Ras inhibitors
Inventors
Burnett, G. Leslie • Cregg, James • Edwards, Anne V. • Gill, Adrian L. • Knox, John E. • Koltun, Elena S. • Pitzen, Jennifer • Semko, Christopher
Assignees
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Publication Number
US-12252497-B2
Publication Date
2025-03-18
Expiration Date
Abstract
The invention features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.
Core Innovation
The invention relates to a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, defined by variable groups A, W, X1, m, n, R1, R2, and R3. A is optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heteroarylene, and W is a cross-linking group selected from epoxide, carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, trifluoromethyl ketone, boronic acid, boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivative, oxazolium, or glycal.
X1 is CH2 or O, m is 1 or 2, and n is 0 or 1. R1 is hydrogen or optionally substituted 3 to 10-membered heterocycloalkyl, R2 is optionally substituted C1-C6 alkyl, and R3 is optionally substituted C1-C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl. The disclosure includes embodiments with fluorinated substituents, sulfur-containing heteroaryl motif elements, and stereochemical variants.
The disclosure includes preparation of representative compounds and intermediates within the Formula I framework, including multi-step synthetic routes, deprotection, coupling, borylation, and functionalization sequences. The described examples and tables report structures, yields, and LCMS data for intermediates and final products, and include examples featuring heterocyclic cores such as thiazole, oxazole, phenyl, and other heteroaryl or fused ring systems.
Claims Coverage
The claim coverage centers on one independent Formula I compound claim and one pharmaceutical composition claim. The independent claim defines the broad scaffold through A, W, X1, m, n, R1, R2, and R3, and dependent claims refine A, W, and R2.
Formula I compound scaffold
A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heteroarylene; W is a cross-linking group comprising epoxide, carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, trifluoromethyl ketone, boronic acid, boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivative, oxazolium, or glycal; X1 is CH2 or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen or optionally substituted 3 to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Restricted A group
A is optionally substituted thiazole, optionally substituted oxazole, or optionally substituted phenyl.
A limited to 5 to 10-membered heteroarylene
A is optionally substituted and is a 5- to 10-membered heteroarylene.
R2 selected from illustrated substituent options
R2 is a specified substituent shown in the accompanying structural drawings, including an option labeled CF3.
W includes an epoxide
W includes an epoxide.
The claims are anchored by the Formula I scaffold and its defined variable groups. Dependent claims further narrow A to specific heterocycles or phenyl, constrain A by ring size, specify R2 from illustrated options including CF3, restrict W to include an epoxide, and add a pharmaceutical composition with a pharmaceutically acceptable excipient.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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