Search

US-20260125374-A1 - PI3K-ALPHA INHIBITORS AND METHODS OF MAKING AND USING THE SAME

US20260125374A1US 20260125374 A1US20260125374 A1US 20260125374A1US-20260125374-A1

Abstract

The present disclosure relates to PI3Ka inhibitors, the crystalline forms, salts, and cocrystals thereof, and the compositions and methods of making and use thereof.

Inventors

  • André Lescarbeau
  • Wei Gu
  • Min Lu
  • Yunfei Zhou
  • Xijian Gong
  • Jiahui Chen
  • Xiaohong Wang
  • Changbo Yin
  • Alessandro Boezio
  • Surendra P. Singh
  • Qinglin Che
  • Siyi JIANG
  • Hongyan He
  • Qiuxiang Zhou
  • Jiajia ZHOU
  • Yuan Lin

Assignees

  • RELAY THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20221103
Priority Date
20211103

Claims (20)

  1. 1 . A compound in solid form, wherein the compound is compound I-1: or a solvate thereof.
  2. 2 . The compound of claim 1 , wherein the compound is amorphous.
  3. 3 . The compound of claim 1 , wherein the compound is crystalline.
  4. 4 . The compound of claim 1 , wherein the solid form is Form A.
  5. 5 . The compound of claim 1 , wherein the solid form is Form B.
  6. 6 . The compound of claim 1 , wherein the solid form is Form C.
  7. 7 . A compound in solid form, wherein the compound is a compound of Formula (I): or a solvate thereof; wherein: m is 1, 2, 3, 4, 5, 6, 7, 8, or 9; n is 0, 0.5, 1, 1.5, 2, 2.5, or 3; and X is hydrochloric acid, p-toluene sulfonic acid, methane sulfonic acid, naphthalene-1,5-disulfonic acid, or 2-naphthalene sulfonic acid.
  8. 8 . The compound of claim 1 , wherein the compound is Compound I-2: or a solvate thereof.
  9. 9 . The compound of claim 8 , wherein the solid form is Form A.
  10. 10 . The compound of claim 1 , wherein the compound is Compound I-3: or a solvate thereof.
  11. 11 . The compound of claim 10 , wherein the solid form is Form A or Form B.
  12. 12 . The compound of claim 1 , wherein the compound is Compound I-4: or a solvate thereof.
  13. 13 . The compound of claim 12 , wherein the solid form is Form A.
  14. 14 . The compound of claim 1 , wherein the compound is Compound I-5: or a solvate thereof.
  15. 15 . The compound of claim 14 , wherein the solid form is Form A or Form B.
  16. 16 . A compound in solid form, wherein the compound is of Formula (II) or a solvate thereof, wherein: p is 1, 2, 3, 4, 5, 6, 7, 8, or 9; q is 0, 0.5, 1, 1.5, 2, 2.5, or 3; and X is hydrochloric acid, p-toluene sulfonic acid, methane sulfonic acid, naphthalene-1,5-disulfonic acid, or 2-naphthalene sulfonic acid.
  17. 17 . The compound of claim 16 , wherein the compound is amorphous.
  18. 18 . The compound of claim 16 , wherein the compound is crystalline.
  19. 19 . The compound of claim 16 , wherein the compound is compound II-1: or a solvate thereof.
  20. 20 . The compound of claim 19 , wherein the solid form is Form A, Form B, or Form C.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/263,474, filed Nov. 3, 2021, and International (PCT) Patent Application No. PCT/CN2021/128533, filed Nov. 3, 2021; the entirety of each of which is hereby incorporated by reference. BACKGROUND Phosphatidylinositol 3-kinases (PI3Ks) comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3′ position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3), which, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001)). Of the two Class 1 PI3K sub-classes, Class 1A PI3Ks are heterodimers composed of a catalytic p110 subunit (alpha, beta, or delta isoforms) constitutively associated with a regulatory subunit that can be p85 alpha, p55 alpha, p50 alpha, p85 beta, or p55 gamma. The Class 1B sub-class has one family member, a heterodimer composed of a catalytic p110 gamma subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1A PI3Ks. Class 1B PI3K is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)). Consequently, the resultant phospholipid products of Class I PI3Ks link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)). In many cases, PIP2 and PIP3 recruit Aid, the product of the human homologue of the viral oncogene v-Akt, to the plasma membrane where it acts as a nodal point for many intracellular signaling pathways important for growth and survival (Fantl et al., Cell 69:413-423 (1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)). Aberrant regulation of PI3K, which often increases survival through Aid activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3′ position of the inositol ring, and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the p110 alpha isoform, PIK3CA, and for Akt are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85 alpha that serve to up-regulate the p85-p110 complex have been described in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang et el., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations show that deregulation of phosphoinositol-3 kinase, and the upstream and downstream components of this signaling pathway, is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4:988-1004 (2005)). In view of the above, inhibitors of PI3Ka would be of particular value in the treatment of proliferative disease and other disorders. While multiple inhibitors of PI3Ks have been developed (for example, taselisib, alpelisib, buparlisib and others), these molecules inhibit multiple Class TA PI3K isoforms. Inhibitors that are active against multiple Class TA PI3K isoforms are known as “pan-PI3K” inhibitors. A major hurdle for the clinical development of existing PI3K inhibitors has been the inability to achieve the required level of target inhibition in tumors while avoiding toxicity in cancer patients. Pan-PI3K inhibitors share certain target-related toxicities including diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors is dependent on their isoform selectivity profile. Inhibition of PI3Kα is associated with hyperglycemia and rash, whereas inhibition of P