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US-20260124310-A1 - METHODS AND MATERIALS FOR MODULATING NRF2 PATHWAY

US20260124310A1US 20260124310 A1US20260124310 A1US 20260124310A1US-20260124310-A1

Abstract

The present application provides methods and compounds of modulating Nrf2 pathway. Methods for treating cancer and neurodegenerative conditions are also provided.

Inventors

  • Bakhos Tannous
  • Christian Badr
  • Ralph Mazitschek
  • Neil Connor Payne

Assignees

  • THE GENERAL HOSPITAL CORPORATION
  • PRESIDENT AND FELLOWS OF HARVARD COLLEGE

Dates

Publication Date
20260507
Application Date
20251124

Claims (20)

  1. 1 - 18 . (canceled)
  2. 19 . A compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: X 1 is selected from N and CR 1 ; X 2 is selected from N and CR 2 ; X 3 is selected from N and CR 3 ; X 4 is selected from N and CR 4 ; X 5 is selected from N and CR 5 ; provided that no more than three of X 1 , X 2 , X 3 , X 4 , and X 5 are N; R 1 , R 2 , R 3 , R 4 , R 5 , R 1 , and R 11 are each independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 and S(O) 2 NR c1 R d1 ; R 6 , R 6a , and R 7 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 and S(O) 2 NR c1 R d1 ; m is an integer from 2 to 20; each L is independently selected from N(R N ), O, C(═O), S, S(═O), S(═O) 2 , C 1-6 alkylene, C 3-7 cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C 6-10 arylene, —(OCH 2 CH 2 ) x —, —(CH 2 CH 2 O) x —, —(OCH(CH 3 )CH 2 ) x —, —(CH 2 CH(CH 3 )O) x —, each of which is optionally substituted with 1 or 2 substituents independently selected from OH, NH 2 , C(O)OH, SO 3 H, C 1-3 alkylamino, di(C 1-3 -alkyl)amino, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy; each x is independently an integer from 1 to 2,000; each R N is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; R A is independently selected from H and a targeting ligand capable of selectively binding to a protein; each R b1 is independently selected from H, C 1-12 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 cycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 cycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R g ; each R a1 , R c1 and R d1 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein aid C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 cycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R g ; each R a2 , R b2 , R c2 , and R d2 is in dependently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 cycloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 cycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R g ; or any R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R g ; or any R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R g ; and each R g is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkylene, HO—C 1-3 alkylene, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.
  3. 20 . The compound of claim 19 , wherein the compound of Formula (II) has formula: or a pharmaceutically acceptable salt thereof.
  4. 21 . The compound of claim 20 , wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 1 , and R 11 are each independently selected from H, halo, CN, NO 2 , OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, and di(C 1-6 alkyl)amino; R 6 , R 6a , and R 7 are each selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; m is an integer from 2 to 10; each L is independently selected from N(R N ), O, C(═O), C 1-6 alkylene, C 3-7 cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C 6-10 arylene, —(OCH 2 CH 2 ) x —, and —(CH 2 CH 2 O) x —; each x is independently an integer from 1 to 10; and each R N is independently selected from H and C 1-6 alkyl.
  5. 22 . The compound of claim 21 , wherein the compound has formula: or a pharmaceutically acceptable salt thereof, wherein: R 8 is selected from H and C 1-6 alkoxy.
  6. 23 . The compound of claim 19 , wherein R A is H.
  7. 24 . The compound of claim 19 , wherein R A is a targeting ligand capable of selectively binding to a protein.
  8. 25 . The compound of claim 24 , wherein the protein is implicated in the pathology of cancer.
  9. 26 . The compound of claim 24 , wherein the protein is implicated in the pathology of a neurodegenerative disease or condition.
  10. 27 . The compound of claim 19 , wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.
  11. 28 . A pharmaceutical composition comprising a compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R A is a targeting ligand capable of selectively binding to a protein, and a pharmaceutically acceptable carrier.
  12. 29 . A method of reducing level of a protein in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R A is a targeting ligand capable of selectively binding to the protein.
  13. 30 . The method of claim 29 , wherein contacting the cell is carried out in vitro, in vivo, or ex vivo.
  14. 31 . A method of treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R A is a targeting ligand capable of binding a protein that is implicated in cancer.
  15. 32 . A method of treating a neurological disease or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R A is a targeting ligand capable of binding a protein that is implicated in the neurological disease or condition.
  16. 33 .- 46 . (canceled)
  17. 47 . The compound of claim 19 , wherein the compound is: or a pharmaceutically acceptable salt thereof.
  18. 48 . A compound, which is: or a pharmaceutically acceptable salt thereof.
  19. 49 . A pharmaceutical composition comprising a compound of claim 48 , or a pharmaceutically acceptable salt thereof.
  20. 50 . A method of reducing level of a protein in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 48 , or a pharmaceutically acceptable salt thereof.

Description

CLAIM OF PRIORITY This application is a divisional application of U.S. patent application Ser. No. 17/765,667, filed Mar. 31, 2022, which is a national stage filing under 35 U.S.C. § 371 of PCT International Application No. PCT/US2020/054062, filed Oct. 2, 2020, which claims priority to U.S. Provisional Patent Application Ser. No. 62/909,375, filed on Oct. 2, 2019, the entire contents of which are hereby incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant number NS064983 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named “29539-0433002_SL_ST26.XML.” The XML file, created on Dec. 19, 2025, is 7,705 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD This invention relates to phenylallylidene compounds that are useful, for example, in treating diseases and conditions in which Nrf2/KEAP1 complex is implicated, such as a cancer or inflammatory conditions. BACKGROUND Cancer is one of the leading causes of death in contemporary society. The numbers of new cancer cases and deaths is increasing each year. Currently, cancer incidence is nearly 450 cases of cancer per 100,000 men and women per year, while cancer mortality is nearly 71 cancer deaths per 100,000 men and women per year. Likewise, inflammatory conditions and neurodegenerative diseases affect a significant segment of population. Neurodegenerative diseases especially affect the elderly. Alzheimer's disease (AD), a neurodegenerative disorder that affects approximately 44 million people world-wide, is the sixth leading cause of death with an estimated socioeconomic burden of more than $200 billion. SUMMARY The compounds described herein are capable of binding to cysteine residues and show affinity to cysteine-rich Keap1 protein, a member of CUL3 ubiquitin ligase complex. Advantageously, this binding promotes an overall stress response and results in ubiquitination and proteasomal degradation of KEAP1 and downstream activation of the Nrf2 pathway. The compounds are capable to penetrate the blood-brain barrier and functionally target brain cells and brain tumors. What is more, the compounds possess improved pharmacological properties, including potency, stability, and solubility, when compared to known compound obtusaquinone (“OBT”). The present application also advantageously provides compounds and conjugates useful as proteolysis targeting chimeras (“PROTAC”). That is, the compounds of this disclosure can be used as ubiquitin ligase recruiting moieties. In some embodiments, the present disclosure provides compound selected from of Formula (Ia) and Formula (Ib): or a pharmaceutically acceptable salt thereof, wherein:n is selected from 0, 1, and 2;X1 is selected from N and CR1;X2 is selected from N and CR2;X3 is selected from N and CR3;X4 is selected from N and CR4;X5 is selected from N and CR5;provided that no more than three of X1, X2, X3, X4, and X5 are N;R1, R2, R3, R4, R5 and R11 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRcC(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1 and S(O)2NRc1Rd1;R6 and R7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1 and S(O)2NRc1Rd1;R8 is selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd