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US-20260125346-A1 - Isoquinolinone Derivatives and 4H-Quinolizinone Derivatives and Pharmaceutical Compositions Thereof for the Treatment of Disease

US20260125346A1US 20260125346 A1US20260125346 A1US 20260125346A1US-20260125346-A1

Abstract

Disclosed herein is an isoquinolin-1(2H)-one derivative of Formula (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., L 2A , R 1 , R 2A , R 3 , R 4A , R 4B , R 4C , R 4D , Q 2 , Q 3 , Q 4 ) are as described herein. Also disclosed is a pharmaceutical composition comprising such derivative, and a method for treating or preventing a disorder or a disease responsive to the inhibition of PI3Kα activity in a subject using such derivative.

Inventors

  • Ling Qin
  • Yunhang Guo
  • Zhiwei Wang

Assignees

  • BEONE MEDICINES I GMBH

Dates

Publication Date
20260507
Application Date
20251106
Priority Date
20230511

Claims (20)

  1. 1 . A compound of formula (IV): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen, deuterium, —C 1-6 alkyl, deuterated —C 1-6 alkyl, heterocyclyl, heteroaryl, or aryl; wherein said —C 1-6 alkyl, deuterated —C 1-6 alkyl, heterocyclyl, heteroaryl, or aryl are each independently optionally substituted with at least one substituent R 11a ; each R 11a is independently hydrogen, halogen, oxo, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR 1a , —COR 1a , —CO 2 R 1a , —CONR 1a R 1b , —SO 2 R 1a , —NR 1a R 1b , —NR 1a COR 1b , —NR 1a CONR 1b R 1c or —NR 1a CO 2 R 1b ; wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl are each independently optionally substituted with at least one substituent R 1d ; R 1a , R 1b , and R 1c are each independently hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl; wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl are each independently optionally substituted with at least one substituent R 1d ; each R 1d is independently hydrogen, halogen, oxo, —CN, —NO 2 , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 1-6 haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, —OC 1-6 alkyl, —COC 1-6 alkyl, or —CO 2 C 1-6 alkyl. R 3 is hydrogen, halogen, —C 1-6 alkyl, —OC 1-6 alkyl, —CN, or —NO 2 ; wherein said —C 1-6 alkyl or —OC 1-6 alkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, —C 1-6 alkyl, —CN, and —NO 2 ; R 4A and R 4B , which may be the same or different, are each independently hydrogen, deuterium, halogen, —C 1-6 alkyl, or deuterated —C 1-6 alkyl; wherein said —C 1-6 alkyl or deuterated —C 1-6 alkyl is each independently optionally substituted with at least one substituent selected from halogen, —C 1-6 alkyl, —C 1-6 haloalkyl, —CN, —NO 2 , —OC 1-6 alkyl, —COC 1-6 alkyl, and —CO 2 C 1-6 alkyl; R 4C is hydrogen, halogen, —C 1-6 alkyl or deuterated —C 1-6 alkyl; wherein said —C 1-6 alkyl or deuterated —C 1-6 alkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OC 1-6 alkyl, —COC 1-6 alkyl, and —CO 2 C 1-6 alkyl; R 5 is hydrogen, halogen, —C 1-6 alkyl, —OC 1-6 alkyl, —CN, or —NO 2 ; wherein said —C 1-6 alkyl or —OC 1-6 alkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, —C 1-6 alkyl, —CN, and —NO 2 ; R 6 is hydrogen, halogen, —C 1-6 alkyl, —OC 1-6 alkyl, —CN, or —NO 2 ; wherein said —C 1-6 alkyl or —OC 1-6 alkyl is each independently optionally substituted with at least one substituent selected from hydrogen, deuterium, halogen, —C 1-6 alkyl, —CN, and —NO 2 ; R 7 is hydrogen, halogen, —C 1-6 alkyl, —OC 1-6 alkyl, —CN, or —NO 2 ; wherein said —C 1-6 alkyl or —OC 1-6 alkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, —C 1-6 alkyl, —CN, and —NO 2 ; -L 2A - is a covalent bond, *—N(R 21a )C(O)—**, **—N(R 21a )C(O)—*, *—(CR 22a R 23a ) m —C(R 22a )═C(R 23a )—(CR 22a R 23a ) n —**, or * refers to the position attached to the isoquinolin-1(2H)-one; ** refers to the position attached to R 2A ; m and n are each independently 0, 1, 2, or 3; R 21a is hydrogen or —C 1-6 alkyl; wherein said —C 1-6 alkyl is optionally substituted with at least one substituent R 211b ; each R 211b is independently hydrogen or halogen; R 22a and R 23a are each independently hydrogen, halogen, or —C 1-6 alkyl; wherein said —C 1-6 alkyl is each independently optionally substituted with at least one substituent R 223a ; each R 223a is independently hydrogen or halogen; R 2A is —C 1-6 alkyl, 3- to 15-membered cycloalkyl, unsaturated 3- to 15-membered heterocyclyl comprising at least one carbon-carbon double bond, 5- to 12-membered aryl, or 5- to 15-membered heteroaryl; wherein each of said —C 1-6 alkyl, 3- to 15-membered cycloalkyl, unsaturated 3- to 15-membered heterocyclyl comprising at least one carbon-carbon double bond, 5- to 12-membered aryl, or 5- to 15-membered heteroaryl is optionally substituted with at least one R Y1 ; each R Y1 is independently hydrogen, halogen, oxo, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, —O-heterocyclyl, —CO-heterocyclyl, aryl, heteroaryl, —P(O)(C 1-6 alkyl) 2 , —OH, —CN, —OC 1-6 alkyl, —SC 1-6 alkyl, or —NO 2 , wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, —OC 1-6 alkyl, or —SC 1-6 alkyl are each independently optionally substituted with at least one substituent R Y1a ; and each R Y1a is independently hydrogen, halogen, —C 1-6 alkyl, —NHC 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, —OH, —CN, —CONH 2 , —COCH 3 , —OC 1-6 alkyl, or —NO 2 .
  2. 2 . The compound according to claim 1 , wherein: L 2A is a covalent bond, *—NHC(O)—**, **—NHC(O)—*, *—CH═CH—**, or *—C≡C—**.
  3. 3 . The compound according to claim 1 , wherein L 2A is a covalent bond.
  4. 4 . The compound according to claim 1 , wherein: R 2A is selected from methyl, n Z is each independently selected from 0, 1, 2, or 3; and n1 is each independently selected from 0, 1, 2, or 3.
  5. 5 . The compound according to claim 1 , wherein: R 2A is X is C(R Y12 ) or N; R Y11 , R Y12 , R Y13 , R Y14 , and R Y15 are each independently hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, —O-heterocyclyl, —CO-heterocyclyl, aryl, heteroaryl, —P(O)(C 1-6 alkyl) 2 , —OH, —CN, —OC 1-6 alkyl, —SC 1-6 alkyl, or —NO 2 , wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, —OC 1-6 alkyl or —SC 1-6 alkyl are each independently optionally substituted with at least one substituent R Y1a ; or (R Y11 and R Y12 ), (R Y12 and R Y13 ), (R Y13 and R Y14 ), or (R Y14 and R Y15 ), together with the atoms to which they are attached, form a C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 4- to 12-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, 6- to 12-membered aryl, or 4- to 12-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, and optionally substituted with at least one substituent R Y1a ; and each R Y1a is independently hydrogen, halogen, —C 1-6 alkyl, —NHC 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, —OH, —CN, —CONH 2 , —COCH 3 , —OC 1-6 alkyl, or —NO 2 .
  6. 6 . The compound according to claim 5 , wherein R Y11 and R Y15 are hydrogen; and 1, 2, or 3 of R Y12 , R Y13 , and R Y14 is hydrogen.
  7. 7 . (canceled)
  8. 8 . The compound according to claim 6 , wherein: R Y12 and R Y14 are hydrogen; and R Y13 is halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, —O-heterocyclyl, —CO-heterocyclyl, aryl, heteroaryl, —P(O)(C 1-6 alkyl) 2 , —OH, —CN, —OC 1-6 alkyl, —SC 1-6 alkyl, or —NO 2 , wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, —OC 1-6 alkyl or —SC 1-6 alkyl are each independently optionally substituted with at least one substituent R Y1a .
  9. 9 . The compound according to claim 6 , wherein R Y12 , R Y13 , and R Y14 are selected from hydrogen, halogen, —C 1-6 alkyl, —P(O)(C 1-6 alkyl) 2 , —OH, —CN, —OC 1-6 alkyl, —SC 1-6 alkyl, or —NO 2 .
  10. 10 . The compound according to claim 6 , wherein R Y12 and R Y13 , together with the atoms to which they are attached, form a 4- to 12-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, or 4- to 12-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, and optionally substituted with at least one substituent R Y1a .
  11. 11 - 17 . (canceled)
  12. 18 . The compound according to claim 1 , wherein: R 2A is methyl,
  13. 19 . The compound according to claim 1 , wherein: R 4A and R 4B are different, and are each independently hydrogen, deuterium, halogen, —C 1-6 alkyl, or deuterated —C 1-6 alkyl, and wherein the carbon atom to which R 4A and R 4B are attached is S or R configuration.
  14. 20 - 23 . (canceled)
  15. 24 . The compound according to claim 1 , the compound having formula (IV-1) or a tautomer or pharmaceutically acceptable salt thereof.
  16. 25 . The compound according to claim 1 , wherein R 4C is hydrogen.
  17. 26 . (canceled)
  18. 27 . The compound according to claim 1 , wherein R 1 is hydrogen, methyl, —CH 2 CN, —CH 2 OCH 3 , —CH 2 CH 3 , —CH 2 CH 3 CN, —CH 2 SO 2 CH 3 , —COCH 3 , —CH 2 OH, —CH 2 CH 2 OCH 3 ,
  19. 28 . The compound according to claim 1 , wherein R 1 is methyl or —CD 3 .
  20. 29 . (canceled)

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Application No. PCT/CN2024/092225, filed May 10, 2024, which claims priority to International Application No. PCT/CN2023/093652, filed May 11, 2023, and International Application No. PCT/CN2023/108473, filed Jul. 20, 2023, the disclosures of each of which are hereby incorporated by reference in their entireties. FIELD OF THE DISCLOSURE Disclosed herein are an isoquinolin-1(2H)-one derivative and a 4H-quinolizin-4-one derivative, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof useful as a PI3Kα inhibitor, and a pharmaceutical composition comprising the same. Also disclosed herein is a method of treating cancer using an isoquinolin-1(2H)-one derivative, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a PI3Kα inhibitor. Further disclosed herein is a method of treating cancer using a 4H-quinolizin-4-one derivative, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a PI3Kα inhibitor. BACKGROUND OF THE DISCLOSURE Phosphoinositide 3-kinase (PI3K) signaling is one of the most frequently aberrantly activated pathways in human cancers. Under physiological conditions, the PI3K pathway is activated in response to insulin, growth factors and cytokines. Activated PI3K regulates key metabolic processes, including glucose metabolism, biosynthesis of macromolecules and maintenance of redox balance, to support both systemic metabolic homeostasis and the growth of individual cells. Oncogenic activation of the PI3K pathway in cancer cells reprograms cellular metabolism by augmenting the activity of nutrient transporters and metabolic enzymes, thereby supporting the anabolic demands of aberrantly growing cells. The PI3K signaling network is activated downstream of receptor tyrosine kinases (RTKs), cytokine receptors, integrins and G protein-coupled receptors (GPCRs) and plays a central role in promoting cell survival and growth (Fruman et al., 2017). Class IA PI3K exists as heterodimers of a catalytic subunit (p110α, p110β or p110δ) associated with a regulatory subunit (p85α or p85β, or shorter variants thereof)(Thorpe, Yuzugullu, & Zhao, 2015). Activation of PI3K at the plasma membrane stimulates phosphorylation of its phospholipid substrate phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to produce the second messenger, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 accumulation at the plasma membrane, and perhaps at other intracellular membranes, creates docking sites to recruit downstream effector proteins that contain a subclass of pleckstrin homology (PH) domain, including protein kinase (such as AKT and BTK), adaptor proteins and regulators of GTPase, to regulate their activities. Genetic events leading to growth factor-independent activation of the PI3K pathway are one of the most frequently occurring drivers of human cancer. Among the genetic alternations, PIK3CA mutation is one of the most frequently mutated kinase genes in solid tumors, with mutation rate of ˜14% across all cancers (Zhang et al., 2017). It is now evident that cancers of the endometrium, breast, colon, lung, as well as benign tumors of the skin are among the tumor types with the highest frequencies of PIK3CA mutations (Samuels & Waldman, 2010). Oncogenic mutation of PIK3CA is highly enriched at hotspot mutations in the helical (E542K, E545K) and kinase (H1047R) domains (Arafeh & Samuels, 2019). Given the oncogenic functions of PIK3CA mutation in cancer progression, several inhibitors of PI3Kα have been developed, and one p110α-selective PI3K inhibitor Alpelisib (BYL719) has shown improved clinical responses when used in combination with estrogen receptor antagonist (Andre et al., 2019), which was thus approved by FDA to treat HR+Her2− metastasis breast cancer harboring PIK3CA mutation. Though there is drug approved and also several inhibitors being continuously investigated in clinical trials, the efficacy of p110α-selective PI3K inhibitors are modest, in part due to the on-target toxicity of hyperglycemia and/or hyperinsulinemia. Targeted inhibition of PI3Kα disrupts glucose metabolism in multiple tissues, which prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in hyperglycemia. Hyperglycemia is usually transient at the early stage of PI3Kα inhibition, due to compensatory insulin release from the pancreas. However, the hyperglycemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, requires discontinuation of therapy (Mayer et al., 2017). In addition, it is reported in pre-clinical study that high level of insulin in circulation would activate PI3K-mTOR signaling axis in tumors, compromising the effectiveness of PI3Kα inhibitors (Hopkins et al., 2018). Hence, there is a need to improve the therapeutic index of PI3Kα inhibitors by identifying compounds with increased sel