Aza-tetracyclic oxazepine compounds and uses thereof
Inventors
LANDRY, Matthew Leo • NILEWSKI, Christian • Siu, Michael • Villemure, Elisia • Wei, BinQing • Do, Steven • Gazzard, Lewis John • GREEN, Samantha Alyson
Assignees
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Publication Number
US-12338256-B2
Publication Date
2025-06-24
Expiration Date
Abstract
Provided herein are aza-tetracyclic oxazepinyl compounds useful in the treatment of cancers.
Core Innovation
The invention relates to compounds of formula (I), or an atropisomer, or a pharmaceutically acceptable salt thereof, defined by a fused ring framework in which n and m together make a 6- or 7-membered ring Ring A. The structural scope includes X as NR6, p as 0, 1, or 2, and variable substituent groups R1 through R6, together with L1 and the substituent groups R7A, R9, R10, and R11.
Ring A and the attached substituents are defined by R1 as (E2) or (E3), with each R7A independently hydrogen, halogen, unsubstituted C1-3 alkyl, or unsubstituted C1-3 haloalkyl, and at least one R7A as unsubstituted C1-3 haloalkyl. L1 is R(L1)-substituted or unsubstituted C1-4 alkylene, and R(L1) is halogen or unsubstituted C1-3 alkyl, or two R(L1) together form an unsubstituted C3-4 cycloalkyl. R2 is an R9-substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, and O.
The invention further defines R3 as hydrogen, —CN, halogen, unsubstituted C1-3 alkyl, or unsubstituted cyclopropyl, with R4 as hydrogen and one R4 as methyl. R5 is independently halogen, oxo, unsubstituted C1-3 alkyl, or unsubstituted C1-3 haloalkyl, or two R5 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 one of O or NR11; R11 is hydrogen, C(O)CH3, or unsubstituted C1-3 alkyl, and R6 is hydrogen.
Claims Coverage
The independent claim coverage includes a broad compound of formula (I) and a separate selection claim directed to specific compounds from a group of structural variants, each including atropisomers and pharmaceutically acceptable salts. The main inventive scope is the defined fused Ring A scaffold and the detailed substituent-variable definitions across the formula.
Compound of formula (I) with fused Ring A
A compound of formula (I), or an atropisomer, or a pharmaceutically acceptable salt thereof, wherein X is NR6; m is 1 or 2; n is 1 or 2; n and m together make a 6- or 7-membered ring Ring A; and p is 0, 1, or 2.
R1 and R7A substitution pattern
R1 is (E2) or (E3), each R7A is independently hydrogen, halogen, unsubstituted C1-3 alkyl, or unsubstituted C1-3 haloalkyl, and at least one R7A is unsubstituted C1-3 haloalkyl.
L1-defined linker group
L1 is R(L1)-substituted or unsubstituted C1-4 alkylene, where R(L1) is halogen or unsubstituted C1-3 alkyl, or two R(L1) together form an unsubstituted C3-4 cycloalkyl.
Heterocycle-defined R2 substituent
R2 is an R9-substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, and O.
R3, R4, R5, R11, and R6 constraints
R3 is hydrogen, —CN, halogen, unsubstituted C1-3 alkyl, or unsubstituted cyclopropyl; one R4 is hydrogen and one R4 is methyl; R5 is independently halogen, oxo, unsubstituted C1-3 alkyl, or unsubstituted C1-3 haloalkyl, or two R5 together form a bridge between two carbon atoms of Ring A; R11 is hydrogen, C(O)CH3, or unsubstituted C1-3 alkyl; and R6 is hydrogen.
Selected group of specific compounds
A compound selected from the group consisting of specific structural variants, or an atropisomer, or a pharmaceutically acceptable salt thereof.
Claim coverage centers on a formula (I) fused-ring genus with extensive substituent and bridging constraints, together with a separate selection claim for specific structural variants, including atropisomers and pharmaceutically acceptable salts.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Cancer treatment using compounds as KRas mutant inhibitors/modulators, including KRas G12D mutant protein.
Pharmaceutical compositions with pharmaceutically acceptable excipients.
Tissue-agnostic treatment of cancer patients with KRas mutations, including lung, pancreatic, and colorectal cancers.
Assays for evaluating Ras signaling and kit/article-of-manufacture concepts.
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