Amido-substituted azole compounds

Patent metadata

Field	Value
Publication number	US-9884063-B2
Application number	US-201515301443-A
Country	US
Kind code	B2
Filing date	Apr 1, 2015
Priority date	Apr 2, 2014
Publication date	Feb 6, 2018
Grant date	Feb 6, 2018

Abstract

The present invention relates to amido-substituted azole compounds of general formula (I), in which X 1 , X 2 , R 1 , R 2 , R 4 , R 5 , R 7 and R 8 are as defined in the claims which are inhibitors of TNKS1 and/or TNKS2, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
X 1 is NR 3 or O;
X 2 is CR 6 or N;
R 1 is a group selected from:
—OR 9 and —N(R 10 )R 11 ;

R 2 is a group selected from:
hydrogen, C 1 -C 3 -alkyl, and C 3 -C 4 -cycloalkyl;

R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5 is a group selected from:
hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, and halogen;

R 6 is a group selected from:
hydrogen and halogen;

R 7 is a hydrogen atom;
R 8 is a group selected from:
aryl and heteroaryl,
wherein said aryl and heteroaryl groups are optionally substituted with one, two, or three substituents, which are independently selected from:
C 1 -C 6 -alkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, halogen, cyano, nitro, hydroxy, (C 1 -C 6 -alkyl)-S—, (C 1 -C 6 -alkyl)-S(═O)—, (C 1 -C 6 -alkyl)-S(═O) 2 —, —S(═O)(═NR 15 )R 16 , —N(R 10 )R 11 , R 10 (R 11 )N—(C 1 -C 6 -alkyl)-, R 10 (R 11 )N—(C 2 -C 6 -alkoxy)-, phenyl, phenoxy, —N(R 12 )C(═O)R 13 , —C(═O)OH, —C(═O)OR 9 , and —C(═O)N(R 12 ) 2 ,
wherein two substituents of said aryl group, when positioned ortho to each other, are optionally linked to one another to form methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl, or butane-1,4-diyl;

R 9 is a group selected from:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -hydroxyalkyl-, and (C 1 -C 3 -alkoxy)-(C 1 -C 6 -alkyl)-;

R 10 and R 11 are independently selected from:
hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(C 1 -C 6 -alkyl)-, C 2 -C 6 -hydroxyalkyl, (C 1 -C 3 -alkoxy)-(C 2 -C 6 -alkyl)-, C 1 -C 6 -haloalkyl, H 2 N—(C 2 -C 6 -alkyl)-, (C 1 -C 3 -alkyl)N(H)(C 2 -C 6 -alkyl)-, (C 1 -C 3 -alkyl) 2 N(C 2 -C 6 -alkyl)-, HOC(═O)—(C 1 -C 6 -alkyl)-, R 9 OC(═O)—(C 1 -C 6 -alkyl)-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)-(C 2 -C 6 -alkyl)-, aryl, heteroaryl, aryl-(C 1 -C 6 -alkyl)-, and heteroaryl-(C 1 -C 6 -alkyl)-,
wherein said 4-6-membered heterocycloalkyl groups are optionally substituted with one or two substituents, which are independently selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkoxy, amino, hydroxy, halogen, and cyano, and
wherein said aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from:
C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OH, —C(═O)OR 9 , and —C(═O)N(R 12 ) 2 ;

or
R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a 4-6-membered heterocycloalkyl group, wherein one carbon atom of said 4-6 membered heterocycloalkyl group is optionally replaced by an additional heteroatom-containing group selected from NR 14 , O, S, S(═O), and S(═O) 2 , and wherein one additional ring atom is optionally replaced by C(═O),
wherein said 4-6-membered heterocycloalkyl group is optionally substituted with one or two substituents, which are independently selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkoxy, amino, hydroxy, halogen, and cyano;

or
R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a group selected from:

wherein * indicates the point of attachment of said group to the rest of the molecule;

R 12 is a group selected from:
hydrogen and C 1 -C 3 -alkyl;

R 13 is a group selected from:
hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, (C 1 -C 3 -alkoxy)-(C 1 -C 6 -alkyl)-, aryl, and heteroaryl,
wherein said aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from:
C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, halogen, cyano, and hydroxyl;

R 14 is a group selected from:
hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 3 -C 4 -cycloalkyl;

R 15 is a group selected from:
hydrogen, cyano, (C 1 -C 3 -alkyl)-C(═O)—, and (C 1 -C 3 -haloalkyl)-C(═O)—; and

R 16 is a group selected from:
C 1 -C 4 -alkyl and C 3 -C 4 -cycloalkyl,

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

2. The compound according to claim 1 , wherein:
X 1 is NR 3 or O;
X 2 is CR 6 or N;
R 1 is a group selected from:
—OR 9 and —N(R 10 )R 11 ;

R 2 is a group selected from:
hydrogen and C 1 -C 3 -alkyl;

R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5 is a group selected from:
hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, and C 1 -C 3 -haloalkoxy;

R 6 is a group selected from:
hydrogen and halogen;

R 7 is a hydrogen atom;
R 8 is a group selected from:
aryl and heteroaryl,
wherein said aryl and heteroaryl groups are optionally substituted with one, two, or three substituents, which are independently selected from:
C 1 -C 6 -alkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, halogen, cyano, nitro, hydroxy, (C 1 -C 6 -alkyl)-S—, (C 1 -C 6 -alkyl)-S(═O)—, (C 1 -C 6 -alkyl)-S(═O) 2 —, —S(═O)(═NR 15 )R 16 , —N(R 10 )R 11 , R 10 (R 11 )N—(C 1 -C 6 -alkyl)-, R 10 (R 11 )N—(C 2 -C 6 -alkoxy)-, phenyl, phenoxy, —N(R 12 )C(═O)R 13 , —C(═O)OH, —C(═O)OR 9 , and —C(═O)N(R 12 ) 2 ,
wherein two substituents of said aryl group, when positioned ortho to each other, are optionally linked to one another to form methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl, or butane-1,4-diyl;

R 9 is a group selected from:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -hydroxyalkyl-, and (C 1 -C 3 -alkoxy)-(C 1 -C 6 -alkyl)-;

R 10 and R 11 are independently selected from:
hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(C 1 -C 6 -alkyl)-, C 2 -C 6 -hydroxyalkyl, (C 1 -C 3 -alkoxy)-(C 2 -C 6 -alkyl)-, C 1 -C 6 -haloalkyl, H 2 N—(C 2 -C 6 -alkyl)-, (C 1 -C 3 -alkyl)N(H)(C 2 -C 6 -alkyl)-, (C 1 -C 3 -alkyl) 2 N(C 2 -C 6 -alkyl)-, HOC(═O)—(C 1 -C 6 -alkyl)-, R 9 OC(═O)—(C 1 -C 6 -alkyl)-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)-(C 2 -C 6 -alkyl)-, aryl, heteroaryl, aryl-(C 1 -C 6 -alkyl)-, and heteroaryl-(C 1 -C 6 -alkyl)-,
wherein said 4-6-membered heterocycloalkyl groups are optionally substituted with one or two substituents, which are independently selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkoxy, amino, hydroxy, halogen, and cyano, and
wherein said aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from:
C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OH, —C(═O)OR 9 , and —C(═O)N(R 12 ) 2 ;

or
R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a 4-6-membered heterocycloalkyl group, wherein one carbon atom of said 4-6 membered heterocycloalkyl group is optionally replaced by an additional heteroatom-containing group selected

Assignees

• Bayer Pharma AG

Inventors

• Eis Knut
• Ackerstaff Jens
• Wagner Sarah
• Basting Daniel
• Golz Stefan
• Bender Eckhard
• Li Volkhart Min Jian
• Lienau Philip
• Liu Ningshu
• Siegel Franziska
• Bauser Marcus
• Suelzle Detlev
• Holton Simon
• Bairlein Michaela
• Buchgraber Philipp
• Bálint József

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D413/12

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