Cbl-b Inhibitors and Methods of Use Thereof

Patent metadata

Field	Value
Publication number	US-2024425497-A1
Application number	US-202418654773-A
Country	US
Kind code	A1
Filing date	May 3, 2024
Priority date	May 5, 2023
Publication date	Dec 26, 2024
Grant date	—

Abstract

Disclosed herein are compounds that are Cbl-b inhibitors 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 haloalkyl, —C 1 -C 6 hydroxyalkyl, —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 ; 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, and —C 1 -C 3 alkoxy;
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;
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, O, and S; and said 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 4e 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;
R a and R b are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, phenyl, or —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl); or
R a and R b taken together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl optionally having one additional ring heteroatom selected from N, O, and S; wherein said 4- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halo, —CN, —C 1 -C 6 alkyl, and —C 1 -C 6 alkoxy.

2 . (canceled)

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

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

5 .- 6 . (canceled)

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

8 . (canceled)

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or —C 3 -C 4 cycloalkyl.

10 . (canceled)

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring formed by X 1 , X 2 , X 3 , and X 4 is selected from the group consisting of:

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to Formula Ia or Formula Ib:

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , when present, is —CN, —C 1 -C 6 haloalkyl, or —C 3 -C 4 cycloalkyl.

14 .- 15 . (canceled)

16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is phenyl, pyrazolyl, or pyridyl.

17 .- 19 . (canceled)

20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to Formula Id-1:

wherein m is 0 or 1.

21 . (canceled)

22 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently halo or —C 1 -C 6 alkyl.

23 . (canceled)

24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, phenyl, or —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl).

25 .- 26 . (canceled)

27 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a and R b taken together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl optionally having one

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
• Yin Xianglin
• Yu Kai
• Yu Tzu-Yu

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K45/06

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

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title