Cbl-b inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2025011318-A1
Application number	US-202418673794-A
Country	US
Kind code	A1
Filing date	May 24, 2024
Priority date	May 25, 2023
Publication date	Jan 9, 2025
Grant date	—

Abstract

Disclosed herein are compounds having a structure according to Formula I, and compositions containing those compounds. Methods of preparing the compounds, and methods of using the compounds for the treatment of diseases, disorders, or conditions are also described.

First claim

1 . A compound having a structure according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
A has a formula selected from the group consisting of:

wherein:
R 1 is selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, -(Q 1 )-O—(C 1 -C 3 alkyl), —C(O)NH 2 , —C(O)—(C 1 -C 6 -alkyl), -(Q 1 )-NR 1a R 1b , -(Q 1 )-(C 3 -C 7 cycloalkyl), -(Q 1 )-(5- to 6-membered heteroaryl), and -(Q 1 )-(4- to 8-membered heterocycloalkyl); wherein said 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S; said 4- to 8-membered heterocycloalkyl has 1-3 ring heteroatom or heteroatom groups independently selected from N, O, S, and S(O) 2 ; said C 1 -C 3 alkyl is unsubstituted or substituted with —C 1 -C 3 alkoxy; and said C 3 -C 7 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are unsubstituted or substituted with 1-2 substituents independently selected from halo, —OH, —C 1 -C 3 alkyl, —C 1 -C 3 alkoxy, and —C(O)(C 1 -C 3 alkyl);
Q 1 is absent, unsubstituted —(C 1 -C 3 alkylene)-, or —(C 1 -C 3 alkylene)- substituted with 1-3 R q ;
each R q is independently halo, —OH, or —NH 2 ;
R 1a and R 1b are independently selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, phenyl, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), —S(O) 2 (C 1 -C 6 alkyl), 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, and 4- to 8-membered heterocycloalkyl having 1-3 ring heteroatom or heteroatom groups independently selected from N, O, S, and S(O) 2 ; wherein said phenyl, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), 5- to 6-membered heteroaryl, and 4- to 8-membered heterocycloalkyl are unsubstituted or substituted with 1-3 R 1c ;
each R 1c , when present, is independently halo, —OH, —C 1 -C 3 alkyl, —C 1 -C 3 hydroxyalkyl, or —C 1 -C 3 haloalkyl;
R 2 , when present, is —H, halo, —CN, —C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, —C 3 -C 4 cycloalkyl, —S(O) 2 (C 1 -C 3 alkyl), —C(O)—NR 2a R 2b , or 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; or
R 1 and R 2 taken together with the atoms to which they are attached form —C 3 -C 6 cycloalkyl;
R 2a and R 2b are independently —H, or —C 1 -C 3 alkyl;
R 3 , when present, is —H, —CN, halo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —C 2 -C 3 alkenyl, —C 3 -C 4 cycloalkyl, —S(O) 2 (C 1 -C 6 alkyl), —C(O)OH, or 5- to 6-membered heteroaryl having 1 to 4 ring heteroatoms independently selected from N, S, and O; and the 5- to 6-membered heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from —C 1 -C 3 alkyl;
X 1 , X 2 and X 3 are each independently N or CH;
X 4 is N or CR 4 ;
R 4 , when present, is —H, halo, —CN, —OH, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —NR 4a R 4b or —C 3 -C 8 cycloalkyl;
R 4a and R 4b are independently —H, —C 1 -C 3 alkyl, or —(C 1 -C 3 alkylene)-NR 4c R 4d ;
R 4c and R 4d are independently —H, or —C 1 -C 3 alkyl;
Y is phenyl, or 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S;
m is 0, 1, 2, or 3;
each R 5 when present, is independently halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or —C 1 -C 6 alkoxy;
when ring A has a structure of formula (i), (ii), (iii), (iv), (v), or (vi), R 6 is a 5- to 6-membered heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S, wherein R 6 is unsubstituted or substituted with 1-3 R 6a ; or
when ring A has a structure of formula (vii), (viii), or (ix), R 6 is a 6-membered heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S, wherein R 6 is unsubstituted or substituted with 1-3 R 6a ; and
each R 6a is independently selected from the group consisting of —CN, —C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, and —C 1 -C 3 hydroxyalkyl.

2 . (canceled)

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, -(Q 1 )-O—(C 1 -C 3 alkyl), -(Q 1 )-NR 1a R 1b , -(Q 1 )-(C 3 -C 7 cycloalkyl), -(Q 1 )-(5- to 6-membered heteroaryl), and -(Q 1 )-(4- to 8-membered heterocycloalkyl); wherein said 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S; said 4- to 8-membered heterocycloalkyl has 1-3 ring heteroatom or heteroatom groups independently selected from N, O, S, and S(O) 2 ; said C 1 -C 3 alkyl is unsubstituted or substituted with —C 1 -C 3 alkoxy; and said C 3 -C 7 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are unsubstituted or substituted with 1-2 substituents independently selected from halo, —OH, —C 1 -C 3 alkyl, —C 1 -C 3 alkoxy, and —C(O)(C 1 -C 3 alkyl); Q 1 is absent, unsubstituted —(C 1 -C 3 alkylene)- or —(C 1 -C 3 alkylene)- substituted with 1-3 R q ; each R q is independently halo, —OH, or —NH 2 ; R 1a and R 1b are independently selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), and 4- to 8-membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; wherein said —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), and 4- to 8-membered heterocycloalkyl are unsubstituted or substituted with 1-3 R 1c ; and each R 1c , when present, is independently halo, —OH, —C 1 -C 3 alkyl, or —C 1 -C 3 hydroxyalkyl.

4 . (canceled)

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C 1 -C 6 hydroxyalkyl, -(Q 1 )-NR 1a R 1b or -(Q 1 )-(4- to 8-membered heterocycloalkyl) having 1-3 ring heteroatom or heteroatom groups independently selected from N, O, S, and S(O) 2 ; and said 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1-2 substituents independently selected from halo, —OH, —C 1 -C 3 alkyl, and —C 1 -C 3 alkoxy.

6 . (canceled)

7 . (canceled)

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 , when present is —H or —CN.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 taken together with the atoms to which they are attached form —C 5 -C 6 cycloalkyl.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 , when present, is —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 3 -C 4 cycloalkyl, or —S(O) 2 (C 1 -C 6 alkyl).

11 . (canceled)

12 . (canceled)

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure of Formula Ia:

14 .- 16 . (canceled)

17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —H, —CN, —F, —Cl, —CH 3 , —CF 3 , —OH, —OCH 3 , —OCH 2 CH 3 ,

Assignees

• Arcus Biosciences Inc

Inventors

• Gangam Srikanth Kumar
• Hardman Clayton
• Lawson Kenneth Victor
• Leleti Manmohan Reddy
• Liu Dongdong
• Mailyan Artur Karenovich
• Podunavac Masa
• Qu Shiwei
• Wang Zhang
• Yin Xianglin
• Yu Kai
• Yu Tzu-Yu

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61K31/5386

  spiro-condensed or forming part of bridged ring systems · CPC title