Aza-tetracyclic oxazepine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-2026062425-A1
Application number	US-202519190368-A
Country	US
Kind code	A1
Filing date	Apr 25, 2025
Priority date	May 19, 2022
Publication date	Mar 5, 2026
Grant date	—

Abstract

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

First claim

1 - 81 . (canceled)

82 . A method of treating lung cancer comprising a KRas G12D mutation in a patient having such lung cancer, the method comprising administering to the patient an effective amount of a compound of formula (I)

or an atropisomer, or pharmaceutically acceptable salt thereof,
wherein:
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; and
one R 4 is hydrogen and one R 4 is methyl.

83 . The method of claim 82 , wherein L 1 is methylene.

84 . The method of claim 82 , wherein R 2 is:

or a stereoisomer thereof,
wherein:
R 9 is independently halogen or R 10 -substituted or unsubstituted C 1-3 alkylidene;
each R 10 is independently hydrogen or halogen; and
r is 1 or 2.

85 . The method of claim 82 , wherein R 2 is:

86 . The method of claim 82 , wherein R 1 is:

87 . The method of claim 82 , wherein the compound of formula (I) is selected from the group consisting of:

or an atropisomer, or pharmaceutically acceptable salt thereof.

88 . The method of claim 8 , wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.

89 . The method of claim 82 , wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.

90 . The method of claim 82 , wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.

91 . The method of claim 82 , wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.

92 . The method of claim 82 , wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.

93 . The method of claim 82 , wherein the compound of formula (I) is:

94 . The method of claim 82 , wherein the compound of formula (I) is:

95 . The method of claim 82 , wherein the compound of formula (I) is:

96 . The method of claim 82 , wherein the compound of formula (I) is:

97 . The method of claim 82 , wherein the compound of formula (I) is:

98 . A method of treating pancreatic cancer comprising a KRas G12D mutation in a patient having such lung cancer, the method comprising administering to the patient an effective amount of a compound of formula (I)

or an atropisomer, or pharmaceutically acceptable salt thereof,
wherein:
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 L i-substituted or unsubstituted C 1-4 alkylene;
R L i 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

Assignees

• Genentech Inc

Inventors

• Landry Matthew Leo
• Nilewski Christian
• Siu Michael
• Villemure Elisia
• Wang Yong
• Wei Binqing
• Ashley Melissa Ann
• 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