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CN-122003407-A - Benzopyridones and benzopyrimidinones as PI3K inhibitors

CN122003407ACN 122003407 ACN122003407 ACN 122003407ACN-122003407-A

Abstract

Novel PI3K inhibitors of formula (1) and methods for their preparation and their use in the treatment of diseases associated with elevated or activated PI3K pathway are described, Wherein R 1 to R 8 and X 1 、X 2 、X 3 and X 4 are as defined.

Inventors

  • J.F. Black
  • M. L. Bose
  • D. A. Maresca
  • J. N. Payet
  • C. A. Schulte
  • B. Jestrepsky
  • ZHAO QIAN

Assignees

  • 恩库勒治疗公司

Dates

Publication Date
20260508
Application Date
20240808
Priority Date
20230811

Claims (20)

  1. 1. A compound of formula (1) Or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, Wherein: r 1 is selected from ; Each a is independently C 1 -C 4 alkyl, fluoroalkyl, C 3 -C 7 cycloalkyl, N (R a ) 2 、(CH 2 ) 0-5 -NR a -C(O)-C 3 -C 7 cycloalkyl, (CH 2 ) 1-5 -O-(CH 2 ) 0-5 -C 1 -C 4 alkyl, (CH 2 ) 1-5 -O-C 1 -C 3 cycloalkyl 、(CH 2 ) 1-5 -O-(CH 2 ) 0-5 -CF 3 、(CH 2 ) 1-5 -O-(CH 2 ) 1-5 -C 1 -C 3 fluoroalkyl, (CH 2 ) 0-5 -aryl, (CH 2 ) 0-5 -heteroaryl, (CH 2 ) 0-5 -heterocyclyl, (CH 2 ) 0-5 -NR a -(CH 2 ) 0-5 -heteroaryl, or (CH 2 ) 0-5 -NR a -(CH 2 ) 1-5 -N-heterocyclyl), wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are substituted or unsubstituted, or alternatively, a and a together with the attached-P (=o) -moiety may form a substituted or unsubstituted heterocyclyl ring; Each B is independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl 、(CH 2 ) 1-5 -OH、(CH 2 ) 0-5 -N(R a ) 2 、(CH 2 ) 1-5 -NR a -C(O)-C 3 -C 7 cycloalkyl, (CH 2 ) 0-5 -aryl, (CH 2 ) 0-5 -heteroaryl, (CH 2 ) 0-5 -heterocyclyl, (CH 2 ) 0-5 -C(O)-(CH 2 ) 1-5 -O-C 1 -C 4 alkyl, (CH 2 ) 1-5 -NR a -(CH 2 ) 0-5 -heteroaryl, or (CH 2 ) 1-5 -NR a -(CH 2 ) 2-5 -N-heterocyclyl, O-C 1-5 -alkyl, O-C 0-5 -cycloalkyl, O-C 0-5 -heterocyclyl), wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are substituted or unsubstituted, or alternatively, B and B together with the attached- [ O or NH ] -P (=o) -O-moiety can form a substituted or unsubstituted heterocyclyl ring, or alternatively, a and B together with the attached-P (=o) -O-moiety can form a substituted or unsubstituted heterocyclyl ring; Each R a is independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C (O) C 1 -C 3 alkyl, (CH 2 ) 1-5 -fluoroalkyl 、(CH 2 ) 1-5 -OH、(CH 2 ) 1-5 -NH 2 、(CH 2 ) 1-5 -NH(C 1- C 4 alkyl), (CH 2 ) 1-5 -N(C 1- C 4 alkyl) 2 , or C (O) - (CH 2 ) 1-5 -O-C 1 -C 3 alkyl, wherein the alkyl and cycloalkyl are substituted or unsubstituted, or alternatively, for-S (=o) (a) (=nr a ) or for-S (=o) (a) (NR a ),R a and a together with the attached atoms may form a substituted or unsubstituted heterocyclyl ring; r 2 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, CF 3 、CFH 2 or CF 2 H, and wherein R 2 is not H, the carbon atom attached to R 2 is a chiral center and is present as a (R) -and (S) -racemic mixture or as the (R) -or (S) -enantiomer; R 3 is H or C 1 -C 4 alkyl; r 4 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, halogen, CN, CF 3 、OCF 3 、CFH 2 or CF 2 H; r 6 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, a heteroaromatic group, CF 3 、CFH 2 or CF 2 H; R 7 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, halogen, CN, CF 3 、OCF 3 、CFH 2 or CF 2 H; each R 8 is independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, halogen, CN, CF 3 、OCF 3 、CFH 2 or CF 2 H; Each of X 1 、X 2 and X 3 is independently N, CH or substituted C; x 4 is CH or substituted C; r 5 is Halogen; -O-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -R 9 ; -S-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -R 9 ; -S(O)-L 1 -L 2 -L 3 -L 5 -L 6 -L 7 -R 9 ; -S(O) 2 -L 1 -L 2 -L 3 -L 5 -L 6 -L 7 -R 9 ; -(NR 10 )-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -R 9 ; Or (b) -L 8 -L 9 -L 10 -L 11 -L 12 -R 14 , Wherein: Each of L 1 、L 2 、L 3 、L 6 and L 7 is independently (CHR 11 )、(CHR 11 -O)、(CHR 11 -S)、(C 3 -C 7 cycloalkyl), (CH 2 ) 1-4 , or a bond; L 4 is c= O, C =s or a bond; L 5 is NR 10 , S, O or a bond; R 9 is H、C(=O)R 12 、C(=O)NR 12 R 13 、NR 12 R 13 、C(=O)OR 12 、C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted, or alternatively, when NR 10 is present, R 9 and R 10 together with the attached nitrogen atom can form a substituted or unsubstituted ring; Each of R 10 and R 11 is independently H or C 1 -C 4 alkyl (such as CH 3 、CH 2 CH 3 or CH (CH 3 ) 2 ), wherein the C 1 -C 4 alkyl is unsubstituted or substituted; Each of R 12 and R 13 is independently H, C 1 -C 6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the C 1 -C 6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted, or alternatively, R 12 and R 13 together with the nitrogen atom to which they are attached can form a substituted or unsubstituted ring; l 8 is (CHR 15 )、(CHR 15 -O)、(CHR 15 -S)、(CHR 15 -NR 16 ), c= O, C =s or a bond; L 9 is C 3 -C 7 cycloalkyl (which is optionally part of a bridged, fused or spiro ring system), C (R 15 )=C(R 15 ), C≡C or a bond; L 10 is independently (CHR 15 )、O、S、(NCR 15 ), N (c=o), or a bond; L 11 is (CHR 15 ), c= O, C =s or a bond; L 12 is H, (C 3 -C 7 cycloalkyl), heterocyclyl, aryl, heteroaryl, or a bond, wherein each of the C 3 -C 7 cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted, and the C 3 -C 7 cycloalkyl and/or heterocyclyl is optionally part of a bridged, fused, or spiro ring system; R 14 is H、CR 15 R 16 R 17 、OR 17 、SR 17 、NR 16 R 17 、C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted, Each of R 15 and R 16 is independently H or C 1 -C 3 alkyl, and Each R 17 is independently H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted, or alternatively, R 16 and R 17 together with the attached nitrogen atom may form a substituted or unsubstituted ring, Provided that when R 5 is-L 8 -L 9 -L 10 -L 11 -L 12 -R 14 , at least one of L 8 、L 9 、L 10 、L 11 、L 12 and R 14 is a carbon-containing moiety and R 5 is directly attached to the (isoquinolone) core structure through a carbon atom; Or R 5 is a non-aromatic N-linked heterocyclic ring Wherein the heterocyclic ring is substituted or unsubstituted, optionally containing one or more additional ring atoms selected from N, O, si and S, and is optionally part of a bridged, fused or spiro ring system.
  2. 2. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is -(NR 10 )-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -R 9 , wherein L 1 to L 7 、R 9 and R 10 are as defined.
  3. 3. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is-O-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -R 9 , wherein L 1 to L 7 and R 9 are as defined.
  4. 4. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is -S-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -R 9 ;-S(O)-L 1 -L 2 -L 3 -L 5 -L 6 -L 7 -R 9 ; or-S (O) 2 -L 1 -L 2 -L 3 -L 5 -L 6 -L 7 -R 9 , wherein L 1 to L 7 and R 9 are as defined.
  5. 5. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is-L 8 -L 9 -L 10 -L 11 -L 12 -R 14 , wherein L 8 to L 12 and R 14 are as defined.
  6. 6. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is a non-aromatic N-linked heterocyclyl ring Wherein the heterocyclyl ring is substituted or unsubstituted, optionally containing one or more additional ring atoms selected from N, O, si and S, and is optionally part of a bridged, fused or spiro ring system.
  7. 7. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from Wherein a and B are as defined in claim 1.
  8. 8. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from Wherein A, B and R a are as defined in claim 1.
  9. 9. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from Wherein B is as defined in claim 1.
  10. 10. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X 4 is CH or CF.
  11. 11. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is CH 3 or CH 2 F.
  12. 12. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
  13. 13. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X 1 is N, and X 2 and X 3 are independently CH or substituted C.
  14. 14. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X 2 is N, and X 1 and X 3 are independently CH or substituted C.
  15. 15. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X 3 is N, and X 1 and X 3 are independently CH or substituted C.
  16. 16. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X 1 and X 3 are N, and X 2 is CH or substituted C.
  17. 17. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are N, and X 3 is CH or substituted C.
  18. 18. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X 2 and X 3 are N, and X 1 is CH or substituted C.
  19. 19. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X 1 、X 2 and X 3 are N.
  20. 20. The compound or solvate, enantiomer, diastereomer, tautomer, polymorph or isotopically-labeled compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X 1 、X 2 and X 3 are independently CH or substituted C.

Description

Benzopyridones and benzopyrimidinones as PI3K inhibitors Cross Reference to Related Applications The present application claims priority from U.S. provisional application Ser. No. 63/532,175 filed on 8/11/2023 and U.S. provisional application Ser. No. 63/600,371 filed on 11/17/2023, the disclosures of which are incorporated herein by reference in their entirety for all purposes. Background Phosphatidylinositol lipids (PIs) and their various phosphorylated subtypes are second messengers involved in a wide range of cellular vesicle transport and signal transduction processes. Phosphoinositide 3 'kinases (PI 3 Ks) are a family of enzymes responsible for phosphorylating the 3' hydroxyl position of the PIs inositol ring. PI3Ks are subdivided into three categories depending on their structure and substrate. Class II PI3Ks (PI 3K-C2. Alpha., PI 3K-C2. Beta., PI 3K-C2. Gamma.) and class III PI3Ks (vps 34) are monomeric enzymes, primarily associated with endocytosis and autophagy (Posor et al, biochim Biophys Acta2015, 1851, 794; backer, biochem J.2016, 473, 2251). Class I PI3Ks are heterodimers consisting of catalytic kinase subunits (p110α, β, γ, δ) and one of several regulatory subunits that determine binding partners and subcellular localization. Class I PI3Ks are activated upon interaction with Receptor Tyrosine Kinases (RTKs), ras-related gtpases, G-protein coupled receptors, and/or related adaptor proteins, and convert phosphatidylinositol 4, 5-bisphosphate (PIP 2) to phosphatidyl 3,4, 5-triphosphate (PIP 3) in its active form (Fruman et al, cell2017, 170, 605). High local concentrations of PIP3 will promote recruitment and activation of downstream signaling partners, including AKT and mTOR. Activation of the AKT/mTOR pathway is involved in several growth-related actions and pathologies, including glucose regulation, cell survival, angiogenesis and proliferation (pora et al, front oncol.2014, 4, 1), suggesting the role of class I PI3Ks as key upstream mediators of these functions. Class I PI3Ks are further subdivided into four subtypes (α, β, γ and δ) which play a unique role in cell physiology, based on the characteristics of their catalytic (p110α, p110β, p110γ or p110δ) and regulatory subunits (p85α or its various splice variants p85β, p55γ or p101) (Vanhaesebroeck et al, J Mol Med (Berl). 2016, 94, 5). Pi3kγ and pi3kδ are mainly expressed in leukocytes and play an important role in the pro-inflammatory pathway (Hawkins et al Biochimica et Biophysica Acta, 1851, 882; okkenhaug et al Science2002, 297, 1031; ali et al Nature2004, 431, 1007). PI3kα and β are more widely expressed and have similar, but not identical, effects. For example, pi3kα has a non-redundant role in angiogenesis (Soler et al, J Exp med.2013, 210, 1937), whereas pi3kβ is known to perform specific functions in platelet aggregation (Liu et al, nat Rev Drug discovery.2009, 8, 627; jackson et al, nat med.2005, 11, 507). Elevated or constitutive activation of the PI3K pathway is one of the most common events in human cancers. The PI3K pathway is overactivated by a variety of mechanisms, including activation mutations in the PI3K subtype, upregulation of the PI3K subtype, deletion or inactivation of the tumor suppressor PTEN, or superactivation of the tyrosine kinase growth factor receptor or other upstream signaling partner (Yang et al, mol Cancer2019, 18, 1). In many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate and skin cancers, mutations in the gene encoding pi3kα have been found to occur or to cause up-regulation of pi3kα (Goncalves et al, N Eng J med.2018, 379,2052). In particular, the gene PIK3CA encoding the p110α subunit of pi3kα is frequently mutated or amplified in a variety of tumor types. Missense mutations occur in all domains of p110α, but are concentrated mainly in two 'hot spots', most commonly E542K and E545K in the helical domain, and H1047R in the kinase domain. The helical domain mutation reduces p85 inhibition of p110α or promotes direct interaction of p110α with insulin receptor substrate 1 (IRS 1) 37, whereas the kinase domain mutation increases p110α interaction with lipid membranes, which is accompanied by up-regulation of signaling events. (Thorpe et al NAT REV CANCER, 2015, 15, 7). Development of inhibitors against the PI3K pathway has been challenging because administration sufficient to inhibit tumors cannot be achieved without adverse events. PI3K inhibitors in clinical applications (apicalist (alpelisib), bupirist (buparlisib), copanlisib, du Weili sibirist (duvelisib), idarubicin (idelalisib), pi Keti Li Xibu (pictilisib), tasilist (tasselisib), etc.) have heretofore caused dose-dependent adverse events such as hyperglycemia, rash, fatigue, diarrhea, etc. (Jiang et al, mol Biol rep.2020, 47, 4587), which are known to be at target toxicity. Hyperglycemia is caused by the body not producing enough insulin or abnormal utilization. The pancreas regulates the r