Crystalline forms of pyrimidoazacyclo compounds, methods for their preparation, and applications.

Abstract

This invention relates to crystalline forms of pyrimidoazacyclo compounds, methods for preparing them, and their applications. Specifically, this invention discloses a series of crystalline forms of compounds of formula A, which have excellent stability. This invention further discloses methods for preparing the above crystalline forms and their applications in the prevention and / or treatment of tumors.

Claims

1. The crystalline form of the compound of formula A, The aforementioned crystal form is selected from the group consisting of free base crystal form III, fumarate crystal form I, and malate crystal form I. Formula (A): 【Chemistry 1】 Here, The X-ray powder diffraction pattern of the free base crystal form III shows characteristic peaks at 2θ values ​​of 5.1±0.2°, 5.8±0.2°, 7.3±0.2°, 8.2±0.2°, 9.3±0.2°, 10.4±0.2°, 10.7±0.2°, 13.0±0.2°, 13.3±0.2°, 14.7±0.2°, 16.7±0.2°, 18.4±0.2°, 19.0±0.2°, and 23.4±0.2°. The X-ray powder diffraction pattern of the fumarate crystal form I shows characteristic peaks at 2θ values ​​of 6.0±0.2°, 8.7±0.2°, 10.6±0.2°, 14.6±0.2°, 15.5±0.2°, 17.5±0.2°, 18.0±0.2°, 19.2±0.2°, and 27.1±0.2°. The X-ray powder diffraction pattern of the malate crystal form I is characterized by having characteristic peaks at 2θ values ​​of 6.0±0.2°, 9.3±0.2°, 10.7±0.2°, 11.2±0.2°, 11.8±0.2°, 15.3±0.2°, 17.3±0.2°, 17.6±0.2°, 18.3±0.2°, 19.0±0.2°, 23.5±0.2°, 25.7±0.2°, and 28.0±0.2°.

2. The X-ray powder diffraction patterns of the aforementioned free base crystal form III show characteristic peaks at 2θ values ​​of 5.1±0.2°, 5.8±0.2°, 7.3±0.2°, 7.8±0.2°, 8.2±0.2°, 9.3±0.2°, 10.4±0.2°, 10.7±0.2°, 11.0±0.2°, 13.0±0.2°, 13.3±0.2°, 14.0±0.2°, 14.7±0.2°, 15.2±0.2°, 16.7±0.2°, 17.5±0.2°, 18.4±0.2°, 19.0±0.2°, 21.1±0.2°, 22.2±0.2°, 23.4±0.2°, and 29.5±0.2°. The X-ray powder diffraction pattern of the fumarate crystal form I shows characteristic peaks at 2θ values ​​of 6.0±0.2°, 8.7±0.2°, 10.6±0.2°, 11.0±0.2°, 11.9±0.2°, 12.1±0.2°, 12.5±0.2°, 14.6±0.2°, 15.5±0.2°, 15.9±0.2°, 17.5±0.2°, 18.0±0.2°, 19.2±0.2°, 26.7±0.2°, and 27.1±0.2°. The X-ray powder diffraction pattern of the malate crystal form I is characterized by having characteristic peaks at 2θ values ​​of 6.0±0.2°, 9.3±0.2°, 10.2±0.2°, 10.7±0.2°, 11.2±0.2°, 11.8±0.2°, 13.2±0.2°, 15.3±0.2°, 16.2±0.2°, 17.3±0.2°, 17.6±0.2°, 18.3±0.2°, 19.0±0.2°, 23.5±0.2°, 24.8±0.2°, 25.7±0.2°, 27.6±0.2°, and 28.0±0.2°. The crystal form described in claim 1.

3. The X-ray powder diffraction patterns of the free base crystal form III were 5.1±0.2°, 5.8±0.2°, 7.3±0.2°, 7.8±0.2°, 8.2±0.2°, 9.3±0.2°, 10.4±0.2°, 10.7±0.2°, 11.0±0.2°, 13.0±0.2°, 13.3±0.2°, 14.0±0.2°, 14.7±0.2°, 15.2±0.2°, and 16.7±0.2°. There are characteristic peaks in the 2θ values ​​at 17.5±0.2°, 18.4±0.2°, 19.0±0.2°, 21.1±0.2°, 21.6±0.2°, 22.2±0.2°, 23.4±0.2°, 24.9±0.2°, 25.9±0.2°, 26.3±0.2°, 27.9±0.2°, 28.4±0.2°, 29.5±0.2°, 30.0±0.2°, and 35.6±0.2°. The X-ray powder diffraction patterns of the fumarate crystal form I are 6.0±0.2°, 8.2±0.2°, 8.7±0.2°, 9.9±0.2°, 10.6±0.2°, 11.0±0.2°, 11.9±0.2°, 12.1±0.2°, 12.5±0.2°, 14.6±0.2°, 15.5±0.2°, 15 There are characteristic peaks in the 2θ values ​​at 9±0.2°, 16.5±0.2°, 17.5±0.2°, 18.0±0.2°, 19.2±0.2°, 21.2±0.2°, 22.2±0.2°, 23.9±0.2°, 25.5±0.2°, 26.7±0.2°, 27.1±0.2°, and 28.8±0.2°. The X-ray powder diffraction patterns of the aforementioned malate crystal form I are 6.0±0.2°, 9.3±0.2°, 10.2±0.2°, 10.7±0.2°, 11.2±0.2°, 11.8±0.2°, 12.1±0.2°, 13.2±0.2°, 15.3±0.2°, 16.2±0.2°, 16.8±0.2°, and 17.1± It is characterized by distinctive peaks at 2θ values ​​of 0.2°, 17.3±0.2°, 17.6±0.2°, 18.3±0.2°, 19.0±0.2°, 23.5±0.2°, 24.8±0.2°, 25.2±0.2°, 25.7±0.2°, 27.6±0.2°, 28.0±0.2°, and 29.7±0.2°. The crystal form described in claim 1.

4. The X-ray powder diffraction pattern of the free base crystal form III is basically as shown in Figure 5. The X-ray powder diffraction pattern of the fumarate crystal form I is basically as shown in Figure 37. The X-ray powder diffraction pattern of the malate crystal form I is basically as shown in Figure 41. The crystal form described in claim 1.

5. The aforementioned crystal form is selected from the group consisting of fumarate crystal form I and malate crystal form I. The crystal form described in claim 1.

6. The aforementioned crystalline form is characterized by being fumarate crystalline form I. The crystal form described in claim 1.

7. A method for preparing free base crystal form III, The above method is selected from the group consisting of the following methods: Method 1: The compound shown in formula A is mixed with solvent m, dissolved and made transparent, and crystals are precipitated. The solvent m is selected from n-butanone, acetone, and acetonitrile. Method 2: A method for preparing the free base crystal form III, characterized in that the compound shown in formula A is mixed with solvent n, slurryed at high temperature, and crystals are precipitated, and the solvent n is selected from one of ethyl acetate, isopropyl acetate, and methyl t-butyl ether.

8. A method for preparing fumarate crystal form I or malate crystal form I, The above method is selected from the group consisting of the following methods: Method 1: Dissolve the compound of formula A in an organic solvent, stir at room temperature, then add fumaric acid or malic acid, continue stirring, and perform solid-liquid separation to obtain the fumarate crystal form I or malate crystal form I. Method 2: A method for preparing the fumarate crystalline form I or malate crystalline form I, characterized by adding an organic solvent to the fumarate or malate of the compound of formula A, suspending and stirring, and performing solid-liquid separation to obtain the fumarate crystalline form I or malate crystalline form I.

9. The use of the crystal form described in claim 1, Used in the preparation of drugs, said drug is 1) Treatment of diseases or conditions related to RET regulation, 2) Treatment of tumors, 3) The use characterized by being used in an application selected from the group consisting of inhibiting cell proliferation.

10. The tumor is characterized by being selected from the group consisting of thyroid cancer and non-small cell lung cancer. Use as described in claim 9.

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