Biaryl derivatives as YAP/TAZ-TEAD protein-protein interaction inhibitors

Patent metadata

Field	Value
Publication number	US-12083101-B2
Application number	US-202117201268-A
Country	US
Kind code	B2
Filing date	Mar 15, 2021
Priority date	Mar 16, 2020
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;

a method for manufacturing said compound, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition comprising said compound.

First claim

The invention claimed is:

1. A compound of formula (Ia), or a pharmaceutically acceptable salt thereof,

wherein
X is selected from CH and N;
A is selected from
(i) phenyl, wherein the phenyl is optionally substituted with halo; or haloC 1 -C 3 alkoxy;
(ii) a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, wherein the aromatic heterocyclic ring is optionally substituted with hydroxy; C 1 -C 3 alkoxy; or oxo; and
(iii) a halobenzodioxole moiety of formula

R w is selected from (i) hydrogen; (ii) hydroxy; (iii) C 1 -C 3 alkoxy; (iv) hydroxy-C 1 -C 3 alkyl; (v) C 1 -C 3 alkyl; and (vi) C 1 -C 3 alkoxy-C 1 -C 3 alkyl;
Q is selected from (i) —C(R 7 ) 2 -N(R 8 )—R 1 ; (ii) 9- or 10-membered partially saturated heteroaryl comprising at least one N heteroatom; and (iii) 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom or heteroatom group selected from N, O, S, —S(═O) and —S(═O) 2 , with the proviso that at least one N heteroatom is present, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo and C 1 -C 3 alkylene forming a bridge between two ring atoms of the saturated heterocyclic ring, thus forming a bridged bicyclic structure;
R 1 is selected from (i) hydrogen; (ii) C 1 -C 6 alkyl which is optionally deuterated; and (iii) (CH 2 ) 0-2 R 1a ;
R 1a is selected from (i) hydroxyC 1 -C 4 alkyl; (ii) C 1 -C 3 alkoxy; (iii) a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O, wherein the saturated heterocyclic ring is optionally substituted with one or more substituents independently selected from C 1 -C 3 alkyl; (CH 2 ) 0-1 C(O)di(C 1 -C 3 alkyl)amino; SO 2 C 1 -C 3 alkyl; C(O)C 1 -C 3 alkyl; or oxo; and (iv) C 3 -C 6 cycloalkyl optionally substituted with one or more substituents independently selected from hydroxy; hydroxyC 1 -C 4 alkyl; C 1 -C 6 alkoxy; C(O)OC 1 -C 3 alkyl; CO 2 H; SO 2 C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; NHR 1b ; (CH 2 ) 0-1 C(O)NR 1c R 1d ; C 1 -C 6 alkyl; haloC 1 -C 3 alkoxy-C 1 -C 3 alkyl; halo; a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S; and two R 1c groups,
wherein the two R 1c attached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O, or a C 3 -C 6 cycloalkyl, wherein the saturated heterocyclic ring or cycloalkyl are optionally substituted with hydroxy or oxo;
R 1b is selected from (i) C(O)C 1 -C 3 alkyl; and (ii) SO 2 C 1 -C 3 alkyl;
R 1c and R 1d are each independently selected from (i) hydrogen; (ii) C 1 -C 3 alkyl; and (iii) hydroxyC 1 -C 4 alkyl;
R 2 is selected from (i) hydrogen; and (ii) halo;
R 3 is selected from (i) halo; (ii) haloC 1 -C 3 alkyl; and (iii) cyano;
R 4 is selected from (i) hydrogen; (ii) halo; and (iii) C 1 -C 3 alkyl;
R 5 is selected from (i) hydrogen; (ii) C 1 -C 6 alkoxy optionally substituted with C 3 -C 6 cycloalkyl; CO 2 H; SO 2 C 1 -C 3 alkyl; a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S; or a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O, wherein the ring is optionally substituted with C(O)C 1 -C 3 alkyl; (iii) halo; (iv) hydroxyC 1 -C 6 alkoxy, wherein the alkoxy is optionally deuterated; (v) haloC 1 -C 6 alkoxy optionally substituted with hydroxy; (vi) S-haloC 1 -C 3 alkyl optionally substituted with hydroxy; (vii) C 1 -C 3 alkoxyC 1 -C 3 alkoxy; (viii) NR 5a R 5b ; (ix) C 1 -C 3 alkyl; (x) a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S; and (xi) hydroxy;
R 5a and R 5b are each independently selected from (i) hydrogen; and (ii) C 1 -C 3 alkyl; or
R 5a and R 5b together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring, wherein the saturated heterocyclic ring optionally in addition carries a hydroxy group;
R 6 is selected from (i) hydrogen; (ii) cyano; (iii) C(O)NR 6a ; (iv) NHR 6b ; and (v) C 1 -C 3 alkoxy substituted with NH 2 or hydroxy;
R 6a is selected from (i) hydrogen; (ii) C 1 -C 3 alkyl; (iii) C 3 -C 6 cycloalkyl; and (iv) a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, wherein the aromatic heterocyclic ring is optionally substituted with C 1 -C 3 alkyl;
R 6b is C 1 -C 3 alkyl substituted with NH 2 or hydroxy;
R 7 is each independently selected from hydrogen and C 1 -C 3 alkyl; and
R 8 is hydrogen or C 1 -C 3 -alkyl.

2. A compound of formula (Ia) according to claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound of formula (Ic)

or a pharmaceutically acceptable salt thereof.

3. A compound of formula (Ia) according to claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound of formula (Id)

or a pharmaceutically acceptable salt thereof.

4. A compound of formula (Ia) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
X is selected from CH and N;
A is selected from
(i) phenyl, wherein the phenyl is optionally substituted with halo; or haloC 1 -C 3 alkoxy;
(ii) a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, wherein the aromatic heterocyclic ring is optionally substituted with hydroxy; C 1 -C 3 alkoxy; or oxo; and
(iii) a halobenzodioxole moiety of formula

R w is selected from (i) hydrogen; (ii) hydroxy; (iii) C 1 -C 3 alkoxy; (iv) hydroxy-C 1 -C 3 alkyl; (v) C 1 -C 3 alkyl; and (vi) C 1 -C 3 alkoxy-C 1 -C 3 alkyl;
Q is selected from (i) —C(R 7 ) 2 —N(R 8 )—R 1 ; (ii) 9- or 10-membered partially saturated heteroaryl comprising at least one N heteroatom; and (iii) 4-, 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O and S, with the proviso that at least one N heteroatom is present, and wherein the N is optionally present in the α-position to the atom binding Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo and a methylene group, wherein the methylene group forms a bridge between two ring atoms of the saturated heterocyclic ring, thus forming a bridged bicyclic structure;
R 1 is selected from hydrogen; C 1 -C 6 alkyl; and (CH 2 ) 0-2 R 1a wherein
R 1a is selected from (i) C 1 -C 3 alkoxy; (ii) C 3 -C 6 cycloalkyl optionally substituted with one or more substituents independently selected from hydroxy;
hydroxyC 1 -C 4 alkyl; C 1 -C 4 alkoxy; C(O)OC 1 -C 3 alkyl; CO 2 H; C(O)NR 1c R 1d ; C 1 -C 6 alkyl; halo; haloC 1 -C 3 alkoxy-C 1 -C 3 alkyl; SO 2 C 1 -C 3 alkyl; haloC 1 -C 3 alkyl; NHR 1b ; C(O)NR 1c R 1d ; a 5- or 6-membered

Assignees

• Novartis Ag

Inventors

• Bordas Vincent
• Brocklehurst Cara
• Chene Patrick
• Furet Pascal
• Guagnano Vito
• Imbach-Weese Patricia
• Kallen Joerg
• Le Douget Mickael
• Lorthiois Edwige Liliane Jeanne
• Mckenna Joseph
• Salem Bahaa
• Schmelzle Tobias
• Sellner Holger
• Soldermann Nicolas
• Voegtle Markus
• Wartmann Markus

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D491/04

  Ortho-condensed systems · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title