Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer
Inventors
ABBOTT, Jason • BROEKER, Joachim • CUI, Jianwen • FESIK, Steve W. • Gollner, Andreas • HODGES, Tim • KAROLYI-OEZGUER, Jale • Little, Andrew • Mantoulidis, Andreas • Phan, Jason • Sarkar, Dhruba • Smethurst, Christian Alan Paul • Sun, Qi • Treu, Matthias • Waterson, Alex
Assignees
Boehringer Ingelheim International GmbH • Vanderbilt University
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Publication Number
US-12545670-B2
Publication Date
2026-02-10
Expiration Date
Abstract
The present invention encompasses compounds of formula (I) wherein R1a, R1b, R2a, R2b, Z, R3 to R5, A, p, U, V, W, L and E have the meanings given in the claims and specification, their use as inhibitors of mutant Ras family proteins, pharmaceutical compositions and preparations containing such compounds and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases.
Core Innovation
The disclosure concerns compounds of formula (II), including salts, defined by multiple independently selectable structural variables. The scaffold includes R1a/R1b and R2a/R2b with optional cyclopropane ring formation, Z defined as —(CR6aR6b)n— with n selected from 0, 1 and 2, and ring A selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole.
Further variability is provided by R3, optional R4, p selected from 0, 1, 2 and 3, and U, V, and W each selected from nitrogen or carbon substituted with RA, RB, or RC. The substituent sets RA, RB, and RC and the R5 group are defined by broad lists of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, cyano, hydroxyl, carbonyl-containing, sulfonyl-containing, cycloalkyl, heterocyclyl, aryl, and heteroaryl classes.
The structure also includes a linker L defined as —L1—L2—L3—, where L1 is linked to the hydrogen of residue H-L- and each linker segment is selected from defined bond, heteroatom-containing, alkylene, cycloalkylene, phenylene, heterocyclylene, and heteroarylene classes with optional substitution. The disclosure also states that the compounds are inhibitors of mutant Ras family proteins, with emphasis on KRAS G12C, and that the compounds covalently bind KRAS G12C via an electrophilic moiety characterized as a Michael acceptor.
Claims Coverage
The provided claim coverage centers on one independent claim: a compound of formula (II) or a salt thereof. The inventive features comprise six core feature groups: variable R1a/R1b and R2a/R2b with optional cyclopropane formation, variable Z and ring A selection, R3 and optional R4, U/V/W defined as nitrogen or carbon-substituted forms with RA/RB/RC, R5 selection, and the three-part linker L1-L2-L3.
Compound of formula (II) with variable R1 and R2 substituents
R1a and R1b are independently selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, halogen, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C3-5 cycloalkyl and 3-5 membered heterocyclyl; R2a and R2b are independently selected from the same group; and one of R1a or R1b and one of R2a or R2b can together with the carbon atoms they are attached form a cyclopropane ring.
Variable Z and ring A selection
Z is —(CR6aR6b)n— with n selected from 0, 1 and 2, each R6a and R6b being independently selected from hydrogen and the listed C1-4 substituent classes, and ring A is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole.
R3, optional R4, and heteroatom-defined U, V, W
R3 is selected from hydrogen and the listed C1-6 substituent classes, each R4 if present is independently selected from the listed C1-6 substituent classes, and U, V, and W are each selected from nitrogen or carbon substituted with RA, RB, or RC as defined by the listed substituent options.
R5 selection from Ra1 and Rb1 classes
R5 is selected from Ra1 and Rb1, with Ra1 selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 3-11 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more identical or different Rb1 and/or Rc1.
Three-segment linker L1-L2-L3
L is —L1—L2—L3—, with L1 linked to the hydrogen of residue H-L- and each of L1, L2 and L3 selected from defined bond, heteroatom-containing, alkylene, cycloalkylene, phenylene, heterocyclylene, and heteroarylene classes with optional substitution as stated.
The claim coverage is centered on a formula (II) compound or salt with variable substituent architecture, optional cyclopropane ring formation, defined Z and ring A selection, U/V/W substitution patterning, R5 class selection, and a constrained three-segment linker L1-L2-L3.
Stated Advantages
Inhibits mutant Ras family proteins, particularly KRAS G12C.
Covalently binds KRAS G12C via an electrophilic moiety.
Impairs access to the active conformation.
Provides selective antiproliferative cellular effects.
Modulates biomarker pERK.
Shows favorable selectivity, permeability, solubility, and PK properties.
Documented Applications
Cancer treatment and/or cancer prevention using pharmaceutical compositions comprising the compounds.
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