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US-20260125376-A1 - IRREVERSIBLE INACTIVATORS TARGETING ARAF/MEK COMPLEXES

US20260125376A1US 20260125376 A1US20260125376 A1US 20260125376A1US-20260125376-A1

Abstract

The disclosure relates to compounds that act as irreversible inactivators that target ARAF/MEK complexes; pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.

Inventors

  • Thomas Gero
  • David A. Scott
  • Michael Eck
  • Tyler Beyett
  • Javier Vinals-Camallonga

Assignees

  • Thomas Gero
  • DANA-FARBER CANCER INSTITUTE, INC.

Dates

Publication Date
20260507
Application Date
20231002

Claims (20)

  1. 1 .- 41 . (canceled)
  2. 42 . A compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein each R 2 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halo, —CN, —OH, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ; n is 1 or 2; R 1 is selected from the group consisting of L 3 is selected from the group consisting of a bond, C 1 -C 4 alkyl, and NH; each of R E1 , R E2 , and R E3 is independently selected from the group consisting of H, halo, —CN, and C 1 -C 6 alkyl; a is 1 or 2; and each z is independently 0, 1, or 2, provided that the compound of Formula I is not
  3. 43 . The compound of claim 42 , wherein the compound of Formula I is a compound of Formula Ia: or a pharmaceutically acceptable salt thereof, wherein R E1 is H or halo and wherein R 2 is halo.
  4. 44 . The compound of claim 42 , wherein the compound of Formula I is selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  5. 45 . A pharmaceutical composition comprising a compound of claim 42 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  6. 46 . A method of inactivating ARAF in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 42 .
  7. 47 . A method of treating an ARAF-mediated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 42 , wherein the ARAF-mediated cancer may be melanoma or a carcinoma, including uterine corpus endometrial carcinoma, cholangiocarcinoma, and esophageal adenocarcinoma.
  8. 48 . A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  9. 49 . A pharmaceutical composition comprising a compound of claim 48 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  10. 50 . A method of inactivating ARAF in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 48 .
  11. 51 . A method of treating an ARAF-mediated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 48 , wherein the ARAF-mediated cancer may be melanoma or a carcinoma, including uterine corpus endometrial carcinoma, cholangiocarcinoma, and esophageal adenocarcinoma.
  12. 52 . A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  13. 53 . A pharmaceutical composition comprising a compound of claim 52 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  14. 54 . A method of inactivating ARAF in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 52 .
  15. 55 . A method of treating an ARAF-mediated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 52 , wherein the ARAF-mediated cancer may be melanoma or a carcinoma, including uterine corpus endometrial carcinoma, cholangiocarcinoma, and esophageal adenocarcinoma.
  16. 56 . A compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein A is N, CR 3 , or CR 4 ; R t is H or C 1-6 alkyl; R 2 is selected from the group consisting of H, halo, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocycloalkyl, —OR 6 , —NR 6 R 6 , —SO 2 R 6 , —SO 2 NHR 6 , —NHSO 2 R 6 , —C(O)OR 6 , —C(O)NHR 6 , —C(O)R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkyl, alkenyl, and alkynyl are optionally substituted one, two, or three times with R 7 ; each R 3 is independently selected from the group consisting of H, halo, C 1-3 alkyl, C 1-3 haloalkyl, and C 1 -3 alkoxy; and each R 6 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl; each R 7 is independently selected from the group consisting of halo, —OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and —CN; R 4 is selected from the group consisting of L 3 is selected from the group consisting of a bond, C 1 -C 4 alkyl, and NH; each of R E1 , R E2 , and R E3 is independently selected from the group consisting of H, halo, —CN, and C 1 -C 6 alkyl; a is 1 or 2; and each z is independently 0, 1, or 2.
  17. 57 . The compound of claim 56 , wherein the compound of Formula II is a compound of Formula IIa: or a pharmaceutically acceptable salt thereof; R 3 is H or halo; A is N or CH; and R 4
  18. 58 . The compound of claim 56 , wherein the compound of Formula II is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  19. 59 . A pharmaceutical composition comprising a compound of claim 56 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  20. 60 . A method of inactivating ARAF in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 56 .

Description

RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63/378,160 filed Oct. 3, 2022, the entire content of which is incorporate by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R35CA242461 awarded by the National Institutes of Health (NIH) and Grant No. F32CA247198 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention. BACKGROUND Mitogen-activated protein kinase kinase (MEK) is the central kinase in the three-tiered RAF/MEK/ERK cascade (also called the MAP kinase cascade). MEK can be activated by one or more of three RAF proteins ARAF, BRAF, or CRAF. Current MEK kinase inhibitors are relatively toxic and poorly tolerated, at least in part because they block most or all signaling through MEK, irrespective of how it was activated. Each of the three RAF isoforms can be mutationally activated in cancer. BRAF is very frequently mutated in cancer, whereas ARAF and CRAF are much less frequently mutated. As such, it would be desirable to have MEK inhibitors that could block signaling in a RAF-selective manner; i.e., MEK inhibitors that preferentially inhibit BRAF/MEK or ARAF/MEK, with relative sparing of signaling through the other isoforms. Treatment of cancers or other diseases by preferential inhibition of ARAF/MEK signaling is preferred. Activating ARAF mutations, though rare, have been identified in diverse cancers (doi: 10.1016/j.cell.2018.03.035). Additionally, activating ARAF mutations occur in Langerhans Cell Histiocytosis (doi: 10.1182/blood-2013-06-511139) and central conducting lymphatic anomaly (doi: 10.1038/s41591-019-0479-2). Activating mutations in ARAF have also been identified in intrahepatic cholangiocarcinoma (DOI: 10.1038/ncomms7087) and altered expression of ARAF has been implicated in development of hepatocellular carcinoma (Shilo et al. RNA 20:505-515). Treatment of these or other indications with the ARAF/MEK inhibitors disclosed herein could selectively block the signaling through ARAF. Additionally, signaling through ARAF has been identified as a mechanism of resistance to the Type II RAF inhibitor belvarafenib (https://doi.org/10.1038/s41586-021-03515-1). Treatment with an irreversible ARAF/MEK inhibitor of the present disclosure could be used to treat belvarafenib-resistant cancers in which this mechanism is at play. Finally, these compounds could be useful as a tool for studying the role of ARAF is cell signaling, development, or other contexts. The compounds provided herein are designed to irreversibly inactivate ARAF signaling through the ARAF/MEK pathway. They bind in a pocket in the ARAF/MEK complex that is formed primarily by MEK but is closed on one end by ARAF. The ARAF portion of the pocket includes a cysteine residue, ARAFCys514, that is unique to ARAF. These inactivators are designed to form a covalent bond with Cys514, resulting in irreversible inactivation of ARAF. They are not expected to irreversibly inactivate BRAF or CRAF, because these isoforms lack the target cysteine residue. Therefore, the compounds disclosed herein provide the potential for more selective inhibition of signaling through ARAF/MEK complexes, which should be more effective and/or better tolerated than current agents that indiscriminately inhibit MEK signaling. SUMMARY In an aspect, provided herein is a compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein the variables are defined herein. In an embodiment, the compound of Formula I is a compound of Formula Ia: or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein the variables are defined herein. In an embodiment, the compound of Formula II is a compound of Formula Ila: or a pharmaceutically acceptable salt thereof. In an aspect, provided herein is a method of treating cancer or a proliferation disease, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier. In one embodiment, the cancer is melanoma or carcinoma. In another aspect, provided herein is a method of inactivating the activity of ARAF in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier. The disclosure also provides a kit comprising a compound capable of inactivating ARAF activity selected from a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and instructions for use in treating cancer. DETAILED DESCRIPTION The present disclosure describes the selective inhibition of aberrant signaling through the RAF/MEK/ERK