Solid forms of FGFR inhibitors

Abstract

The present disclosure relates to solid forms of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which are useful in preparing pharmaceutical compositions and dosage forms for treating diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 63 / 287,212, filed December 8, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases (RTKs) that bind members of the fibroblast growth factor family of proteins. Deregulation of the fibroblast growth factor / FGF receptor network occurs frequently in tumors. Thus, therapeutics that target abnormal FGFR kinase activity are desirable for use in the treatment of cancer and other disorders. 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide is one such modulator of FGFR kinases. Summary of the Invention

[0003] The present disclosure relates to a solid form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (hereinafter referred to as Compound 1). The molecular structure of Compound 1 is shown below.

[0004] [ka]

[0005] Disclosed herein is a solid form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1).

[0006] Disclosed herein is a solid form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which is crystalline.

[0007] Disclosed herein is a solid crystalline form of Compound 1, which is crystalline. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 11.8°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 7.9°±0.3 and 13.7°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 9.5°±0.3, 18.9°±0.3, and 26.8°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 15.9°±0.3, 20.5°±0.3, and 22.3°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 20.8°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3.In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG. 4. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram comprising an endothermic peak at 193.1°±5.0°. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram as shown in FIG. 5. In some embodiments, the solid form exhibits a weight loss of less than 1.1%±0.5 up to 200°C±10.0° as determined by thermogravimetric analysis. In some embodiments, the solid form exhibits a thermogravimetric analysis thermogram as shown in Figure 5. In some embodiments, the solid form is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the solid form is substantially free of impurities. In some embodiments, the amount of impurities is 2% or less.

[0008] Disclosed herein is a solid crystalline form of Compound 1, which is crystalline. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 8.7°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 5.0°±0.3 and 12.8°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 23.9°±0.3 and 24.3°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 11.5°±0.3, 20.3°±0.3, and 21.2°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 11.6°±0.3, 15.9°±0.3, and 25.8°±0.3. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3.In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG. 7. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram comprising endothermic peaks at 164.0°±5.0 and 190.6°±5.0. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram as shown in FIG. 8. In some embodiments, the solid form exhibits a weight loss of less than 2.9%±0.5 at up to 205° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the solid form exhibits a thermogravimetric analysis thermogram as shown in FIG. 8. In some embodiments, the solid form is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the solid form is substantially free of impurities. In some embodiments, the amount of impurities is 2% or less.

[0009] Disclosed herein is a solid crystalline form of Compound 1, which is crystalline. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 5.1°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 10.2°±0.3 and 8.6°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 12.2°±0.3 and 17.3°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 6.4°±0.3, 13.4°±0.3, and 15.3°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 15.8°±0.3 and 26.0°±0.3 2θ values. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3.In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG. 9. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram including endothermic peaks at 66.2° C.±5.0, 106.4° C.±5.0, and 193.6° C.±5.0. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram as shown in FIG. 10. In some embodiments, the solid form exhibits a weight loss of less than 2.9%±0.5 at up to 94° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the solid form exhibits a thermogravimetric analysis thermogram as shown in FIG. 10. In some embodiments, the solid form is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the solid form is substantially free of impurities. In some embodiments, the amount of impurities is 2% or less.

[0010] Disclosed herein is a solid crystalline form of Compound 1, which is crystalline. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 5.1°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 10.4°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 6.4°±0.3 and 25.6°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 8.7°±0.3, 11.9°±0.3, and 15.6°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 13.5°±0.3 and 25.8°±0.3 2θ values. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3.In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG. 11. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram comprising an endothermic peak at 105.8°±5.0°. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram as shown in FIG. 12. In some embodiments, the solid form exhibits a weight loss of less than 2.1%±0.5 at up to 101°±10.0° as determined by thermogravimetric analysis. In some embodiments, the solid form exhibits a thermogravimetric analysis thermogram as shown in FIG. 12. In some embodiments, the solid form is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the solid form is substantially free of impurities. In some embodiments, the amount of impurities is 2% or less.

[0011] Disclosed herein is a solid crystalline form of Compound 1, which is crystalline. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 9.5°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 5.2°±0.3 and 23.7°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 5.7°±0.3, 10.2°±0.3, and 19.5°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 6.5°±0.3, 15.5°±0.3, and 26.8°±0.3 2θ values. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 7.4°±0.3, 15.0°±0.3, 19.0°±0.3, and 24.7°±0.3 2θ values. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3.In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG. 13. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram comprising endothermic peaks at 112.3°±5.0 and 193.7°±5.0. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram as shown in FIG. 14. In some embodiments, the solid form exhibits a weight loss of less than 4.3%±0.5 at up to 126° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the solid form exhibits a thermogravimetric analysis thermogram as shown in FIG. 14. In some embodiments, the solid form is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the solid form is substantially free of impurities. In some embodiments, the amount of impurities is 2% or less.

[0012] Disclosed herein is a solid crystalline form of Compound 1, which is crystalline. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.4°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 9.8°±0.3 and 23.4°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.0°±0.3 and 15.2°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 10.1°±0.3, 13.6°±0.3, and 26.7°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 9.1°±0.3, 25.6°±0.3, and 27.2°±0.3. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3.In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG. 15. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram comprising endothermic peaks at 120.8°±5.0 and 195.1°±5.0. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram as shown in FIG. 16. In some embodiments, the solid form exhibits a weight loss of less than 3.9%±0.5 at up to 119° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the solid form exhibits a thermogravimetric analysis thermogram as shown in FIG. 16. In some embodiments, the solid form is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the solid form is substantially free of impurities. In some embodiments, the amount of impurities is 2% or less.

[0013] Disclosed herein is a solid crystalline form of Compound 1, which is crystalline. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.8°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.2°±0.3 and 15.2°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.0°±0.3 and 10.1°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 8.4°±0.3, 9.8°±0.3, and 23.4°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 10.4°±0.3, 14.2°±0.3, and 25.5°±0.3. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3.In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG. 17. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram comprising endothermic peaks at 108.7°±5.0 and 195.1°±5.0. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram as shown in FIG. 18. In some embodiments, the solid form exhibits a weight loss of less than 7.4%±0.5 at up to 140° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the solid form exhibits a thermogravimetric analysis thermogram as shown in FIG. 18. In some embodiments, the solid form is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the solid form is substantially free of impurities. In some embodiments, the amount of impurities is 2% or less.

[0014] Disclosed herein is a solid crystalline form of Compound 1, which is crystalline. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 12.3°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 6.1°±0.3 and 13.4°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 7.9°±0.3 and 10.5°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 11.8°±0.3, 25.0°±0.3, and 25.7°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 2θ values ​​of 18.6°±0.3, 23.0°±0.3, and 25.2°±0.3. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3.In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG. 19. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram comprising an endothermic peak at 179.3°±5.0°. In some embodiments, the solid form exhibits a differential scanning calorimetry thermogram as shown in FIG. 20. In some embodiments, the solid form exhibits a weight loss of less than 2.9%±0.5 up to 245°±10.0° as determined by thermogravimetric analysis. In some embodiments, the solid form exhibits a thermogravimetric analysis thermogram as shown in Figure 20. In some embodiments, the solid form is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the solid form is substantially free of impurities. In some embodiments, the amount of impurities is 2% or less.

[0015] Disclosed herein is a solid crystalline form of Compound 1, which is amorphous. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern as shown in FIG.

[0016] Disclosed herein is a pharmaceutical composition comprising any one of the solid forms provided herein and a pharma- ceutically acceptable excipient.In some embodiments, the pharmaceutical composition further comprises a disintegrant.

[0017] Disclosed herein is a method of treating cancer in a patient in need of treatment, the method comprising administering to the patient a composition comprising any one of the solid forms provided herein and at least one pharma- ceutically acceptable excipient.

[0018] Disclosed herein are methods of treating cancer in a patient in need of treatment comprising administering to the patient any of the solid forms provided herein. [Brief description of the drawings]

[0019] The features of the present invention are set forth with particularity in the appended claims. A better understanding of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Figure 1] FIG. 1 shows the X-ray diffraction pattern of amorphous Compound 1. [Diagram 2] FIG. 2 shows the X-ray diffraction pattern of crystalline Form I of Compound 1. [Diagram 3] FIG. 3 shows differential scanning calorimetry and thermogravimetry of Form I of Compound 1. [Figure 4] FIG. 4 shows the X-ray diffraction pattern of crystalline Form II of Compound 1. [Diagram 5] FIG. 5 shows differential scanning calorimetry and thermogravimetry of Form II of Compound 1. [Figure 6] FIG. 6 shows the dynamic vapor sorption isotherm and mass plots of crystalline Form II of Compound 1. [Figure 7] FIG. 7 shows the X-ray diffraction pattern of crystalline Form III of Compound 1. [Figure 8] FIG. 8 shows differential scanning calorimetry and thermogravimetry of Form III of Compound 1. [Figure 9] FIG. 9 shows the X-ray diffraction pattern of crystalline Form IV of Compound 1. [Figure 10]FIG. 10 shows differential scanning calorimetry and thermogravimetry of Form IV of Compound 1. [Figure 11] FIG. 11 shows the X-ray diffraction pattern of crystalline form V of compound 1. [Figure 12] FIG. 12 shows differential scanning calorimetry and thermogravimetry of Form V of Compound 1. [Figure 13] FIG. 13 shows the X-ray diffraction pattern of crystalline Form VI of Compound 1. [Figure 14] FIG. 14 shows differential scanning calorimetry and thermogravimetry of Form VI of Compound 1. [Figure 15] FIG. 15 shows the X-ray diffraction pattern of crystalline Form VII of Compound 1. [Figure 16] FIG. 16 shows differential scanning calorimetry and thermogravimetry of Form VII of Compound 1. [Figure 17] FIG. 17 shows the X-ray diffraction pattern of crystalline Form VIII of Compound 1. [Figure 18] FIG. 18 shows differential scanning calorimetry and thermogravimetry of Form VIII of Compound 1. [Figure 19] FIG. 19 shows the X-ray diffraction pattern of crystalline Form IX of Compound 1. [Figure 20] FIG. 20 shows differential scanning calorimetry and thermogravimetry of Form IX of Compound 1. [Figure 21] FIG. 21 shows conversion maps for selected solid forms of Compound 1. [Figure 22] FIG. 22 shows an exemplary tablet manufacturing process for a pharmaceutical formulation containing a solid form of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Provided herein are ten solid forms of Compound 1. The solid forms of Compound 1 are identified as an amorphous form and nine crystalline forms designated as Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, and Form IX. In some embodiments, disclosed herein is a pharmaceutical composition comprising a solid form of Compound 1. In some embodiments, disclosed herein is a pharmaceutical composition comprising an amorphous form, Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, or any combination thereof.

[0021] Nine crystalline forms were identified, including a monohydrate (Form I), four anhydrates (Forms II, III, V, and IX), a hemihydrate (Form IV), and three solvates (Forms VI, VII, and VIII), designated as Forms I to IX. Characterization data for these forms are shown in Table 15. Interconversion studies suggested that Form II was the most stable form in non-aqueous solvents, being physically stable with aw≦0.35 at room temperature and aw≦0.55 at 50°C. Form I also showed superior stability compared to the other forms, with aw≧0.75 at 50°C and aw≧0.55 at room temperature. The three solvates (Forms VI, VII, and VIII) were converted to Form II after desolvation and recrystallization during heating by DSC. The conversion maps of the different forms are shown in Figure 21. Form II was evaluated by DVS, solubility tests, and stability tests. DVS results showed that Form II was slightly hygroscopic with 0.47% water uptake at 90% RH. Solubility results showed that it had the highest solubility in SGF (0.8 mg / mL) and low solubility in water (approximately 3 μg / mL). The solubility in FeSSIF was approximately 30 times higher than that in FaSSIF at 24 hours. Form II was physically stable at room temperature / 92.5% RH for 2 days and physically and chemically stable at 40°C / 75% RH for 6 days. Purity decreased by approximately 0.3% at 60°C for 3 and 7 days, mainly due to an increase in impurities at RRTs of 0.9, 0.91, and 1.07.

[0022] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0023] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0024] The terms "hydrate" and "solvate" are meant to describe a form of crystalline Compound 1 that contains an amount of water or solvent, as supported by data from differential scanning calorimetry (DSC) experiments, thermogravimetric analysis (TGA) experiments, X-ray diffraction experiments, and / or procedures for producing solid crystalline forms. In some embodiments, the solvate or hydrate crystalline form contains at least 1.5%, 1.75%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, or 20.0% of the total weight of the sample as water, solvent, or a combination thereof, as determined by TGA. In some embodiments, the solvate or hydrate crystalline form exhibits at least one DSC endotherm onset before or within 30° C. of the boiling point of the water or solvent used in producing the crystalline form. For example, a hydrate crystal form may have a DSC endotherm onset at 108°C with an endothermic peak located at 124°C.

[0025] The crystalline solid forms referred to as "solvates" or "hydrates" are not meant to be limiting. For example, a solvate or hydrate may include a combination of water and a solvent in the crystalline solid form.

[0026] The terms "type", "form" and "pattern" are meant to be used interchangeably and refer to a particular crystalline material having the properties described herein. For example, "crystalline type A", "crystalline form A" and "XRPD pattern A" refer to the same crystalline material. Roman numerals and integers are also meant to be interchangeable, for example, "form 1" and "form I" are equivalent.

[0027] When referring to a number or numerical range, the term "about" means that the number or numerical range referred to is approximate within experimental variability (or within statistical experimental error), and thus the number or numerical range will vary, in some cases, between 1% and 15% of the stated number or numerical range.

[0028] As used herein, the term "substantially similar" refers to an analytical spectrum, such as an XRPD pattern, DSC thermogram, or TGA thermogram, that closely resembles a reference spectrum in both peak positions and peak intensities.

[0029] Characterization of compounds and solid state forms In one embodiment, the present invention provides a solid-state form of Compound 1. In one embodiment, the crystalline form is characterized by the interstitial spacing determined by X-ray powder diffraction (XRPD) diffractogram. A diffractogram is typically represented by a plot of peak intensity versus peak position, i.e., diffraction angle (2θ) in degrees. Characteristic peaks of a given compound can be selected according to peak position and their relative intensity to distinguish the compound and crystal structure from others. Peak tables are provided with corresponding d-spacings to aid in the conversion of 2θ measurements across X-ray radiation sources (e.g., copper and molybdenum). Amorphous solid-state forms have also been characterized by XRPD. Amorphous solid-state forms exhibit an absence of interstitial spacing.

[0030] Those skilled in the art will recognize that measurements of X-ray diffraction (XRD) peak positions and / or intensities for a given crystalline form of the same compound will vary within a range of error. The value of the degree 2θ allows for an appropriate margin of error. Typically, the margin of error is expressed as "±". For example, a degree 2θ of "8.716°±0.3" indicates a range from 8.716°+0.3, i.e., 9.016°, to 8.716°-0.3, i.e., 8.416°. Depending on the sample preparation technique, the calibration technique applied to the instrument, human operating variation, and collection temperature, those skilled in the art will recognize that the margin of error for XRD may be ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, ±0.05, or less than ±0.05. Further details of the method and apparatus used for XRD analysis are provided in the Examples section.

[0031] In one embodiment, the crystalline form is characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC thermograms are typically represented by diagrams plotting normalized heat flow in units of watts / gram ("W / g") versus measured sample temperature in °C. DSC thermograms are generally evaluated for estimated onset and end (onset) temperatures, peak temperature, and heat of fusion. A single maximum in a DSV thermogram is often used as a characteristic peak to distinguish one crystalline form from another. TGA thermograms are typically represented by diagrams plotting percent weight loss (%) versus measured sample temperature (°C). In the figures disclosed herein, DSC and TGA thermograms are plotted sharing an X-axis (temperature), but with separate Y-axes of weight % and heat flow corresponding to TGA and DSC measurements, respectively.

[0032] Those skilled in the art will recognize that measurements of DSC and TGA thermograms for a given crystalline form of the same compound will vary within a range of error. The value of the single maximum, expressed in degrees C, allows for an appropriate margin of error. Typically, the margin of error is expressed as "±". For example, a single maximum of "53.1°C ±10.0" means a range from 53.1°C +10.0, i.e. 63.1°C, to about 53.1°C -10.0, i.e. 43.1°C. Depending on the sample preparation technique, crystallization conditions, calibration techniques applied to the instrument, human operational variations, etc., those skilled in the art will recognize that an appropriate margin of error for the single maximum may be ±10.0, ±7.5, ±5.0, ±2.5, ±2, ±1.5, ±1, ±0.5, or less for any of the powder diffraction reflections described herein.

[0033] Further details of the methods and instruments used for the DSC and TGA thermogram analyses are provided in the Examples section.

[0034] Crystalline form I of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (compound 1) Provided herein is crystalline Form I of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

[0035] Provided herein is crystalline Form I of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.0°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 10.1°±0.3 and 17.1°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 8.5°±0.3, 24.8°±0.3, and 25.8°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 9.3°±0.3, 13.0°±0.3, and 16.4°±0.3, hi some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 12.1°±0.3 and 15.2°±0.3.

[0036] Provided herein is crystalline Form I of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 5.0°±0.3, 8.5°±0.3, 9.3°±0.3, 10.1°±0.3, 12.1°±0.3, 13.0°±0.3, 15.2°±0.3, 16.4°±0.3, 17.1°±0.3, 24.8°±0.3, and 25.8°±0.3. In some embodiments, the crystalline form I is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.5°±0.3, 9.3°±0.3, 10.1°±0.3, 12.1°±0.3, 13.0°±0.3, 15.2°±0.3, 16.4°±0.3, 17.1°±0.3, 24.8°±0.3, and 25.8°±0.3. In some embodiments, the crystalline form I is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.5°±0.3, 9.3°±0.3, 10.1°±0.3, 12.1°±0.3, 13.0°±0.3, 15.2°±0.3, 16.4°±0.3, 17.1°±0.3, 24.8°±0.3, and 25.8°±0.3. In some embodiments, the crystalline form I is characterized by at least four X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.5°±0.3, 9.3°±0.3, 10.1°±0.3, 12.1°±0.3, 13.0°±0.3, 15.2°±0.3, 16.4°±0.3, 17.1°±0.3, 24.8°±0.3, and 25.8°±0.3. In some embodiments, the crystalline form I is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.5°±0.3, 9.3°±0.3, 10.1°±0.3, 12.1°±0.3, 13.0°±0.3, 15.2°±0.3, 16.4°±0.3, 17.1°±0.3, 24.8°±0.3, and 25.8°±0.3.In some embodiments, the crystalline form I is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.5°±0.3, 9.3°±0.3, 10.1°±0.3, 12.1°±0.3, 13.0°±0.3, 15.2°±0.3, 16.4°±0.3, 17.1°±0.3, 24.8°±0.3, and 25.8°±0.3.

[0037] Provided herein is crystalline Form I of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits an X-ray powder diffraction pattern as shown in FIG.

[0038] [Table 1-1]

[0039] [Table 1-2]

[0040] [Table 1-3]

[0041] Provided herein is crystalline Form I of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in FIG. 3. In some embodiments, the crystalline form exhibits less than about 4.9%±0.5 weight loss at up to 76° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits less than about 3.9%±0.5 weight loss at up to 76° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits at least about 2.9%±0.5 weight loss at up to 76° C.±10.0 as determined by thermogravimetric analysis.

[0042] Provided herein is crystalline Form I of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, the DSC of which is characterized by endothermic peaks at 53.5° C.±10.0, 106.5° C.±5.0, and 193.7° C.±5.0 as shown in Figure 3. In some embodiments, the DSC is characterized by an endothermic peak at 106.5° C.±5.0.

[0043] In some embodiments, compositions are provided herein in which crystalline form I is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0044] In some embodiments, provided herein is a composition wherein crystalline Form I is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0045] Crystalline Form II of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Provided herein is crystalline Form II of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide).

[0046] Provided herein is crystalline Form II of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at 2θ values ​​of 11.8°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 7.9°±0.3 and 13.7°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 9.5°±0.3, 18.9°±0.3, and 26.8°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 15.9°±0.3, 20.5°±0.3, and 22.3°±0.3, hi some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 20.8°±0.3, 25.7°±0.3, and 26.3°±0.3.

[0047] Provided herein is crystalline Form II of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the crystalline Form II is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the crystalline Form II is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the crystalline Form II is characterized by at least four X-ray diffraction pattern reflections selected from 2θ values ​​of 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3. In some embodiments, the crystalline Form II is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3.In some embodiments, the crystalline Form II is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.3.

[0048] Provided herein is crystalline Form II of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits an X-ray powder diffraction pattern as shown in FIG.

[0049] [Table 2-1]

[0050] [Table 2-2]

[0051] Provided herein is crystalline Form II of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in Figure 5. In some embodiments, the crystalline form exhibits less than 0.1% ± 0.5 weight loss at up to 200°C ± 10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits less than 1.1% ± 0.5 weight loss at up to 200°C ± 10.0 as determined by thermogravimetric analysis.

[0052] Provided herein is crystalline Form II of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by an endothermic peak at 193.1° C.±5.0° C. as shown in FIG. 5 by DSC.

[0053] In some embodiments, compositions are provided herein in which crystalline form II is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0054] In some embodiments, provided herein is a composition wherein crystalline Form II is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0055] Crystalline Form III of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Provided herein is crystalline Form III of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1).

[0056] Provided herein is crystalline Form III of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at 2θ values ​​of 8.7°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.0°±0.3 and 12.8°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 23.9°±0.3 and 24.3°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 11.5°±0.3, 20.3°±0.3, and 21.2°±0.3, hi some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 11.6°±0.3, 15.9°±0.3, and 25.8°±0.3.

[0057] Provided herein is crystalline Form III of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the crystalline Form III is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the crystalline Form III is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the crystalline Form III is characterized by at least four X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3. In some embodiments, the crystalline Form III is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3.In some embodiments, the crystalline Form III is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.3.

[0058] Provided herein is crystalline Form III of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits an X-ray powder diffraction pattern as shown in FIG.

[0059] [Table 3-1]

[0060] [Table 3-2]

[0061] Provided herein is crystalline Form III of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in FIG. 8. In some embodiments, the crystalline form exhibits a weight loss of less than 2.9%±0.5 at up to 205° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of less than 1.9%±0.5 at up to 205° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of at least 0.9%±0.5 at up to 205° C.±10.0 as determined by thermogravimetric analysis.

[0062] Provided herein is crystalline Form III of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, the DSC of which is characterized by endothermic peaks at 164.0° C.±5.0 and 190.6° C.±5.0 as shown in Figure 8. In some embodiments, the DSC is characterized by an endothermic peak at 190.6° C.±5.0.

[0063] In some embodiments, compositions are provided herein in which crystalline form III is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0064] In some embodiments, provided herein is a composition wherein crystalline Form III is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0065] Crystalline Form IV of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Provided herein is crystalline Form IV of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

[0066] Provided herein is crystalline Form IV of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.1°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 10.2°±0.3 and 8.6°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 12.2°±0.3 and 17.3°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.4°±0.3, 13.4°±0.3, and 15.3°±0.3, hi some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 15.8°±0.3 and 26.0°±0.3.

[0067] Provided herein is crystalline Form IV of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, crystalline form IV is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, crystalline form IV is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, crystalline Form IV is characterized by at least four X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3. In some embodiments, crystalline Form IV is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3.In some embodiments, crystalline Form IV is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.3.

[0068] Provided herein is crystalline Form IV of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits an X-ray powder diffraction pattern as shown in FIG.

[0069] [Table 4-1]

[0070] [Table 4-2]

[0071] Provided herein is crystalline Form IV of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in FIG. 10. In some embodiments, the crystalline form exhibits a weight loss of less than 2.9%±0.5 at up to 94° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of less than 1.9%±0.5 at up to 94° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of at least 0.9%±0.5 at up to 94° C.±10.0 as determined by thermogravimetric analysis.

[0072] Provided herein is crystalline Form IV of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, the DSC of which is characterized by endothermic peaks at 66.2° C.±5.0, 106.4° C.±5.0, and 193.6° C.±5.0 as shown in Figure 10. In some embodiments, the DSC is characterized by an endothermic peak at 106.4° C.±5.0.

[0073] In some embodiments, compositions are provided herein in which crystalline form IV is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0074] In some embodiments, provided herein is a composition wherein crystalline Form IV is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0075] Crystal form V of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (compound 1) Provided herein is crystalline Form V of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

[0076] Provided herein is crystalline form V of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at a 2θ value of 5.1°±0.3. In some embodiments, the crystalline form exhibits an X-ray powder diffraction reflection at a 2θ value of 10.4°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.4°±0.3 and 25.6°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 8.7°±0.3, 11.9°±0.3, and 15.6°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 13.5°±0.3 and 25.8°±0.3.

[0077] Provided herein is crystalline Form V of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, wherein Form V is characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, crystalline form V is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, crystalline form V is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, crystalline form V is characterized by at least four X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, crystalline form V is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3. In some embodiments, crystalline form V is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.3.

[0078] Provided herein is crystalline Form V of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits an X-ray powder diffraction pattern as shown in FIG.

[0079] [Table 5]

[0080] Provided herein is crystalline form V of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in FIG. 12. In some embodiments, the crystalline form exhibits a weight loss of less than 2.1%±0.5 at up to 101° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of less than 1.1%±0.5 at up to 101° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of at least 0.6%±0.5 at up to 101° C.±10.0 as determined by thermogravimetric analysis.

[0081] Provided herein is crystalline Form V of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by an endothermic peak at 105.8° C.±5.0° C. as shown in FIG. 12 by DSC.

[0082] In some embodiments, compositions are provided herein in which crystalline form V is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0083] In some embodiments, provided herein is a composition wherein crystalline Form V is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0084] Crystalline Form VI of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Provided herein is crystalline Form VI of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

[0085] Provided herein is crystalline Form VI of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at 2θ values ​​of 9.5°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.2°±0.3 and 23.7°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.7°±0.3, 10.2°±0.3, and 19.5°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.5°±0.3, 15.5°±0.3, and 26.8°±0.3, hi some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 7.4°±0.3, 15.0°±0.3, 19.0°±0.3, and 24.7°±0.3.

[0086] Provided herein is crystalline Form VI of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which has a crystallinity of 5.2° and characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, crystalline Form VI is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, crystalline Form VI is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, crystalline Form VI is characterized by at least four X-ray diffraction pattern reflections selected from 2θ values ​​of 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3.In some embodiments, crystalline Form VI is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3. In some embodiments, crystalline Form VI is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.3.

[0087] Provided herein is crystalline Form VI of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits the X-ray powder diffraction pattern as shown in FIG.

[0088] [Table 6-1]

[0089] [Table 6-2]

[0090] Provided herein is crystalline Form VI of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in FIG. 14. In some embodiments, the crystalline form exhibits a weight loss of less than 5.3%±0.5 at up to 126° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of less than 4.3%±0.5 at up to 126° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of at least 3.3%±0.5 at up to 126° C.±10.0 as determined by thermogravimetric analysis.

[0091] Provided herein is crystalline Form VI of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, the DSC of which is characterized by endothermic peaks at 112.3° C.±5.0 and 193.7° C.±5.0 as shown in FIG. 14. In some embodiments, the DSC is characterized by an endothermic peak at 193.7° C.±5.0. In some embodiments, the DSC is characterized by an exothermic peak at 151° C.±5.0.

[0092] In some embodiments, compositions are provided herein in which crystalline form VI is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0093] In some embodiments, provided herein is a composition wherein crystalline Form VI is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0094] Crystalline Form VII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Provided herein is crystalline Form VII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

[0095] Provided herein is crystalline Form VII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.4°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 9.8°±0.3 and 23.4°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.0°±0.3 and 15.2°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 10.1°±0.3, 13.6°±0.3, and 26.7°±0.3, hi some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 9.1°±0.3, 25.6°±0.3, and 27.2°±0.3.

[0096] Provided herein is crystalline Form VII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, crystalline Form VII is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, crystalline Form VII is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, crystalline Form VII is characterized by at least four X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3. In some embodiments, crystalline Form VII is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3.In some embodiments, crystalline Form VII is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.3.

[0097] Provided herein is crystalline Form VII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits an X-ray powder diffraction pattern as shown in FIG.

[0098] [Table 7]

[0099] Provided herein is crystalline Form VII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in FIG. 16. In some embodiments, the crystalline form exhibits a weight loss of less than 3.9%±0.5 at up to 119° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of less than 2.9%±0.5 at up to 119° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of at least 1.9%±0.5 at up to 119° C.±10.0 as determined by thermogravimetric analysis.

[0100] Provided herein is crystalline Form VII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, the DSC of which is characterized by endothermic peaks at 120.8° C.±5.0 and 195.1° C.±5.0 as shown in FIG. 16. In some embodiments, the DSC is characterized by an endothermic peak at 195.1° C.±5.0. In some embodiments, the DSC is characterized by an exothermic peak at 163.3° C.±5.0.

[0101] In some embodiments, compositions are provided herein in which crystalline form VII is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0102] In some embodiments, provided herein is a composition wherein crystalline Form VII is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0103] Crystalline Form VIII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Provided herein is crystalline Form VIII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

[0104] Provided herein is crystalline Form VIII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at 2θ values ​​of 5.8°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.2°±0.3 and 15.2°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.0°±0.3 and 10.1°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 8.4°±0.3, 9.8°±0.3, and 23.4°±0.3, hi some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 10.4°±0.3, 14.2°±0.3, and 25.5°±0.3.

[0105] Provided herein is crystalline Form VIII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the crystalline Form VIII is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the crystalline Form VIII is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the crystalline Form VIII is characterized by at least four X-ray diffraction pattern reflections selected from 2-theta values ​​of 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3. In some embodiments, the crystalline Form VIII is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3.In some embodiments, the crystalline Form VIII is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.3.

[0106] Provided herein is crystalline Form VIII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits an X-ray powder diffraction pattern as shown in FIG.

[0107] [Table 8-1]

[0108] [Table 8-2]

[0109] Provided herein is crystalline Form VIII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in FIG. 18. In some embodiments, the crystalline form exhibits a weight loss of less than 7.4%±0.5 at up to 140° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of less than 6.4%±0.5 at up to 140° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of at least 5.4%±0.5 at up to 140° C.±10.0 as determined by thermogravimetric analysis.

[0110] Provided herein is crystalline Form VIII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, the DSC of which is characterized by endothermic peaks at 108.7° C.±5.0 and 195.1° C.±5.0 as shown in FIG. 18. In some embodiments, the DSC is characterized by an endothermic peak at 108.7° C.±5.0 or 195.1° C.±5.0. In some embodiments, the DSC is characterized by an exothermic peak at 169.2.

[0111] In some embodiments, compositions are provided herein in which crystalline form VIII is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0112] In some embodiments, provided herein is a composition wherein crystalline Form VIII is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0113] Crystalline Form IX of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Provided herein is crystalline Form IX of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

[0114] Provided herein is crystalline Form IX of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized in that it exhibits an X-ray powder diffraction reflection at 2θ values ​​of 12.3°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.1°±0.3 and 13.4°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 7.9°±0.3 and 10.5°±0.3. In some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 11.8°±0.3, 25.0°±0.3, and 25.7°±0.3, hi some embodiments, the crystalline form exhibits X-ray powder diffraction reflections at 2θ values ​​of 18.6°±0.3, 23.0°±0.3, and 25.2°±0.3.

[0115] Provided herein is crystalline Form IX of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the crystalline Form IX is characterized by at least two X-ray diffraction pattern reflections selected from 2θ values ​​of 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the crystalline Form IX is characterized by at least three X-ray diffraction pattern reflections selected from 2θ values ​​of 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the crystalline Form IX is characterized by at least four X-ray diffraction pattern reflections selected from 2θ values ​​of 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3. In some embodiments, the crystalline Form IX is characterized by at least five X-ray diffraction pattern reflections selected from 2θ values ​​of 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3.In some embodiments, the crystalline Form IX is characterized by at least six X-ray diffraction pattern reflections selected from 2θ values ​​of 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.3.

[0116] Provided herein is crystalline Form IX of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, which exhibits an X-ray powder diffraction pattern as shown in FIG.

[0117] [Table 9-1]

[0118] [Table 9-2]

[0119] [Table 9-3]

[0120] Provided herein is crystalline Form IX of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, exhibiting a TGA pattern as shown in FIG. 20. In some embodiments, the crystalline form exhibits a weight loss of less than 2.9%±0.5 at up to 245° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of less than 1.9%±0.5 at up to 245° C.±10.0 as determined by thermogravimetric analysis. In some embodiments, the crystalline form exhibits a weight loss of at least 0.9%±0.5 at up to 245° C.±10.0 as determined by thermogravimetric analysis.

[0121] Provided herein is crystalline Form IX of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, characterized by an endothermic peak at 179.3° C.±5.0° C. as shown in FIG. 20 by DSC.

[0122] In some embodiments, compositions are provided in which crystalline Form IX is substantially free of other crystalline or non-crystalline forms. In some embodiments, the amount of other crystalline or non-crystalline forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or non-crystalline forms is 1% (w / w) or less.

[0123] In some embodiments, provided herein is a composition wherein crystalline Form IX is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0124] Amorphous form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) In some embodiments, the present invention provides an amorphous solid state of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, also known as Compound 1. In some embodiments, the amorphous solid state of Compound 1 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG.

[0125] In some embodiments, provided herein are compositions in which the amorphous solid state of Compound 1 is substantially free of crystalline form. In some embodiments, the amount of crystalline form is 20% (w / w) or less. In some embodiments, the amount of crystalline form is 15% (w / w) or less. In some embodiments, the amount of crystalline form is 10% (w / w) or less. In some embodiments, the amount of crystalline form is 5% (w / w) or less. In some embodiments, the amount of crystalline form is 1% (w / w) or less.

[0126] In some embodiments, provided herein are compositions in which the amorphous solid state of Compound 1 is substantially free of impurities. In some embodiments, the amount of impurities is 20% (w / w) or less. In some embodiments, the amount of impurities is 15% (w / w) or less. In some embodiments, the amount of impurities is 10% (w / w) or less. In some embodiments, the amount of impurities is 5% (w / w) or less. In some embodiments, the amount of impurities is 2% (w / w) or less. In some embodiments, the amount of impurities is 1% (w / w) or less. In some embodiments, the amount of impurities is 0.5% (w / w) or less. In some embodiments, the amount of impurities is 0.1% (w / w) or less. In some embodiments, the amount of impurities is 0.01% (w / w) or less.

[0127] Pharmaceutical Compositions In some embodiments, Compound 1 is administered as a pure chemical. In other embodiments, Compound 1 is combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as a pharma- ceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0128] Provided herein are pharmaceutical compositions comprising at least one of Compound 1 together with one or more pharma- ceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition (i.e., the subject or patient).

[0129] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and Compound 1.

[0130] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing Compound 1 and a pharma- ceutically acceptable carrier.

[0131] In certain embodiments, Compound 1 is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, e.g., unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic method.

[0132] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0133] In some embodiments, the formulation comprises Compound 1, a pharma- ceutically acceptable carrier, and a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is croscarmellose sodium.

[0134] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and an amorphous form of Compound 1.

[0135] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form I of Compound 1.

[0136] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form II of Compound 1.

[0137] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form III of Compound 1.

[0138] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form IV of Compound 1.

[0139] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form V of Compound 1.

[0140] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form VI of Compound 1.

[0141] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form VII of Compound 1.

[0142] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form VIII of Compound 1.

[0143] One embodiment provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and crystalline Form IX of Compound 1.

[0144] The dosage of the composition comprising Compound 1 varies depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include general health, age, and other factors.

[0145] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, the appropriate dose and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms). The optimal dose generally depends on the patient's mass, weight, or blood volume.

[0146] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0147] One embodiment provides compound 1 for use in a method of treatment of the human or animal body.

[0148] One embodiment provides compound 1 for use in a method of treatment of cancer or a neoplastic disease.

[0149] One embodiment provides the use of Compound 1 in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0150] In some embodiments, described herein are methods of treating cancer in a patient, comprising administering to the patient Compound 1. In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, comprising administering to the patient a pharmaceutical composition comprising Compound 1 and a pharma- ceutical acceptable excipient.

[0151] In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, the methods comprising administering to the patient an amorphous form of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, the methods comprising administering to the patient a pharmaceutical composition comprising an amorphous form of Compound 1 and a pharma- ceutical acceptable excipient.

[0152] In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, the methods comprising administering to the patient crystalline Form I of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, the methods comprising administering to the patient a pharmaceutical composition comprising crystalline Form I of Compound 1 and a pharma- ceutical acceptable excipient.

[0153] In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, the methods comprising administering to the patient crystalline Form II of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, the methods comprising administering to the patient a pharmaceutical composition comprising crystalline Form II of Compound 1 and a pharma- ceutical acceptable excipient.

[0154] In some embodiments, described herein are methods of treating cancer in a patient in need of such treatment, comprising administering to the patient crystalline Form III of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising crystalline Form III of Compound 1 and a pharma- ceutical acceptable excipient.

[0155] In some embodiments, described herein are methods of treating cancer in a patient in need thereof, the methods comprising administering to the patient crystalline Form IV of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, the methods comprising administering to the patient a pharmaceutical composition comprising crystalline Form IV of Compound 1 and a pharma- ceutical acceptable excipient.

[0156] In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, comprising administering to the patient crystalline Form V of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, comprising administering to the patient a pharmaceutical composition comprising crystalline Form V of Compound 1 and a pharma- ceutical acceptable excipient.

[0157] In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, comprising administering to the patient crystalline Form VI of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising crystalline Form VI of Compound 1 and a pharma- ceutical acceptable excipient.

[0158] In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, comprising administering to the patient crystalline Form VI of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising crystalline Form VI of Compound 1 and a pharma- ceutical acceptable excipient.

[0159] In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, comprising administering to the patient crystalline Form VII of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising crystalline Form VII of Compound 1 and a pharma- ceutical acceptable excipient.

[0160] In some embodiments, described herein are methods of treating cancer in a patient in need thereof, the methods comprising administering to the patient crystalline Form VIII of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, the methods comprising administering to the patient a pharmaceutical composition comprising crystalline Form VIII of Compound 1 and a pharma- ceutical acceptable excipient.

[0161] In some embodiments, described herein are methods of treating cancer in a patient in need of treatment, the methods comprising administering to the patient crystalline Form IX of Compound 1. In some embodiments, described herein are methods of treating cancer in a patient, the methods comprising administering to the patient a pharmaceutical composition comprising crystalline Form IX of Compound 1 and a pharma- ceutical acceptable excipient.

[0162] Methods are provided herein where the pharmaceutical composition is administered orally.Methods are provided herein where the pharmaceutical composition is administered by injection.

[0163] Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way. EXAMPLES

[0164] The present disclosure is further illustrated by the following examples, which should not be construed as limiting in any way. The experimental procedures for generating the data shown are discussed in more detail below. It is to be understood that the present disclosure has been described in an illustrative manner, and that the terms used are intended to be of a descriptive nature, rather than limiting.

[0165] General Experimental, Equipment, and Method Details The general synthesis of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide is described in paragraph PCT / US2020 / 057132.

[0166] X-ray powder diffraction (XRPD) A Bruker D8 Advance X-ray powder diffractometer equipped with a LynxEye detector was used for XRPD analysis. The XRPD parameters used are listed in Table 10.

[0167] [Table 10]

[0168] Differential Scanning Calorimetry (DSC) DSC was performed using a Discovery DSC 250 (TA Instruments, USA). Samples were placed in aluminum pin-hole hermetic pans and the weight was accurately recorded. Samples were heated at a rate of 10°C / min from 25°C to the final temperature. The DSC parameters used are listed in Table 11.

[0169] [Table 11]

[0170] Thermogravimetric analysis (TGA) TGA was performed on a Discovery TGA 55 (TA Instruments, USA). Samples were loaded into open tared aluminum pans, automatically weighed, and inserted into the TGA furnace. Samples were heated from ambient temperature to the final temperature at a rate of 10° C. / min. The TGA parameters used are listed in Table 12.

[0171] [Table 12]

[0172] Dynamic Vapor Sorption (DVS) Moisture absorption / desorption data was collected on a DVS Intrinsic PLUS (SMS, UK). Samples were loaded into a Tared sample chamber and automatically weighed. Samples were dried at 40° C. / 0% RH until dm / dt was less than 0.002% and cooled to 25° C. The DVS parameters used are listed in Table 13.

[0173] [Table 13]

[0174] Polarized Light Microscopy (PLM) Optical microscopy was performed using a polarizing microscope ECLIPSE LV100POL (Nikon, Japan). A small amount of sample was placed on a glass slide with or without immersion oil, and the glass slip was placed on top. The sample was observed under the microscope.

[0175] Proton Nuclear Magnetic Resonance (1H-NMR) On a Bruker 400 MHz instrument 1H-NMR spectra were collected. Samples were prepared in DMSO-d6 solvent unless otherwise stated. Data were analyzed using MestReNova.

[0176] High performance liquid chromatography (HPLC) method HPLC analysis was performed using an Agilent HPLC 1260 series instrument. The HPLC methods for solubility and stability tests are listed in Table 14.

[0177] [Table 14]

[0178] Example 1: Synthesis of Crystalline Form I of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Form I was initially identified from a slurry experiment in water at 50°C, and then obtained from drop-solvent grinding in water and anti-solvent precipitation in aqueous systems including MeOH / water, EtOH / water, acetone / water, ACN / water, and THF / water. A weight loss of 3.87% due to water was observed by TGA, and an endothermic peak from room temperature to 76°C due to dehydration was observed by DSC. The theoretical water content in 1 mol of water is 3.3%, suggesting that Form I is a monohydrate. DSC further showed two melting peaks at 104°C and 194°C after dehydration, corresponding to the melting of Form V and Form II, respectively.

[0179] Example 2: Synthesis of Crystalline Form II of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Form II was obtained from slurry experiments in a number of solvents, including MEK and IPAC at room temperature, and MTBE, MEK, toluene, IPA, EA at 50° C. Additionally, Form II was prepared by anti-solvent precipitation in THF / n-heptane or acetone / MTBE and slow-cooling crystallization form EA. No weight loss was observed by TGA, and DSC showed an endothermic peak at 191° C. due to melting. Thus, Form II is anhydrous. DVS results showed that Form II was slightly hygroscopic with 0.47% water uptake at 90% RH, and the crystal morphology remained unchanged after DVS testing.

[0180] Example 3: Synthesis of Crystalline Form III of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Form III was obtained from a slurry experiment in n-heptane at 50 °C. Form III is anhydrous with a melting point of 155 °C and hygroscopic. A weight loss of about 1.9% from room temperature to 205 °C in two steps was observed by TGA, which was attributed to adsorbed water. DSC showed that the melting peak was immediately followed by a phase transition peak at 161 °C and a melting peak at 191 °C, suggesting that Form III converts to Form II during heating.

[0181] Example 4: Synthesis of Crystalline Form IV of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Form IV was obtained from a 3-day slurry experiment in water at room temperature. A two-step weight loss of 1.8% from room temperature to 94°C and a broad endothermic peak from 41°C to 66°C due to dehydration were observed by TGA and DSC, respectively. The theoretical water content for 0.5 mol was 1.65%, suggesting that Form IV was a hemihydrate. Based on the DSC data, Form IV could be converted to Form V after dehydration and then to Form II during heating.

[0182] Example 5: Synthesis of Crystalline Form V of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Form V can be obtained by dehydrating Form I. Form V is anhydrous with a melting point of 102° C. and hygroscopicity. A weight loss of about 1% was observed in TGA at room temperature to 100° C. due to loss of adsorbed water.

[0183] Example 6: Synthesis of Crystalline Form VI of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) A slurry study in toluene at room temperature produced Form VI. Based on TGA, DSC, and 1H NMR data, Form VI is a toluene solvate (3.5% toluene by NMR). After desolvation, Form VI converts to Form II during heating by DSC.

[0184] Example 7: Synthesis of Crystalline Form VII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Form VII was identified from a slurry study in IPA at room temperature. Form VII is an IPA solvate with a weight loss of 2.9% at room temperature to 140°C in TGA due to 2.8% IPA in NMR. The theoretical IPA content in 1 mol IPA was 10.3%. After desolvation, Form VII is converted to Form II during heating.

[0185] Example 8: Synthesis of Crystalline Form VIII of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Form VIII was obtained from IPA by rapid crystallization. Similar to Form VII, Form VIII may also be a solvate of IPA with a weight loss of 6.3% from room temperature to 140°C in two steps in TGA, mainly due to a loss of 5% IPA in NMR. The theoretical IPA content of 1 mol of IPA is 10.3%, suggesting that Form VIII is a hemi-IPA solvate. After desolvation, Form VIII also converts to Form II during heating.

[0186] Example 9: Synthesis of Crystalline Form IX of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Form IX was precipitated from EA at 60° C. TGA showed a two-step weight loss of 1.8% from room temperature to 245° C., attributed to adsorbed water and residual solvent, respectively, based on 1H-NMR data. DSC showed a sharp endothermic peak at 176° C. upon melting, suggesting that Form IX is anhydrous with residual solvent released during melting.

[0187] Example 10: Synthesis of amorphous form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) Slow evaporation in ACN, acetone, methanol, MEK, ethanol, ethyl acetate, and isopropyl alcohol produced amorphous compound 1.

[0188] Example 10: Characterization and comparison of solid forms of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 1) A summary of the characterization data for the identified solid state forms of Compound 1 is shown below in Table 15. Figure 21 shows the conversion map of the solid state forms of Compound 1.

[0189] [Table 15]

[0190] Solubility Test The preliminary solubility of Compound 1 (Form V) was estimated in 14 selected solvents at room temperature using the solvent addition method by visual evaluation of the samples. The results are summarized in Table 16. Compound 1 showed relatively high solubility in MeOH, THF, acetone, MEK, and ACN (>20 mg / mL), while being virtually insoluble (<1 mg / mL) in non-polar solvents and water.

[0191] [Table 16]

[0192] Slurry Test Slurry studies were carried out using Form V as starting material in a number of solvents at room temperature for 3 days and at 50° C. for 1 day. The results are summarized in Table 17. Form II was obtained from the majority of the solvents. Form I and Form III were obtained from water and heptane at 50° C., respectively. Form IV, Form VI, and Form VII were obtained from toluene and IPA at room temperature, respectively.

[0193] [Table 17]

[0194] Interconversion test Competitive slurries of Forms I, II, and V were performed in IPAC at room temperature and at 50°C. The results showed that each mixture converted completely to Form II after 3 days. Competitive slurries of Forms III and II were performed in IPA and IPAC at room temperature and at 50°C, respectively, and all mixtures converted to Form II after 1 day. Additionally, competitive slurries of Forms II and IX were performed in IPA and IPAC at room temperature and at 50°C. The results showed that the mixtures converted completely to Form II in IPA at 50°C after 1 day. In IPA at room temperature, and in IPA and EA at room temperature and at 50°C, all mixtures tended to convert to Form II. Form II was found to be the most stable form in non-aqueous solvents.

[0195] Water Activity Test Furthermore, water activity studies of Forms I, II, and V were performed in IPA / water with different water contents at room temperature and 50° C. The results showed that Form II was physically stable at room temperature with aw≦0.35 and aw≦0.55 at 50° C., while Form I was more stable than Form II with aw≧0.75 at 50° C. and aw≧0.55 at room temperature. Form II was found to be the more stable form in non-aqueous solvents and was also found to be physically stable at room temperature with aw≦0.35 and aw≦0.55 at 50° C.

[0196] Stability testing The solid state stability of Form II was evaluated at 60°C for 7 days, 40°C / 75% RH for 6 days, and room temperature / 92.5% RH for 2 days, respectively. Form II was physically and chemically stable at 40°C / 75% RH for 6 days. The purity of compound 1 decreased by about 0.3% at 60°C for 3 and 7 days, mainly due to the increase of impurities at RRTs of 0.9, 0.91, and 1.07. Form II was physically stable for 2 days in high humidity conditions.

[0197] Drug product formulation and manufacturing process The drug product formulation provides immediate release of Compound 1 over a period of approximately 1 hour. When the tablet is exposed to water and begins to disintegrate, the drug substance is rapidly released from the tablet core. The tablet is intended to dissolve completely in the stomach, where solubility is highest. To allow for rapid dissolution, a superdisintegrant, such as croscarmellose sodium, is added to the formulation. Other components of the formulation include microcrystalline cellulose, fillers such as mannitol, glidants such as silicon dioxide, and lubricants such as magnesium stearate. The tablet is film coated using a non-functional coating containing polymers such as polyvinyl alcohol, plasticizers such as PEG, titanium dioxide, and other color pigments as needed.

[0198] Figure 22 shows the manufacturing process used for the exemplary drug product. To improve the blend flow in the tablet press and the weight uniformity of the tablet core formulation, dry granulation was selected for tablet manufacturing. The tablet manufacturing process includes first blending Compound 1, microcrystalline cellulose, mannitol, and croscarmellose sodium in a blender. The mixed material is passed through a Comil to break up any agglomerates, after which magnesium stearate is added and further mixed. The lubricated blend is dry granulated by a process such as roller compaction to increase the density of the material, followed by milling. Croscarmellose sodium, silicon dioxide, and magnesium stearate are added to the granulated milled material. This mixture of granules and extra-granular excipients is blended to prepare the final composition for tableting. The tablet core is compressed using a rotary tablet press. After compression, the tablet core is coated using an aqueous film coating system in a pan coater.

[0199] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in carrying out the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents are covered thereby.

Claims

1. Compound 1 below 【Chemistry 1】 A solid form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, represented as

2. A solid form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide in crystalline form.

3. 3. The solid form of claim 2, exhibiting an X-ray powder diffraction reflection at a 2θ value of 11.8°±0.

3. (i) exhibiting X-ray powder diffraction reflections at 2θ values ​​of 7.9°±0.3 and 13.7°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 9.5°±0.3, 18.9°±0.3, and 26.8°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 15.9°±0.3, 20.5°±0.3, and 22.3°±0.3; or (iv) The solid form of claim 3, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 20.8°±0.3, 25.7°±0.3, and 26.3°±0.

3.

5. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 7.9°±0.3, 9.5°±0.3, 11.8°±0.3, 13.7°±0.3, 15.9°±0.3, 18.9°±0.3, 20.5°±0.3, 20.8°±0.3, 22.3°±0.3, 25.7°±0.3, and 26.3°±0.

3.

6. (i) exhibiting a differential scanning calorimetry thermogram including an endothermic peak at 193.1°C ± 5.0°C; or (ii) The solid form of any one of claims 3 to 5, exhibiting a weight loss of less than 1.1%±0.5 up to 200°C±10.0 as determined by thermogravimetric analysis.

7. The solid form of claim 2, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 5.0°±0.

3. (i) exhibiting X-ray powder diffraction reflections at 2θ values ​​of 10.1°±0.3 and 17.1°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 8.5°±0.3, 24.8°±0.3, and 25.8°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 9.3°±0.3, 13.0°±0.3, and 16.4°±0.3; or (iv) The solid form of claim 7, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 12.1°±0.3 and 15.2°±0.

3.

9. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 5.0°±0.3, 8.5°±0.3, 9.3°±0.3, 10.1°±0.3, 12.1°±0.3, 13.0°±0.3, 15.2°±0.3, 16.4°±0.3, 17.1°±0.3, 24.8°±0.3, and 25.8°±0.

3. (i) exhibiting a differential scanning calorimetry thermogram containing endothermic peaks at 53.5°C ± 10.0, 106.5°C ± 5.0, and 193.7°C ± 5.0; or (ii) The solid form of any one of claims 7 to 9, which exhibits a weight loss of less than 4.9%±0.5 at up to 76°C±10.0 as determined by thermogravimetric analysis.

11. The solid form of claim 2, exhibiting an X-ray powder diffraction reflection at a 2θ value of 8.7°±0.

3. (i) exhibiting X-ray powder diffraction reflections at 2θ values ​​of 5.0°±0.3 and 12.8°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 23.9°±0.3 and 24.3°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 11.5°±0.3, 20.3°±0.3, and 21.2°±0.3; or (iv) The solid form of claim 11, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 11.6°±0.3, 15.9°±0.3, and 25.8°±0.

3.

13. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 5.0°±0.3, 8.7°±0.3, 11.5°±0.3, 11.6°±0.3, 12.8°±0.3, 15.8°±0.3, 20.3°±0.3, 21.2°±0.3, 23.9°±0.3, 24.3°±0.3, and 25.8°±0.

3. (i) exhibiting a differential scanning calorimetry thermogram containing endothermic peaks at 164.0°C ± 5.0°C and 190.6°C ± 5.0°C; or (ii) The solid form of any one of claims 11 to 13, exhibiting a weight loss of less than 2.9%±0.5 at up to 205°C±10.0 as determined by thermogravimetric analysis.

15. The solid form of claim 2, exhibiting an X-ray powder diffraction reflection at a 2θ value of 5.1°±0.

3. (i) exhibiting X-ray powder diffraction reflections at 2θ values ​​of 10.2°±0.3 and 8.6°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 12.2°±0.3 and 17.3°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.4°±0.3, 13.4°±0.3, and 15.3°±0.3; or (iv) The solid form of claim 15, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 15.8°±0.3 and 26.0°±0.

3.

17. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 5.1°±0.3, 6.4°±0.3, 8.6°±0.3, 10.2°±0.3, 12.2°±0.3, 13.4°±0.3, 15.3°±0.3, 15.8°±0.3, 17.3°±0.3, and 26.0°±0.

3. (i) exhibiting a differential scanning calorimetry thermogram containing endothermic peaks at 66.2°C ± 5.0, 106.4°C ± 5.0, and 193.6°C ± 5.0; or (ii) The solid form of any one of claims 15 to 17, exhibiting a weight loss of less than 2.9%±0.5 at up to 94°C±10.0 as determined by thermogravimetric analysis.

19. The solid form of claim 2, exhibiting an X-ray powder diffraction reflection at a 2θ value of 5.1°±0.

3. (i) exhibiting an X-ray powder diffraction reflection at a 2θ value of 10.4°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.4°±0.3 and 25.6°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 8.7°±0.3, 11.9°±0.3, and 15.6°±0.3; or (iv) The solid form of claim 19, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 13.5°±0.3 and 25.8°±0.

3.

21. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 5.1°±0.3, 6.4°±0.3, 8.7°±0.3, 10.4°±0.3, 11.9°±0.3, 13.5°±0.3, 15.6°±0.3, 25.8°±0.3, and 25.6°±0.

3. (i) exhibiting a differential scanning calorimetry thermogram including an endothermic peak at 105.8°C ± 5.0°C; or (ii) The solid form of any one of claims 19 to 20, exhibiting a weight loss of less than 2.1% ± 0.5 at up to 101°C ± 10.0 as determined by thermogravimetric analysis.

23. The solid form of claim 2, exhibiting an X-ray powder diffraction reflection at a 2θ value of 9.5°±0.

3. (i) exhibiting X-ray powder diffraction reflections at 2θ values ​​of 5.2°±0.3 and 23.7°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.7°±0.3, 10.2°±0.3, and 19.5°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.5°±0.3, 15.5°±0.3, and 26.8°±0.3; or (iv) The solid form of claim 23, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 7.4°±0.3, 15.0°±0.3, 19.0°±0.3, and 24.7°±0.

3.

25. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 5.2°±0.3, 5.7°±0.3, 6.5°±0.3, 7.4°±0.3, 9.5°±0.3, 10.2°±0.3, 15.0°±0.3, 15.5°±0.3, 19.0°±0.3, 19.5°±0.3, 23.7°±0.3, 24.7°±0.3, and 26.8°±0.

3. (i) exhibiting a differential scanning calorimetry thermogram containing endothermic peaks at 112.3°C ± 5.0°C and 193.7°C ± 5.0°C; or (ii) The solid form of any one of claims 23 to 25, exhibiting a weight loss of less than 4.3%±0.5 at up to 126°C±10.0 as determined by thermogravimetric analysis.

27. The solid form of claim 2, exhibiting an X-ray powder diffraction reflection at a 2θ value of 5.4°±0.

3. (i) exhibiting X-ray powder diffraction reflections at 2θ values ​​of 9.8°±0.3 and 23.4°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.0°±0.3 and 15.2°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 10.1°±0.3, 13.6°±0.3, and 26.7°±0.3; or (iv) The solid form of claim 27, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 9.1°±0.3, 25.6°±0.3, and 27.2°±0.

3.

29. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 5.0°±0.3, 5.4°±0.3, 9.1°±0.3, 9.8°±0.3, 10.1°±0.3, 13.6°±0.3, 15.2°±0.3, 23.4°±0.3, 25.6°±0.3, 26.7°±0.3, and 27.2°±0.

3. (i) exhibiting a differential scanning calorimetry thermogram containing endothermic peaks at 120.8°C ± 5.0°C and 195.1°C ± 5.0°C; or (ii) The solid form of any one of claims 27 to 29, exhibiting a weight loss of less than 3.9%±0.5 at up to 119°C±10.0 as determined by thermogravimetric analysis.

31. The solid form of claim 2, exhibiting an X-ray powder diffraction reflection at a 2θ value of 5.8°±0.

3. (i) exhibiting X-ray powder diffraction reflections at 2θ values ​​of 5.2°±0.3 and 15.2°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 5.0°±0.3 and 10.1°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 8.4°±0.3, 9.8°±0.3, and 23.4°±0.3; or (iv) The solid form of claim 31, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 10.4°±0.3, 14.2°±0.3, and 25.5°±0.

3.

33. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 5.0°±0.3, 5.2°±0.3, 5.8°±0.3, 8.4°±0.3, 9.8°±0.3, 10.1°±0.3, 10.4°±0.3, 14.2°±0.3, 15.2°±0.3, 23.4°±0.3, and 25.5°±0.

3. (i) exhibiting a differential scanning calorimetry thermogram including endothermic peaks at 108.7°C ± 5.0°C and 195.1°C ± 5.0°C; or (ii) The solid form of any one of claims 31 to 33, which exhibits a weight loss of less than 7.4%±0.5 at up to 140°C±10.0 as determined by thermogravimetric analysis.

35. The solid form of claim 2, exhibiting an X-ray powder diffraction reflection at a 2θ value of 12.3°±0.

3. (i) exhibiting X-ray powder diffraction reflections at 2θ values ​​of 6.1°±0.3 and 13.4°±0.3; or (ii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 7.9°±0.3 and 10.5°±0.3; or (iii) exhibits X-ray powder diffraction reflections at 2θ values ​​of 11.8°±0.3, 25.0°±0.3, and 25.7°±0.3; or (iv) The solid form of claim 35, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 18.6°±0.3, 23.0°±0.3, and 25.2°±0.

3.

37. The solid form of claim 2, exhibiting at least one X-ray powder diffraction reflection selected from 6.1°±0.3, 7.9°±0.3, 10.5°±0.3, 11.8°±0.3, 12.3°±0.3, 13.4°±0.3, 18.6°±0.3, 23.0°±0.3, 25.0°±0.3, 25.2°±0.3, and 25.7°±0.

3. (i) exhibiting a differential scanning calorimetry thermogram including an endothermic peak at 179.3°C ± 5.0°C; or (ii) The solid form of any one of claims 35 to 37, which exhibits a weight loss of less than 2.9%±0.5 at up to 245°C±10.0 as determined by thermogravimetric analysis.

39. The solid form of claim 1, which is amorphous.

40. The solid form of claim 39, which exhibits an X-ray powder diffraction pattern as shown in FIG.

1.

41. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 5, 7 to 9, 11 to 13, 15 to 17, 19 to 21, 23 to 25, 27 to 29, 31 to 33, 35 to 37, and 39 to 40, and a pharmaceutically acceptable excipient.

42. A pharmaceutical composition comprising the crystalline form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide described in any one of claims 3 to 5, and a pharmaceutically acceptable excipient.

43. A pharmaceutical composition comprising the crystalline form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide described in any one of claims 7 to 9, and a pharmaceutically acceptable excipient.

44. The pharmaceutical composition of claim 42, further comprising a disintegrant.

45. The pharmaceutical composition of claim 43, further comprising a disintegrant.

46. ​​A pharmaceutical composition comprising the solid form of claim 1 and at least one pharmaceutically acceptable excipient for use in a method for treating cancer in a patient in need thereof, said method comprising administering said pharmaceutical composition to said patient.

47. A pharmaceutical composition comprising the solid form of claim 1 for use in a method for treating cancer in a patient in need thereof, said method comprising administering said solid form to said patient.

48. A pharmaceutical composition comprising the solid form of claim 42 for use in a method for treating cancer in a patient in need thereof, the method comprising administering the pharmaceutical composition to the patient.

49. A pharmaceutical composition comprising the solid form of claim 43 for use in a method for treating cancer in a patient in need thereof, the method comprising administering the pharmaceutical composition to the patient.

50. A pharmaceutical composition comprising a crystalline form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide as defined in claim 3 for use in a method of treating cancer in a patient in need thereof, said method comprising the step of administering to said patient said crystalline form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

51. A pharmaceutical composition comprising a crystalline form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide according to claim 23 for use in a method of treating cancer in a patient in need thereof, said method comprising the step of administering to said patient said crystalline form of 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

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