Substituted benzylindazoles for use as Bub1 kinase inhibitors in the treatment of hyperproliferative diseases

Patent metadata

Field	Value
Publication number	US-10266548-B2
Application number	US-201715438254-A
Country	US
Kind code	B2
Filing date	Feb 21, 2017
Priority date	Oct 6, 2011
Publication date	Apr 23, 2019
Grant date	Apr 23, 2019

Abstract

Compounds of formula (I) which are inhibitors of Bub 1 kinase, processes for their production and their use as pharmaceuticals.

First claim

The invention claimed is:

1. A compound of formula 1-5

wherein:
R 1 is hydrogen, halogen, or 1-3C-alkyl;
R 6 is
(a) hydrogen,
(b) hydroxyl,
(c) cyano,
(d) 1-6C-alkoxy optionally substituted independently one or more times with
(d1) OH,
(d2) —O-(1-6C-alkyl),
(d3) C(O)OR 9 ,
(d4) C(O)NR 10 R 11 ,
(d5) NR 10 R 11 ,
(d6) —S-(1-6C-alkyl),
(d7) —S(O)-(1-6C-alkyl),
(d8) —SO 2 -(1-6C-alkyl),
(d9) SO 2 NR 10 R 11 ,
(d10) heterocyclyl, which is optionally substituted with C(O)OR 9 or oxo (═O), or
(d11) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR 9 , C(O)NR 10 R 11 , or (1-6C-alkylen)-O-(1-6C-alkyl);

(e) SO 2 NR 10 R 11 ,
(f) 3-7C-cycloalkoxy,
(g) 1-6C-haloalkoxy,
(h) COOR 9 ,
(i) —C(O)NR 10 R 11 ,
(j) —O-heteroaryl optionally substituted with CN,
(k)

 wherein the * indicates the point of attachment, or
(l) —O-(2-6C-alkylen)-O-(1-6C-alkyl) which is optionally substituted with hydroxyl or NH(CO)OR 9 ;

R 7 is
(a) hydrogen,
(b)1-6C-alkyl, which is optionally substituted with heteroaryl,
(c) 1-6C-haloalkyl,
(d) 1-6C-hydroxyalkyl,
(e)

 wherein the * indicates the point of attachment,
(f) —C(O)-(1-6C-alkyl),
(g) —C(O)-(1-6C-alkylen)-O-(1-6C-alkyl),
(h) —C(O)-(1-6C-alkylen)-O-(2-6C-alkylen)-O-(1-6C-alkyl),
(i) —C(O)-heterocyclyl,
(j) benzyl wherein the phenyl ring is optionally substituted with 1-5 substituents independently selected from the group consisting of hydrogen, halogen, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, and C(O)OR 9 , or
(k) heteroaryl;

or
R 6 and R 7 are taken together with the nitrogen atom to which R 7 is attached to form a 6-membered ring which optionally contains one additional heteroatom selected from the group consisting of O, S, and N, and which is optionally substituted by (1-6C-alkyl)-OH or (1-6C-alkyl)-NR 10 R 11 ;

R 8 is hydrogen, halogen, hydroxy, cyano, 1-6C-alkyl, 1-6C-hydroxyalkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR 9 , or C(O)NR 10 R 11 ;
m is 0-4;
R 9 is
(a) hydrogen, or
(b) 1-6C-alkyl which is optionally substituted with hydroxyl; and

R 10 and R 11 are independently hydrogen, 1-4C-alkyl, 1-4C-hydroxyalkyl, 1-4C-alkoxy, —(CO)-(1-6C-alkyl), CHO, or COOR 9 ,
or
R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a 4-6-membered heterocyclic ring optionally containing one additional heteroatom selected from the group consisting of O, S and N, and which is optionally substituted with 1-2 fluorine atoms or COOR 9 .

2. A compound of formula 1-4

wherein:
R 1 is hydrogen, halogen, or 1-3C-alkyl;
R 2 and R 3 are independently fluorine, chlorine or bromine;
each R 4 is independently hydrogen, hydroxy, halogen, cyano, NO 2 , 1-6C-alkyl, 2-6C-alkenyl, 2-6C-alkynyl, 1-6C-haloalkyl, 1-6C-hydroxyalkyl, 1-6C-alkoxy, —O-(2-6C-alkylen)-O—C(O)-(1-6C-alkyl), 1-6C-haloalkoxy, —C(O)OR 9 , -(1-6C-alkylen)—C(O)OR 9 , —C(O)-(1-6C-alkyl), —C(O)NR 10 R 11 , 3-7C-cycloalkyl, —S-(1-6C-haloalkyl), SF 5 , —SO 2 NH-(3-7C-cycloalkyl), —SO 2 NR 10 R 11 , NR 10 R 11 , or heteroaryl which is optionally substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR 9 , or C(O)NR 10 R 11 ,
wherein two of R 2 , R 3 , and (R 4 ) n , when positioned ortho to each other, are optionally taken together with the two carbon atoms to which they are attached to form a heterocyclic 5-, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from the group consisting of O and N, and optionally contains an additional double bond and/or optionally substituted by an oxo (═O) group and/or a 1-4C-alkyl group;

n is 0-3;
R 6 is
(a) hydrogen,
(b) hydroxyl,
(c) cyano,
(d) 1-6C-alkoxy optionally substituted independently one or more times with
(d1) OH,
(d2) —O-(1-6C-alkyl),
(d3) C(O)OR 9 ,
(d4) C(O)NR 10 R 11 ,
(d5) NR 10 R 11 ,
(d6) —S-(1-6C-alkyl),
(d7) —S(O)-(1-6C-alkyl),
(d8) —SO 2 -(1-6C-alkyl),
(d9) SO 2 NR 10 R 11 ,
(d10) heterocyclyl, which is optionally substituted with C(O)OR 9 or oxo (═O), or
(d11) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR 9 , C(O)NR 10 R 11 , or (1-6C-alkylen)-O-(1-6C-alkyl);

(e) SO 2 NR 10 R 11 ,
(f) 3-7C-cycloalkoxy,
(g) 1-6C-haloalkoxy,
(h) COOR 9 ,
(i) —C(O)NR 10 R 11 ,
(j) —O-heteroaryl optionally substituted with CN,
(k)

 wherein the * indicates the point of attachment, or
(l) —O-(2-6C-alkylen)-O-(1-6C-alkyl) which is optionally substituted with hydroxyl or NH(CO)OR 9 ;

R 9 is
(a) hydrogen, or
(b) 1-6C-alkyl which is optionally substituted with hydroxyl; and

R 10 and R 11 are independently hydrogen, 1-4C-alkyl, 1-4C-hydroxyalkyl, 1-4C-alkoxy, —(CO)-(1-6C-alkyl), CHO, or COOR 9 ,
or
R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a 4-6-membered heterocyclic ring optionally containing one additional heteroatom selected from the group consisting of O, S and N, and which is optionally substituted with 1-2 fluorine atoms or COOR 9 .

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG

Inventors

• Hitchcock Marion
• Mengel Anne
• Pütter Vera
• Siemeister Gerhard
• Wengner Antje Margret
• Briem Hans
• Eis Knut
• Schulze Volker
• Fernandez-Montalvan Amaury Ernesto
• Prechtl Stefan
• Holton Simon
• Fanghänel Jörg
• Lienau Philip
• Preusse Cornelia
• Gnoth Mark Jean

Classifications

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title