Disubstituted alkyne derivatives

Patent metadata

Field	Value
Publication number	US-12351570-B2
Application number	US-201917311930-A
Country	US
Kind code	B2
Filing date	Dec 20, 2019
Priority date	Dec 21, 2018
Publication date	Jul 8, 2025
Grant date	Jul 8, 2025

Abstract

The present invention relates to disubstituted alkyne derivatives. These compounds are useful for the prevention and/or treatment of several medical conditions including hyperproliferative disorders and diseases.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
W denotes CR W1 or N;
R W1 is H, halogen, R a or —OR a ;
R 1 is —OH, —OR a , —NH 2 , —NHR a , —NR a R b , —N(H)OH, —N(H)O—R a , —N(H)CN, —N(H)—C(═O)—R a or —N(H)—SO 2 —R a ; or R 1 together with R 2 forms a divalent —O—CH 2 — or —N—CH 2 — radical;
R 2 is H, halogen, —CN, R a , —OH, —OR a , NH 2 , —NH—R a or —NR a R b ;
R 3 is H, halogen, R a , —OH, —OR a , NH 2 , —NH—R a , —NR a R b , —NO 2 or unsubstituted or substituted phenyl;
or

R 2 and R 3 form together with the carbon atoms to which they are attached to an unsubstituted or substituted six-membered aromatic ring; or form together a divalent —NH—CH 2 —CH 2 —NH— radical;
R 4 is H or R a ;
R 5 is H or halogen;
R 6 is H, halogen, R a , —OR a , NH 2 , —NHR a , —NR a R b , —NO 2 or Ar A ;
R 7 is H, halogen, R a , —OR a , NH 2 , —NHR a , —NR a R b , —N(H)—C(═O)—R a or —C(═O)—NHR a ;
R 8 is H, halogen or R a ;
n is an integer selected from 0 and 1;
L 1 is a divalent —NH—, —N(R a )— or —CH 2 — radical; and
L 2 is a divalent —SO 2 — radical; and
L 3 is a divalent —CH═CH— radical;
or

L 1 is a divalent —N(CHO)—, —N(C(═O)—R a )—, —N(C(═O)—NH 2 )—, —N(C(═O)—NHR a )— or —N(C(═O)—NR a R b )— radical; and
L 2 is a divalent —CH 2 — radical; and
L 3 is a divalent —CH 2 — radical;
or

L 1 is a divalent —CH 2 — radical;
L 2 is a divalent —N(CHO)—, —N(C(═O)—R a )—, —N(C(═O)—NH 2 )—, —N(C(═O)—NHR a )— or —N(C(═O)—NR a R b )— radical; and
L 3 is a single bond;
or

L 1 is a divalent —N=radical;
L 2 is a divalent ═S(═O)(R a )— radical; and
L 3 is a single bond;
A is a ring selected from the group consisting of Ar A , Hetar A , Cyc A and Hetcyc A ;
Ar A is a mono-, bi- or tricyclic aryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents R A1 , R A2 , R A3 , R A4 , R A5 , R A6 and/or R A7 which may be the same or different, with the proviso that Ar A is not 4-methylphenyl;
Hetar A is a mono-, bi- or tricyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents R A1 , R A2 , R A3 , R A4 R A5 , R A6 and/or R A7 which may be the same or different;
Cyc A is a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with R A8 , R A9 , R A10 and/or R A11 which may be the same or different;
Hetcyc A is a saturated or partially unsaturated, mono-, bi- or tricyclic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with R A8 , R A9 , R A10 and/or R A11 which may be the same or different;
R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 are independently from each other H, halogen, R a , —OR a , —NH 2 , —NHR a , —NR a R b , —N(H)—C(═O)—R a , Ar B , —O—Ar B , Hetar B , Cyc B or Hetcyc B ;
and/or

two adjacent R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 may form together a divalent —C 1-3 -alkylene-O— or —O—C 1-3 -alkylene-O— radical which C 1-3 -alkylene may be unsubstituted or mono- or disubstituted with R a or halogen; or may form together with the ring atoms to which they are attached to a Cyc C ;
R A8 , R A9 , R A10 , R 11 are independently from each other H or R a ; or a pair of R A8 , R A9 , R A10 and/or R A11 form a ═O radical;
Ar B is a phenyl ring, wherein that phenyl ring may be unsubstituted or substituted with substituents R B1 , R B2 and/or R B3 which may be the same or different;
Hetar B is a monocyclic heteroaryl with 5, 6, 7 ring atoms wherein 1, 2, 3, 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroryl may be unsubstituted or substituted with substituents R B1 , R B2 and/or R B3 which may be the same or different;
Cyc B is a mono- or bicyclic saturated or partially unsaturated carbocycle with 5, 6, 7, 8, 9, 10 ring carbon atoms wherein that carbocycle may be unsubstituted or mono-, di- or trisubstituted with R B4 , R B5 and/or R B6 which may be the same or different;
Hetcyc B is a saturated or partially unsaturated monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1, 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or mono-, di- or trisubstituted with R B4 , R B5 and/or R B6 which may be the same or different;
Cyc C is a mono- or bicyclic saturated or partially unsaturated carbocycle with 5, 6, 7, 8, 9, 10 ring carbon atoms wherein that carbocycle is fused to Ar A or Hetar A via 2 adjacent ring atoms of said Ar A or Hetar A and wherein that carbocycle may be unsubstituted or substituted with R C1 , R C2 , R C3 , R C4 , R C5 , R C6 which may be the same or different;
R B1 , R B2 and/or R B3 are independently from each other H, halogen, R a , —OR a or —SR a ;
R B4 , R B5 , R B6 , R C1 , R C2 , R C3 , R C4 , R C5 , R C6 are independently from each other H or R a ;
R a , R b are independently from each other unsubstituted or substituted, straight-chain or branched C 1-6 -aliphatic or may form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 4, 5, 6, 7 ring atoms wherein 1, 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms;
or derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and/or the pharmaceutically acceptable salts of each of the foregoing;
with the proviso that
(a) 4-{2-[5-chloro-2-(4-chlorobenzenesulfonamido)phenyl]ethynyl}-benzoic acid;
(b) methyl 4-{2-[5-chloro-2-(4-chlorobenzenesulfonamido)phenyl]-ethynyl}benzoate; and
(c) methyl 4-{2-[2-(N-benzyl-2,2,2-trifluoroacetamido)phenyl]ethynyl}-benzoate
are excluded.

2. A compound of formula (I)

wherein
W denotes CR W1 or N;
R W1 is H, halogen, R a or —OR a ;
R 1 is —OH, —OR a , —NH 2 , —NHR a , —NR a R b , —N(H)OH, —N(H)O—R a , —N(H)CN, —N(H)—C(═O)—R a or —N(H)—SO 2 —R a ; or R 1 together with R 2 forms a divalent —O—CH 2 — or —N—CH 2 — radical;
R 2 is H, halogen, —CN, R a , —OH, —OR a , NH 2 , —NH—R a or —NR a R b ;
R 3 is H, halogen, R a , —OH, —OR a , NH 2 , —NH—R a , —NR a R b , —NO 2 or unsubstituted or substituted phenyl;
or

R 2 and R 3 form together with the carbon atoms to which they are attached to an unsubstituted or substituted six-membered aromatic ring; or form together a divalent —NH—CH 2 —CH 2 —NH— radical;
R 4 is H or R a ;
R 5 is H or halogen;
R 6 is H, halogen, R a , —OR a , NH 2 , —NHR a , —NR a R b , —NO 2 or Ar A ;
R 7 is H, halogen, R a , —OR a , NH 2 , —NHR

Assignees

• Merck Patent Gmbh
• Ryvu Therapeutics S A

Inventors

• Heinrich Timo
• Petersson Carl
• Krier Mireille
• Gondela Andrzej
• Galezowski Michal Mikolaj
• Fabritius Charles-Henry Robert Yves
• Nowak Mateusz Oktawian
• Krol Marcin

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/12

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

• C07D319/18

  Ethylenedioxybenzenes, not substituted on the hetero ring · CPC title

• C07D215/36

  Sulfur atoms (C07D215/24 takes precedence) · CPC title