Tetrahydrobenzoazepinones and related analogs for inhibiting YAP/TAZ-TEAD

Patent metadata

Field	Value
Publication number	US-12378202-B2
Application number	US-202218145902-A
Country	US
Kind code	B2
Filing date	Dec 23, 2022
Priority date	Dec 23, 2021
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

The present disclosure relates to novel compounds, to said compounds for use as a medicine, more in particular for the prevention or treatment of diseases mediated by activity of YAP/TAZ-TEAD transcription, yet more in particular for the prevention or treatment of cancer or fibrosis. The present disclosure also relates to a method for the prevention or treatment of said diseases comprising the use of the novel compounds.

First claim

The invention claimed is:

1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
p is 0, 1, or 2;
R 1 is selected from the group consisting of:
(i) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5)
—OZ 1 ,
(6) C 2 -C 6 alkenyl, and
(7) C 2 -C 6 alkynyl,

(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 ,

(c) C 2 -C 6 alkynyl,

(ii) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl,
(f) —OZ 1 , and
(g) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,
(iii) unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl,
(f) —OZ 1 , and
(g) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,

(iv)unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl, and
(f) —OZ 1 ,

(v) unsubstituted or substituted C 3 -C 6 heterocycle, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl, and
(f) —OZ 1 ,
(vi) —S(═O) 2 Z 2 , and
(vii) —C(═O)Z 2 ;

R 2 and R 3 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or
R 2 and R 3 taken together with the carbon atom to which they are attached form a —C(═O)— group;
R 4 is selected from the group consisting of hydrogen and —NR 10a R 10b ;
R 5 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each R 6 and R 7 is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 8 and R 9 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or
R 8 and R 9 taken together with the carbon atom to which they are attached form a —C(═O)— group;
R 10a is selected from the group consisting of:
(i) —C(═O)Z 2
(ii) —C(═O)OZ 2 ,
(iii) —C(═O)NZ 3 Z 4 ,
(iv) —S(═O) 2 Z 2 ,
(v) —S(═O) 2 NZ 3 Z 4 ,
(vi) —S(═O)(═NZ)Z 2 ,
(vii) —S(═NZ 5 )(═NZ 6 )Z 2 ,
(viii) —S(═O)(═NZ 5 )NZ 3 Z 4 , and
(ix) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) cyano,
(b) hydroxy,
(c) —OZ 1 ,
(d) —C(═O)OH
(e) —C(═O)Z 2
(f) —C(═O)OZ 2 ,
(g) —C(═O)NZ 3 Z 4 ,
(h) —S(═O) 2 Z 2 ,
(i) —S(═O) 2 NZ 3 Z 4 ,
(j) —S(═O)(═NZ 5 )Z 2 ,
(k) —S(═NZ 5 )(═NZ 6 )Z 2 ,
(l) —S(═O)(═NZ 5 )NZ 3 Z 4 , and
(m) —NZ 3 Z 4 ,

R 10b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each Z 1 is independently selected from the group consisting of:
(i) hydrogen,
(ii) C 1 -C 6 alkyl,
(iii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 2 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , and 4- to 8-membered heterocycle,
(iv) C 2 -C 6 alkynyl,
(v) C 3 -C 6 cycloalkyl,
(vi) C 3 -C 6 cycloalkenyl, and
(vii) C 1 -C 6 haloalkyl;

each Z 2 is independently selected from the group consisting of:
(i) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C 2 -C 6 alkynyl;
(ii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 2 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , 4- to 8-membered heterocycle,
(iii) C 2 -C 6 alkynyl,
(iv) C 3 -C 6 cycloalkyl,
(v) C 3 -C 6 cycloalkenyl,
(vi) C 1 -C 6 haloalkyl,
(vii) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 , and
(viii) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ;
each Z 3 and Z 4 are independently selected from the group consisting of:
(i) hydrogen;
(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl,
(6) —OZ 1 ,
(7) C 2 -C 6 alkenyl, and
(8) C 2 -C 6 alkynyl,

(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 ,

(c) unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl,
(6) —OZ 1 ,
(7) C 2 -C 6 alkenyl, and
(8) C 2 -C 6 alkynyl,

(d) cyano,
(e) hydroxy,
(f) —OZ 1 , and
(g) —NZ 3 Z 4 ,

(iii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 2 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , 4- to 8-membered heterocycle,
(iv) C 2 -C 6 alkynyl,
(v) C 3 -C 6 cycloalkyl,
(vi) C 3 -C 6 cycloalkenyl, and
(vii) C 1 -C 6 haloalkyl;

each Z 5 and Z 6 are independently selected from the group consisting of:
(i) hydrogen,
(ii) C 1 -C 6 alkyl, and
(iii) C 3 -C 6 cycloalkyl;

X is selected from the group consisting of —CR 11a ═ and —N═;
X 1 is selected from the group consisting of —CR 11b ═ and —N═;
X 2 is selected from the group consisting of —CR 11c ═ and —N═;
X 3 is selected from the group consisting of —CR 11d ═ and —N═; and
each R 11a , R 11b , R 11c , and R 11d is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and —NZ 3 Z 4 .

2. The compound of claim 1 of Formula II:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

3. The compound of c

Assignees

• The Katholieke Univ Leuven
• Springworks Therapeutics Inc
• Vib Vzw
• Univ Leuven Kath

Inventors

• Vanderhoydonck Bart
• Marchand Arnaud
• Candi Aurélie
• Versele Matthias

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D215/227

  only one oxygen atom which is attached in position 2 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/4704

  2-Quinolinones, e.g. carbostyril · CPC title