WO2022242658A1 - 杂环取代的嘌呤酮衍生物的盐型及晶型 - Google Patents
杂环取代的嘌呤酮衍生物的盐型及晶型 Download PDFInfo
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention relates to a salt form, a crystal form and a preparation method of a heterocyclic substituted purinone derivative.
- DNA breaks especially double-strand breaks (DSBs), are extremely serious injuries that can cause loss of genetic material, genetic recombination, and thus lead to cancer or cell death.
- Eukaryotic cells have evolved a variety of mechanisms to deal with the serious threat of DNA double-strand breaks. This is the DNA damage response mechanism (DDR), which mainly includes DNA damage detection, signal transduction and damage repair.
- DDR DNA damage response mechanism
- DNA double-strand break repair mainly includes homologous end joining (HR) repair and non-homologous end joining (NHEJ) repair.
- DNA-PKcs which belongs to the phosphoinositide-3-kinase-related protein (PI3K-relatedkinase, PIKK) family, mainly targets the non-homologous ends of DNA double-strand breaks Junction (NHEJ) repair is an important member of DNA damage repair.
- NHEJ DNA double-strand breaks Junction
- the Ku70/Ku80 heterodimer is specifically connected to the double-strand damage through a pre-formed channel, recognizes the double-strand break and binds to the broken end respectively, and then along the DNA in an ATP-dependent manner
- the strands slide a certain distance to both ends, forming a KU-DNA complex and recruiting DNA-PKcs to the double-strand break to bind with it, then the Ku dimer moves inward, activates DNA-PKcs and phosphorylates itself, and finally , phosphorylated DNA-PKcs guides damage signaling and recruits DNA end processing-related proteins such as PNKP, XRCC4, XLF, Pol X and DNA ligase IV to participate in the completion of double-strand break repair.
- DNA end processing-related proteins such as PNKP, XRCC4, XLF, Pol X and DNA ligase IV to participate in the completion of double-strand break repair.
- DNA-damaging chemotherapy drugs such as bleomycin, topoisomerase II inhibitors such as etoposide and doxorubicin
- radiotherapy commonly used in cancer treatment
- DNA-PK DNA-damaging chemotherapy drugs
- bleomycin topoisomerase II inhibitors
- doxorubicin doxorubicin
- radiotherapy commonly used in cancer treatment
- high expression of DNA-PK is found in tumor tissues treated with radiotherapy and chemotherapy, and the increase of DNA-PKcs activity enhances the repair of damaged DNA to a certain extent, prevents the death of tumor cells, and leads to the effect of radiotherapy and chemotherapy. develop tolerance.
- DNA-PK inhibitors can inhibit the activity of DNA-PKcs, thereby greatly reducing tumor DNA repair, inducing cells to enter apoptosis, and achieving better therapeutic effects.
- ATM plays an important role in homologous end-joining (HR) repair.
- HR homologous end-joining
- the present invention aims to find a small molecule inhibitor of DNA-PK, which can not only exert a therapeutic effect in tumors with defects in other DNA repair pathways as a single drug. It can also be used in combination with radiotherapy and chemotherapy drugs to enhance the sensitivity of tumor tissue to radiotherapy and chemotherapy, overcome the problem of drug resistance, and enhance the inhibitory effect on various solid tumors and hematological tumors.
- the present invention provides the A crystal form of the compound of formula (I),
- the Cu K ⁇ radiation X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.26 ⁇ 0.20°, 19.47 ⁇ 0.20°, 22.69 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.26 ⁇ 0.20°, 11.50 ⁇ 0.20°, 17.03 ⁇ 0.20°, 19.47 ⁇ 0.20° , 22.69 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.26 ⁇ 0.20°, 11.50 ⁇ 0.20°, 13.52 ⁇ 0.20°, 17.03 ⁇ 0.20° , 18.75 ⁇ 0.20°, 19.47 ⁇ 0.20°, 22.69 ⁇ 0.20°, 27.74 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.77 ⁇ 0.20°, 9.26 ⁇ 0.20°, 11.50 ⁇ 0.20°, 13.52 ⁇ 0.20° , 17.03 ⁇ 0.20°, 17.50 ⁇ 0.20°, 18.75 ⁇ 0.20°, 19.47 ⁇ 0.20°, 22.69 ⁇ 0.20°, 23.84 ⁇ 0.20°, 24.42 ⁇ 0.20°, 26.76 ⁇ 0.20°, 27.74 ⁇ 0.20°
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.77 ⁇ 0.20°, 9.26 ⁇ 0.20°, 11.50 ⁇ 0.20°, 13.52 ⁇ 0.20° , 14.50 ⁇ 0.20°, 15.60 ⁇ 0.20°, 17.03 ⁇ 0.20°, 17.50 ⁇ 0.20°, 18.75 ⁇ 0.20°, 19.47 ⁇ 0.20°, 22.69 ⁇ 0.20°, 23.84 ⁇ 0.20°, 24.42 ⁇ 0.20°, 26.76 ⁇ 0.20° , 27.74 ⁇ 0.20°, 30.40 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.26 ⁇ 0.20°, 19.47 ⁇ 0.20°, 22.69 ⁇ 0.20°, and/or 5.77 ⁇ 0.20°, and/or 11.50 ⁇ 0.20°, and/or 13.52 ⁇ 0.20°, and/or 14.50 ⁇ 0.20°, and/or 15.16 ⁇ 0.20°, and/or 15.60 ⁇ 0.20°, and/or 17.03 ⁇ 0.20 °, and/or 17.28 ⁇ 0.20°, and/or 17.50 ⁇ 0.20°, and/or 18.47 ⁇ 0.20°, and/or 18.75 ⁇ 0.20°, and/or 19.27 ⁇ 0.20°, and/or 23.84 ⁇ 0.20°, and/or 24.42 ⁇ 0.20°, and/or 26.76 ⁇ 0.20°, and/or 27.74 ⁇ 0.20°, and/or 28.43 ⁇ 0.20°, and/or 29.77
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.77°, 9.26°, 11.50°, 13.52°, 14.50°, 15.16°, 15.60 °, 17.03°, 17.28°, 17.50°, 18.47°, 18.75°, 19.27°, 19.47°, 22.69°, 23.84°, 24.42°, 26.76°, 27.74°, 28.43°, 29.77°, 30.40°, 32.08°.
- the XRPD spectrum of the above crystal form A is shown in FIG. 1 .
- the XRPD pattern of the above crystal form A is basically as shown in FIG. 1 .
- the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A shows an onset point of an endothermic peak at 257.8°C ⁇ 3°C.
- the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A shows an onset point of an endothermic peak at 257.8°C ⁇ 5°C.
- the DSC spectrum of the above crystal form A is shown in FIG. 2 .
- the DSC spectrum of the above crystal form A is basically as shown in FIG. 2 .
- thermogravimetric analysis (TGA) curve of the above crystal form A has a weight loss of 1.39% at 230.0°C ⁇ 3°C.
- the TGA spectrum of the above crystal form A is shown in FIG. 3 .
- the TGA spectrum of the above crystal form A is basically as shown in FIG. 3 .
- the present invention also provides mesylate and p-toluenesulfonate of the compound of formula (I),
- m and n are independently selected from 0.6-2.5.
- m is selected from 0.8, 0.9, 1.0, 1.1, 1.2, 1.5, 1.8, 1.9, 2.0, 2.1 and 2.2;
- n is selected from 0.8, 0.9, 1.0, 1.1, 1.2, 1.5, 1.8, 1.9, 2.0, 2.1 and 2.2.
- m is selected from 1.0, 2.0 and 2.2.
- n is selected from 1.0, 2.0 and 2.1.
- the above-mentioned compound of formula (II) is selected from the compound of formula (II-1), and the compound of above-mentioned formula (III) is selected from the compound of formula (III-1),
- the present invention also provides the B crystal form of the compound of formula (II-1),
- the Cu K ⁇ radiation X-ray powder diffraction pattern of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 16.56 ⁇ 0.20°, 21.25 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 10.66 ⁇ 0.20°, 13.98 ⁇ 0.20°, 16.56 ⁇ 0.20° , 21.25 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 10.66 ⁇ 0.20°, 13.98 ⁇ 0.20°, 16.56 ⁇ 0.20° , 21.25 ⁇ 0.20°, 29.98 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 9.29 ⁇ 0.20°, 10.66 ⁇ 0.20°, 13.98 ⁇ 0.20° , 16.56 ⁇ 0.20°, 21.25 ⁇ 0.20°, 29.98 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 9.29 ⁇ 0.20°, 10.66 ⁇ 0.20°, 13.98 ⁇ 0.20° , 16.56 ⁇ 0.20°, 20.51 ⁇ 0.20°, 21.25 ⁇ 0.20°, 26.14 ⁇ 0.20°, 28.08 ⁇ 0.20°, 29.98 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 9.29 ⁇ 0.20°, 10.66 ⁇ 0.20°, 13.98 ⁇ 0.20° , 16.56 ⁇ 0.20°, 20.51 ⁇ 0.20°, 21.25 ⁇ 0.20°, 26.14 ⁇ 0.20°, 28.08 ⁇ 0.20°, 29.98 ⁇ 0.20°, 35.07 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 9.29 ⁇ 0.20°, 10.66 ⁇ 0.20°, 13.98 ⁇ 0.20° , 16.56 ⁇ 0.20°, 18.54 ⁇ 0.20°, 19.11 ⁇ 0.20°, 20.51 ⁇ 0.20°, 21.25 ⁇ 0.20°, 22.25 ⁇ 0.20°, 23.14 ⁇ 0.20°, 23.77 ⁇ 0.20°, 26.14 ⁇ 0.20°, 28.08 ⁇ 0.20° , 29.98 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 9.29 ⁇ 0.20°, 10.66 ⁇ 0.20°, 13.98 ⁇ 0.20° , 16.56 ⁇ 0.20°, 18.54 ⁇ 0.20°, 19.11 ⁇ 0.20°, 20.51 ⁇ 0.20°, 21.25 ⁇ 0.20°, 22.25 ⁇ 0.20°, 23.14 ⁇ 0.20°, 23.77 ⁇ 0.20°, 26.14 ⁇ 0.20°, 28.08 ⁇ 0.20° , 29.98 ⁇ 0.20°, 35.07 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02 ⁇ 0.20°, 16.56 ⁇ 0.20°, 21.25 ⁇ 0.20°, and/or 13.98 ⁇ 0.20°, and/or 10.66 ⁇ 0.20°, and/or 29.98 ⁇ 0.20°, and/or 9.29 ⁇ 0.20°, and/or 26.14 ⁇ 0.20°, and/or 20.51 ⁇ 0.20°, and/or 30.57 ⁇ 0.20 °, and/or 35.33 ⁇ 0.20°, and/or 28.08 ⁇ 0.20°, and/or 22.25 ⁇ 0.20°, and/or 23.14 ⁇ 0.20°, there are characteristic diffraction peaks.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02°, 9.29°, 10.66°, 13.98°, 16.56°, 18.54°, 19.11° °, 20.51°, 21.25°, 21.98°, 22.25°, 23.14°, 23.77°, 26.14°, 27.27°, 28.08°, 29.98°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.02°, 9.29°, 10.66°, 13.98°, 16.56°, 18.54°, 19.11° °, 20.51°, 21.25°, 21.98°, 22.25°, 23.14°, 23.77°, 26.14°, 27.27°, 28.08°, 29.98°, 30.67°, 33.75°, 35.07°, 35.33°, 37.17°.
- the XRPD spectrum of the above crystal form B is shown in FIG. 4 .
- the XRPD spectrum of the above crystal form B is basically as shown in FIG. 4 .
- the differential scanning calorimetry (DSC) curve of the above crystal form B shows an onset point of an endothermic peak at 286.6°C ⁇ 3°C.
- the differential scanning calorimetry (DSC) curve of the above crystal form B shows an onset point of an endothermic peak at 286.6°C ⁇ 5°C.
- the DSC spectrum of the above crystal form B is shown in FIG. 5 .
- the DSC spectrum of the above crystal form B is basically as shown in FIG. 5 .
- thermogravimetric analysis (TGA) curve of the above crystal form B reaches a weight loss of 0.58% at 200.0°C ⁇ 3°C.
- the TGA spectrum of the above crystal form B is shown in FIG. 6 .
- the TGA spectrum of the above crystal form B is basically as shown in FIG. 6 .
- the 1 H NMR spectrum of the above crystal form B is shown in FIG. 7 .
- the 1 H NMR spectrum of the above crystal form B is basically as shown in FIG. 7 .
- the present invention also provides a method for preparing the above crystal form B, the method comprising the following steps:
- the compound Z is selected from the compound of formula (I), the crystal form of compound A of formula (I) and the crystal form of compound K of formula (VIII-1);
- the solvent X is selected from dimethyl sulfoxide, methanol, ethanol, acetonitrile, acetone, tetrahydrofuran and dichloromethane;
- the solvent Y does not exist, or the solvent Y is selected from methyl tert-butyl ether, ethyl acetate and n-heptane;
- the molar ratio of the methanesulfonic acid to the crystal form of compound A of the formula (I) is 1.0:1 ⁇ 1.2:1.
- the present invention also provides the C crystal form of the compound of formula (III-1),
- the Cu K ⁇ radiation X-ray powder diffraction pattern of the C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 15.16 ⁇ 0.20°, 17.83 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 10.23 ⁇ 0.20°, 15.16 ⁇ 0.20°, 17.83 ⁇ 0.20° , 23.19 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 7.05 ⁇ 0.20°, 10.23 ⁇ 0.20°, 15.16 ⁇ 0.20° , 17.83 ⁇ 0.20°, 22.11 ⁇ 0.20°, 23.19 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 7.05 ⁇ 0.20°, 10.23 ⁇ 0.20°, 11.89 ⁇ 0.20° , 15.16 ⁇ 0.20°, 17.83 ⁇ 0.20°, 19.09 ⁇ 0.20°, 19.96 ⁇ 0.20°, 22.11 ⁇ 0.20°, 23.19 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 7.05 ⁇ 0.20°, 10.23 ⁇ 0.20°, 11.89 ⁇ 0.20° , 15.16 ⁇ 0.20°, 16.67 ⁇ 0.20°, 17.54 ⁇ 0.20°, 17.83 ⁇ 0.20°, 18.75 ⁇ 0.20°, 19.09 ⁇ 0.20°, 19.96 ⁇ 0.20°, 20.67 ⁇ 0.20°, 21.6 ⁇ 0.20°, 22.11 ⁇ 0.20° , 23.19 ⁇ 0.20°, 23.83 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 15.16 ⁇ 0.20°, 17.83 ⁇ 0.20°, and/or 7.05 ⁇ 0.20°, and/or 8.08 ⁇ 0.20°, and/or 10.23 ⁇ 0.20°, and/or 11.89 ⁇ 0.20°, and/or 12.30 ⁇ 0.20°, and/or 12.99 ⁇ 0.20°, and/or 14.01 ⁇ 0.20 °, and/or 16.67 ⁇ 0.20°, and/or 17.54 ⁇ 0.20°, and/or 18.75 ⁇ 0.20°, and/or 19.09 ⁇ 0.20°, and/or 19.47 ⁇ 0.20°, and/or 19.96 ⁇ 0.20°, and/or 20.67 ⁇ 0.20°, and/or 21.6 ⁇ 0.20°, and/or 22.11 ⁇ 0.20°, and/or 23.19 ⁇ 0.20°, and/or 23.83 ⁇ 0.20°, and/or
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96°, 7.05°, 8.08°, 10.23°, 11.89°, 12.30°, 12.99° °, 14.01°, 15.16°, 16.67°, 17.54°, 17.83°, 18.75°, 19.09°, 19.47°, 19.96°, 20.67°, 21.6°, 22.11°, 23.19°, 23.83°, 25.18°, 26.69°, 28.32°, 29.90°, 30.48°, 32.39°, 35.02°.
- the X-ray powder diffraction pattern of the above crystal form C is shown in FIG. 8 .
- the X-ray powder diffraction pattern of the above crystal form C is basically as shown in FIG. 8 .
- the differential scanning calorimetry (DSC) curve of the above crystal form C shows an initial value of an endothermic peak at 255.4 ⁇ 3°C.
- the differential scanning calorimetry (DSC) curve of the above crystal form C shows an initial value of an endothermic peak at 255.4 ⁇ 5°C.
- the DSC spectrum of the above crystal form C is shown in FIG. 9 .
- the DSC spectrum of the above crystal form C is basically as shown in FIG. 9 .
- thermogravimetric analysis (TGA) curve of the above crystal form C has a weight loss of 2.90% at 150.0°C ⁇ 3°C.
- the TGA spectrum of the above crystal form C is shown in FIG. 10 .
- the TGA spectrum of the above crystal form C is basically as shown in FIG. 10 .
- the 1 H NMR spectrum of the above crystal form C is shown in FIG. 11 .
- the 1 H NMR spectrum of the above crystal form C is basically as shown in FIG. 11 .
- the present invention also provides a method for preparing the above crystal form C, the method comprising the following steps:
- the present invention also provides the D crystal form of the compound of formula (II-2),
- the Cu K ⁇ radiation X-ray powder diffraction pattern of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.45 ⁇ 0.20°, 11.75 ⁇ 0.20°, 17.41 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.45 ⁇ 0.20°, 11.75 ⁇ 0.20°, 16.23 ⁇ 0.20°, 17.41 ⁇ 0.20° , 20.21 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.45 ⁇ 0.20°, 11.75 ⁇ 0.20°, 16.23 ⁇ 0.20°, 17.41 ⁇ 0.20° , 19.10 ⁇ 0.20°, 20.21 ⁇ 0.20°, 22.06 ⁇ 0.20°, 24.32 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.39 ⁇ 0.20°, 9.45 ⁇ 0.20°, 11.75 ⁇ 0.20°, 12.99 ⁇ 0.20° , 16.23 ⁇ 0.20°, 17.41 ⁇ 0.20°, 19.10 ⁇ 0.20°, 20.21 ⁇ 0.20°, 22.06 ⁇ 0.20°, 24.32 ⁇ 0.20°, 22.82 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.39 ⁇ 0.20°, 9.45 ⁇ 0.20°, 11.75 ⁇ 0.20°, 12.99 ⁇ 0.20° , 16.23 ⁇ 0.20°, 16.70 ⁇ 0.20°, 17.41 ⁇ 0.20°, 17.64 ⁇ 0.20°, 19.10 ⁇ 0.20°, 20.21 ⁇ 0.20°, 21.62 ⁇ 0.20°, 22.06 ⁇ 0.20°, 22.82 ⁇ 0.20°, 24.32 ⁇ 0.20° , 27.09 ⁇ 0.20°, 29.99 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.45 ⁇ 0.20°, 11.75 ⁇ 0.20°, 17.41 ⁇ 0.20°, and/or 7.39 ⁇ 0.20°, and/or 8.69 ⁇ 0.20°, and/or 12.99 ⁇ 0.20°, and/or 13.62 ⁇ 0.20°, and/or 14.65 ⁇ 0.20°, and/or 15.68 ⁇ 0.20°, and/or 16.23 ⁇ 0.20 °, and/or 16.7 ⁇ 0.20°, and/or 17.64 ⁇ 0.20°, and/or 18.02 ⁇ 0.20°, and/or 19.1 ⁇ 0.20°, and/or 19.33 ⁇ 0.20°, and/or 20.21 ⁇ 0.20°, and/or 21.62 ⁇ 0.20°, and/or 22.06 ⁇ 0.20°, and/or 22.82 ⁇ 0.20°, and/or 23.57 ⁇ 0.20°, and/or 24.08 ⁇ 0.20°, and
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.39°, 8.69°, 9.45°, 11.75°, 12.99°, 13.62°, 14.65° °, 15.68°, 16.23°, 16.7°, 17.41°, 17.64°, 18.02°, 19.1°, 19.33°, 20.21°, 21.62°, 22.06°, 22.82°, 23.57°, 24.08°, 24.32°, 25.29°, 26.02°, 27.09°, 28.02°, 28.51°, 29.99°, 32.18°, 35.13°, 35.43°, 38.16°.
- the XRPD spectrum of the above-mentioned crystal form D is shown in FIG. 12 .
- the XRPD pattern of the above-mentioned crystal form D is basically as shown in FIG. 12 .
- the differential scanning calorimetry (DSC) curve of the above crystal form D shows the onset of endothermic peaks at 43.1°C ⁇ 3°C and 227.4°C ⁇ 3°C.
- the differential scanning calorimetry (DSC) curve of the above crystal form D shows an onset point of an endothermic peak at 227.4°C ⁇ 5°C.
- the DSC spectrum of the above-mentioned crystal form D is shown in FIG. 13 .
- the DSC spectrum of the above-mentioned crystal form D is basically as shown in FIG. 13 .
- thermogravimetric analysis (TGA) curve of the above crystal form D reaches a weight loss of 5.65% at 150.0°C ⁇ 3°C.
- the TGA spectrum of the above crystal form D is shown in FIG. 14 .
- the TGA spectrum of the above-mentioned crystal form D is basically as shown in FIG. 14 .
- the 1 H NMR spectrum of the above crystal form D is shown in FIG. 15 .
- the 1 H NMR spectrum of the above crystal form D is basically as shown in FIG. 15 .
- the present invention also provides the crystal form E of the compound of formula (III-2),
- the Cu K ⁇ radiation X-ray powder diffraction pattern of the E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.78 ⁇ 0.20°, 17.02 ⁇ 0.20°, 18.49 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.78 ⁇ 0.20°, 7.77 ⁇ 0.20°, 11.90 ⁇ 0.20°, 17.02 ⁇ 0.20° , 17.97 ⁇ 0.20°, 18.49 ⁇ 0.20°, 18.95 ⁇ 0.20°, 23.33 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.78 ⁇ 0.20°, 7.77 ⁇ 0.20°, 11.90 ⁇ 0.20°, 14.43 ⁇ 0.20° , 15.24 ⁇ 0.20°, 17.02 ⁇ 0.20°, 17.97 ⁇ 0.20°, 18.49 ⁇ 0.20°, 18.95 ⁇ 0.20°, 21.06 ⁇ 0.20°, 23.33 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.78 ⁇ 0.20°, 17.02 ⁇ 0.20°, 18.49 ⁇ 0.20°, and/or 7.77 ⁇ 0.20°, and/or 8.50 ⁇ 0.20°, and/or 11.90 ⁇ 0.20°, and/or 13.34 ⁇ 0.20°, and/or 14.43 ⁇ 0.20°, and/or 15.24 ⁇ 0.20°, and/or 16.38 ⁇ 0.20 °, and/or 17.67 ⁇ 0.20°, and/or 17.97 ⁇ 0.20°, and/or 18.95 ⁇ 0.20°, and/or 19.87 ⁇ 0.20°, and/or 20.78 ⁇ 0.20°, and/or 21.06 ⁇ 0.20°, and/or 21.66 ⁇ 0.20°, and/or 21.90 ⁇ 0.20°, and/or 23.04 ⁇ 0.20°, and/or 23.33 ⁇ 0.20°, and/or 23.89
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.78°, 7.77°, 8.50°, 11.90°, 13.34°, 14.43°, 15.24° °, 16.38°, 17.02°, 17.67°, 17.97°, 18.49°, 18.95°, 19.87°, 20.78°, 21.06°, 21.66°, 21.90°, 23.04°, 23.33°, 23.89°, 24.45°, 24.84°, 25.85°, 26.82°, 27.97°, 28.65°, 29.92°, 30.25°, 31.22°, 33.01°, 33.85°, 35.61°.
- the X-ray powder diffraction pattern of the above-mentioned E crystal form is shown in FIG. 16 .
- the X-ray powder diffraction pattern of the above crystal form E is basically as shown in FIG. 16 .
- the differential scanning calorimetry (DSC) curve of the above crystal form E shows an onset point of an endothermic peak at 268.6 ⁇ 3°C.
- the DSC spectrum of the above-mentioned E crystal form is shown in FIG. 17 .
- the DSC spectrum of the above crystal form E is basically as shown in FIG. 17 .
- thermogravimetric analysis (TGA) curve of the above crystal form E has a weight loss of 0.76% at 150.0°C ⁇ 3°C.
- the TGA spectrum of the above-mentioned E crystal form is shown in FIG. 18 .
- the TGA spectrum of the above crystal form E is basically as shown in FIG. 18 .
- the 1 H NMR spectrum of the above crystal form E is shown in FIG. 19 .
- the 1 H NMR spectrum of the above crystal form E is basically as shown in FIG. 19 .
- the present invention also provides benzenesulfonate, oxalate, hydrobromide, hydrochloride and hydrate of the compound of formula (I), its benzenesulfonate structure is shown in formula (IV), its oxalate Shown in formula (V), its hydrobromide is shown in formula (VI), its hydrochloride is shown in formula (VII), and its hydrate is shown in formula (VIII),
- p, q and r are independently selected from 0.5-2.5; s and t are independently selected from 0.5-3.5.
- p is selected from 1.0, 1.2 and 2.0.
- q is selected from 0.6, 0.9 and 1.4.
- r is selected from 1.0, 1.2 and 1.3.
- s is selected from 0.8, 0.9, 1.0, 2.0, 2.2, 2.5 and 3.0.
- t is selected from 0.8, 0.9, 1.0, 2.0, 2.2, 2.5 and 3.0.
- the compound of formula (IV) is selected from compounds of formula (IV-1) and (IV-2), the compound of formula (V) is selected from compounds of formula (V-1), and the compound of formula (VI) is selected from From formula (VI-1) compound, formula (VII) compound is selected from formula (VII-1) compound, formula (VIII) compound is selected from formula (VIII-1) compound,
- the present invention also provides the F crystal form of the compound of formula (IV-1),
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.21 ⁇ 0.20°, 6.97 ⁇ 0.20°, 13.58 ⁇ 0.20°, 15.90 ⁇ 0.20°, 17.81 ⁇ 0.20°, 19.76 ⁇ 0.20°, 20.73 ⁇ 0.20°, 22.17 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.21 ⁇ 0.20°, 6.97 ⁇ 0.20°, 13.58 ⁇ 0.20°, and/or 7.84 ⁇ 0.20°, and/or 10.58 ⁇ 0.20°, and/or 13.17 ⁇ 0.20°, and/or 13.90 ⁇ 0.20°, and/or 15.65 ⁇ 0.20°, and/or 15.90 ⁇ 0.20°, and/or 16.83 ⁇ 0.20 °, and/or 17.21 ⁇ 0.20°, and/or 17.81 ⁇ 0.20°, and/or 18.51 ⁇ 0.20°, and/or 19.12 ⁇ 0.20°, and/or 19.76 ⁇ 0.20°, and/or 19.99 ⁇ 0.20°, and/or 20.73 ⁇ 0.20°, and/or 22.17 ⁇ 0.20°, and/or 23.39 ⁇ 0.20°, and/or 23.69 ⁇ 0.20°, and/or 24.19 ⁇ 0.20°, and/or
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the above F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.21°, 6.97°, 7.84°, 10.58°, 13.17°, 13.58°, 13.90° °, 15.65°, 15.90°, 16.83°, 17.21°, 17.81°, 18.51°, 19.12°, 19.76°, 19.99°, 20.73°, 22.17°, 23.39°, 23.69°, 24.19°, 24.83°, 26.38°, 28.30°, 29.58°, 30.62°, 32.50°, 34.06°, 37.83°.
- the X-ray powder diffraction pattern of the above-mentioned F crystal form is shown in FIG. 20 .
- the X-ray powder diffraction pattern of the above-mentioned F crystal form is basically as shown in FIG. 20 .
- the differential scanning calorimetry (DSC) curve of the above crystal form F shows that there are three starting points of thermal signals at 216.9°C ⁇ 3°C, 219.6°C ⁇ 3°C and 240.7°C ⁇ 3°C.
- the differential scanning calorimetry (DSC) curve of the above crystal form F shows that there are endothermic peak starting points at 216.9°C ⁇ 3°C and 240.7°C ⁇ 3°C.
- the differential scanning calorimetry (DSC) curve of the above crystal form F shows an exothermic peak starting point at 219.6°C ⁇ 3°C.
- the DSC spectrum of the above-mentioned F crystal form is basically as shown in FIG. 21 .
- thermogravimetric analysis (TGA) curve of the above crystal form F reaches a weight loss of 3.19% at 150.0°C ⁇ 3°C.
- the TGA spectrum of the above-mentioned F crystal form is shown in FIG. 22 .
- the TGA spectrum of the above-mentioned F crystal form is basically as shown in FIG. 22 .
- the 1 H NMR spectrum of the above crystal form F is basically as shown in FIG. 23 .
- the present invention also provides the G crystal form of the compound of formula (IV-2),
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the G crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.83 ⁇ 0.20°, 8.06 ⁇ 0.20°, 12.27 ⁇ 0.20°, 16.56 ⁇ 0.20°, 18.67 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the G crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.83 ⁇ 0.20°, 8.06 ⁇ 0.20°, 12.27 ⁇ 0.20°, and/or 13.06 ⁇ 0.20°, and/or 14.75 ⁇ 0.20°, and/or 15.72 ⁇ 0.20°, and/or 16.56 ⁇ 0.20°, and/or 18.23 ⁇ 0.20°, and/or 18.67 ⁇ 0.20°, and/or 19.69 ⁇ 0.20 °, and/or 20.64 ⁇ 0.20°, and/or 21.11 ⁇ 0.20°, and/or 21.91 ⁇ 0.20°, and/or 22.57 ⁇ 0.20°, and/or 23.33 ⁇ 0.20°, and/or 24.25 ⁇ 0.20°, and/or 26.09 ⁇ 0.20°, and/or 29.00°.
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the G crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.83°, 8.06°, 12.27°, 13.06°, 14.75°, 15.72°, 16.56° °, 18.23°, 18.67°, 19.69°, 20.64°, 21.11°, 21.91°, 22.57°, 23.33°, 24.25°, 26.09°, 29.00°.
- the X-ray powder diffraction pattern of the above-mentioned G crystal form is shown in FIG. 24 .
- the X-ray powder diffraction pattern of the above-mentioned G crystal form is basically as shown in FIG. 24 .
- the differential scanning calorimetry (DSC) curve of the above-mentioned G crystal form shows initial values of endothermic peaks at 224.4°C ⁇ 3°C and 251.5°C ⁇ 3°C, and at 233.7°C ⁇ 3°C. has a thermal signal initiation point.
- the DSC spectrum of the above crystal form G is shown in FIG. 25 .
- the DSC spectrum of the above-mentioned G crystal form is basically as shown in FIG. 25 .
- the 1 H NMR spectrum of the above crystal form G is shown in FIG. 26 .
- the 1 H NMR spectrum of the above crystal form G is basically as shown in FIG. 26 .
- the present invention also provides the H crystal form of the compound of formula (V-1),
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the H crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.31°, 8.52°, 11.28°, 12.75°, 13.32°, 14.52°, 15.4°, 16.48°, 17.19° °, 18.32°, 18.87°, 19.09°, 19.78°, 20.4°, 21.28°, 25.4°, 26.99°, 27.34°, 29.22°, 29.93°, 30.69°, 35.02°, 36.16°.
- the X-ray powder diffraction pattern of the above H crystal form is shown in FIG. 27 .
- the X-ray powder diffraction pattern of the above H crystal form is basically as shown in FIG. 27 .
- the present invention also provides the I crystal form of the compound of formula (VI-1),
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the I crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.27°, 8.02°, 8.59°, 10.14°, 13.90°, 14.99°, 15.56°, 16.07°, 16.95° °, 17.20°, 17.82°, 19.16°, 20.39°, 21.10°, 21.44°, 22.94°, 23.92°, 24.26°, 24.91°, 25.57°, 26.58°, 27.42°, 28.26°, 29.39°, 31.19°, 32.02°, 33.52°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form I is shown in FIG. 28 .
- the X-ray powder diffraction pattern of the above-mentioned crystal form I is basically as shown in FIG. 28 .
- the present invention also provides the J crystal form of the compound of formula (VII-1),
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the J crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.14°, 8.58°, 10.33°, 11.36°, 12.15°, 14.47°, 15.08°, 15.86°, 16.85° °, 17.25°, 17.58°, 18.08°, 18.58°, 19.54°, 20.69°, 21.44°, 21.81°, 22.10°, 23.35°, 24.33°, 24.66°, 25.29°, 25.96°, 27.88°, 28.71°, 29.53°, 29.84°, 31.74°, 32.71°, 34.04°, 37.79°.
- the X-ray powder diffraction pattern of the above-mentioned J crystal form is shown in FIG. 29 .
- the X-ray powder diffraction pattern of the above-mentioned J crystal form is basically as shown in FIG. 29 .
- the present invention also provides the K crystal form of the compound of formula (VIII-1),
- the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the K crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.99°, 7.34°, 8.33°, 9.22°, 9.92°, 10.56°, 10.97°, 13.35°, 13.96° °, 14.60°, 15.13°, 15.83°, 16.36°, 16.91°, 18.48°, 19.58°, 20.62°, 20.99°, 22.22°, 22.67°, 23.78°, 25.77°, 26.19°, 26.84°, 27.46°, 31.21°, 37.22°.
- the X-ray powder diffraction pattern of the above-mentioned K crystal form is shown in FIG. 30 .
- the X-ray powder diffraction pattern of the above-mentioned K crystal form is basically as shown in FIG. 30 .
- the present invention also provides the application of the mesylate, p-toluenesulfonate, B crystal form, C crystal form or A crystal form of the above compound in the preparation of DNA-PK inhibitor related drugs.
- the present invention also provides mesylate, p-toluenesulfonate, benzenesulfonate, oxalate, hydrobromide, hydrochloride, hydrate, A crystal form, B crystal form and C crystal of the above compounds Application of crystal form, D crystal form, E crystal form, F crystal form, G crystal form, H crystal form, I crystal form, J crystal form or K crystal form in the preparation of DNA-PK inhibitor related drugs.
- the compound of the present invention exhibits good DNA-PK kinase inhibitory activity.
- the PK results show that the compound of the present invention has longer half-life and higher drug exposure, excellent pharmacokinetics in vivo, and is a good molecule that can be developed for oral administration.
- the intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
- pharmaceutically acceptable salt refers to the salt of the compound, which is prepared from the compound with a relatively non-toxic acid or base; the nature of the compound of formula (I) of the basic invention is preferably prepared with a relatively non-toxic acid. Acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, hydrogensulfate radical, hydriodic acid, phosphorous acid, etc.; Alkenedic acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids.
- inorganic acids including, for example, hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, hydrogensulfate radical, hydriodic acid, phosphorous acid, etc.
- Alkenedic acid lactic acid, mandelic acid, phthalic acid,
- Formula (I) compound in the present invention the pharmaceutically acceptable salt of formula (I) compound, include but not limited to hydrobromide, methanesulfonate, oxalate, p-toluenesulfonic acid and solvate; Wherein, hydrate The substance is a case of a solvate.
- the pharmaceutically acceptable salt or solvate of the compound of formula (I) in the present invention the amount of combined acid or solvent is represented by the molar ratio of the acid or solvent to the compound of formula (I).
- the compound of formula (I) It represents the addition salt of the compound of formula (I) and methanesulfonic acid, and in the acid addition salt, the molar ratio of methanesulfonic acid to the compound of formula (I) is 2:1.
- the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
- SXRD single crystal X-ray diffraction
- ACN stands for acetonitrile
- DMSO dimethylsulfoxide
- N 2 nitrogen
- RH relative humidity
- mL milliliter
- L liter
- min minute
- °C degree Celsius
- ⁇ m micrometer
- mm millimeter
- ⁇ L microliter
- moL/L mole per liter
- mg milligram
- s second
- nm nanometer
- MPa megapascal
- lux lux
- ⁇ w/cm 2 microwatt per square centimeter
- h hour
- Kg kilogram
- DSC stands for Differential Scanning Calorimetry
- TGA stands for Thermogravimetric Analysis
- 1 H NMR stands for Proton Nuclear Magnetic Resonance.
- the compounds of the present invention are named according to the conventional naming principles in this field or used
- the software is named, the commercially available compounds adopt the supplier catalog name, and all the solvents used in the present invention are commercially available.
- Test method About 10 mg of sample is used for XRPD detection.
- Test conditions Take a sample (about 10 mg) and place it in a DVS sample tray for testing.
- ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
- Fig. 1 is the XRPD pattern of formula (I) compound A crystal form
- Fig. 2 is the DSC spectrogram of formula (I) compound A crystal form
- Fig. 3 is the TGA spectrogram of formula (I) compound A crystal form
- Fig. 4 is the XRPD spectrogram of formula (II-1) compound B crystal form
- Fig. 5 is the DSC spectrogram of formula (II-1) compound B crystal form
- Fig. 6 is the TGA spectrogram of formula (II-1) compound B crystal form
- Fig. 7 is the 1 H NMR spectrogram of formula (II-1) compound B crystal form
- Fig. 8 is the XRPD pattern of formula (III-1) compound C crystal form
- Fig. 9 is the DSC spectrogram of formula (III-1) compound C crystal form
- Figure 10 is the TGA spectrum of formula (III-1) compound C crystal form
- Figure 11 is the 1 H NMR spectrum of the C crystal form of the compound of formula (III-1)
- Figure 12 is the XRPD spectrum of formula (II-2) compound D crystal form
- Fig. 13 is the DSC spectrogram of formula (II-2) compound D crystal form
- Figure 14 is the TGA spectrum of formula (II-2) compound D crystal form
- Figure 15 is the 1 H NMR spectrum of the D crystal form of the compound of formula (II-2)
- Figure 16 is the XRPD spectrum of Formula (III-2) compound E crystal form
- Fig. 17 is the DSC spectrogram of formula (III-2) compound E crystal form
- Fig. 18 is the TGA spectrogram of formula (III-2) compound E crystal form
- Figure 19 is the 1 H NMR spectrum of the crystal form of compound E of formula (III-2)
- Figure 20 is the XRPD spectrum of Formula (IV-1) compound F crystal form
- Figure 21 is the DSC spectrum of Formula (IV-1) compound F crystal form
- Figure 22 is the TGA spectrum of formula (IV-1) compound F crystal form
- Figure 23 is the 1 H NMR spectrum of Formula (IV-1) compound F crystal form
- Figure 24 is the XRPD spectrum of Formula (IV-2) compound G crystal form
- Figure 25 is the DSC spectrum of formula (IV-2) compound G crystal form
- Figure 26 is the 1 H NMR spectrum of the G crystal form of the compound of formula (IV-2)
- Figure 27 is the XRPD spectrum of formula (V-1) compound H crystal form
- Figure 28 is the XRPD spectrum of formula (VI-1) compound I crystal form
- Figure 29 is the XRPD spectrum of Formula (VII-1) compound J crystal form
- Figure 30 is the XRPD spectrum of formula (VIII-1) compound K crystal form
- Figure 31 is the DVS spectrum of formula (II-1) compound B crystal form
- Figure 32 is the photo of the tumor on the 21st day
- Embodiment 1 the preparation of formula (I) compound
- Embodiment 2 the preparation of formula (VIII-1) compound K crystal form
- Embodiment 3 Preparation of formula (I) compound A crystal form
- Method 1 Weigh about 20 mg of compound K crystal form solid of formula (VIII-1) and acetone (0.5 ml) to make a slurry and stir at room temperature for 6 days, and dry in the open at room temperature (40-60% RH/19-21°C) overnight Afterwards, the compound A crystal form of formula (I) is obtained.
- Method 2 Add 1500 mL of acetonitrile to compound K crystal form (74 g) of formula (VIII-1), and stir at 60° C. for 24 hours after the addition. Cool to room temperature, filter, and vacuum-dry the filter cake at 25° C. for 3 hours to obtain the compound A crystal form of formula (I).
- the XRPD spectrum is basically shown in Figure 1
- the DSC spectrum is basically shown in Figure 2
- the TGA spectrum is basically shown in Figure 3.
- Embodiment 4 Preparation of formula (II-1) compound B crystal form
- Method 1 Weigh about 20 mg (1eq) of compound K crystal form (VIII-1) and methanesulfonic acid (1eq) into ethanol/water (19:1, v/v, 0.5mL), and the suspension Stir at room temperature for 3 days. After centrifugation, the collected solid was vacuum-dried at room temperature for 4 hours to obtain the compound B crystal form of formula (II-1).
- Method 2 at 25°C, the crystal form K of compound (VIII-1) (2g, 4.90mmol, 1eq) was dissolved in acetonitrile (19mL), and methanesulfonic acid (476.6mg, 4.96mmol, 1.01eq) was slowly added dropwise in acetonitrile (1 mL) solution. After the dropwise addition was completed, the mixture was stirred at 25° C. for 16 hours. After filtering, the filter cake was washed with n-heptane (20 mL*2), and dried in vacuum at 25° C. for 1 hour to obtain the compound B crystal form of formula (II-1).
- Method 3 At 25°C, the crystal form of compound A (30g, 73.63mmol, 1eq) of formula (I) was diluted with DMSO (300mL), heated to 60°C, and stirred to dissolve. Methanesulfonic acid (3.54g, 36.82mmol, 0.5eq) was added dropwise to the reaction solution and stirred at 60°C for 1 hour, then methanesulfonic acid (3.89g, 40.50mmol, 0.55eq) was added dropwise to the reaction solution and in Stir at 60°C for 12 hours. Methyl tert-butyl ether (450 mL) was added dropwise to the reaction solution and stirring was continued at 60° C. for 1 hour.
- reaction solution was slowly cooled to 25 °C. After filtering, the filter cake was washed with methyl tert-butyl ether (100 mL*3), and dried in vacuum at 25° C. for 1 hour to obtain the compound B crystal form of formula (II-1).
- the XRPD spectrum is basically shown in FIG. 4
- the DSC spectrum is basically shown in FIG. 5
- the TGA spectrum is basically shown in FIG. 6
- the 1 H NMR spectrum is basically shown in FIG. 7 .
- Embodiment 5 Preparation of D crystal form of compound of formula (II-2)
- Embodiment 6 the preparation of formula (III-1) compound C crystal form
- Embodiment 7 the preparation of formula (III-2) compound E crystal form
- Embodiment 8 Preparation of Formula (IV-1) compound F crystal form
- Embodiment 9 Preparation of Formula (IV-2) Compound G Crystal Form
- Embodiment 10 Preparation of H crystal form of compound of formula (V-1)
- Embodiment 11 Preparation of Formula (VI-1) Compound I Crystal Form
- Embodiment 12 Preparation of crystal form of compound J of formula (VII-1)
- Embodiment 13 solid stability test of formula (II-1) compound B crystal form
- XRPD tests were carried out on all stability samples to detect changes in crystal forms, and the results are shown in Table 16.
- the hygroscopic weight gain of compound B crystal form of formula (II-1) at 25°C and 80% RH is 2%> ⁇ W% ⁇ 0.2%, which is slightly hygroscopic.
- Experimental example 1 DNA-dependent protein kinase (DNA-PK) inhibitory activity screening experiment
- the compound of the present invention has good inhibitory activity on DNA-PK.
- test compound was mixed with 0.5% CMC-Na+0.2% (V:V) Tween80 aqueous solution, vortexed and sonicated to prepare a 3 mg/mL homogeneous suspension. SD male rats were selected, and the candidate compound solution was orally administered at a dose of 30 mg/kg. Whole blood was collected for a certain period of time to prepare plasma, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).
- C max the highest blood drug concentration after administration
- T max the time required to reach the peak drug concentration after administration
- T 1/2 the time required for the blood drug concentration to drop by half
- T last the last test
- AUC 0-last the area under the drug-time curve, which refers to the area surrounded by the blood drug concentration curve on the time axis.
- Test results See Table 19 for the test results.
- the compound of the present invention exhibits longer half-life, higher drug exposure, and better in vivo pharmacokinetic properties.
- mice female BALB/c nude mice, 6-8 weeks old, weighing 18-22 grams; supplier: Shanghai Xipuer-Bicai Laboratory Animal Co., Ltd. Experimental methods and procedures:
- NCI-H1703 cells Human non-small cell lung cancer NCI-H1703 cells were cultured in vitro, RPMI1640 medium was added with 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, and cultured in a 5% CO 2 incubator at 37°C. Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
- the compound of formula (I) is prepared into 3mg/mL, 6mg/mL, 9mg/mL suspension solution with 98.5% water+0.5%HPMC+1%Tween 80.
- Tumor diameters were measured twice a week with vernier calipers.
- RTV relative tumor volume
- TGI %, reflecting tumor growth inhibition rate
- T/C relative tumor proliferation rate
- T/C (%) T RTV /C RTV ⁇ 100%
- T RTV represents the average value of RTV in the treatment group
- C RTV represents the average value of RTV in the negative control group.
- TGI (%) [1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group)/(Average tumor volume at the end of treatment of vehicle control group-Average at the beginning of treatment of vehicle control group Tumor volume)] ⁇ 100%.
- TW tumor weight
- Table 20 The tumor inhibitory effect of the compound of the present invention on human lung cancer NCI-H1703 xenograft tumor model
- the compound of formula (I) has a significant tumor inhibitory effect compared with the control group at doses of 60 mg/kg and 90 mg/kg, and it is dose-dependent.
- the tumor-bearing mice showed good tolerance to the compound of the present invention.
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Abstract
Description
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 5.77 | 586.27 | 15.42 | 13 | 19.27 | 1428.42 | 37.56 |
2 | 9.26 | 1316.63 | 34.62 | 14 | 19.47 | 2536.63 | 66.71 |
3 | 11.50 | 1326.39 | 34.88 | 15 | 22.69 | 3802.68 | 100.00 |
4 | 13.52 | 947.57 | 24.92 | 16 | 23.84 | 967.59 | 25.44 |
5 | 14.50 | 409.18 | 10.76 | 17 | 24.42 | 686.03 | 18.04 |
6 | 15.16 | 129.18 | 3.40 | 18 | 26.76 | 1068.12 | 28.09 |
7 | 15.60 | 427.66 | 11.25 | 19 | 27.74 | 1226.40 | 32.25 |
8 | 17.03 | 1342.38 | 35.30 | 20 | 28.43 | 101.75 | 2.68 |
9 | 17.28 | 788.64 | 20.74 | 21 | 29.77 | 111.22 | 2.92 |
10 | 17.50 | 656.55 | 17.27 | 22 | 30.40 | 298.34 | 7.85 |
11 | 18.47 | 795.01 | 20.91 | 23 | 32.08 | 48.53 | 1.28 |
12 | 18.75 | 1206.93 | 31.74 | - | - | - |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 7.02 | 17003.86 | 65.93 | 12 | 23.14 | 262.20 | 1.02 |
2 | 9.29 | 417.16 | 1.62 | 13 | 23.77 | 222.80 | 0.86 |
3 | 10.66 | 2082.57 | 8.07 | 14 | 26.14 | 333.95 | 1.29 |
4 | 13.98 | 3377.68 | 13.10 | 15 | 27.27 | 120.81 | 0.47 |
5 | 16.56 | 25791.82 | 100.00 | 16 | 28.08 | 327.37 | 1.27 |
6 | 18.54 | 226.48 | 0.88 | 17 | 29.98 | 2120.07 | 8.22 |
7 | 19.11 | 199.53 | 0.77 | 18 | 30.67 | 163.54 | 0.63 |
8 | 20.51 | 303.83 | 1.18 | 19 | 33.75 | 134.07 | 0.52 |
9 | 21.25 | 4534.37 | 17.58 | 20 | 35.07 | 437.00 | 1.69 |
10 | 21.98 | 202.05 | 0.78 | 21 | 35.33 | 432.24 | 1.68 |
11 | 22.25 | 273.41 | 1.06 | 22 | 37.17 | 87.96 | 0.34 |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 5.96 | 16844.73 | 100.00 | 15 | 19.47 | 149.60 | 0.89 |
2 | 7.05 | 875.78 | 5.20 | 16 | 19.96 | 468.03 | 2.78 |
3 | 8.08 | 196.16 | 1.16 | 17 | 20.67 | 387.01 | 2.30 |
4 | 10.23 | 980.16 | 5.82 | 18 | 21.60 | 332.62 | 1.97 |
5 | 11.89 | 635.46 | 3.77 | 19 | 22.11 | 752.03 | 4.46 |
6 | 12.30 | 279.05 | 1.66 | 20 | 23.19 | 1132.61 | 6.72 |
7 | 12.99 | 153.38 | 0.91 | 21 | 23.83 | 356.85 | 2.12 |
8 | 14.01 | 93.76 | 0.56 | 22 | 25.18 | 113.71 | 0.68 |
9 | 15.16 | 4151.59 | 24.65 | 23 | 26.69 | 78.69 | 0.47 |
10 | 16.67 | 326.15 | 1.94 | 24 | 28.32 | 163.25 | 0.97 |
11 | 17.54 | 1155.51 | 6.86 | 25 | 29.90 | 140.55 | 0.83 |
12 | 17.83 | 1701.96 | 10.10 | 26 | 30.48 | 113.78 | 0.68 |
13 | 18.75 | 465.76 | 2.76 | 27 | 32.39 | 136.59 | 0.81 |
14 | 19.09 | 549.77 | 3.26 | 28 | 35.02 | 151.07 | 0.90 |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 7.39 | 238.42 | 7.43 | 17 | 21.62 | 434.32 | 13.53 |
2 | 8.69 | 146.37 | 4.56 | 18 | 22.06 | 1281.55 | 39.93 |
3 | 9.45 | 1873.51 | 58.38 | 19 | 22.82 | 483.21 | 15.06 |
4 | 11.75 | 1767.36 | 55.07 | 20 | 23.57 | 212.23 | 6.61 |
5 | 12.99 | 262.23 | 8.17 | 21 | 24.08 | 627.59 | 19.56 |
6 | 13.62 | 190.14 | 5.92 | 22 | 24.32 | 651.33 | 20.30 |
7 | 14.65 | 105.20 | 3.28 | 23 | 25.29 | 223.58 | 6.97 |
8 | 15.68 | 195.17 | 6.08 | 24 | 26.02 | 293.31 | 9.14 |
9 | 16.23 | 1623.03 | 50.57 | 25 | 27.09 | 428.97 | 13.37 |
10 | 16.70 | 449.70 | 14.01 | 26 | 28.02 | 134.01 | 4.18 |
11 | 17.41 | 3209.30 | 100.00 | 27 | 28.51 | 206.68 | 6.44 |
12 | 17.64 | 658.23 | 20.51 | 28 | 29.99 | 303.95 | 9.47 |
13 | 18.02 | 209.50 | 6.53 | 29 | 32.18 | 100.28 | 3.12 |
14 | 19.10 | 561.28 | 17.49 | 30 | 35.13 | 108.14 | 3.37 |
15 | 19.33 | 500.40 | 15.59 | 31 | 35.43 | 116.31 | 3.62 |
16 | 20.21 | 1177.56 | 36.69 | - | 38.16 | 99.52 | 3.10 |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 5.78 | 4072.98 | 100.00 | 18 | 21.90 | 160.02 | 3.93 |
2 | 7.77 | 877.37 | 21.54 | 19 | 23.04 | 479.05 | 11.76 |
3 | 8.50 | 323.93 | 7.95 | 20 | 23.33 | 792.90 | 19.47 |
4 | 11.90 | 1007.68 | 24.74 | 21 | 23.89 | 307.99 | 7.56 |
5 | 13.34 | 443.31 | 10.88 | 22 | 24.45 | 355.08 | 8.72 |
6 | 14.43 | 718.73 | 17.65 | 23 | 24.84 | 203.16 | 4.99 |
7 | 15.24 | 617.91 | 15.17 | 24 | 25.85 | 203.46 | 5.00 |
8 | 16.38 | 252.49 | 6.20 | 25 | 26.82 | 348.10 | 8.55 |
9 | 17.02 | 1712.80 | 42.05 | 26 | 27.97 | 258.75 | 6.35 |
10 | 17.67 | 720.89 | 17.70 | 27 | 28.65 | 207.34 | 5.09 |
11 | 17.97 | 883.45 | 21.69 | 28 | 29.92 | 113.17 | 2.78 |
12 | 18.49 | 2073.96 | 50.92 | 29 | 30.25 | 101.06 | 2.48 |
13 | 18.95 | 759.21 | 18.64 | 30 | 31.22 | 87.48 | 2.15 |
14 | 19.87 | 519.82 | 12.76 | 31 | 33.01 | 38.44 | 0.94 |
15 | 20.78 | 508.06 | 12.47 | 32 | 33.85 | 49.75 | 1.22 |
16 | 21.06 | 621.96 | 15.27 | 33 | 35.61 | 98.70 | 2.42 |
17 | 21.66 | 259.70 | 6.38 | - | - | - | - |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 6.21 | 3665.40 | 100.00 | 16 | 19.99 | 577.66 | 15.76 |
2 | 6.97 | 1888.74 | 51.53 | 17 | 20.73 | 801.72 | 21.87 |
3 | 7.84 | 423.24 | 11.55 | 18 | 22.17 | 1011.98 | 27.61 |
4 | 10.58 | 234.12 | 6.39 | 19 | 23.39 | 363.14 | 9.91 |
5 | 13.17 | 257.62 | 7.03 | 20 | 23.69 | 322.62 | 8.80 |
6 | 13.58 | 571.82 | 15.60 | 21 | 24.19 | 175.69 | 4.79 |
7 | 13.90 | 182.38 | 4.98 | 22 | 24.83 | 96.77 | 2.64 |
8 | 15.65 | 709.83 | 19.37 | 23 | 26.38 | 88.93 | 2.43 |
9 | 15.90 | 1099.04 | 29.98 | 24 | 28.30 | 106.35 | 2.90 |
10 | 16.83 | 617.16 | 16.84 | 25 | 29.58 | 118.23 | 3.23 |
11 | 17.21 | 599.16 | 16.35 | 26 | 30.62 | 140.20 | 3.82 |
12 | 17.81 | 619.20 | 16.89 | 27 | 32.50 | 44.17 | 1.21 |
13 | 18.51 | 289.19 | 7.89 | 28 | 34.06 | 52.79 | 1.44 |
14 | 19.12 | 385.70 | 10.52 | 29 | 37.83 | 30.88 | 0.84 |
15 | 19.76 | 677.49 | 18.48 | - | - | - | - |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 5.83 | 2976.45 | 100.00 | 10 | 19.69 | 130.64 | 4.39 |
2 | 8.06 | 875.80 | 29.42 | 11 | 20.64 | 250.49 | 8.42 |
3 | 12.27 | 470.26 | 15.80 | 12 | 21.11 | 451.88 | 15.18 |
4 | 13.06 | 116.89 | 3.93 | 13 | 21.91 | 319.36 | 10.73 |
5 | 14.75 | 213.26 | 7.16 | 14 | 22.57 | 222.20 | 7.47 |
6 | 15.72 | 240.47 | 8.08 | 15 | 23.33 | 359.20 | 12.07 |
7 | 16.56 | 993.57 | 33.38 | 16 | 24.25 | 122.90 | 4.13 |
8 | 18.23 | 554.14 | 18.62 | 17 | 26.09 | 212.77 | 7.15 |
9 | 18.67 | 1745.41 | 58.64 | 18 | 29.00 | 133.84 | 4.50 |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 4.31 | 807.33 | 29.30 | 13 | 19.78 | 217.17 | 7.88 |
2 | 8.52 | 796.80 | 28.91 | 14 | 20.40 | 293.58 | 10.65 |
3 | 11.28 | 43.53 | 1.58 | 15 | 21.28 | 276.77 | 10.04 |
4 | 12.75 | 1405.29 | 50.99 | 16 | 25.40 | 142.88 | 5.18 |
5 | 13.32 | 1400.98 | 50.84 | 17 | 26.99 | 1478.93 | 53.67 |
6 | 14.52 | 193.61 | 7.03 | 18 | 27.34 | 2755.77 | 100.00 |
7 | 15.40 | 360.38 | 13.08 | 19 | 29.22 | 94.43 | 3.43 |
8 | 16.48 | 678.63 | 24.63 | 20 | 29.93 | 231.77 | 8.41 |
9 | 17.19 | 336.12 | 12.20 | 21 | 30.69 | 104.88 | 3.81 |
10 | 18.32 | 1391.94 | 50.51 | 22 | 35.02 | 42.54 | 1.54 |
11 | 18.87 | 724.23 | 26.28 | 23 | 36.16 | 53.92 | 1.96 |
12 | 19.09 | 546.48 | 19.83 | - | - | - | - |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 6.27 | 626.52 | 45.11 | 15 | 21.44 | 445.48 | 32.07 |
2 | 8.02 | 1389.00 | 100.00 | 16 | 22.94 | 214.03 | 15.41 |
3 | 8.59 | 143.55 | 10.34 | 17 | 23.92 | 342.38 | 24.65 |
4 | 10.14 | 395.37 | 28.46 | 18 | 24.26 | 294.13 | 21.18 |
5 | 13.90 | 75.89 | 5.46 | 19 | 24.91 | 159.91 | 11.51 |
6 | 14.99 | 556.98 | 40.10 | 20 | 25.57 | 362.76 | 26.12 |
7 | 15.56 | 439.95 | 31.67 | 21 | 26.58 | 173.10 | 12.46 |
8 | 16.07 | 262.74 | 18.92 | 22 | 27.42 | 224.17 | 16.14 |
9 | 16.95 | 268.39 | 19.32 | 23 | 28.26 | 262.30 | 18.88 |
10 | 17.20 | 484.23 | 34.86 | 24 | 29.39 | 173.15 | 12.47 |
11 | 17.82 | 229.71 | 16.54 | 25 | 31.19 | 189.29 | 13.63 |
12 | 19.16 | 138.22 | 9.95 | 26 | 32.02 | 129.41 | 9.32 |
13 | 20.39 | 178.57 | 12.86 | 27 | 33.52 | 96.99 | 6.98 |
14 | 21.10 | 219.33 | 15.79 | - | - | - | - |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 7.14 | 366.08 | 16.78 | 17 | 21.81 | 1988.21 | 91.13 |
2 | 8.58 | 76.34 | 3.50 | 18 | 22.10 | 204.08 | 9.35 |
3 | 10.33 | 416.43 | 19.09 | 19 | 23.35 | 895.06 | 41.03 |
4 | 11.36 | 538.48 | 24.68 | 20 | 24.33 | 501.38 | 22.98 |
5 | 12.15 | 285.42 | 13.08 | 21 | 24.66 | 402.48 | 18.45 |
6 | 14.47 | 356.16 | 16.32 | 22 | 25.29 | 701.92 | 32.17 |
7 | 15.08 | 143.54 | 6.58 | 23 | 25.96 | 179.36 | 8.22 |
8 | 15.86 | 2181.72 | 100.00 | 24 | 27.88 | 527.68 | 24.19 |
9 | 16.85 | 614.50 | 28.17 | 25 | 28.71 | 502.40 | 23.03 |
10 | 17.25 | 344.72 | 15.80 | 26 | 29.53 | 438.88 | 20.12 |
11 | 17.58 | 304.31 | 13.95 | 27 | 29.84 | 239.02 | 10.96 |
12 | 18.08 | 90.69 | 4.16 | 28 | 31.74 | 487.14 | 22.33 |
13 | 18.58 | 603.24 | 27.65 | 29 | 32.71 | 421.26 | 19.31 |
14 | 19.54 | 1122.21 | 51.44 | 30 | 34.04 | 118.56 | 5.43 |
15 | 20.69 | 196.21 | 8.99 | 31 | 37.79 | 29.50 | 1.35 |
16 | 21.44 | 474.01 | 21.73 | - | - | - | - |
编号 | 衍射角2θ | 峰高 | 相对强度% | 编号 | 衍射角2θ | 峰高 | 相对强度% |
1 | 6.99 | 2948.60 | 100.00 | 15 | 18.48 | 138.53 | 4.70 |
2 | 7.34 | 2087.30 | 70.79 | 16 | 19.58 | 1108.68 | 37.60 |
3 | 8.33 | 257.73 | 8.74 | 17 | 20.62 | 714.58 | 24.23 |
4 | 9.22 | 1358.47 | 46.07 | 18 | 20.99 | 600.93 | 20.38 |
5 | 9.92 | 488.45 | 16.57 | 19 | 22.22 | 214.80 | 7.28 |
6 | 10.56 | 565.01 | 19.16 | 20 | 22.67 | 154.95 | 5.26 |
7 | 10.97 | 804.48 | 27.28 | 21 | 23.78 | 184.49 | 6.26 |
8 | 13.35 | 338.84 | 11.49 | 22 | 25.77 | 836.23 | 28.36 |
9 | 13.96 | 655.05 | 22.22 | 23 | 26.19 | 1382.89 | 46.90 |
10 | 14.60 | 1236.10 | 41.92 | 24 | 26.84 | 412.81 | 14.00 |
11 | 15.13 | 1451.49 | 49.23 | 25 | 27.46 | 505.00 | 17.13 |
12 | 15.83 | 532.35 | 18.05 | 26 | 31.21 | 44.76 | 1.52 |
13 | 16.36 | 874.04 | 29.64 | 27 | 37.22 | 42.01 | 1.42 |
14 | 16.91 | 1374.26 | 46.61 | - | - | - | - |
参数 | TGA | DSC |
方法 | 线性升温 | 线性升温 |
样品盘 | 铝盘,敞开 | 铝盘,压盖 |
温度范围 | 室温-设置终点温度 | 25℃-设置终点温度 |
扫描速率(℃/分钟) | 10 | 10 |
保护气体 | 氮气 | 氮气 |
离子色谱仪 | ThermoFisher ICS-1100 |
色谱柱 | IonPac AS18 Analytical Column,4×250mm |
流动相 | 25mMNaOH |
运行时间 | 7min(氯离子);18min(溴离子) |
流速 | 1.0毫升/分钟 |
进样体积 | 25微升 |
电流 | 80毫安 |
柱温 | 35℃ |
供试品 | DNA-PK激酶抑制活IC 50(nM) |
式(II-1)化合物B晶型 | 0.6 |
参数 | C max(nM) | T max(h) | T 1/2(h) | T last(h) | AUC 0-1ast(nM.h) |
式(VIII-1)化合物K晶型 | 21728 | 1.50 | 2.42 | 32.0 | 127313 |
式(I)化合物A晶型 | 14552 | 0.67 | 1.59 | ND | 83483 |
式(II-1)化合物B晶型 | 11057 | 1.33 | 4.07 | ND | 87413 |
Claims (31)
- 根据权利要求4所述的B晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.02±0.20°,10.66±0.20°,13.98±0.20°,16.56±0.20°,21.25±0.20°。
- 根据权利要求5所述的B晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.02±0.20°,9.29±0.20°,10.66±0.20°,13.98±0.20°,16.56±0.20°,21.25±0.20°,29.98±0.20°。
- 根据权利要求6所述的B晶型,其XRPD图谱如图4所示。
- 根据权利要求4~7任意一项所述的B晶型,其差示扫描量热曲线在286.6℃±3℃处具有吸热峰的起始点。
- 根据权利要求8所述的B晶型,其DSC图谱如图5所示。
- 根据权利要求4~7任意一项所述的B晶型,其热重分析曲线在200.0℃±3℃时失重达0.58%。
- 根据权利要求10所述的B晶型,其TGA图谱如图6所示。
- 根据权利要求13所述的C晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.96±0.20°,7.05±0.20°,10.23±0.20°,15.16±0.20°,17.83±0.20°,22.11±0.20°,23.19±0.20°。
- 根据权利要求14所述的C晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.96±0.20°,7.05±0.20°,10.23±0.20°,11.89±0.20°,15.16±0.20°,17.83±0.20°,19.09±0.20°,19.96±0.20°,22.11±0.20°,23.19±0.20°。
- 根据权利要求15所述的C晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.96°,7.05°,8.08°,10.23°,11.89°,12.30°,12.99°,14.01°,15.16°,16.67°,17.54°,17.83°,18.75°,19.09°,19.47°,19.96°,20.67°,21.6°,22.11°,23.19°,23.83°,25.18°,26.69°,28.32°,29.90°,30.48°,32.39°,35.02°。
- 根据权利要求16所述的C晶型,其XRPD图谱如图8所示。
- 根据权利要求13~17任意一项所述的C晶型,其差示扫描量热曲线在255.4±3℃处具有吸热峰的起始点。
- 根据权利要求18所述的C晶型,其DSC图谱如图9所示。
- 根据权利要求13~17任意一项所述的C晶型,其热重分析曲线在150.0℃±3℃时失重达2.90%。
- 根据权利要求20所述的C晶型,其TGA图谱如图10所示。
- 根据权利要求22所述的A晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:9.26±0.20°,11.50±0.20°,13.52±0.20°,17.03±0.20°,18.75±0.20°,19.47±0.20°,22.69±0.20°,27.74±0.20°。
- 根据权利要求23所述的A晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.77±0.20°,9.26±0.20°,11.50±0.20°,13.52±0.20°,17.03±0.20°,17.50±0.20°,18.75±0.20°,19.47±0.20°,22.69±0.20°,23.84±0.20°,24.42±0.20°,26.76±0.20°,27.74±0.20°。
- 根据权利要求24所述的A晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰::5.77°,9.26°,11.50°,13.52°,14.50°,15.16°,15.60°,17.03°,17.28°,17.50°,18.47°,18.75°,19.27°,19.47°,22.69°,23.84°,24.42°,26.76°,27.74°,28.43°,29.77°,30.40°,32.08°。
- 根据权利要求25所述的A晶型,其XRPD图谱如图1所示。
- 根据权利要求22~26任意一项所述的A晶型,其差示扫描量热曲线在257.8℃±3℃处具有吸热峰的起始点。
- 根据权利要求27所述的A晶型,其DSC图谱如图2所示。
- 根据权利要求22~26任意一项所述的A晶型,其热重分析曲线在230.0℃±3℃时失重达1.39%。
- 根据权利要求29所述的A晶型,其TGA图谱如图3所示。
- 根据权利要求1~3任意一项所述的甲磺酸盐或对甲苯磺酸盐、权利要求4~11任意一项所述的B晶型、权利要求13~21任意一项所述的C晶型、根据权利要求22~30任一项所述的A晶型或根据权利要求12的方法制备得到的晶型在制备DNA-PK抑制剂相关药物中的应用。
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