Aza-tetracyclic oxazepine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-12338256-B2
Application number	US-202418676200-A
Country	US
Kind code	B2
Filing date	May 28, 2024
Priority date	May 19, 2022
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

Provided herein are aza-tetracyclic oxazepinyl compounds useful in the treatment of cancers.

First claim

What is claimed is:

1. A compound of formula (I):

or an atropisomer, or pharmaceutically acceptable salt thereof,
wherein:
X is NR 6 ;
m is 1 or 2;
n is 1 or 2;
wherein n and m together make a 6- or 7-membered ring Ring A;
p is 0, 1, or 2;
R 1 is (E2) or (E3)

each R 7A is independently hydrogen, halogen, unsubstituted C 1-3 alkyl or unsubstituted C 1-3 haloalkyl; wherein at least one R 7A is unsubstituted C 1-3 haloalkyl;
L 1 is R L1 -substituted or unsubstituted C 1-4 alkylene;
R L1 is halogen or unsubstituted C 1-3 alkyl, or two R L1 together form an unsubstituted C 3-4 cycloalkyl;
R 2 is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, and O;
each R 9 is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3 alkyl, R 10 -substituted or unsubstituted C 1-3 haloalkyl, unsubstituted C 1-3 alkoxy, R 10 -substituted or unsubstituted C 1-3 alkylidene, R 10 -substituted or unsubstituted C 3-4 cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle;
or two R 9 together form an R 10 -substituted or unsubstituted C 3-5 cycloalkyl or an R 10 -substituted or unsubstituted C 3-5 heterocycle comprising one or more oxygen atoms;
or two R 9 together form a bridge between two carbon atoms of the heterocycle, wherein the bridge comprises 1-3 carbons;
each R 10 is independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;
R 3 is hydrogen, —CN, halogen, unsubstituted C 1-3 alkyl, or unsubstituted cyclopropyl;
one R 4 is hydrogen and one R 4 is methyl;
each R 5 is independently halogen, oxo, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl;
or two R 5 together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N;
or two R 5 together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of O or NR 11 ;
R 11 is hydrogen, C(O)CH 3 , or unsubstituted C 1-3 alkyl; and
R 6 is hydrogen.

2. The compound or an atropisomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein L 1 is methylene.

3. The compound or an atropisomer, or pharmaceutically acceptable salt thereof, of claim 1 , wherein R 2 is

wherein:
each R 9 is independently halogen or R 10 -substituted or unsubstituted C 1-3 alkylidene;
r is an integer of 0-12;
j is 1, 2, or 3; and
k is 1 or 2.

4. The compound or an atropisomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 2 is:

5. The compound or an atropisomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 2 is:

wherein X 3 is CR 9 , NR 9 , or O; and r is 0 or 1.

6. The compound or an atropisomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 2 is:

and r is 0 or 1.

7. The compound or an atropisomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is fluoro.

8. The compound or an atropisomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein two R 5 together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 2 carbon atoms.

9. The compound or an atropisomer, or pharmaceutically acceptable salt thereof of claim 8 , wherein the compound of formula (I) is a compound of the formula:

or an atropisomer, or pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound of claim 4 , or an atropisomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

11. The compound or an atropisomer, or pharmaceutically acceptable salt thereof, of claim 1 , wherein R 1 is:

12. The compound or an atropisomer, pharmaceutically acceptable salt thereof, of claim 11 , wherein R 1 is:

13. The compound or an atropisomer or pharmaceutically acceptable salt thereof, of claim 1 , wherein m and n are both 1.

14. The compound or an atropisomer or pharmaceutically acceptable salt thereof, of claim 1 , wherein
m and n are both 1;
p is 2, and the two R 5 together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 2 carbon atoms;
L 1 is methylene;
R 2 is

wherein:
each R 9 is independently halogen or R 10 -substituted or unsubstituted C 1-3 alkylidene;
r is an integer of 0-12;
j is 1, 2, or 3; and
k is 1 or 2;

and R 3 is fluoro.

15. A compound selected from the group consisting of:

or an atropisomer, or pharmaceutically acceptable salt thereof.

16. The compound of claim 15 , wherein the compound is selected from the group consisting of:

or an atropisomer, or pharmaceutically acceptable salt thereof.

17. The compound of claim 16 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 16 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 16 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 16 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 16 , wherein the compound is:

Assignees

• Genentech Inc

Inventors

• Landry Matthew Leo
• Nilewski Christian
• Siu Michael
• Villemure Elisia
• Wei Binqing
• Do Steven
• Gazzard Lewis John
• Green Samantha Alyson

Classifications

• 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

• C07D498/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title