Inhibitors of KEAP1-Nrf2 protein-protein interaction

Patent metadata

Field	Value
Publication number	US-11897900-B2
Application number	US-202017127569-A
Country	US
Kind code	B2
Filing date	Dec 18, 2020
Priority date	Aug 20, 2018
Publication date	Feb 13, 2024
Grant date	Feb 13, 2024

Abstract

Sultam compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with the KEAP1-Nrf2 interaction, such as inflammatory bowel disease, including Crohn's disease and ulcerative colitis.

First claim

What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof

(I)
wherein
X is CH or N;
Q is CH or N;
M is CH;
wherein
when X is N, Q is CH;
when Q is N, X is CH;
R 15 is CH 3 or Cl;
R 13 is H, F or C 1 -C 4 alkyl;
R 14 is H, F or C 1 -C 4 alkyl;
HetA is selected from the group consisting of

wherein
R 1 is selected from the group consisting of C 3 -C 4 cycloalkyl, C 1 -C 4 alkyl and C 1 -C 4 alkyl monosubstituted with cyclopropyl or cyclobutyl;
R 2 is selected from the group consisting of H, C 1 -C 4 alkyl and C 1 -C 4 perhaloalkyl;
R 3 is H or C 1 -C 4 alkyl;
R 4 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 perhaloalkyl and C 3 -C 4 cycloalkyl;
R 7 is H or C 1 -C 4 alkyl;
R 8 is C 1 -C 4 alkyl;
R 9 is C 1 -C 4 alkyl;
R 10 is selected from the group consisting of H, —OC 3 -C 4 cycloalkyl and —OC 1 -C 4 perhaloalkyl;
HetB is selected from the group consisting of

wherein
Z is selected from the group consisting of O, CH 2 , NH and N(CH 3 );
T is CH or N;
Y is CH or N;
W is CH or N;
V is O or N(CH 3 );
R 16 is H or F;
R 17 is H or F;
n is 0, 1 or 2;
R 18 is selected from the group consisting of H, —CN, halo, C(O)NH 2 , C 1 -C 4 alkyl and C 1 -C 4 perhaloalkyl;
R 19 is selected from the group consisting of H; CN; halo; C(O)NH 2 ;
N(R 38 )C 1 -C 6 alkyl; C 1 -C 4 alkyl; C 1 -C 4 perhaloalkyl;

OC 1 -C 6 alkyl;
OC 1 -C 6 alkyl substituted with one or two substituents selected from the group consisting of —OH, —OCH 3 , —O(CH 2 ) 3 OH, —N(R 36 )R 37 , C 1 -C 4 alkyl,

—N(R 38 )C 1 -C 6 alkyl substituted with one or two substituents selected from the group consisting of OH, —OCH 3 , —N(R 36 )R 37 , C 1 -C 4 alkyl,

and
C 1 -C 4 alkyl monosubstituted with a substituent selected from the group consisting of —C(O)NHCH 2 CH 2 OH, —C(O)NHCH 2 CH 2 OCH 2 CH 2 NH 2 , C(O)NH 2 and OH;
R 20 is H or C 1 -C 4 alkyl;
R 21 is selected from the group consisting of H, —CN, halo, C 1 -C 4 alkyl and C 1 -C 4 perhaloalkyl;
R 22 and R 23 are taken together with the carbon to which they are attached to form
(a) the moiety

wherein R is selected from the group consisting of CH 2 , NR 38 and O, m is 0 or 1, and p is 0 or 1; or
(b) the moiety

R 22′ is selected from the group consisting of H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, and
R 23′ is selected from the group consisting of H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl;
R 24 is selected from the group consisting of H; CN; halo; C(O)NH 2 ;
C(O)(NH)C 3 -C 4 cycloalkyl; N(R 38 )C 1 -C 6 alkyl; C 1 -C 4 alkyl; C 1 -C 4 perhaloalkyl;

OC 1 -C 6 alkyl;
OC 1 -C 6 alkyl substituted with one or two substituents selected from the group consisting of —OH, —OCH 3 , —O(CH 2 ) 3 OH, —N(R 36 )R 37 , C 1 -C 4 alkyl;

N(R 38 )C 1 -C 6 alkyl substituted with one or two substituents selected from the group consisting of OH, —OCH 3 , —N(R 36 )R 37 , C 1 -C 4 alkyl,

and
C 1 -C 4 alkyl monosubstituted with a substituent selected from the group consisting of —C(O)NHCH 2 CH 2 OH, —C(O)NHCH 2 CH 2 OCH 2 CH 2 NH 2 , C(O)NH 2 and OH;
R 25 is selected from the group consisting of H; CN; halo; C(O)NH 2 ;
N(R 38 )C 1 -C 6 alkyl; C 1 -C 4 alkyl; C 1 -C 4 perhaloalkyl;

OC 1 -C 6 alkyl;
OC 1 -C 6 alkyl substituted with one or two substituents selected from the group consisting of —OH, —OCH 3 , —O(CH 2 ) 3 OH, —N(R 36 )R 37 , C 1 -C 4 alkyl,

—N(R 38 )C 1 -C 6 alkyl substituted with one or two substituents selected from the group consisting of —OH, —OCH 3 , —N(R 36 )R 37 , C 1 -C 4 alkyl,

and
C 1 -C 4 alkyl monosubstituted with a substituent selected from the group consisting of —C(O)NHCH 2 CH 2 OH, —C(O)NHCH 2 CH 2 OCH 2 CH 2 NH 2 , C(O)NH 2 and OH;
R 26 is selected from the group consisting of H, —CN, halo, C 1 -C 4 alkyl and C 1 -C 4 perhaloalkyl;
R 27 is H or C 1 -C 4 alkyl;
R 36 and R 37 are independently selected from the group consisting of H and C 1 -C 4 alkyl;
R 38 is H or C 1 -C 4 alkyl;
provided that when HetA is

then HetB is not

2. The compound as claimed in claim 1 , wherein HetA is

3. The compound as claimed in claim 1 , wherein HetB is selected from the group consisting of

4. The compound as claimed in claim 1 , wherein R 1 is C 1 -C 2 alkyl, R 10 is H and R 2 is CH 3 .

5. The compound as claimed in claim 1 , wherein R 4 is C 1 -C 4 alkyl or C 1 -C 4 perhaloalkyl.

6. The compound as claimed in claim 1 , wherein R 4 is C 1 -C 2 perhaloalkyl, R 3 is C 1 -C 2 alkyl and R 7 is H.

7. The compound as claimed in claim 1 , wherein HetB is

R 22 and R 23 are taken together with the carbon to which they are attached to form the moiety

wherein R is CH 2 or O, m is 0 or 1, and p is 0 or 1.

8. The compound as claimed in claim 1 , wherein HetB is

R 22 and R 23 are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 0 or 1, and p is 0 or 1.

9. The compound as claimed in claim 1 , wherein HetB is

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Barbay J Kent
• Chai Wenying
• Hirst Gavin C
• Kreutter Kevin D
• Kummer David A
• Mcclure Kelly J
• Nishimura Rachel T
• Shih Amy Y
• Venable Jennifer D
• Venkatesan Hariharan
• Wei Jianmei

Classifications

• C07D513/14 Primary

  Ortho-condensed systems · CPC title

• C07D417/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D419/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title