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

Patent metadata

Field	Value
Publication number	US-12060367-B2
Application number	US-202318314445-A
Country	US
Kind code	B2
Filing date	May 9, 2023
Priority date	Dec 1, 2021
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

Abstract

The present invention encompasses compounds of formula (I)

wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 to R 5 , A, p, U, V and W have the meanings given in the claims and specification, their use as inhibitors of KRAS, 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;
or R 6a and R 6b together with the carbon atom they are attached to form a cyclopropane ring;
n is selected from the group consisting of 0, 1 and 2;
R 3 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, —N 3 , C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more, identical or different R 7 and/or R 8 ;
each R 7 is independently selected from the group consisting of —OR 8 , —NR 8 R 8 , halogen, —CN, —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 8 , —NHC(═O)OR 8 and the bivalent substituent ═O;
each R 8 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 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 9 and/or R 10 ;
each R 9 is independently selected from the group consisting of —OR 10 , —NR 10 R 10 and —C(O)NR 10 R 10 ;
each R 10 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, C 3-10 cycloalkyl and 3-11 membered heterocyclyl optionally substituted with C 1-6 alkyl;

W is nitrogen (—N═) or —CH═;
V is nitrogen (—N═) or —CH═;
U is nitrogen (—N═) or —C(R 11 )═;
R 11 is selected from hydrogen, halogen and C 1-4 alkoxy;

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 of 0, 1, 2 and 3;
R 5 is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different C 1-6 alkyl, C 1-6 alkoxy or a 5-6 membered heterocyclyl, wherein the C 1-6 alkyl is optionally substituted with cyclopropyl;
or R 5 is —O—C 1-6 alkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R 12 ,
each R 12 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen and 3-11 membered heterocyclyl;

or a salt thereof.

2. A compound according to claim 1 of the formula (Ia) or its salt

 wherein
A, V, U, W, R 3 and R 5 are defined as in claim 1 .

3. A compound according to claim 1 of the formula (Ib) or its salt

 wherein
A, V, U, W, R 3 and R 5 are defined as in claim 1 .

4. The compound or its salt according to claim 1 , wherein
ring A is selected from

5. The compound or its salt according to claim 1 , wherein
R 3 is selected from the group consisting of 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more, identical or different R 7 and/or R 8 ;
each R 7 is independently selected from the group consisting of —OH, C 1-6 alkoxy, —NR 8 R 8 , halogen, —CN, —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 8 , —NHC(═O)OR 8 and the bivalent substituent ═O;
each R 8 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 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 9 and/or R 10 ;
each R 9 is independently selected from the group consisting of —OR 10 , —NR 10 R 10 and —C(O)NR 10 R 10 ;
each R 10 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, C 3-10 cycloalkyl and 3-11 membered heterocyclyl optionally substituted with C 1-6 alkyl.

6. The compound or its salt according to claim 1 , wherein
R 3 is selected from the group consisting of 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the 3-11 membered heterocyclyl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more, identical or different R 7 and/or R 8 ;
each R 7 is independently selected from the group consisting of —OR 8 , —NR 8 R 8 , halogen, —CN, —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 8 , —NHC(═O)OR 8 and the bivalent substituent ═O;
each R 8 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 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 9 and/or R 10 ;
each R 9 is —OH or C 1-6 alkoxy;
each R 10 is independently selected from the group consisting of C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

7. The compound or its salt according to claim 1 , wherein
R 5 is selected from the group consisting of

8. The compound or its salt according to claim 7 , wherein
R 5 is selected from the group consisting of

Assignees

• Boehringer Ingelheim Int
• Univ Vanderbilt

Inventors

• Broeker Joachim
• Abbott Jason
• Cui Jianwen
• Fesik Stephen W
• Fuchs Julian
• Gollner Andreas
• Herdeis Lorenz
• Hodges Tim
• Little Andrew
• Mantoulidis Andreas
• Phan Jason
• Ramharter Juergen
• Sarkar Dhruba
• Smethurst Christian Alan Paul
• Sokol Kevin
• Stadtmueller Heinz
• Sun Qi
• Treu Matthias
• Waterson Alex
• Wilding Birgit
• Wunberg Tobias

Classifications

• C07B2200/07

  Optical isomers · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/10

  Spiro-condensed systems · CPC title

• C07D495/10

  Spiro-condensed systems · CPC title