°、14.055±0.20°、15.539±0.20°、17.943±0.20°、20.805±0.20°、23.929±0.20°、24.913±0.20°和28.342±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the dihydrobromide salt form I further includes peaks at diffraction angles (2θ) of 4.681±0.20°, 6.086±0.20°, 14.055±0.20°, 15.539±0.20°, 17.943±0.20°, 20.805±0.20°, 23.929±0.20°, 24.913±0.20° and 28.342±0.20°;
    优选地，所述二氢溴酸盐晶型I的X-射线粉末衍射图具有如表1-8所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the dihydrobromide salt form I has a diffraction angle (2θ) as shown in Tables 1-8, wherein the error range of the 2θ angle is ±0.20°:
    表1-8

    Table 1-8

    优选地，所述二氢溴酸盐晶型I具有如表1-8所示的X-射线粉末衍射强度；Preferably, the dihydrobromide salt form I has an X-ray powder diffraction intensity as shown in Table 1-8;
    优选地，所述二氢溴酸盐晶型I具有基本如图9-2所示的X射线粉末衍射图；Preferably, the dihydrobromide salt form I has an X-ray powder diffraction pattern substantially as shown in FIG9-2;
    优选地，所述二氢溴酸盐晶型I在约80.50℃和241.96℃的温度处具有吸热峰的DSC热谱图；Preferably, the dihydrobromide salt form I has a DSC thermogram with endothermic peaks at temperatures of about 80.50° C. and 241.96° C.;
    优选地，所述二氢溴酸盐晶型I具有基本如图11所示的DSC图；Preferably, the dihydrobromide salt form I has a DSC graph substantially as shown in Figure 11;
    优选地，所述二氢溴酸盐晶型I具有基本如图11所示的TGA图；Preferably, the dihydrobromide salt form I has a TGA graph substantially as shown in Figure 11;
    优选地，化合物Ⅰ-85的甲磺酸盐晶型I，其特征在于，X-射线粉末衍射图包括位于11.995±0.2°、14.607±0.2°、19.374±0.2°、21.027±0.2°和23.536±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt form I of compound I-85 is characterized in that the X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 11.995±0.2°, 14.607±0.2°, 19.374±0.2°, 21.027±0.2° and 23.536±0.2°;
    优选地，所述甲磺酸盐晶型I的X-射线粉末衍射图(XRPD)包括位于11.995±0.2°、14.607±0.2°、16.538±0.2°、19.374±0.2°、20.739±0.2°、21.027±0.2°、22.577±0.2°和23.536±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt Form I has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 11.995±0.2°, 14.607±0.2°, 16.538±0.2°, 19.374±0.2°, 20.739±0.2°, 21.027±0.2°, 22.577±0.2° and 23.536±0.2°;
    优选地，所述甲磺酸盐晶型I的X-射线粉末衍射图(XRPD)包括位于11.995±0.2°、14.095±0.2°、14.607±0.2°、15.803±0.2°、16.538±0.2°、19.374±0.2°、20.739±0.2°、21.027±0.2°、22.577±0.2°和23.536±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt Form I has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 11.995±0.2°, 14.095±0.2°, 14.607±0.2°, 15.803±0.2°, 16.538±0.2°, 19.374±0.2°, 20.739±0.2°, 21.027±0.2°, 22.577±0.2° and 23.536±0.2°;
    优选地，所述甲磺酸盐晶型I的X-射线粉末衍射图具有如表1-9所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the mesylate salt form I has a diffraction angle (2θ) as shown in Tables 1-9, wherein the error range of the 2θ angle is ±0.20°:
    表1-9
    Table 1-9
    优选地，所述甲磺酸盐晶型I具有如表1-9所示的X-射线粉末衍射强度；Preferably, the mesylate salt form I has an X-ray powder diffraction intensity as shown in Table 1-9;
    优选地，所述甲磺酸盐晶型I具有基本如图12所示的X射线粉末衍射图；Preferably, the mesylate salt Form I has an X-ray powder diffraction pattern substantially as shown in Figure 12;
    优选地，所述甲磺酸盐晶型I在约279.98℃的温度处具有吸热峰的DSC热谱图；Preferably, the mesylate salt form I has a DSC thermogram with an endothermic peak at a temperature of about 279.98°C;
    优选地，所述甲磺酸盐晶型I具有基本如图13所示的DSC图；Preferably, the mesylate salt Form I has a DSC graph substantially as shown in Figure 13;
    优选地，所述甲磺酸盐晶型I具有基本如图13所示的TGA图；Preferably, the mesylate salt Form I has a TGA graph substantially as shown in Figure 13;
    优选地，化合物Ⅰ-85的对甲苯磺酸盐晶型I，其X-射线粉末衍射图包括位于4.970±0.20°、8.869±0.20°和18.586±0.20°的衍射角(2θ)处的峰；Preferably, the p-toluenesulfonate salt form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.970±0.20°, 8.869±0.20° and 18.586±0.20°;
    优选地，所述对甲苯磺酸盐晶型I的X-射线粉末衍射图还包括位于4.970±0.20°、8.869±0.20°、10.459±0.20°、14.516±0.20°和18.586±0.20°的衍射角(2θ)处的峰； Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I further includes peaks at diffraction angles (2θ) of 4.970±0.20°, 8.869±0.20°, 10.459±0.20°, 14.516±0.20° and 18.586±0.20°;
    优选地，所述对甲苯磺酸盐晶型I的X-射线粉末衍射图还包括位于4.970±0.20°、8.869±0.20°、10.459±0.20°、12.610±0.20°、14.516±0.20°、18.586±0.20°、20.121±0.20°和23.391±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I further includes peaks at diffraction angles (2θ) of 4.970±0.20°, 8.869±0.20°, 10.459±0.20°, 12.610±0.20°, 14.516±0.20°, 18.586±0.20°, 20.121±0.20° and 23.391±0.20°;
    优选地，所述对甲苯磺酸盐晶型I的X-射线粉末衍射图具有如表1-10所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I has a diffraction angle (2θ) as shown in Tables 1-10, wherein the error range of the 2θ angle is ±0.20°:
    表1-10
    Table 1-10
    优选地，所述对甲苯磺酸盐晶型I具有如表1-10所示的X-射线粉末衍射强度；Preferably, the p-toluenesulfonate salt form I has an X-ray powder diffraction intensity as shown in Table 1-10;
    优选地，所述对甲苯磺酸盐晶型I具有基本如图14-1所示的X射线粉末衍射图；Preferably, the p-toluenesulfonate salt Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 14-1;
    优选地，所述对甲苯磺酸盐晶型I在约81.13℃和153.27℃的温度处具有吸热峰的DSC热谱图；Preferably, the p-toluenesulfonate salt form I has a DSC thermogram with endothermic peaks at temperatures of about 81.13° C. and 153.27° C.;
    优选地，所述对甲苯磺酸盐晶型I具有基本如图15所示的DSC图；Preferably, the p-toluenesulfonate salt Form I has a DSC graph substantially as shown in Figure 15;
    优选地，所述对甲苯磺酸盐晶型I具有基本如图15所示的TGA图；Preferably, the p-toluenesulfonate salt Form I has a TGA graph substantially as shown in Figure 15;
    优选地，化合物Ⅰ-85的对甲苯磺酸盐晶型II，其X-射线粉末衍射图包括位于9.473±0.20°、15.881±0.20°、16.721±0.20°和20.687±0.20°的衍射角(2θ)处的峰；Preferably, the p-toluenesulfonate crystalline form II of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 9.473±0.20°, 15.881±0.20°, 16.721±0.20° and 20.687±0.20°;
    优选地，所述对甲苯磺酸盐晶型II的X-射线粉末衍射图还包括位于9.473±0.20°、15.881±0.20°、16.721±0.20°、18.954±0.20°、20.687±0.20°和21.553±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form II further includes peaks at diffraction angles (2θ) of 9.473±0.20°, 15.881±0.20°, 16.721±0.20°, 18.954±0.20°, 20.687±0.20° and 21.553±0.20°;
    优选地，所述对甲苯磺酸盐晶型II的X-射线粉末衍射图还包括位于8.738±0.20°、9.473±0.20°、13.727±0.20°、15.881±0.20°、16.721±0.20°、18.954±0.20°、20.687±0.20°、21.553±0.20°和25.597±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form II further includes peaks at diffraction angles (2θ) of 8.738±0.20°, 9.473±0.20°, 13.727±0.20°, 15.881±0.20°, 16.721±0.20°, 18.954±0.20°, 20.687±0.20°, 21.553±0.20° and 25.597±0.20°;
    优选地，所述对甲苯磺酸盐晶型II的X-射线粉末衍射图具有如表1-11所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form II has a diffraction angle (2θ) as shown in Table 1-11, wherein the error range of the 2θ angle is ±0.20°:
    表1-11

    Table 1-11

    优选地，所述对甲苯磺酸盐晶型II具有如表1-11所示的X-射线粉末衍射强度；Preferably, the p-toluenesulfonate salt form II has an X-ray powder diffraction intensity as shown in Table 1-11;
    优选地，所述对甲苯磺酸盐晶型II具有基本如图14-2所示的X射线粉末衍射图；Preferably, the p-toluenesulfonate salt Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 14-2 ;
    优选地，所述对甲苯磺酸盐晶型II在约69.82℃、203.86℃和225.31℃的温度处具有吸热峰的DSC热谱图；Preferably, the p-toluenesulfonate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 69.82°C, 203.86°C and 225.31°C;
    优选地，所述对甲苯磺酸盐晶型II具有基本如图16所示的DSC图；Preferably, the p-toluenesulfonate salt Form II has a DSC graph substantially as shown in Figure 16;
    优选地，所述对甲苯磺酸盐晶型II具有基本如图16所示的TGA图；Preferably, the p-toluenesulfonate salt Form II has a TGA graph substantially as shown in Figure 16;
    优选地，化合物Ⅰ-85的对甲苯磺酸盐晶型III，其X-射线粉末衍射图包括位于4.641±0.20°、9.263±0.20°和17.286±0.20°的衍射角(2θ)处的峰；Preferably, the p-toluenesulfonate salt form III of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.641±0.20°, 9.263±0.20° and 17.286±0.20°;
    优选地，所述对甲苯磺酸盐晶型III的X-射线粉末衍射图还包括位于4.641±0.20°、9.263±0.20°、15.028±0.20°、17.286±0.20°和23.011±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form III further includes peaks at diffraction angles (2θ) of 4.641±0.20°, 9.263±0.20°, 15.028±0.20°, 17.286±0.20° and 23.011±0.20°;
    优选地，所述对甲苯磺酸盐晶型III的X-射线粉末衍射图还包括位于4.641±0.20°、6.927±0.20°、9.263±0.20°、15.028±0.20°、17.286±0.20°、19.388±0.20°、20.227±0.20°和23.011±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form III further includes peaks at diffraction angles (2θ) of 4.641±0.20°, 6.927±0.20°, 9.263±0.20°, 15.028±0.20°, 17.286±0.20°, 19.388±0.20°, 20.227±0.20° and 23.011±0.20°;
    优选地，所述对甲苯磺酸盐晶型III的X-射线粉末衍射图具有如表1-12所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form III has a diffraction angle (2θ) as shown in Table 1-12, wherein the error range of the 2θ angle is ±0.20°:
    表1-12

    Table 1-12

    优选地，所述对甲苯磺酸盐晶型III具有如表1-12所示的X-射线粉末衍射强度；Preferably, the p-toluenesulfonate salt form III has an X-ray powder diffraction intensity as shown in Table 1-12;
    优选地，所述对甲苯磺酸盐晶型III具有基本如图14-3所示的X射线粉末衍射图；Preferably, the p-toluenesulfonate salt Form III has an X-ray powder diffraction pattern substantially as shown in Figure 14-3;
    优选地，所述对甲苯磺酸盐晶型III在约144.62℃、202.96和219.07℃的温度处具有吸热峰的DSC热谱图；Preferably, the p-toluenesulfonate salt form III has a DSC thermogram with endothermic peaks at temperatures of about 144.62° C., 202.96° C., and 219.07° C.;
    优选地，所述对甲苯磺酸盐晶型III具有基本如图17所示的DSC图；Preferably, the p-toluenesulfonate salt Form III has a DSC graph substantially as shown in Figure 17;
    优选地，所述对甲苯磺酸盐晶型III具有基本如图17所示的TGA图；Preferably, the p-toluenesulfonate salt Form III has a TGA graph substantially as shown in Figure 17;
    优选地，化合物Ⅰ-85的磷酸盐晶型I，其X-射线粉末衍射图包括位于12.598±0.20°、18.205±0.20°和22.722±0.20°的衍射角(2θ)处的峰；Preferably, the phosphate form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 12.598±0.20°, 18.205±0.20° and 22.722±0.20°;
    优选地，所述磷酸盐晶型I的X-射线粉末衍射图还包括位于10.223±0.20°、12.598±0.20°、18.205±0.20°、19.058±0.20°和22.722±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the phosphate crystal form I further includes peaks at diffraction angles (2θ) of 10.223±0.20°, 12.598±0.20°, 18.205±0.20°, 19.058±0.20° and 22.722±0.20°;
    优选地，所述磷酸盐晶型I的X-射线粉末衍射图还包括位于10.223±0.20°、12.598±0.20°、14.186±0.20°、18.205±0.20°、19.058±0.20°、21.593±0.20°、22.722±0.20°和22.957±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the phosphate crystalline form I further includes peaks at diffraction angles (2θ) of 10.223±0.20°, 12.598±0.20°, 14.186±0.20°, 18.205±0.20°, 19.058±0.20°, 21.593±0.20°, 22.722±0.20° and 22.957±0.20°;
    优选地，所述磷酸盐晶型I的X-射线粉末衍射图具有如表1-13所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the phosphate crystal form I has a diffraction angle (2θ) as shown in Table 1-13, wherein the error range of the 2θ angle is ±0.20°:
    表1-13
    Table 1-13
    优选地，所述磷酸盐晶型I具有如表1-13所示的X-射线粉末衍射强度；Preferably, the phosphate crystal form I has an X-ray powder diffraction intensity as shown in Table 1-13;
    优选地，所述磷酸盐晶型I具有基本如图18-1所示的X射线粉末衍射图；Preferably, the phosphate crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG. 18-1;
    优选地，所述磷酸盐晶型I在约83.01℃、146.52℃、175.51和242.76℃的温度处具有吸热峰的DSC热谱图；Preferably, the phosphate crystal form I has a DSC thermogram with endothermic peaks at temperatures of about 83.01°C, 146.52°C, 175.51 and 242.76°C;
    优选地，所述磷酸盐晶型I具有基本如图19所示的DSC图；Preferably, the phosphate crystal form I has a DSC graph substantially as shown in Figure 19;
    优选地，所述磷酸盐晶型I具有基本如图19所示的TGA图；Preferably, the phosphate crystal form I has a TGA graph substantially as shown in Figure 19;
    优选地，化合物Ⅰ-85的磷酸盐晶型II，其X-射线粉末衍射图包括位于6.913±0.20°、11.981±0.20°和18.205±0.20°的衍射角(2θ)处的峰； Preferably, the phosphate form II of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.913±0.20°, 11.981±0.20° and 18.205±0.20°;
    优选地，所述磷酸盐晶型II的X-射线粉末衍射图还包括位于6.913±0.20°、11.981±0.20°、13.688±0.20°、17.101±0.20°和18.205±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the phosphate crystal form II further includes peaks at diffraction angles (2θ) of 6.913±0.20°, 11.981±0.20°, 13.688±0.20°, 17.101±0.20° and 18.205±0.20°;
    优选地，所述磷酸盐晶型II的X-射线粉末衍射图还包括位于6.913±0.20°、9.473±0.20°、11.981±0.20°、13.688±0.20°、15.829±0.20°、17.101±0.20°、18.205±0.20°和21.317±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the phosphate crystal form II further includes peaks at diffraction angles (2θ) of 6.913±0.20°, 9.473±0.20°, 11.981±0.20°, 13.688±0.20°, 15.829±0.20°, 17.101±0.20°, 18.205±0.20° and 21.317±0.20°;
    优选地，所述磷酸盐晶型II的X-射线粉末衍射图具有如表1-14所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the phosphate crystal form II has a diffraction angle (2θ) as shown in Table 1-14, wherein the error range of the 2θ angle is ±0.20°:
    表1-14
    Table 1-14
    优选地，所述磷酸盐晶型II具有如表1-14所示的X-射线粉末衍射强度；Preferably, the phosphate crystal form II has an X-ray powder diffraction intensity as shown in Table 1-14;
    优选地，所述磷酸盐晶型II具有基本如图18-2所示的X射线粉末衍射图；Preferably, the phosphate crystal form II has an X-ray powder diffraction pattern substantially as shown in FIG. 18-2;
    优选地，所述磷酸盐晶型II在约133.16℃和254.39℃的温度处具有吸热峰的DSC热谱图；Preferably, the phosphate crystal form II has a DSC thermogram with endothermic peaks at temperatures of about 133.16° C. and 254.39° C.;
    优选地，所述磷酸盐晶型II具有基本如图20所示的DSC图；Preferably, the phosphate crystal form II has a DSC graph substantially as shown in Figure 20;
    优选地，所述磷酸盐晶型II具有基本如图20所示的TGA图；Preferably, the phosphate crystal form II has a TGA graph substantially as shown in Figure 20;
    优选地，化合物Ⅰ-85的酒石酸盐晶型I，其X-射线粉末衍射图包括位于14.305±0.20°、17.128±0.20°和22.118±0.20°的衍射角(2θ)处的峰；Preferably, the tartrate salt form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 14.305±0.20°, 17.128±0.20° and 22.118±0.20°;
    优选地，所述酒石酸盐晶型I的X-射线粉末衍射图还包括位于5.969±0.20°、14.305±0.20°、17.128±0.20°、20.765±0.20°和22.118±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the tartrate salt form I further includes peaks at diffraction angles (2θ) of 5.969±0.20°, 14.305±0.20°, 17.128±0.20°, 20.765±0.20° and 22.118±0.20°;
    优选地，所述酒石酸盐晶型I的X-射线粉末衍射图还包括位于5.969±0.20°、7.582±0.20°、14.305±0.20°、15.513±0.20°、17.128±0.20°、19.885±0.20°、20.765±0.20°和22.118±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the tartrate salt form I further includes peaks at diffraction angles (2θ) of 5.969±0.20°, 7.582±0.20°, 14.305±0.20°, 15.513±0.20°, 17.128±0.20°, 19.885±0.20°, 20.765±0.20° and 22.118±0.20°;
    优选地，所述酒石酸盐晶型I的X-射线粉末衍射图具有如表1-15所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the tartrate salt form I has a diffraction angle (2θ) as shown in Tables 1-15, wherein the error range of the 2θ angle is ±0.20°:
    表1-15

    Table 1-15

    优选地，所述酒石酸盐晶型I具有如表1-15所示的X-射线粉末衍射强度；Preferably, the tartrate salt form I has an X-ray powder diffraction intensity as shown in Table 1-15;
    优选地，所述酒石酸盐晶型I具有基本如图21所示的X射线粉末衍射图；Preferably, the tartrate salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 21;
    优选地，所述酒石酸盐晶型I在约69.83℃和199.00℃的温度处具有吸热峰的DSC热谱图；Preferably, the tartrate salt form I has a DSC thermogram with endothermic peaks at temperatures of about 69.83°C and 199.00°C;
    优选地，所述酒石酸盐晶型I具有基本如图22所示的DSC图；Preferably, the tartrate salt form I has a DSC graph substantially as shown in Figure 22;
    优选地，所述酒石酸盐晶型I具有基本如图22所示的TGA图；Preferably, the tartrate salt form I has a TGA graph substantially as shown in Figure 22;
    优选地，化合物Ⅰ-85的富马酸盐晶型I，其X-射线粉末衍射图包括位于6.953±0.20°、15.224±0.20°和20.267±0.20°的衍射角(2θ)处的峰；Preferably, the fumarate salt form I of compound I-85 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.953±0.20°, 15.224±0.20° and 20.267±0.20°;
    优选地，所述富马酸盐晶型I的X-射线粉末衍射图还包括位于6.953±0.20°、15.224±0.20°、20.267±0.20°、24.757±0.20°和27.067±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the fumarate salt form I further includes peaks at diffraction angles (2θ) of 6.953±0.20°, 15.224±0.20°, 20.267±0.20°, 24.757±0.20° and 27.067±0.20°;
    优选地，所述富马酸盐晶型I的X-射线粉末衍射图还包括位于6.953±0.20°、10.090±0.20°、15.224±0.20°、18.665±0.20°、20.976±0.20°、20.267±0.20°、24.757±0.20°和27.067±0.20°的衍射角(2θ)处的峰；Preferably, the X-ray powder diffraction pattern of the fumarate salt form I further includes peaks at diffraction angles (2θ) of 6.953±0.20°, 10.090±0.20°, 15.224±0.20°, 18.665±0.20°, 20.976±0.20°, 20.267±0.20°, 24.757±0.20° and 27.067±0.20°;
    优选地，所述富马酸盐晶型I的X-射线粉末衍射图具有如表1-16所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the fumarate salt form I has a diffraction angle (2θ) as shown in Table 1-16, wherein the error range of the 2θ angle is ±0.20°:
    表1-16
    Table 1-16
    优选地，所述富马酸盐晶型I具有如表1-16所示的X-射线粉末衍射强度；Preferably, the fumarate salt form I has an X-ray powder diffraction intensity as shown in Table 1-16;
    优选地，所述富马酸盐晶型I具有基本如图23所示的X射线粉末衍射图；Preferably, the fumarate salt Form I has an X-ray powder diffraction pattern substantially as shown in Figure 23;
    优选地，所述富马酸盐晶型I在约176.61℃的温度处具有吸热峰的DSC热谱图；Preferably, the fumarate salt form I has a DSC thermogram with an endothermic peak at a temperature of about 176.61°C;
    优选地，所述富马酸盐晶型I具有基本如图24所示的DSC图；Preferably, the fumarate salt Form I has a DSC graph substantially as shown in Figure 24;
    优选地，所述富马酸盐晶型I具有基本如图24所示的TGA图；Preferably, the fumarate salt Form I has a TGA graph substantially as shown in Figure 24;
    优选地，化合物Ⅰ-85的甲磺酸盐晶型II，其X-射线粉末衍射图(XRPD)包括位于7.832±0.2°、9.828±0.2°、12.362±0.2°、22.852±0.2°和24.140±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt form II of compound I-85 has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 7.832±0.2°, 9.828±0.2°, 12.362±0.2°, 22.852±0.2° and 24.140±0.2°;
    优选地，所述甲磺酸盐晶型II，其X-射线粉末衍射图(XRPD)包括位于7.832±0.2°、9.828±0.2°、12.362±0.2°、15.329±0.2°、16.486±0.2°、22.852±0.2°、24.140±0.2°和26.897±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt form II has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 7.832±0.2°, 9.828±0.2°, 12.362±0.2°, 15.329±0.2°, 16.486±0.2°, 22.852±0.2°, 24.140±0.2° and 26.897±0.2°;
    优选地，所述甲磺酸盐晶型II，其X-射线粉末衍射图(XRPD)包括位于7.832±0.2°、8.251±0.2°、9.828±0.2°、12.362±0.2°、13.805±0.2°、15.329±0.2°、16.486±0.2°、22.852±0.2°、24.140±0.2°和26.897±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt form II has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 7.832±0.2°, 8.251±0.2°, 9.828±0.2°, 12.362±0.2°, 13.805±0.2°, 15.329±0.2°, 16.486±0.2°, 22.852±0.2°, 24.140±0.2° and 26.897±0.2°;
    优选地，所述甲磺酸盐晶型II的X-射线粉末衍射图具有如表1-17所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the mesylate salt form II has a diffraction angle (2θ) as shown in Table 1-17, wherein the error range of the 2θ angle is ±0.20°:
    表1-17
    Table 1-17
    优选地，所述甲磺酸盐晶型II具有如表1-17所示的X-射线粉末衍射强度；Preferably, the mesylate salt form II has an X-ray powder diffraction intensity as shown in Table 1-17;
    优选地，所述甲磺酸盐晶型II具有基本如图25所示的X射线粉末衍射图；Preferably, the mesylate salt Form II has an X-ray powder diffraction pattern substantially as shown in Figure 25;
    优选地，所述甲磺酸盐晶型II在约71.31℃、111.93℃和273.09℃的温度处具有吸热峰的DSC热谱图；Preferably, the mesylate salt form II has a DSC thermogram with endothermic peaks at temperatures of about 71.31°C, 111.93°C and 273.09°C;
    优选地，所述甲磺酸盐晶型II具有基本如图26所示的DSC图；Preferably, the mesylate salt Form II has a DSC graph substantially as shown in Figure 26;
    优选地，所述甲磺酸盐晶型II具有基本如图26所示的TGA图；Preferably, the mesylate salt Form II has a TGA graph substantially as shown in Figure 26;
    优选地，化合物Ⅰ-85的甲磺酸盐晶型III，其X-射线粉末衍射图(XRPD)包括位于6.939±0.2°、9.079±0.2°、17.234±0.2°、20.030±0.2°和22.984±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt form III of compound I-85 has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 6.939±0.2°, 9.079±0.2°, 17.234±0.2°, 20.030±0.2° and 22.984±0.2°;
    优选地，所述甲磺酸盐晶型III，其X-射线粉末衍射图(XRPD)包括位于6.939±0.2°、9.079±0.2°、17.234±0.2°、20.030±0.2°、22.984±0.2°、25.058±0.2°、26.070±0.2°和27.922±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt form III has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 6.939±0.2°, 9.079±0.2°, 17.234±0.2°, 20.030±0.2°, 22.984±0.2°, 25.058±0.2°, 26.070±0.2° and 27.922±0.2°;
    优选地，所述甲磺酸盐晶型III，其X-射线粉末衍射图(XRPD)包括位于6.939±0.2°、9.079±0.2°、17.234±0.2°、20.030±0.2°、22.315±0.2°、22.984±0.2°、23.614±0.2°、25.058±0.2°、26.070±0.2°和27.922±0.2°的衍射角(2θ)处的峰；Preferably, the mesylate salt form III has an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 6.939±0.2°, 9.079±0.2°, 17.234±0.2°, 20.030±0.2°, 22.315±0.2°, 22.984±0.2°, 23.614±0.2°, 25.058±0.2°, 26.070±0.2° and 27.922±0.2°;
    优选地，所述甲磺酸盐晶型III的X-射线粉末衍射图具有如表1-18所示的衍射角(2θ)，其中所述2θ角度的误差范围为±0.20°：Preferably, the X-ray powder diffraction pattern of the mesylate salt form III has a diffraction angle (2θ) as shown in Table 1-18, wherein the error range of the 2θ angle is ±0.20°:
    表1-18
    Table 1-18
    优选地，所述甲磺酸盐晶型III具有如表1-18所示的X-射线粉末衍射强度； Preferably, the mesylate salt form III has an X-ray powder diffraction intensity as shown in Table 1-18;
    优选地，所述甲磺酸盐晶型III具有基本如图27所示的X射线粉末衍射图；Preferably, the mesylate salt Form III has an X-ray powder diffraction pattern substantially as shown in Figure 27;
    优选地，所述甲磺酸盐晶型III在约81.24℃、167.30℃、178.52℃和276.79℃的温度处具有吸热峰的DSC热谱图；Preferably, the mesylate salt form III has a DSC thermogram with endothermic peaks at temperatures of about 81.24°C, 167.30°C, 178.52°C and 276.79°C;
    优选地，所述甲磺酸盐晶型III具有基本如图28所示的DSC图；Preferably, the mesylate salt Form III has a DSC graph substantially as shown in Figure 28;
    优选地，所述甲磺酸盐晶型III具有基本如图28所示的TGA图。Preferably, the mesylate salt Form III has a TGA graph substantially as shown in Figure 28.
  9. 一种药物组合物，其包含式I所示的化合物药学上可接受的盐或其多晶型：
    A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound represented by Formula I or a polymorph thereof:
    其中，所述药学上可接受的盐或其多晶型如上所述；Wherein, the pharmaceutically acceptable salt or its polymorphic form is as described above;
    优选地，所述药物组合物，其包含权利要求7或8所述化合物I-85或化合物I-87的药学上可接受的盐或所述晶型中的至少一种作为活性成分；Preferably, the pharmaceutical composition comprises at least one of the pharmaceutically acceptable salts or the crystalline forms of Compound I-85 or Compound I-87 according to claim 7 or 8 as an active ingredient;
    优选地，所述的药物组合物进一步包含治疗有效量的权利要求7或8所述化合物I-85或I-87的药学上可接受的盐或所述晶型中的至少一种和药学上可接受的载体。Preferably, the pharmaceutical composition further comprises a therapeutically effective amount of a pharmaceutically acceptable salt of compound I-85 or I-87 or at least one of the crystalline forms according to claim 7 or 8 and a pharmaceutically acceptable carrier.
  10. 权利要求7或8所述化合物I-85和/或化合物I-87的药学上可接受的盐或所述晶型中的至少一种或所述药物组合物在制备用于治疗与抑制癌症的药物中的用途；Use of the pharmaceutically acceptable salt of compound I-85 and/or compound I-87 or at least one of the crystalline forms or the pharmaceutical composition according to claim 7 or 8 in the preparation of a drug for treating and inhibiting cancer;
    优选地，所述癌症包括白血病(如急性髓系白血病)、肝癌、结肠癌、卵巢癌、食道癌、结直肠癌、胰腺癌、淋巴瘤、胶质瘤、神经母细胞瘤、鼻咽癌、肺癌、乳腺癌、胃癌、胆管癌、肾癌、膀胱癌、宫颈癌、前列腺癌、肉瘤。 Preferably, the cancer includes leukemia (such as acute myeloid leukemia), liver cancer, colon cancer, ovarian cancer, esophageal cancer, colorectal cancer, pancreatic cancer, lymphoma, glioma, neuroblastoma, nasopharyngeal carcinoma, lung cancer, breast cancer, gastric cancer, bile duct cancer, kidney cancer, bladder cancer, cervical cancer, prostate cancer, and sarcoma.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019032863A1 (en) * 2017-08-11 2019-02-14 Forma Therapeutics, Inc. Carboxamides as ubiquitin-specific protease inhibitors
WO2020224652A1 (en) * 2019-05-09 2020-11-12 北京普济远成生物科技有限公司 Ubiquitin-specific protease inhibitors, and preparation method therefor and application thereof
CN112867712A (en) * 2018-08-09 2021-05-28 瓦洛早期发现股份有限公司 Carboxamides as ubiquitin-specific protease inhibitors
CN112898314A (en) * 2020-11-06 2021-06-04 刘丽萍 Preparation and application of deubiquitinase inhibitor
CN116969976A (en) * 2022-04-28 2023-10-31 杭州普济远成生物医药科技有限公司 Deubiquitinase inhibitor and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019032863A1 (en) * 2017-08-11 2019-02-14 Forma Therapeutics, Inc. Carboxamides as ubiquitin-specific protease inhibitors
CN112867712A (en) * 2018-08-09 2021-05-28 瓦洛早期发现股份有限公司 Carboxamides as ubiquitin-specific protease inhibitors
WO2020224652A1 (en) * 2019-05-09 2020-11-12 北京普济远成生物科技有限公司 Ubiquitin-specific protease inhibitors, and preparation method therefor and application thereof
CN112898314A (en) * 2020-11-06 2021-06-04 刘丽萍 Preparation and application of deubiquitinase inhibitor
CN116969976A (en) * 2022-04-28 2023-10-31 杭州普济远成生物医药科技有限公司 Deubiquitinase inhibitor and application thereof

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