Bicyclic HPK1 inhibitors

Patent metadata

Field	Value
Publication number	US-12486264-B2
Application number	US-202017442655-A
Country	US
Kind code	B2
Filing date	Mar 24, 2020
Priority date	Mar 26, 2019
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as HPK1 inhibitors, useful for treating diseases such as cancer.

First claim

The invention claimed is:

1 . A compound of Formula (I)

or a tautomer or a stereoisomeric form thereof, wherein
the dotted bond towards R 1b is an optional bond that may be present when R 1b and R 4b are taken together to form a monocyclic or bicyclic aromatic heterocyclyl as defined herein;
A 1 represents CH or N; A 2 represents CH; A 3 represents CH or N;
provided that only one of A 1 and A 3 represents N;
A 4 represents CH or N; A 5 represents N or CR 3b ; A 6 represents CH;
R 1a represents hydrogen;
R 1b represents hydrogen or CH 3 ;
R 4a represents hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl;
R 4b represents hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or
a carbon linked monocyclic 4-, 5-, 6- or 7-membered non-aromatic heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from the group consisting of N, O, and S;
wherein said S-atom might be substituted to form S(═O), S(═O) 2 , or S(═O)(═NR x );
or
R 1b and R 4b are taken together to form together with the atoms to which they are attached a monocyclic 5-membered aromatic heterocyclyl or a monocyclic 4-, 5-, 6- or 7-membered fully saturated heterocyclyl, each containing 1 N-atom and optionally 1 or 2 additional heteroatoms each independently selected from the group consisting of N, O, S; wherein said optional S-atom might be substituted to form S(═O), S(═O) 2 , or S(═O)(═NR x ); or
a bicyclic 6- to 12-membered aromatic or fully saturated heterocyclyl containing 1 N-atom and optionally 1 or 2 additional heteroatoms each independently selected from the group consisting of N, O, S; wherein said optional S-atom might be substituted to form S(═O), S(═O) 2 , or S(═O)(═NR x );
wherein said monocyclic or bicyclic, aromatic or fully saturated heterocyclyl might be substituted on one or more of the carbon atoms with in total 1, 2 or 3 substituents each independently selected from the group consisting of —OH, CN, halo, R 7 , —O—R 7 , —S(═O) 2 —R 7 , —C(═O)—R 7 , —NR 6c R 6d , —C(═O)—NR 6a R 6b , and Het c ;
wherein said monocyclic or bicyclic, aromatic or fully saturated heterocyclyl might be substituted on the optional additional nitrogen atoms with in total 1 or 2 substituents each independently selected from the group consisting of R 7 , —S(═O) 2 —R 7 , —C(═O)—R 7 , —C(═O)—NR 6a R 6b and Het d ;
provided that in case R 1b and R 4b are taken together, R 4a represents hydrogen; and
R 1a represents hydrogen or R 1a is absent when the dotted bond towards R 1b is a bond;
or
R 4a and R 4b are taken together to form together with the N-atom to which they are attached a monocyclic 5-, 6- or 7-membered aromatic heterocyclyl or a monocyclic 4-, 5-, 6- or 7-membered fully saturated heterocyclyl, each containing 1 N-atom and optionally 1 or 2 additional heteroatoms each independently selected from the group consisting of N, O, S;
wherein said optional S-atom might be substituted to form S(═O), S(═O) 2 , or S(═O)(═NR x ); or
a bicyclic 6- to 12-membered aromatic or fully saturated heterocyclyl containing 1 N-atom and optionally 1 or 2 additional heteroatoms each independently selected from the group consisting of N, O, S; wherein said optional S-atom might be substituted to form S(═O), S(═O) 2 , or S(═O)(═NR x );
wherein said monocyclic or bicyclic, aromatic or fully saturated heterocyclyl might be substituted on one or more of the carbon atoms with in total 1, 2 or 3 substituents each independently selected from the group consisting of —OH, CN, halo, R 7 , —O—R 7 , —S(═O) 2 —R 7 , —C(═O)—R 7 , —NR 6c R 6d , —C(═O)—NR 6a R 6b , and Het c ;
wherein said monocyclic or bicyclic, aromatic or fully saturated heterocyclyl might be substituted on the nitrogen atoms with in total 1 or 2 substituents each independently selected from the group consisting of R 7 , —S(═O) 2 —R 7 , —C(═O)—R 7 , —C(═O)—NR 6a R 6b , and Het d ;
in case R 4a and R 4b are taken together, R 1a represents hydrogen, and R 1b represents hydrogen;
R 2 is;
C 1-6 alkyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, —OH, cyano, and —O—C 1-4 alkyl;
C 3-6 cycloalkyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, —OH, cyano and —O—C 1-4 alkyl; and
C 3-6 cycloalkenyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, —OH, cyano and —O—C 1-4 alkyl;
R 3a represents hydrogen, halo, cyano, —NR 6e R 6f , —C(═O)—NR 6g R 6h , or
C 1-4 alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, CF 3 , —NR 6e R 6f and —C(═O)—NR 6g R 6h ;
R 3b represents hydrogen, halo, cyano, or C 1-4 alkyl optionally substituted by 1, 2 or 3 halo atoms;
R 6a , R 6b , R 6c , and R 6d are each independently selected from the group consisting of hydrogen;
C 3-6 cycloalkyl optionally substituted with one —OR 5 ; and C 1-4 alkyl optionally substituted with one —OR 5 , wherein two hydrogen atoms on the same carbon atom of said C 1-4 alkyl might be taken together to form C 3-6 cycloalkyl;
R 6e , R 6f , R 6g , and R 6h are each independently selected from the group consisting of hydrogen;
—S(═O) 2 —R 7 ; C 3-6 cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of —OR 5 , Het g , and Het e ; and C 1-6 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of —OR 5 , —NR 9a —C(═O)—R 9b , Het 9 , and Het e , wherein two hydrogen atoms on the same carbon atom of said C 1-6 alkyl might be taken together to form C 3-6 cycloalkyl wherein optionally one carbon atom is replaced by an heteroatom selected from nitrogen, oxygen and sulfur;
R 5 represents hydrogen or C 1-4 alkyl;
R 8a , R 8c , and R 8d are each independently selected from the group consisting of hydrogen;
C 1-4 alkyl optionally substituted with one —OH or —O—C 1-4 alkyl; and C 3-6 cycloalkyl optionally substituted with one —OH or —O—C 1-4 alkyl;
R 8b is selected from the group consisting C 1-4 alkyl optionally substituted with one —OH or —O—C 1-4 alkyl; and C 3-6 cycloalkyl optionally substituted with one —OH or —O—C 1-4 alkyl;
or
R 8a and R 8b , or R 8c and R 8d are taken together to form together with the N-atom to which they are attached a monocyclic fully saturated heterocyclyl containing 1 N-atom and optionally 1 or 2 additional heteroatoms each independently selected from the group consisting of N, O, S;
wherein said optional S-atom might be substituted to form S(═O), S(═O) 2 , or S(═O)(═NR x );
wherein said monocyclic 4-, 5-, 6- or 7-membered fully saturated heterocyclyl might be substituted on one or more of the carbon atoms with in total 1, 2 or 3 substituents each independently selected from the group consisting of —OH, CN, halo, R 7 , —O—R 7 , —S(═O) 2 —R 7 , —C(═O)—R 7 , —NR 6c R 6d , and
—C(═O)—NR 6a R 6b ;
wherein said monocyclic fully saturated heterocyclyl might be substituted on the nitrogen atoms with in total 1 or 2 substituents each independently selected from the group consisting of R 7 , —S(═O) 2 —R 7 , —C(═O)—R 7 , and —C(═O)—NR 6a R 6b ;
R 9a represents hydrogen or C 1-4 alkyl;
R 9b represents hydrogen or C 1-4 alkyl optionally substituted with 1, 2 or 3 halo atoms;
each Het c independen

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Mevellec Laurence Anne
• Vialard Jorge Eduardo
• Coupa Sophie
• Adelinet Christophe Denis Pascal
• Wroblowski Berthold
• Edwards James Patrick

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title