CN-122029161-A - Crystalline forms of PI3K inhibitors and uses thereof

Abstract

Disclosed herein are crystalline forms of phosphatidylinositol 4, 5-bisphosphate 3-kinase (PI 3K) isoform alpha (PI 3K alpha) inhibitors, as well as formulations and uses thereof.

Inventors

• D. Little Saint Jean
• Altak, J.T.
• A.D. JONES
• M.P.Zhao
• BRADLEY WILLIAM DANIEL
• STEWART DUNCAN
• L Buckbinder
• E. Jackson
• Jiao Zhuangyue
• RUDD BRIAN

Assignees

• 蝎子疗法股份有限公司

Dates

Publication Date

20260512

Application Date

20240814

Priority Date

20230815

Claims (20)

1. 1. A crystalline form of (R) -1- (2-aminopyrimidin-5-yl) -3- (1- (5, 7-difluoro-3-methylbenzofuran-2-yl) -2, 2-trifluoroethyl) urea or a pharmaceutically acceptable salt and/or solvate thereof.
2. 2. The crystalline form of claim 1, wherein the (R) -1- (2-aminopyrimidin-5-yl) -3- (1- (5, 7-difluoro-3-methylbenzofuran-2-yl) -2, 2-trifluoroethyl) urea is present in the form of a pharmaceutically acceptable solvate.
3. 3. The crystalline form of any one of claims 1-2, wherein the crystalline form is form 1, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 18.3 ± 0.2 degrees 2Θ.
4. 4. The crystalline form of claim 3, wherein the XRPD pattern has peaks at 15.8 ± 0.2 degrees 2Θ.
5. 5. The crystalline form of any one of claims 3-4, wherein the XRPD pattern has peaks at 6.4 ± 0.2 degrees 2Θ.
6. 6. The crystalline form of any one of claims 3-5, wherein the XRPD pattern has peaks at 22.3 ± 0.2 degrees 2Θ.
7. 7. The crystalline form of any one of claims 3-6, wherein the XRPD pattern has peaks at 20.8 ± 0.2 degrees 2Θ.
8. 8. The crystalline form of any one of claims 3-7, wherein the XRPD pattern has peaks at 19.3 ± 0.2 degrees 2Θ.
9. 9. The crystalline form of any one of claims 3-8, wherein the XRPD pattern has peaks at 24.0 ± 0.2 degrees 2Θ.
10. 10. The crystalline form of any one of claims 3-9, wherein the XRPD pattern has peaks at 26.9 ± 0.2 degrees 2Θ.
11. 11. The crystalline form of any one of claims 3-10, wherein the XRPD pattern has peaks at 14.6 ± 0.2 degrees 2Θ.
12. 12. The crystalline form of any one of claims 3-11, wherein the XRPD pattern has peaks at 31.3 ± 0.2 degrees 2Θ.
13. 13. The crystalline form of any one of claims 3-12, wherein the XRPD pattern has peaks at 28.3 ± 0.2 degrees 2Θ.
14. 14. The crystalline form of any one of claims 1-2, wherein the crystalline form is form 1, and wherein the XRPD pattern has peaks (±0.2 degrees 2Θ) at 6.4, 15.8, and 18.3.
15. 15. The crystalline form of any one of claims 1-2, wherein the crystalline form is form 1, and wherein the XRPD pattern has peaks (±0.2 degrees 2Θ) at 6.4, 14.6, 15.8, 18.3, 19.3, 20.8, 22.3, 24.0, 26.9, 28.3, 29.2, and 31.3.
16. 16. The crystalline form of any one of claims 1-2, wherein the crystalline form is form 1, characterized by an XRPD pattern substantially the same as the pattern shown in figure 4.
17. 17. The crystalline form of any one of claims 1-16, wherein the crystalline form is form 1, which is characterized by a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 112.5 ℃.
18. 18. The crystalline form of any one of claims 1-17, wherein the crystalline form is form 1, which TGA profile is characterized by a weight loss of about 17.6% at about 245 ℃.
19. 19. The crystalline form of any one of claims 1-18, wherein the crystalline form is form 1 having a TGA profile substantially the same as the TGA profile shown in figure 28.
20. 20. The crystalline form of any one of claims 1-19, wherein the crystalline form is form 1, prepared by a process comprising: (a) Dissolving (R) -1- (2-aminopyrimidin-5-yl) -3- (1- (5, 7-difluoro-3-methylbenzofuran-2-yl) -2, 2-trifluoroethyl) urea or a pharmaceutically acceptable salt and/or solvate thereof in isopropanol to form a solution; (b) Adding water to the solution to form a mixture; (c) Reducing the temperature of the mixture and then maintaining the temperature for a first period of time; (d) Increasing the temperature of the mixture and then maintaining the temperature for a second period of time; (e) Lowering the temperature of the mixture and then maintaining the temperature for a third period of time, and (F) Form 1 is isolated from the mixture.

Description

Crystalline forms of PI3K inhibitors and uses thereof Cross Reference to Related Applications The present application claims the benefit of priority from U.S. provisional application No. 63/532,700, filed on 8/15 of 2023, which is incorporated herein by reference in its entirety, including any figures. Sequence listing The present application contains a sequence table that has been electronically submitted as an XML file named "50006-0100WO1_ST26_SL.XML". The size of the XML file created at month 8 and 12 of 2024 is 2,961 bytes. The material in the XML file is incorporated herein by reference in its entirety. Technical Field Disclosed herein are crystalline forms of phosphatidylinositol 4, 5-bisphosphate 3-kinase (PI 3K) isoform alpha (PI 3K alpha) inhibitors. Background 1- (2-Aminopyrimidin-5-yl) -3- (1- (5, 7-difluoro-3-methylbenzofuran-2-yl) -2, 2-trifluoroethyl) urea is a phosphatidylinositol 4, 5-bisphosphate 3-kinase (PI 3K) isoform alpha (PI 3K alpha) inhibitor disclosed in WO 2022/265993, which is incorporated herein by reference in its entirety. PIK 3kα encoded by the PIK3CA gene is part of the PI3K/AKT/TOR signaling network and is altered in several human cancers. Several researchers have demonstrated that the effects of PI3K/AKT signaling are involved in physiological and pathophysiological functions that drive tumor progression such as metabolism, cell growth, proliferation, angiogenesis, and metastasis. (see Fruman, d.a. Cell 2017, 170, 605-635 and Janku, f. Et al, nat. Rev. Clin. Oncol. 2018, 15, 273-291.). Inhibition (e.g., pharmacological or genetic) of PI3K/AKT/TOR signaling may lead to cancer cell death and regression of tumor growth. Polymorphism, the appearance of different crystalline forms, is a property of some molecules and molecular complexes. A given compound may produce a variety of polymorphs having different crystal structures and physical properties such as melting point, thermal behavior, X-ray diffraction patterns, IR spectra, and solid-state 13 C NMR spectra. One or more of these techniques may be used to distinguish between different polymorphic forms of a compound. Different salts and crystalline forms (including solvated forms) of the active pharmaceutical ingredient may have different properties. Such changes in the nature of the different salts and crystalline forms and solvates may provide a basis for improving formulation and/or clinical properties. Different salts and solvates of the active pharmaceutical ingredient may also produce multiple polymorphs or crystalline forms. Disclosure of Invention Some embodiments provide crystalline forms of (R) -1- (2-aminopyrimidin-5-yl) -3- (1- (5, 7-difluoro-3-methylbenzofuran-2-yl) -2, 2-trifluoroethyl) urea, or pharmaceutically acceptable salts and/or solvates thereof. Some embodiments provide a pharmaceutical composition comprising a crystalline form disclosed herein and a pharmaceutically acceptable carrier. Some embodiments provide a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline form disclosed herein, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising the crystalline form disclosed herein and a pharmaceutically acceptable carrier. Some embodiments provide methods of treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with deregulation of the expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any one thereof, and (b) administering to the subject a therapeutically effective amount of a crystalline form disclosed herein or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising the crystalline form disclosed herein and a pharmaceutically acceptable carrier. Some embodiments provide a method of treating a pi3kα -associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a pi3kα -associated cancer a therapeutically effective amount of a crystalline form disclosed herein, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising the crystalline form disclosed herein and a pharmaceutically acceptable carrier. Some embodiments provide a method of modulating pi3kα in a mammalian cell comprising contacting the mammalian cell with an effective amount of a crystalline form disclosed herein or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising the crystalline form disclosed herein and a pharmaceutically acceptable carrier. Additional definition To facilitate an understanding of the disclosure described herein, some additional terms are defined below. Generally, the terms used herein and laboratory procedures in organic chemistry, pharmaceutical chemistry and pharmacology described herein ar