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US-12624052-B2 - KRAS modulators and uses thereof

US12624052B2US 12624052 B2US12624052 B2US 12624052B2US-12624052-B2

Abstract

Provided herein are KRAS modulating compounds, such as compounds of Formula (I), (II) (II*) (III) or pharmaceutically acceptable salts, solvates, stereoisomers, atom labelled, or tautomers of any of the foregoing, useful for modulating KRAS GD12 and/or other G12 mutants.

Inventors

  • Hong Lin
  • Juan Luengo
  • Neil Johnson
  • Audrey Hospital

Assignees

  • QUANTA THERAPEUTICS, INC.

Dates

Publication Date
20260512
Application Date
20240116

Claims (20)

  1. 1 . A compound of Formula (II): or a pharmaceutically acceptable salt thereof wherein: M is selected from O, NH, and NMe; n is 0; R 1 is selected from an unsaturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —B(OR 20 ) 2 , —OR 20 , —SR 20 , —S(O) 2 (R 20 ), —S(O) 2 N(R 20 ) 2 , —NR 20 S(O) 2 R 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —NO 2 , ═O, ═NO(R 20 ), —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or R 1 is selected from a 7- to 10-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —C(O)R 20 , —S(O) 2 (R 20 ), ═O, C 1-6 cyanoalkyl, and C 1-6 alkyl; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, ═O, —NO 2 , C 1 -C 4 alkyl, C 1-6 aminoalkyl, —S—C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 2 -C 4 hydroxyalkynyl, C 1 -C 3 cyanoalkyl, triazolyl, C 1 -C 3 haloalkyl, —O—C 1 -C 3 haloalkyl, —S—C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, —CH 2 C(═O)N(R 5 ) 2 , —C 3 -C 4 alkynyl-N(R 5 ) 2 , —N(R 5 ) 2 , (C 1 -C 3 alkoxy)haloC 1 -C 3 alkyl-, C 3 -C 12 carbocycle, and 5- to 12-membered heterocycle, wherein the C 3 -C 12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , —NH 2 , —O, —S, —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl; Y is O; R 2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 ; each L is independently selected from a C 1 -C 4 alkylene optionally substituted with one or more substituents selected from hydroxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle, and 3- to 8-membered heterocycle, wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , ═O, ═S, —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , —O, ═S, —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl; each R 6 is independently selected from halogen, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, cyano, C 1 -C 3 aminoalkyl, -Q-phenyl, -Q-phenylSO 2 F, —NHC(O)phenyl, —NHC(O)phenylSO 2 F, C 1 -C 3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH 2 —, —N(R 5 ) 2 , (C 1 -C 3 alkoxy) C 1 -C 3 alkyl-, (C 1 -C 3 alkyl) C(═O)—, oxo, (C 1 -C 3 haloalkyl) C(═O)—, —SO 2 F, (C 1 -C 3 alkoxy) C 1 -C 3 alkoxy, —CH 2 OC(O)N(R 5 ) 2 , —CH 2 NHC(O)OC 1 -C 6 alkyl, —CH 2 NHC(O)N(R 5 ) 2 , —CH 2 NHC(O)C 1 -C 6 alkyl, —CH 2 (pyrazolyl), —CH 2 NHSO 2 C 1 -C 6 alkyl, —CH 2 OC(O)heterocycle, —OC(O)N(R 5 ) 2 , —OC(O)NH(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl), —OC(O)NH(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl)phenyl(C 1 -C 3 alkyl)N(CH 3 ) 2 , —OC(O)NH(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl)phenyl, —OC(O)heterocycle, and —CH 2 heterocycle, wherein the phenyl of —NHC(O)phenyl or —OC(O)NH(C 1 -C 3 alkyl)(C 1 -C 3 alkyl)phenyl is optionally substituted with —C(O) H or —OH and wherein the heterocycle of —CH 2 heterocyclyl is optionally substituted with oxo, wherein Q is O or S; each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , —N(C 1-6 alkyl) 2 , C 1-10 alkyl, —C 1-10 haloalkyl, —O—C 1-10 alkyl, oxo, C 3-12 carbocycle, and 3- to 12-membered heterocycle; and each R 5 is independently selected from hydrogen and C 1 -C 6 alkyl.
  2. 2 . The compound or salt of claim 1 , wherein Mis O.
  3. 3 . The compound or salt of claim 1 , wherein Mis NMe.
  4. 4 . The compound or salt of claim 1 , wherein R 1 is selected from a 7- to 10-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —C(O)R 20 , —S(O) 2 (R 20 ), ═O, C 1-6 cyanoalkyl, and C 1-6 alkyl.
  5. 5 . The compound or salt of claim 1 , wherein R 1 is selected from an unsaturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —B(OR 20 ) 2 , —OR 20 , —SR 20 , —S(O) 2 (R 20 ), —S(O) 2 N(R 20 ) 2 , —NR 20 S(O) 2 R 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —NO 2 , ═O, ═NO(R 20 ), —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
  6. 6 . The compound or salt of claim 5 , wherein R 1 is selected from which is optionally substituted.
  7. 7 . The compound or salt of claim 6 , wherein R 1 is selected from which is optionally substituted with one or more substituents independently selected from halogen, —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —CN, C 1-6 cyanoalkyl, C 1-6 alkyl, and C 2-6 alkynyl.
  8. 8 . The compound or salt of claim 7 , wherein R 1 is
  9. 9 . The compound or salt of claim 7 , wherein R 1 is
  10. 10 . The compound or salt of claim 1 , wherein B is selected from each of which is optionally substituted with one or more substituents.
  11. 11 . The compound or salt of claim 10 , wherein B is selected from each of which is optionally substituted with one or more substituents.
  12. 12 . The compound or salt of claim 11 , wherein the one or more optional substituents are independently selected from oxo, —NH 2 , —CN, halogen, and C 1 -C 3 alkyl.
  13. 13 . The compound or salt of claim 11 , wherein B is selected from
  14. 14 . The compound or salt of claim 1 , wherein L is selected from C 1 -C 4 alkylene.
  15. 15 . The compound or salt of claim 14 , wherein L is selected from unsubstituted C 1 -C 4 alkylene.
  16. 16 . The compound or salt of claim 15 , wherein Y—R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 6 .
  17. 17 . The compound or salt of claim 16 , wherein R 6 of R 2 is independently selected at each occurrence from C 1 -C 3 alkyl and halogen.
  18. 18 . The compound or salt of claim 1 , wherein Y—R 2 is selected from
  19. 19 . The compound or salt of claim 1 , wherein Y—R 2 is
  20. 20 . The compound or salt of claim 1 , wherein Y—R 2 is

Description

CROSS-REFERENCE This application is a continuation of U.S. application Ser. No. 18/362,576, filed on Jul. 31, 2023, which is a continuation of International Patent Application PCT/US23/62235, filed on Feb. 8, 2023, which claims the benefit of U.S. Provisional Patent Applications Nos. 63/308,424 filed on Feb. 9, 2022; 63/368,584 filed on Jul. 15, 2022; 63/373,302 filed on Aug. 23, 2022; 63/378,843 filed on Oct. 7, 2022; and 63/384,374 filed on Nov. 18, 2022; each of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p. 1292-1292 el). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A. G., et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases' ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression. Despite extensive efforts, small molecules have not been identified which block effector binding or restore GTPase activating protein (GAP) sensitivity, though some have been found which block interaction of Ras with the guanine nucleotide exchange factor (GEF), SOS, which activates Ras at the plasma membrane. KRAS G12C mutations, most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP-bound state. KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation. Thus, pharmacological targeting the of inactive state is unlikely to achieve similar results against G12D, despite the existence of a similar binding pocket in the GDP-state. Additionally, a cysteine present at the site of the activating mutation yields itself to covalent chemistry, while aspartic acid does not provide typical medicinal chemistry approaches for selective covalent modification. In order to potentially exploit the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability to achieve selective inhibition of cancer cells while sparing normal Ras function, it is attractive for small molecule inhibitors to bind selectively to the GTP-state and stabilize a conformation that is incompetent for oncogenic signaling interactions with effector proteins. Furthermore, it has been shown that only constitutive activation of Raf, MEK and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferative signaling (e.g., see Drosten, M., et al., Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J, 2010. 29(6): p. 1091-104). As all evidence has indicated that MAPK signaling is essential for the growth effects of Ras in cancer, KRAS-mutant-selective inhibition in this pathway is considered the critical functional readout for potential clinical benefit of novel therapeutic approaches. SUMMARY OF THE INVENTION There is a need to develop new inhibitors for KRAS-driven cancers that demonstrate inhibition of MAPK signals via a mechanism of action that is selective for binding to the active GTP-bound state over the inactive GDP-bound state. The present disclosure relates to Formula (I) or Formula (II) or Formula (III), including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, and to uses thereof in, for example, inhibiting KRas G12D and/or other G12 mutants. In an aspect, the present disclosure provides a compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof wherein:R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, —B(OR20)2, —OR20, —SR20, —S(O)2(R20), —S(O)2N(R20)2, —S(O)N(R20)2, —S(O)R20(═NR20), —NR20S(O)2R20c, —C(O)N(R20)2, —C(═NR20)N(R20)2, —C(O)N