Tetrahydropyridopyrimidines and related analogs for inhibiting YAP/TAZ-TEAD

Patent metadata

Field	Value
Publication number	US-12516064-B2
Application number	US-202318163583-A
Country	US
Kind code	B2
Filing date	Feb 2, 2023
Priority date	Feb 2, 2022
Publication date	Jan 6, 2026
Grant date	Jan 6, 2026

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. The present disclosure furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds as well as to said compositions or preparations for use as a medicine, more preferably 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 processes for the preparation of said compounds.

First claim

The invention claimed is:

1 . A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
R 1 and R 2 are 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) 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) 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 ,
(vi) 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 ;

Y 1 is selected from the group consisting of:
(i) —N(R 4a )—,
(ii) —CR 6e R 6f N(R 4a )—, and
(iii) —CR 6g R 6h CR 6i (NR 5a R 5b )—;

R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 3a is 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) hydroxy,
(b) —OZ 1 ,
(c) 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) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , and —NZ 3 Z 4 ,
(4) C 1 -C 6 haloalkyl,
(5) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and —NZ 3 Z 4 ,
(6) —C(═O) NZ 3 Z 4 ,
(7) —NZ 3 Z 4 ,
(8) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of—NZ 3 Z 4 and 4-to 8-membered heterocycle,
(9) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ 1 , C 1 -C 6 alkyl, cyano, hydroxy, and C 1 -C 6 haloalkyl,
(10) unsubstituted or substituted 4-to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl,
(11) —OZ 1 ,
(12) —C(═O) OH,
(13) hydroxy,
(14) —NZ 5 C(═O) Z 2 ,
(15) —NZ 5 S(═O) 2 Z 2 , and
(16) —NZ 5 S(═O) 2 NZ 3 Z 4 ,

(d) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) C 1 -C 6 alkyl, and
(2) C 1 -C 6 haloalkyl,

(e) unsubstituted or substituted 5-to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , and —NZ 3 Z 4 ,
(4) C 1 -C 6 haloalkyl,
(5) C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and —NZ 3 Z 4 ,
(6) —C(═O) NZ 3 Z 4 ,
(7) —NZ 3 Z 4 ,
(8) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of—NZ 3 Z 4 ,
(9) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ 1 , C 1 -C 6 alkyl, cyano, hydroxy, and C 1 -C 6 haloalkyl,
(10) unsubstituted or substituted 4-to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl,
(11) —OZ 1 ,
(12) —C(═O) OH,
(13) hydroxy, and
(14) —NZ 5 C(═O) Z 2 ,

(iii) C 1 -C 6 haloalkyl;
(iv) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen and C 1 -C 6 alkyl;
(v) unsubstituted or substituted 4-to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of:
(a) C 1 -C 6 alkyl,
(b) —C(—O) Z 2 , and
(c) —S(═O) 2 Z 8 ,

(vi) unsubstituted or substituted 5-to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ 1 , and —NZ 3 Z 4 ,
(d) C 1 -C 6 haloalkyl,
(e) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and —NZ 3 Z 4 ,
(f) —C(═O) NZ 3 Z 4 ,
(g) —NZ 3 Z 4 ,
(h) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ 3 Z 4 and 4-to 8-membered heterocycle
(i) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ 1 , C 1 -C 6 alkyl, cyano, hydroxy, and C 1 -C 6 haloalkyl,
(j) unsubstituted or substituted 4-to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl,
(k) —OZ 1 ,
(l) —C(

Assignees

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

Inventors

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

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D403/04

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title