4,5-annulated 1,2,4-triazolones

Patent metadata

Field	Value
Publication number	US-11787797-B2
Application number	US-202117161615-A
Country	US
Kind code	B2
Filing date	Jan 28, 2021
Priority date	Oct 27, 2016
Publication date	Oct 17, 2023
Grant date	Oct 17, 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 or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A pharmaceutical combination comprising:
one or more first active ingredients of general formula (I)

in which
R 1 represents a group selected from
a C 1 -C 8 -alkyl group, which is optionally substituted with a group selected from
C 3 -C 8 -cycloalkyl, phenyl and monocyclic or bicyclic heteroaryl,
wherein said phenyl substituent is optionally substituted, one, two or three times with one or more substituents independently selected from a halogen atom, a C 1 -C 3 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 3 -alkoxy group and a hydroxy group,

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

a C 2 -C 6 -cyanoalkyl group,
a C 2 -C 6 -hydroxyalkyl group,
a (C 2 -C 6 -hydroxyalkyl)-O—(C 2 -C 6 -alky)- group,
a —(C 2 -C 6 -alkyl)-N(R 7 )(R 8 ) group,
a —(C 1 -C 6 -alkyl)-C(═O)N(R 7 )(R 8 ) group,
a 4- to 7-membered, optionally unsaturated, heterocyclic group, which is 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 C 1 -C 3 -alkyl group, a 5- to 6-membered heteroaryl group, a-C(═O)O(C 1 -C 4 -alkyl) group, a —C(═O)(C 1 -C 6 -alkyl) group, a —C(═O)(C 3 -C 6 -cycloalkyl) group, a —S(═O) 2 (C 1 -C 6 -alkyl) group and a oxo (═O) group,
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 1 -C 6 -hydroxyalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, —(C 1 -C 6 -alkyl)-aryl, -aryl-(C 1 -C 6 -alkyl), C 1 -C 6 -alkoxy, —O(C 2 -C 6 -alkenyl), C 1 -C 6 -haloalkoxy, C 3 -C 8 -cycloalkoxy, hydroxy, 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 ),), —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 —O—(C 2 -C 6 -alkenyl), —S(═O)(═NR 14 )(C 1 -C 3 -alkyl), —N(O) 2 , —P(═O)(C 1 -C 3 -alkyl) 2 and SF 5 ,
or wherein two vicinal substituents of said phenyl groups 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 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, —O(C 2 -C 6 -alkenyl), C 1 -C 6 -haloalkoxy, C 3 -C 8 -cycloalkoxy, 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), —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,
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 -alkinyl 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)-N(H)C(═O)R 6 group,
a —(C 1 -C 6 -alkyl)-N(H)C(═O)OR 15 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 wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group 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)OR 6 , 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 ),

R 4 and R 5 jointly form an optionally unsaturated, heterocyclic ring A of partial formula (i)

whereby ring A in addition to the two mandatory atoms, the nitrogen atom and the carbon atom bridging the two rings, bears additional 3 to 6 members selected from —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O)(═NR 14 )—, —N═, —N(R 7 )—, —C(═O)—, —C(═O)—, —CH═, —CR 11 ═, —C(R 12 ) 2 —, —C(H)(R 13 )—,

R 6 represents a hydrogen atom or a group selected from
a C 1 -C 6 -alkyl group and a benzyl group,

R 7 and R 8 represent, independently from each occurrence, a hydrogen atom or a group selected from
a C 1 -C 6 -alkyl group, a C 2 -C 6 -alkenyl group, a C 2 -C 6 -hydroxyalkyl group, a haloalkyl group, a aryl group, a (C 1 -C 6 -alkyl)-aryl group, and a —(C 2 -C 6 -alkyl)-N(R 9 )(R 10 ) group, or

R 7 and R 8 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted with a group selected from
C 1 -C 6 -alkyl, —S—(C 1 -C 6 -alkyl), —S—(C 2 -C 6 -alkenyl), —S(═O) 2 (C 1 -C 3 -alkyl), —S(═O) 2 —(C 2 -C 6 -alkenyl), and —C(═O)OR 6 —,

R 9 and R 10 represent, independently from each occurrence, a hydrogen atom or a C 1 -C 3 -alkyl group,
or

R 9 and R 10 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,

R 11 represents, independently from each occurrence a hydrogen atom, 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 )

R 12 represents, independently fro

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
• Mueller Thomas
• Sheikh Sherif El
• Zhou Han Jie
• Zhao Changjia
• Sykes David B
• Ferrara Steven James
• Liu Kery
• Herbert Simon Anthony
• Merz Claudia
• Niehues Michael
• Nising Carl Friedrich
• Schäfer Martina
• Zimmermann Katja
• Knäblein Jörg
• Thede Kai
• Faupel Thomas

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title