Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-11945812-B2
Application number	US-202117335620-A
Country	US
Kind code	B2
Filing date	Jun 1, 2021
Priority date	Jun 2, 2020
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

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.

First claim

The invention claimed is:

1. A compound of the formula (I)

wherein
R 1a and R 1b are both independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
R 2a and R 2b are both independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
and/or, optionally, one of R 1a or R 1b and one of R 2a or R 2b together with the carbon atoms they are attached form a cyclopropane ring;
Z is —(CR 6a R 6b ) n —;
each R 6a and R 6b is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
n is selected from the group consisting 0, 1 and 2;
R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, halogen, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole;
each R 4 , if present, is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, halogen, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
p is selected from the group consisting 0, 1, 2 and 3;
U is selected from the group consisting of nitrogen (═N—) and carbon substituted with R A (═C(R A )—);
V is selected from the group consisting of nitrogen (═N—) and carbon substituted with R B (═C(R B )—);
W is selected from the group consisting of nitrogen (═N—) and carbon substituted with R c (═C(R C )—);
R A , R B and R C is each independently selected from the group consisting of hydrogen, to C 1-6 haloalkyl, C 2-6 alkynyl optionally substituted with C 3-5 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , —S—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, C 3-5 cycloalkyl, 3-5 membered heterocyclyl and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 ;
R 5 is selected from the group consisting of R a1 and R b1 ;
R a1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —CN, —C(═O)R c1 , —C(═O)OR c1 , —C(═O)NR c1 R c1 , —S(═O) 2 R c1 , —S(═O) 2 NR c1 R c1 , —NHC(═O)R c1 , —N(C 1-4 alkyl)C(═O)R c1 , —NHS(═O) 2 R c1 , —N(C 1-4 alkyl)S(═O) 2 R c1 , —NHC(═O)OR c1 , —N(C 1-4 alkyl)C(═O)OR c1 and the bivalent substituent ═O;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 , halogen, —CN, —C(═O)R e1 , —C(═O)OR e1 , —C(═O)NR e1 R e1 , —S(═O) 2 R e1 , —S(═O) 2 NR e1 R e1 , —NHC(═O)R e1 , —N(C 1-4 alkyl)C(═O)R e1 , —NHS(═O) 2 R c1 , —N(C 1-4 alkyl)S(═O) 2 R c1 , —NHC(═O)OR e1 , —N(C 1-4 alkyl)C(═O)OR e1 and the bivalent substituent ═O;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C 1-4 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, —OH, C 1-6 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, hydroxy-C 1-4 alkyl, halogen, —CN, —NH 2 , —C(═O)C 1-4 alkyl, —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 and the bivalent substituent ═O;

L is -L 1 -L 2 -L 3 -, wherein L 1 is linked to E;
L 1 is selected from the group consisting of a bond, —NH—, —N(C 1-4 alkyl)-, —O—, —C(═O)—, —NH—C(═O)—, —N(C 1-4 alkyl)-C(═O)—, —C(═O)—NH—, —C(═O)—N(C 1-4 alkyl)-, —C(═O)—, C 1-6 alkylen, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene;
L 2 is selected from the group consisting of C 1-6 alkylen, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene;
L 3 is selected from the group consisting of a bond, —NH—, —N(C 1-4 alkyl)-, —O—, —C(═O)—, —NH—C(═O)—, —N(C 1-4 alkyl)-C(═O)—, —C(═O)—NH—, —C(═O)—N(C 1-4 alkyl)-, —C(═O)—, C 1-6 alkylen, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene;
wherein each C 1-6 alkylen, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene in L 1 , L 2 and L 3 is optionally and independently substituted with one or more, identical or different substituent(s) selected from the group consisting of C 2-6 alkinyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, halogen, —OH, —CN, C 1-6 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)—OC 1-6 alkyl, —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , the bivalent substituent ═O and C 1-6 alkyl optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of halogen, —OH, —CN, C 1-4 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)—OC 1-6 alkyl, —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 ;
E is

represents a double or a triple bond;
Q 1 is selected from the group consisting of a bond, —CH 2 —, —CH(OH)—, —C(═O)—, —C(═O)N(R G1 )—, —C(═O)O—, —S(═O) 2 —, —S(═O) 2 N(R G1 )— and —C(═NR H1 )—;
to each R G1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-C 1-6 alkyl, H 2 N—C 1-6 alkyl, cyano-C 1-6 alkyl, (C 1-4 alkyl)HN—C 1-6 alkyl, (C 1-4 alkyl) 2 N—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl and 3-11 membered heterocyclyl;
each R H1 is independently selected from the group consisting of hydrogen, —OH, C 1-6 alkoxy, —CN an

Assignees

• Boehringer Ingelheim Int
• Univ Vanderbilt

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

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title