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EP-4735452-A2 - HETEROBIFUNCTIONAL COMPOUNDS FOR THE DEGRADATION OF KRAS PROTEIN

EP4735452A2EP 4735452 A2EP4735452 A2EP 4735452A2EP-4735452-A2

Abstract

The invention provides compounds that degrade the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein including mutant forms via the ubiquitination of the KRAS protein and subsequent proteasomal degradation. The compounds are useful for the treatment of various cancers.

Inventors

  • ANDERSON, COREY DON
  • CHENG, Xinpeng

Assignees

  • Merck Patent GmbH

Dates

Publication Date
20260506
Application Date
20240627

Claims (12)

  1. CLAIMS We claim 1. A compound of Formula: or a pharmaceutically acceptable salt thereof; wherein: KRAS Targeting Ligand B is ; Heterocyclic Moiety A is selected from: , and ; Q is CH 2 , NR 2 , , O, or S; R 1 and R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R 1 and R 6 are combined to form a one or two carbon bridge to form a fused cycle; each R 2 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R 9 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 5 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O)R 9 , -S(O) 2 R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O) 2 R 9 , -SC(O)R 9 , -OS(O) 2 R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O) 2 R 9 , -P(O)(R 9 ) 2 , -SP(O)(R 9 ) 2 , -NR 7 P(O)(R 9 ) 2 , and -OP(O)(R 9 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; R 16 is selected from: , , , , and , and R 12 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; R 17 is selected from: , , , , and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; R 18 is a 9-membered heteroaryl attached to the azaglutarimide moiety through a C-N bond, optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R 5 ; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R 5 ; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent; R 12 is the attachment point to Linker; R 7 and R 8 at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R 14 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 9 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 , -OR 7 , and -SR 7 each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 10 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; R 11 and R 13 at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; each R 14 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; each R 15 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl) 2 ; R 29 is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 45 , R 46 , and R 47 ; R 30 and R 31 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR 7 R 8 , -OR 7 , and -SR 7 ; R 33 is selected from: , , and each of which R 33 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR 7 R 8 , -OR 7 , and -SR 7 ; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; and each R 45 , R 46 , and R 47 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; Linker is selected from ; wherein: X 1 and X 2 are independently at each occurrence selected from bond, heterocycle, NR 2 , C(R 2 ) 2 , O, C(O), and S; R 20 , R 21 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-, -C(S)-, -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -C(R 40 R 40 )-, -P(O)(OR 26 )O-, -P(O)(OR 26 )-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 ; R 26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and R 40 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl) 2 , -NHSO 2 (alkyl), -N(alkyl)SO 2 alkyl, -NHSO 2 (aryl, heteroaryl or heterocycle), -N(alkyl)SO 2 (aryl, heteroaryl or heterocycle), -NHSO 2 alkenyl, -N(alkyl)SO 2 alkenyl, -NHSO 2 alkynyl, -N(alkyl)SO 2 alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl. 2. A compound of Formula: ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety B is selected from: , and ; Q is CH 2 , NR 2 , , O, or S; Q 2 is CH2, , O, or S; R 1 and R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R 1 and R 6 are combined to form a one or two carbon bridge to form a fused cycle; each R 2 and R 4 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R 9 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 5 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O)R 9 , -S(O) 2 R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O) 2 R 9 , -SC(O)R 9 , -OS(O) 2 R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O) 2 R 9 , -P(O)(R 9 ) 2 , -SP(O)(R 9 ) 2 , - NR 7 P(O)(R 9 ) 2 , and -OP(O)(R 9 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; R 16 is selected from: , , , , and , and R 12 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; R 16B is selected from: , , , and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; R 17B is selected from: and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R 5 ; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R 5 ; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent; Cycle 2 is a fused heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent; R 12 is the attachment point to Linker; R 7 and R 8 at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R 14 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 9 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 , -OR 7 , and -SR 7 each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 10 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; R 11 and R 13 at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; each R 14 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl) 2 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; each R 15 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl) 2 ; KRAS Targeting Ligand A is selected from: , , , , , , , , and ; R 29 is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 45 , R 46 , and R 47 ; R 30 and R 31 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR 7 R 8 , -OR 7 , and -SR 7 ; R 32 is selected from: and ; wherein attachment point is attached to the Linker and the remaining attachment point is attached to the KRAS Targeting Moiety; R 51 and R 51A are independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR 7 R 8 , -OR 7 , and -SR 7 ; R 88 is selected at each instance from aryl, heteroaryl, heterocycle, bicycle, and spirocycle; z is independently selected at each instance from 0, 1, 2, 3, or 4 as allowed by valence; q is 1, 2, 3, or 4; w is 1, 2, 3, or 4; X A is selected from -CH- and -N-; X B is selected from -CH 2 -, -C(R 51 ) 2 -, -O-, -NH-, -N(R 4 )-, and -S-; R 33 is selected from: , , and each of which R 33 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR 7 R 8 , -OR 7 , and -SR 7 ; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R 38 and R 39 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; R 41 , R 42 , R 43 , and R 44 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; and each R 45 , R 46 , and R 47 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; Linker is selected from ; X 1 and X 2 are independently at each occurrence selected from bond, heterocycle, NR 2 , C(R 2 ) 2 , O, C(O), and S; R 20 , R 21 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-, -C(S)-, -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -C(R 40 R 40 )-, -P(O)(OR 26 )O-, -P(O)(OR 26 )-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1,
  2. 2, 3, or 4 substituents independently selected from R 40 ; R 26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and R 40 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl) 2 , -NHSO 2 (alkyl), -N(alkyl)SO 2 alkyl, -NHSO 2 (aryl, heteroaryl or heterocycle), -N(alkyl)SO 2 (aryl, heteroaryl or heterocycle), -NHSO 2 alkenyl, -N(alkyl)SO 2 alkenyl, -NHSO 2 alkynyl, -N(alkyl)SO 2 alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl.
  3. 3. The compound of claim 2, wherein Heterocyclic Moiety B is selected from , , and .
  4. 4. The compound of claim 1, wherein Heterocyclic Moiety A is .
  5. 5. The compound of claim 4, wherein Q is NH, NCH 3 , O, or S.
  6. 6. The compound of claim 1, wherein Heterocyclic Moiety A is .
  7. 7. The compound of any one of claims 1-6, wherein R 1 is hydrogen.
  8. 8. The compound of any one of claims 1 and 4-7, wherein R 16 and R 17 are selected from , , , , , and .
  9. 9. The compound of any one of claims 1-2 and 4-7, wherein R 16 , R 16B and R 17 are selected from , , , , , , , , , , , . , , , , , and .
  10. 10. The compound of claim 1, wherein Heterocyclic Moiety A is .
  11. 11. The compound of claim 10, wherein R 18 is , , , , , , , , , , , , , , , , , or .
  12. 12. The compound of claim 1 or claim 2, wherein Heterocyclic Moiety A and Heterocyclic Moiety B are or 13. The compound of any one of claims 1-12, wherein R 6 is hydrogen. 14. The compound of any one of claims 1-13, wherein each R 5 is independently selected from hydrogen, alkyl, haloalkyl, and halogen. 15. The compound of any one of claims 1-14, wherein Linker is of formula: . 16. The compound of any one of claims 1-15, wherein X 1 is bond, heterocycle, or -NR 2 -. 17. The compound of any one of claims 1-16, wherein R 23 is bond, heterocycle, or -NR 2 -. 18. The compound of any one of claims 1-17, wherein R 20 is alkyl, heterocycle, aryl, -heteroaryl or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R 40 . 19. The compound of any one of claims 1-18, wherein R 21 is bond, -O-, -NR 2 -, -S-, alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R 40 . 20. The compound of any one of claims 1-19, wherein R 22 is alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R 40 . 21. The compound of any one of claims 2-20, wherein the KRAS Targeting Ligand A is . 22. The compound of any one of claims 2-21, wherein R 32 is selected from , , , , and ; wherein: R 51B is independently selected from halogen, cyano, haloalkyl, -OR 7 , and -SR 7 ; R 51C is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD 3 ; and R 51D and R 51E are independently hydrogen, alkyl, alkenyl, haloalkyl, cyano, -OR 7 , and -SR 7 or together with X B and the carbon atoms to which they are attached, form a 5-, 6-, or 7- membered ring. 23. The compound of any one of claims 1-22, wherein R 29 is . 24. The compound of any one of claims 1-23, wherein R 33 is , , , , , , , , R 52 R 53 X OR 57 N R 54 R 55 , or ; wherein R 52 and R 54 are independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R 53 and R 55 are independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, -NR 7 R 8 , -OR 7 , -SR 7 , alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; and R 57 is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, C(O)R 4 , C(O)NR 7 R 8 , and R 7 . 25. The compound of claim 1 or claim 2, wherein the compound is selected from the compounds of Table 3B or a pharmaceutically acceptable salt thereof. 26. A compound of Table 3A or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition comprising a compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 28. The pharmaceutical composition of claim 27 for the treatment of a KRAS mediated cancer. 29. A method of treating a KRAS mediated cancer comprising administering an effective amount of a compound of any one of claims 1-26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a human patient in need thereof. 30. Use of a compound of any one of claims 1-26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the treatment of a KRAS mediated cancer. 31. Use of a compound of any one of claims 1-26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament to treat a KRAS mediated cancer.

Description

HETEROBIFUNCTIONAL COMPOUNDS FOR THE DEGRADATION OF KRAS PROTEIN CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63/524,516 filed June 30, 2023, which is incorporated by reference herein for all purposes. FIELD OF THE INVENTION The invention provides compounds that degrade a Kirsten rat sarcoma viral oncogene homolog (KRAS) protein, for example a mutant KRAS protein such as G12D-KRAS or gain- of-function KRAS mutations, for the treatment of abnormal cellular proliferation including cancers and tumors as described in more detail below. BACKGROUND OF THE INVENTION The rat sarcoma (RAS) family of viral oncogene homolog GTPases are involved in cellular signal transduction by acting as molecular switches to mediate cell growth, differentiation, and survival. The RAS family includes three distinct members, i.e. Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Neuroblastoma rat sarcoma viral oncogene homolog (NRAS). Upon GTP binding, the RAS GTPases engage effector proteins to initiate a variety of downstream signaling including the RAF-MEK-ERK and PI3K-AKT pathways that control mitogenic processes (Cox, A.D. & Der, C.J. Ras history: The saga continues. Small GTPases. 1(1):2-27(2010 Jul.)). Overexpression or mutation of these genes leads to the accumulation of GTP-bound KRAS and the unrestricted activation of RAF-MEK-ERK and PI3K-AKT signaling pathways and has been implicated in many types of human cancer including colorectal cancer, pancreatic cancer, lung cancer, and non-small cell lung cancer (NSCLC). Single amino acid substitutions caused by missense mutations are associated with 98% of RAS-related cancers and occur at mutational hotspots encoding codons including glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61) (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb. Perspect. Med. 8(9):a031435(2018 Sep)). Mutant KRAS accounts for approximately 84% of all RAS-mutant cancers (Id.). Gain-of-function KRAS mutations are found in approximately 30% of all human cancers (P. Liu et al., “Targeting the untargetable KRAS in cancer therapy”. Acta Pharm. Sinica B 2019; 9(5): 871–879; V. Merz et al., “Targeting KRAS: The Elephant in the Room of Epithelial Cancers”. Front. Oncol.2021, vol. 11, article 638360), including, e.g., pancreatic cancer (>80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, myeloid leukemia breast cancer, cervical cancer, endometrial cancer, liver cancer, bladder cancer, and biliary tract malignancies (S. Jančík et al., “Clinical Relevance of KRAS in Human Cancers” J. Biomed. Biotechnol. 2010; 2010: 150960). Activating or gain- of-function mutations interfere with KRAS’s ability to flip between active and inactive states. Patients with KRAS mutations have historically exhibited poor responses to standard of care therapies. Despite the known role of KRAS as an oncogenic hub, the development of KRAS targeting agents has historically been extremely challenging, even earning the nickname, “the undruggable gene” (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol.15:152(2022)). In 2013, the lab of Kevan Shokat at the University of California San Francisco identified an allosteric pocket, termed the switch-II pocket, on KRAS which could by bound by inhibitors (Ostrem, J. et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477): 548-551). Although this allosteric site is adjacent to the nucleotide binding pocket, it is transiently formed and was not observed in previous crystal structures of the protein. A compound binding in the switch-II pocket alters the relative binding affinity of KRAS to GTP and GDP, favoring the inactive GDP-bound form. Three years later, the first low micromolar compounds against KRAS G12C were disclosed by Wellspring Biosciences (Patricelli, M. et al. Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discovery 6(3):316-29, 2016). In 2018, Wellspring Biosciences published a paper describing improved KRAS binders with a 4- piperazinyl-quinazolinyl-7-phenol pharmacophore (Janes, M. et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor, Cell, 172, 578-589). Only recently have KRAS targeting agents been developed and approved by the United States Food and Drug Administration (FDA), albeit for a specific subset of KRAS mutant patients (Huang, L. et al. KRAS mutation: from undruggable to druggable in cancer. Sig Transduct Target Ther. 6(1):386(2021 Nov 15)). Sotorasib (Lumakras®) and adagrasib (Krazati®), indicated for locally advanced or metastatic non-small cell lung cancer are irreversible inhibitors of KRAS G12C that covalently bind the mutant cysteine of KRA