Methods and materials for modulating Nrf2 pathway

Patent metadata

Field	Value
Publication number	US-12521439-B2
Application number	US-202017765667-A
Country	US
Kind code	B2
Filing date	Oct 2, 2020
Priority date	Oct 2, 2019
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

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

First claim

What is claimed is:

1 . A compound selected from Formula (Ia) and Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:
n is selected from 0, 1, and 2;
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 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 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 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 ,
R 8 is selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, ORal, 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 , ORal, 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 9 and R 10 are each independently selected from H, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;
R 12 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and a peptide, 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, 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 ;
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 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 a2 , R b2 , R c2 , and R d2 is independently 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.

2 . The compound of claim 1 , wherein the compound is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 2 , wherein the compound of Formula (Ia) has formula:

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 , wherein:
R 1 , R 2 , R 3 , R 4 , R 5 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 and R 7 are each selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; R 8 is selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 9 and R 10 are each independently selected from H and C(O)R b1 ; each R b1 is independently C 1-12 alkyl; R 12 is selected from C 1-6 alkyl and a peptide, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OR a1 , SR a1 , C(O)OR a1 , and NR c1 R d1 ; each R a1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, and C(O)R b2 ; and each R b2 is independently selected from C 1-6 alkyl and C 1-4 haloalkyl.

5 . The compound of claim 4 , wherein the compound has formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 8 is C 1-6 alkoxy.

6 . The compound of claim 1 , selected from any one of the following compounds:

Assignees

• Massachusetts Gen Hospital
• Harvard College

Inventors

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

Classifications

• C07C323/16 Primary

  the carbon skeleton containing six-membered aromatic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• C07K5/06026

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• C07K5/0215

  containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu · CPC title