2,4,5-trisubstituted 1,2,4-triazolones useful as inhibitors of DHODH

Patent metadata

Field	Value
Publication number	US-11713304-B2
Application number	US-202117407951-A
Country	US
Kind code	B2
Filing date	Aug 20, 2021
Priority date	Oct 27, 2016
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

The present invention provides triazolone compounds of general formula (I):

in which R 1 , R 2 , R 3 , R 4 , and R 5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and prophylaxis of diseases, in particular hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

First claim

What is claimed is:

1. A method of treatment and/or prophylaxis of brain cancer or head and neck cancer in a subject comprising administering to the subject a compound of formula (I)

in which
R 1 represents a group selected from
a C 5 -C 8 -alkyl group,
a C 2 -C 8 -haloalkyl group,
a C 4 -C 8 -cycloalkyl group,
which is optionally partially unsaturated and which is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
hydroxy, phenyl and —N(R 7 )(R 8 ),
and wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C 1 -C 3 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 3 -alkoxy and hydroxy,

a C 1 -C 6 -alkyl group which is substituted with a C 3 -C 8 -cycloalkyl group,
a C 2 -C 6 -alkyl group which is substituted with a cyano group, a hydroxy group, a phenyl group or a C 3 -C 8 -heterocycloalkyl group,
a C 3 -C 6 -alkyl group which is substituted with a monocyclic or bicyclic heteroaryl group,
a (C 2 -C 6 -hydroxyalkyl)-O—(C 2 -C 6 -alkyl)- group,
a —(C 3 -C 6 -alkyl)-N(R 7 )(R 8 ) group,
a —(C 3 -C 8 -cycloalkyl)-N(R 7 )(R 8 ) group,
a —(C 3 -C 6 -alkyl)-C(═O)N(R 7 )(R 8 ) group,
a 4-7-membered heterocycloalkyl group, a 5- to 7-membered heterocycloalkenyl group,
wherein said 4-7-membered heterocycloalkyl group and said 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom, and which is optionally substituted one or two times, each substituent independently selected from a group selected from
C 1 -C 3 -alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C 1 -C 4 -alkyl),
—C(═O)(C 1 -C 6 -alkyl), —C(═O)(C 3 -C 6 -cycloalkyl), —S(═O) 2 (C 1 -C 6 -alkyl) and oxo (═O),
wherein said 5- to 6-membered heteroaryl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C 1 -C 3 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 3 -alkoxy and hydroxy,

a phenyl group,
which is optionally substituted, one, two, three, four or five times, each substituent independently selected from a halogen atom or a group selected from C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, —(C 1 -C 6 -alkyl)-aryl, -aryl-(C 1 -C 6 -alkyl), hydroxy, cyano, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy, —O(C 2 -C 6 -alkenyl), C 1 -C 6 -haloalkoxy, C 3 -C 8 -cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR 6 , —C(═O)N(R 7 )(R 8 ), —N(R 7 )(R 8 ), —(C 1 -C 6 -alkyl))-N(R 7 )(R 8 ), —(C 1 -C 6 -alkyl)-C(═O)OR 6 , —(C 1 -C 6 -alkyl)-C(═O)N(R 7 )(R 8 ), —O—C(═O)—(C 1 -C 6 -alkyl), —SH, —S—(C 1 -C 6 -alkyl), —S—(C 2 -C 6 -alkenyl), —S(═O) 2 N(R 7 )(R 8 ), —S(═O) 2 (C 1 -C 6 -alkyl), —S(═O) 2 —(C 2 -C 6 -alkenyl), —S(═O)(═NR 11 )(C 1 -C 3 -alkyl), —N(O) 2 , —P(═O)(C 1 -C 3 -alkyl) 2 and SF 5 ,
or
wherein two vicinal substituents may form together a 5- or 6-membered, optionally heterocyclic, aromatic or non-aromatic ring, having optionally 1-3 heteroatoms independently selected from —N═, —NH—, —N(R 7 )—, —O—, —S—, and optionally containing a C(═O) group, and wherein the so formed ring is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, —(C 1 -C 6 -alkyl)-aryl, -aryl-(C 1 -C 6 -alkyl), C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkoxy, —O(C 2 -C 6 -alkenyl), C 1 -C 6 -haloalkoxy, C 3 -C 8 -cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH, —S—(C 1 -C 6 -alkyl), —S—(C 2 -C 6 -alkenyl), —S(═O) 2 (C 1 -C 6 -alkyl), —N(O) 2 , and —N(R 7 )(R 8 )
and

a bicyclic aryl group,
a partially saturated mono- or bicyclic aryl- or heteroaryl group,
a monocyclic- or bicyclic heteroaryl group,
which is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, —(C 1 -C 6 -alkyl)-aryl, -aryl-(C 1 -C 6 -alkyl), C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, —O(C 2 -C 6 -alkenyl), C 3 -C 8 -cycloalkoxy, aryl, —O-aryl, cyano, C(═O)OR 6 , hydroxy, —SH, —S—(C 1 -C 6 -alkyl), —S—(C 2 -C 6 -alkenyl), —S(═O) 2 (C 1 -C 6 -alkyl), —S(═O) 2 —(C 2 -C 6 -alkenyl), —N(O) 2 , and —N(R 7 )(R 8 ),

R 2 represents a hydrogen atom or a halogen atom,
R 3 represents a group selected from,
a C 1 -C 6 -alkyl group,
which is optionally substituted with a C 3 -C 8 -cycloalkyl group,

a C 3 -C 8 -cycloalkyl group,
a C 1 -C 6 -haloalkyl group,
a C 1 -C 6 -hydroxyalkyl group,
a C 2 -C 6 -alkenyl group,
a C 2 -C 6 -alkynyl group,
a C 4 -C 8 -cycloalkenyl group,
a (C 1 -C 6 -alkyl)-N(R 7 )R 8 group,
a —(C 1 -C 6 -alkyl)-(4- to 7-membered nitrogen containing heterocycloalkyl) group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is connected to the alkyl group via a carbon atom of the heterocycloalkyl group and which is optionally substituted with a C 1 -C 3 -alkyl group, and

a phenyl group,
which is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, —(C 1 -C 6 -alkyl)-aryl, -aryl-(C 1 -C 6 -alkyl), C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkoxy, —O(C 2 -C 6 -alkenyl), C 1 -C 6 -haloalkoxy, C 3 -C 8 -cycloalkoxy, aryl, —O-aryl, cyano, —C(O)OH, hydroxy, —SH, —S—(C 1 -C 6 -alkyl), —S—(C 2 -C 6 -alkenyl), —S(═O) 2 (C 1 -C 6 -alkyl), —S(═O) 2 —(C 2 -C 6 -alkenyl), —N(O) 2 , and —N(R 7 )(R 8 )

R 4 represents a group selected from,
a C 1 -C 6 -alkyl group,
which is optionally substituted with a group selected from
C 3 -C 8 -cycloalkyl and phenyl,
wherein said phenyl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, —(C 1 -C 6 -alkyl)-aryl, -aryl-(C 1 -C 6 -alkyl), C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkoxy, —O(C 2 -C 6 -alkenyl), C 1 -C 6 -haloalkoxy, C 3 -C 8 -cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR 6 , hydroxy, —SH, —S—(C 1 -C 6 -alkyl), —S—(C 2 -C 6 -alkenyl), S(═O) 2 (C 1 -C 6 -alkyl), —S(═O) 2 —(C 2 -C 6 -alkenyl), —N(O) 2 , and —N(R 7 )(R 8 )

a C 2 -C 6 -alkenyl group,
a C 3 -C 8 -cycloalkyl group,
a C 2 -C 6 -haloalkyl group,
a C 2 -C 6 -hydroxyalkyl group,
a —(C 2 -C 6 -alkyl)-N(R 7 )(R 8 ) group,

R 5 represents a halogen atom or a group selected from
a C 1 -C 6 -alkyl group,
a C 3 -C 8 -cycloalkyl group,
a C 1 -C 6 -haloalkyl group, which is optionally substituted with a hydroxy group,
a C 1 -C 6 -hydroxyalkyl group,
a —(C 1 -C 6 -alkyl)-N(R 7 )(R 8 ) group,
a —(C 1 -C 6 -alkyl)-O—(C 1 -C 6 -alkyl) group,
a C 2 -C 6 -alkenyl group,
a C 2 -C 6 -alkynyl group,
a C 1 -C 6 -alkoxy group,
a C 1 -C 6 -alkylsulfanyl group, and
a —N(R 7 )(R 8 ) group,
a —C(═O)OR 6 group,
a —C(═O)N(R 7 )(R 8 ) group,
a —S(═O)(═NR 11 )(C 1 -C 3 -alkyl) group, and
a phenyl group
which is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, —(C 1 -C 6 -alkyl)-aryl, -aryl-(C 1 -C 6 -alkyl), C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkoxy, —O(C 2 -C 6 -alkenyl), C 1 -C 6 -haloalkoxy, C 3 -C 8 -cycloalkoxy, aryl, —O-aryl, cyano, —C(═O)OR 6 , hydroxy, —SH, —S—(C 1 -C 6 -alkyl), —S—(C 2 -C 6 -alkenyl), S(═O) 2 (C

Assignees

• Bayer Ag
• Bayer Pharma AG
• Broad Inst Inc
• Harvard College
• Massachusetts Gen Hospital

Inventors

• Gradl Stefan Nikolaus
• Nguyen Duy
• Eis Knut
• Günther Judith
• Stellfeld Timo
• Janzer Andreas
• Christian Sven
• Müller Thomas
• Sheikh Sherif El
• Sykes David B
• Ferrara Steven James
• Kröber Michael
• Merz Claudia
• Niehues Michael
• Schäfer Martina
• Zimmermann Katja
• Nising Carl Friedrich

Classifications

• C07D401/12 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D249/12 Primary

  Oxygen or sulfur atoms · CPC title

• C07D403/12

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

• C07D405/12

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