CN-122029169-A - Crystalline forms of BET inhibitors

Abstract

Provided herein are crystalline forms of bromodomain and additional terminal domain (BET) inhibitors, compositions thereof, methods of making and methods of using the same.

Inventors

• R. Traslow
• S. Rocco

Assignees

• 诺维逊生物股份有限公司

Dates

Publication Date

20260512

Application Date

20240823

Priority Date

20230825

Claims (20)

1. 1.A crystalline form of a compound of formula (I): (I), or a solvate or hydrate thereof.
2. 2. The crystalline form of claim 1, wherein the crystalline form is an anhydrous crystalline form.
3. 3. The crystalline form of claim 2, wherein the crystalline form is characterized by having an X-ray powder diffraction (XRPD) pattern as measured by Cu ka radiation comprising peaks at 2Θ values between about 6.1 and about 8.5 degrees.
4. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is characterized by having an XRPD pattern as measured by Cu ka radiation comprising peaks at 2Θ values of about 6.1, about 8.5, about 11.6, about 17.0, and about 23.4 degrees.
5. 5. The crystalline form of any one of claims 2-4, wherein the crystalline form is characterized by having an XRPD pattern as measured by Cu ka radiation comprising peaks at 2Θ values of about 6.1, about 8.5, about 10.0, about 11.6, about 14.2, about 17.0, about 18.3, about 23.4, and about 24.9.
6. 6. The crystalline form of any one of claims 2-5, wherein the crystalline form is characterized by having an XRPD pattern as measured by Cu ka radiation substantially as shown in figure 1A.
7. 7. The crystalline form of any one of claims 2-6, wherein the crystalline form is characterized by having an endothermic peak at about 163.1 ℃ as determined by DSC.
8. 8. The crystalline form of any one of claims 2-6, wherein the crystalline form is characterized by a DSC profile substantially as shown in figure 1B and/or a TGA profile substantially as shown in figure 1B.
9. 9. The crystalline form of any one of claims 2-8, wherein the crystalline form is characterized by a water absorption of about 2.7 wt% at room temperature, about 80% relative humidity, as determined by DVS.
10. 10. The crystalline form of any one of claims 2-9, wherein the crystalline form is characterized by a DVS plot substantially as shown in figure 1C.
11. 11. The crystalline form of claim 1, wherein the crystalline form is a hydrate or isopropyl alcohol (IPA) and water solvate-hydrate.
12. 12. The crystalline form of claim 11, wherein the crystalline form is isopropanol and water solvate-hydrate.
13. 13. The crystalline form of claim 11, wherein the solvate is a hydrate.
14. 14. The crystalline form of any one of claims 11-13, wherein the crystalline form is characterized by having an XRPD pattern as measured by Cu ka radiation comprising peaks at 2Θ values of about 7.4 and about 10.2 degrees.
15. 15. The crystalline form of any one of claims 11-14, wherein the crystalline form is characterized by having an XRPD pattern as measured by Cu ka radiation comprising peaks at 2Θ values of about 7.4, about 9.2, about 10.2, about 18.1, and about 18.5.
16. 16. The crystalline form of any one of claims 11-15, wherein the crystalline form is characterized by having an XRPD pattern (form II) as measured by Cu ka radiation substantially as shown in figure 2A.
17. 17. The crystalline form of any one of claims 13-16, wherein the crystalline form is characterized by having an endothermic peak at about 127.6 ℃ as determined by DSC.
18. 18. The crystalline form of any one of claims 13-17, wherein the crystalline form is characterized by a DSC profile substantially as shown in figure 2B.
19. 19. The crystalline form of any one of claims 13-18, wherein the crystalline form is characterized by exhibiting a weight loss of about 3.94% after heating from room temperature to about 160 ℃ as determined by TGA.
20. 20. The crystalline form of any one of claims 13-19, wherein the crystalline form is characterized by having a TGA profile substantially as shown in figure 2B.

Description

Crystalline forms of BET inhibitors Cross Reference to Related Applications The present application claims priority and benefit from U.S. provisional application No. 63/578,834, filed 8/25 of 2023, the disclosure of which is hereby incorporated by reference in its entirety. Technical Field Provided herein are crystalline forms of bromodomain and additional terminal domain (BET) inhibitors, compositions thereof, methods of making and methods of using the same. Background Epigenetic regulation abnormalities play a critical role in driving aberrant gene expression leading to various types of cancer. Many components involved in the modulation of epigenetic properties have become attractive targets for therapeutic intervention. Among them, the bromodomain and the extra terminal (BET) family of proteins have been of interest in recent years. BET family proteins include BRD2, BRD3, BRD4 and testis-specific BRDT. Via their Bromodomain (BRD), they bind with high affinity to the acetylation motifs (including acetylated histones in chromatin), thereby regulating gene transcription. Genes regulated by BET family proteins include a number of important oncogenes responsible for cell survival and cell cycle progression. BET proteins are emerging targets in cancer, directly regulating the expression of oncogenes in blood tumors and solid tumors. In addition to occupying the gene promoter, BRD4 also has a strong bias for enhancers and super-enhancers in key driving genes (e.g., c-MYC) (Loven et al, cell 2013; 153 (2): 320-34). BET family proteins are also involved in mediating acute inflammatory responses via the classical NF-KB pathway (Huang et al mol. Cell. Biol. 29:1375-1387 (2009)), leading to up-regulation of genes involved in cytokine production (Nicodeme et al Nature 468:1119-1123, (2010)). Furthermore, bromodomain function is associated with kidney disease (Zhang et al J. Biol. Chem. 287: 28840-28851 (2012)). BRD2 function is also associated with inappropriate regulation of the cause of dyslipidemia or adipogenesis, increased inflammatory features and increased susceptibility to autoimmune diseases (Denis, discovery Medicine 10:489-499 (2010)). Human immunodeficiency virus utilizes BRD4 to initiate transcription of viral RNA from stably integrated viral DNA (Jang et al, mol. Cell, 19:523-534 (2005)). BET bromodomain inhibitors have also been shown to reactivate HIV transcription in both latent T cell infection and latent monocyte infection models (Banerjee et al J. Leukocyte biol. Doi: 10.1189/jlb.0312165). BRDT has an important role in spermatogenesis (Matzuk et al, cell 150:673-684 (2012)). It is potentially desirable to develop therapies (including combination therapies) for treating cancer using BET inhibitors, and it is highly desirable to develop therapies for treating chemotherapy-resistant cancers or cancers that may develop chemotherapy resistance. U.S. patent publication No. US 2021/0002293 A1 or PCT publication No. WO 2021/003310 A1, which is hereby incorporated by reference in its entirety, discloses N-ethyl-7- (2- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5-methyl-4-oxo-4, 5-dihydrothieno [3,2-c ] pyridine-2-carboxamide (hereinafter referred to as "compound of formula (I"), (I), It is a BD2 selective BET inhibitor that inhibits BRD4 (BRD 4-BD1 IC 50 = 2922 nM;BRD4-BD2 IC50 =2 nM). Without being bound by theory, BD1 inhibition can disrupt steady state gene expression and cause toxicity. BD2 inhibition can prevent BET proteins from associating with histones and is effective in cancer disease models. BD2 selectivity can block cancer cells' ability to induce drug resistance pathways and increase tolerance by avoiding BD1 inhibition. Crystalline forms of the compounds of formula (I) are disclosed herein. The crystalline forms disclosed herein may provide the advantages of bioavailability and stability, and may be suitable for use as active agents in pharmaceutical compositions. Variations in the crystal structure of a drug substance can affect the dissolution rate of the drug product (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.). Such variations can affect the method of preparation or formulation of pharmaceutical compositions in different dosage forms or delivery forms (e.g., solid oral dosage forms including tablets and capsules). Crystalline forms may provide desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and/or process control as compared to other forms such as amorphous or amorphous forms. Thus, the crystalline forms disclosed herein may provide the advantage of improving the manufacturing process of the active agent or the stability