Solid forms of a compound for modulating kinases
Forms of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I) were prepared and characterized in the solid state: Also provided are processes of manufacture and methods of using the forms of Compound I.
1. A free acid amorphous form of Compound I:
characterized by an X-ray powder diffractogram as substantially shown in FIG. 18 .
2. A free acid amorphous form of Compound I according to claim 1 characterized by a thermogravimetric analysis (TGA) thermogram showing a weight loss of about 17% up to about 250° C.
3. A free acid amorphous form of Compound I according to claim 1 characterized by a TGA thermogram as substantially shown in FIG. 19 .
4. A free acid amorphous form of Compound I according to claim 1 characterized by a differential scanning calorimetry (DSC) curve that comprises an exotherm with a peak maximum at about 237° C.
5. A free acid amorphous form of Compound I according to claim 1 characterized by a DSC curve as substantially shown in FIG. 20 .
6. A free acid amorphous form of Compound I according to claim 1 molecularly dispersed in a polymer matrix.
7. A free acid amorphous form of Compound I according claim 6 , wherein the polymer matrix comprises hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, polymethylacrylate-based copolymers, or combinations thereof.
8. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, and the free acid amorphous form of Compound I according to claim 1 .
9. A method of treating chronic lymphocytic leukemia (CLL) or Richter's Syndrome in a subject in need thereof comprising administering to the subject an effective amount of the free acid amorphous form of Compound I according to claim 1 , in combination with an effective amount of a Bruton's Tyrosine Kinase (BTK) inhibitor.
10. The method of claim 9 , wherein the BTK inhibitor is ibrutinib.
11. A method of treating chronic lymphocytic leukemia (CLL) in a subject in need thereof comprising administering to the subject an effective amount of the free acid amorphous form of Compound I according to claim 1 , in combination with an effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor.
12. A method of treating uveal melanoma in a subject in need thereof comprising administering to the subject an effective amount of the free acid amorphous form of Compound I according to claim 1 , in combination with an effective amount of a CTLA-4 inhibitor or a checkpoint inhibitor.
13. A method of treating acute myeloid leukemia in a subject in need thereof comprising administering to the subject an effective amount of the free acid amorphous form of Compound I according to claim 1 , in combination with an effective amount of quizartinib.
14. The method of claim 11 , wherein the BCL-2 inhibitor is venetoclax.
15. A method of treating acute myeloid leukemia in a subject in need thereof comprising administering to the subject an effective amount of the free acid amorphous form of Compound I according to claim 1 , in combination with an effective amount of azacitidine.
16. A method of treating myelodysplastic syndromes (MDS) in a subject in need thereof comprising administering to the subject an effective amount of the free acid amorphous form of Compound I according to claim 1 , in combination with an effective amount of azacitidine.
17. A method of treating ovarian cancer in a subject in need thereof comprising administering to the subject in need thereof an effective amount of the free acid amorphous form of Compound I according to claim 1 .
18. A method of treating acute myeloid leukemia (AML) in a subject in need thereof comprising administering to the subject an effective amount of the free acid amorphous form of Compound I according to claim 1 , in combination with an effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor.
19. The method of claim 18 , wherein the BCL-2 inhibitor is venetoclax.