Compounds and methods for modulating HER2
Inventors
Kulyk, Svitlana • Wright, Shawn • Dennis, Joseph • DERRICOTTE, Wallace • Botrous, Iriny • Gomez, Laurent
Assignees
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Publication Number
US-12145948-B2
Publication Date
2024-11-19
Expiration Date
Abstract
Disclosed are compounds of Formula (I):or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein R1, R2, A, E1, E2, and G are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.
Core Innovation
The invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, tautomers, stereoisomers, and deuterated analogs thereof, defined by variables A, E1, E2, R1, R2, G, L1, R3, W, X, Y, R4, L2, and R with extensive structural constraints on ring size, heteroatom content, linkage patterns, and optional substitution counts. The structure specifies A as N or CH, E1 as N or C(CN), E2 as C(R4) or N, and R1 as alkyl, haloalkyl, or halogen, while R2 is an O-linked or NH-linked substituent class selected from enumerated aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and heteroaryl-alkylene-aryl options.
A central feature of the formula is the definition of G as -L1-R3 or -W-X-Y. L1 is selected from a bond, -C(O)-, -S(O)2-, -N(Rc)-, alkylene, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, with optional substitution limits and a specific CH2 attachment restriction in some claim language, and R3 is defined as a 4-9 membered heterocyclic ring or a 7-11 membered spirocyclic group containing at least one nitrogen ring atom, with one nitrogen substituted with -L2-R.
The W-X-Y alternative further defines W as a bond, -C(O)-, or -S(O)2-, X as aryl, heteroaryl, heterocycloalkyl, or cycloalkyl optionally substituted with J2 groups, and Y as a set of linked functional-group and heterocycle-containing moieties, including C0-C4 alkylene-N(Rd)-L2-R and other carbonyl-, heterocycle-, alkylene-, alkynylene-, and pyrrole-2,5-dione-related patterns. The patent also defines L2 as -SO2- or -C(O)-, R as ethenyl or ethynyl optionally substituted with Q groups, or alternative alkylene, cyano, or haloalkyl forms, and includes pharmaceutically acceptable salts, tautomers, stereoisomers, and deuterated analogs as embodiments.
Claims Coverage
The claim coverage centers on a single independent claim defining a broad compound genus of Formula (I) with extensive structural constraints. Dependent claims refine the genus by narrowing substituent selections, ring sizes, substitution counts, and specific templates for G, X, Y, R2, and R.
Formula (I) compound class with defined variable scaffold
A compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein A is N or CH, E1 is N or C(CN), E2 is C(R4) or N, R1 is alkyl, haloalkyl or halogen, and R2 is an O-linked or NH-linked substituent class selected from enumerated aryl, heteroaryl, cycloalkyl, and heterocycloalkyl options with optional substitution limits.
G defined by L1-R3 or W-X-Y linkage rules
G is -L1-R3 or -W-X-Y, where L1 is a bond, -C(O)-, -S(O)2-, -N(Rc)-, alkylene, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and R3 is a 4-9 membered heterocyclic ring or a 7-11 membered spirocyclic group containing at least one nitrogen ring atom, with one nitrogen substituted with -L2-R.
W-X-Y functional-group and linker definition
W is a bond, -C(O)-, or -S(O)2-, X is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl optionally substituted with J2 groups, and Y is selected from defined alkylene-linked, heterocycle-linked, carbonyl-containing, unsaturated, and pyrrole-2,5-dione-related moieties with stated optional substitution limits.
L2 and R substituent system
L2 is -SO2- or -C(O)-, and R is ethenyl optionally substituted with 1-3 Q groups, ethynyl optionally substituted with Q, C1-C4 alkylene-NRaRb, -CH2-CN, or haloalkyl, with Q selected from the enumerated substituent set and further optional substitution rules applying to related variables.
Dependent claim refinements to ring size and substitution counts
Dependent claims refine the genus by specifying narrower forms such as X as a 5-10 membered heteroaryl optionally substituted with 1-3 J2 groups, Y as C0-C4 alkylene-N(H)-L2-R, R as ethenyl optionally substituted with 1-3 Q groups, and additional template constraints for G, R2, and the nested J, J2, J3, and J4 substitution sets.
The claim set is centered on a broad Formula (I) genus and its dependent refinements, which define compounds through tightly constrained variable definitions for the scaffold, linker architecture, ring systems, and substituent classes. The inventive coverage is driven by the coupled definitions of G, R3, W, X, Y, L2, and R, together with enumerated optional substitution limits and narrowed dependent-claim templates.
Stated Advantages
Reduced EGFR-related toxicity while inhibiting wild-type and mutant HER2.
Cell growth inhibition against HER2/EGFR is reported for several examples and stereoisomers.
Actively inhibits HER2-YVMA, HER2 WT, and EGFR WT.
Documented Applications
Treating HER2-mediated diseases, including NSCLC.
HER2, EGFR, and HER2-YVMA cell growth inhibition testing is reported for the examples.
Biological testing of compounds in a HER2/EGFR-targeted kinase inhibitor series, reporting active inhibition of HER2-YVMA, HER2 WT, and EGFR WT.
Therapeutic uses directed to HER2-driven cancers having HER2 YVMA insertion mutations, including use in pharmaceutical compositions and combination therapy with additional listed anticancer agents.
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