NZ787662B2 - Crystalline solid forms of a bet inhibitor - Google Patents

Abstract

The present application relates to crystalline solid forms of compound 1, which is an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t, including methods of preparation thereof, and intermediates in the preparation thereof, where the compound is useful in the treatment of diseases such as cancer.

Claims (29)

The claims defining the ion are as follows:

1. A solid form of a compound having the formula: Compound 1 wherein the solid form is crystalline; and wherein the solid form is selected from: Form Ia, having a teristic XRPD peak, in terms of 2-theta (± 0.2°), of 12.8 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.8, 10.0, 11. , 13.5, 20.0, 21.5, 22.6, and 23.3 degrees; Form III, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 17.5 degrees and two or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 7.8, 12.4, 13.1, 15.2, 15.5, 16.9, and 20.3 degrees; Form IV, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 22.1 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), ed from 11.2, 16.3, and 18.7 degrees; Form V, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 19.8 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), ed from 8.2, 8.5, 14.1, 16.3, 17.1, 18.9, 21.8, and 22.7 degrees; Form Va, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 8.7 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 16.5, 17.3, 19.9, and 21.6 degrees; Form VI, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 20.7 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.5, 9.6, 11.4, 12.1, 13.5, 14.5, 15.2, 17.1, 17.7, 18.1, and 19.2 degrees; Form VII, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 18.8 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 9.9, 12.2, 14.8, 15.7, 17.0, and 17.5 degrees; Form VIII, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 8.1 s and two or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.5, 16.2, 16.6, 17.0, 17.5, 18.0, 18.9, 19.6, and 20.1 degrees; Form IX, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 23.9 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.6, 9.1, 11.4, 13.4, 15.2, 18.2, 22.1, and 22.8 degrees; Form X, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 17.0 degrees and two or more characteristic XRPD peaks, in terms of a (± 0.2°), selected from 14.9, 15.3, 15.8, 17.7, 18.3, and 19.7 degrees; Form XI, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 23.3 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.9, 12.8, 18.0 21.5, and 22.6 s; Form XII, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 44.2 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 5.6, 11.7, 13.8, 14.5, 16.9, 17.7, 18.7, 23.5, 24.6, 34.3, and 44.6 degrees; Form XIII, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 14.8 degrees and two or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 5.7, 8.6, 9.8, 11.8, 12.6, 13.4, 14.1, 16.6, and 19.1 degrees; Form XIV, having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 4.0 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 11.2, 11.9, 14.1, 14.8, and 15.9 degrees; and Form XV having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 15.5 degrees and two or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 7.4, 9.6, 12.4, 13.4, 16.9, 17.7, 19.0, 19.5, 20.6, and 22.5 degrees.

2. The solid form of claim 1, wherein the solid form has Form Ia having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 12.8 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.8, 10.0, 11.7, 13.5, 20.0, 21.5, 22.6, and 23.3 degrees.

3. The solid form of claim 1, wherein the solid form has Form III having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 17.5 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 7.8, 12.4, 13.1, 15.2, 15.5, 16.9, and 20.3 degrees.

4. The solid form of claim 1, wherein the solid form has Form IV having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 22.1 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 11.2, 16.3, and 18.7 degrees.

5. The solid form of claim 1, wherein the solid form has Form V having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 19.8 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.2, 8.5, 14.1, 16.3, 17.1, 18.9, 21.8, and 22.7 degrees.

6. The solid form of claim 1, wherein the solid form has Form Va having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 8.7 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 16.5, 17.3, 19.9, and 21.6

7. The solid form of claim 1, n the solid form has Form VI having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 20.7 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.5, 9.6, 11.4, 12.1, 13.5, 14.5, 15.2, 17.1, 17.7, 18.1, and 19.2 degrees.

8. The solid form of claim 1, wherein the solid form has Form VII having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 18.8 degrees and two or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 9.9, 12.2, 14.8, 15.7, 17.0, and 17.5 degrees.

9. The solid form of claim 1, wherein the solid form has Form VIII having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 8.1 s and two or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.5, 16.2, 16.6, 17.0, 17.5, 18.0, 18.9, 19.6, and 20.1 degrees.

10. The solid form of claim 1, wherein the solid form has Form IX having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 23.9 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.6, 9.1, 11.4, 13.4, 15.2, 18.2, 22.1, and 22.8 degrees.

11. The solid form of claim 1, wherein the solid form has Form X having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 17.0 degrees and two or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), ed from 14.9, 15.3, 15.8, 17.7, 18.3, and 19.7 degrees.

12. The solid form of claim 1, wherein the solid form has Form XI having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 23.3 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.9, 12.8, 18.0 21.5, and 22.6 degrees.

13. The solid form of claim 1, wherein the solid form has Form XII having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 44.2 degrees and two or more characteristic XRPD peaks, in terms of a (± 0.2°), selected from 5.6, 11.7, 13.8, 14.5, 16.9, 17.7, 18.7, 23.5, 24.6, 34.3, and 44.6 degrees.

14. The solid form of claim 1, wherein the solid form has Form XIII having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 14.8 s and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 5.7, 8.6, 9.8, 11.8, 12.6, 13.4, 14.1, 16.6, and 19.1 degrees.

15. The solid form of claim 1, wherein the solid form has Form XIV having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 4.0 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 11.2, 11.9, 14.1, 14.8, and 15.9 degrees.

16. The solid form of claim 1, wherein the solid form has Form XV having a characteristic XRPD peak, in terms of 2-theta (± 0.2°), of 15.5 degrees and two or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), ed from 7.4, 9.6, 12.4, 13.4, 16.9, 17.7, 19.0, 19.5, 20.6, and 22.5 degrees.

17. A pharmaceutical ition comprising a solid form of any one of claims 1 to 16 and at least one pharmaceutically acceptable r.

18. Use of a solid form of any one of claims 1 to 16, or a ceutical composition of claim 17 for the manufacture of a medicament for the inhibition of a BET protein through t with said solid form or said pharmaceutical composition.

19. Use of a therapeutically effective amount of a solid form of any one of claims 1 to 16 or a pharmaceutical composition of claim 17 for the manufacture of a medicament for the treatment of a disease or condition that is associated with a BET protein.

20. Use of a therapeutically effective amount of a solid form of any one of claims 1 to 16 or a pharmaceutical composition of claim 17 for the manufacture of a medicament for the treatment of a proliferative disorder that is associated with a BET protein.

21. The use of claim 20, wherein the erative disorder is cancer.

22. The use of claim 21, wherein the cancer is a hematological .

23. The use of claim 21, wherein the cancer is adenocarcinoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical , colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, n's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, elioma, multiple a, AML, DLBCL, ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, atic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, small intestine cancer, stomach cancer, T-cell leukemia, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, ital cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor.

24. The use of claim 21, wherein the cancer is le myeloma, AML, or DLBCL.

25. The use of claim 20, wherein the proliferative disorder is a non-cancerous proliferative disorder.

26. Use of a therapeutically effective amount of a solid form of any one of claims 1 to 16 or a ceutical composition of claim 17 for the manufacture of a medicament for the treatment of an autoimmune or matory disease that is associated with a BET protein.

27. The use of claim 26, wherein the autoimmune or inflammatory disease is selected from allergy, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, degenerative joint disease, dermatitis, organ rejection, eczema, hepatitis, inflammatory bowel disease, multiple sclerosis, myasthenia , psoriasis, , sepsis me, septic shock, systemic lupus erythematosus, tissue graft rejection, and type I diabetes.

28. Use of a therapeutically effective amount of a solid form of any one of claims 1 to 16 or a pharmaceutical composition of claim 17 for the manufacture of a medicament for the treatment of a viral infection that is associated with a BET protein.

29. The use of claim 28, wherein the viral infection is infection with adenovirus, n- Barr virus, tis B virus, hepatitis C virus, a herpes virus, human immunodeficiency virus, human papilloma virus or a pox virus. 264.67°C 0 102.8J/g Heat Flow (W/g) -4 266.39°C -7.071W/g 20 70