Heteroaryl substituted pyrazoles

Patent metadata

Field	Value
Publication number	US-9682974-B2
Application number	US-201415032957-A
Country	US
Kind code	B2
Filing date	Oct 27, 2014
Priority date	Oct 30, 2013
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

Compounds of formula (I), processes for their preparation and their use as pharmaceuticals.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein

 is a

 group, wherein the * is the point of attachment;
wherein
X 1 is NR 18 , O, or S;
X 2 is CR 4 or N;
X 3 is NR 18 , O, or S;
X 4 is CR 4 or N;
X 5 is CR 4 or N;
X 6 is CR 4 ;
X 7 is NR 18 ;
X 8 is CR 4 ;
X 9 is NR 18 , O, or S;
X 10 is CR 4 or N;
X 11 is CR 4 or N;
X 12 is CR 4 or N; and
E is a

 group,
wherein the * is the point of attachment;
T is CH, CR 17 or N;
Y is CH, CR 17 or N;
wherein one or both of T and Y is CH or CR 17 ;

and
R 1 and R 2 are independently from each other hydrogen or halogen;
each R 3 is independently 1-6C-alkyl, 1-6C-alkoxy, halogen, 2-6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy, or —C(O)OH;
and

n is 0, 1, 2 or 3;
or

R 3 is -(1-6C-alkylene)-S—R 14 , -(1-6C-alkylene)-S(O)—R 14 , -(1-6C-alkylene)-S(O) 2 —R 14 , -(1-6C-alkylene)-S(═O)(═NR 15 )R 14 , —O-(1-6C-alkylene)-S—R 14 , —O-(1-6C-alkylene)-S(O)—R 14 , —O-(1-6C-alkylene)-S(O) 2 —R 14 , or —O-(1-6C-alkylene)-S(═O)(═NR 15 )R 14 ;
and

n is 1;
each R 4 is independently
(a) hydrogen,
(b) hydroxy,
(c) 1-6C-alkoxy optionally substituted with
(c1) 1 or 2 hydroxy,
(c2) —NR 9 R 10 ,
(c3) —S—R 14 ,
(c4) —S(O)—R 14 ,
(c5) —S(O) 2 —R 14 ,
(c6) —S(═O)(═NR 15 )R 14 , or
(c7) —S(O) 2 NR 9 R 10 ,

(d)

 wherein the * is the point of attachment,
(e)

 wherein the * is the point of attachment,
(f) cyano, or
(g) —S(O) 2 -(1-4C-alkyl);
R 5 is
(a) hydrogen,
(b) 2-6C-hydroxyalkyl,
(c)

 wherein the * is the point of attachment,
(d) —C(O)-(1-6C-alkyl),
(e) —C(O)-(1-6C-alkylene)-O-(1-6C-alkyl), or
(f) —C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl);

each R 6 is independently halogen, cyano, C(O)NR 11 R 12 , or C(O)OR 13 ;
m is 0, 1, or 2;
R 7 is hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl, C(O)NR 11 R 12 or —NR 9 R 10 ;
R 8 is hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 1-6C-haloalkoxy, 3-6C-cycloalkyl or —NR 9 R 10 ;
or

R 7 and R 8 come together to form a n-propylene or a n-butylene group;
R 9 and R 10 are independently from each other hydrogen or 1-6C-alkyl;
or

R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclic ring optionally containing one further heteroatom selected from the group consisting of O, S and N;
R 11 and R 12 are independently from each other hydrogen, 1-6C-alkyl, 2-6C-hydroxyalkyl, or (1-4C-alkyl)-S(O) 2 -(1-4C-alkyl);
each R 13 is independently hydrogen or 1-4C-alkyl;
each R 14 is independently a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, phenyl and benzyl,
wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of
hydroxy, halogen, and —NR 9 R 10 ;

each R 15 is independently hydrogen, cyano, or —C(O)R 16 ;
R 16 is 1-6C-alkyl or 1-6C-haloalkyl;
each R 17 is independently halogen, cyano, —C(O)NR 11 R 12 , or —C(O)OR 13 ;
R 18 is
(a) hydrogen,
(b) 1-6C-alkyl optionally substituted with
(b1) 1 or 2 hydroxy,
(b2) 1-6C-alkoxy,
(b3) —C(O)OR 13 ,
(b4) —C(O)NR 11 R 12 ,
(b5) —NR 9 R 10 ,
(b6) —S—R 14 ,
(b7) —S(O)—R 14 ,
(b8) —S(O) 2 —R 14 ,
(b9) —S(═O)(═NR 15 )R 14 , or
(b10) —S(O) 2 NR 9 R 10 ,

(c) —S(O) 2 -(1-4C-alkyl), or
(d) —C(O)-(1-6C-alkyl);

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

2. The compound according to claim 1 ,
wherein

 is a

 group, wherein the * is the point of attachment;
wherein
X 1 is NR 18 , O, or S;
X 2 is CR 4 or N;
X 3 is NR 18 , O, or S;
X 4 is CR 4 or N;
X 5 is CR 4 or N;
X 6 is CR 4 ;
X 7 is NR 18 ;
X 8 is CR 4 ;
X 9 is NR 18 , O, or S;
X 10 is CR 4 or N;
X 11 is CR 4 or N;
X 12 is CR 4 or N; and
E is a

 group,
wherein the * is the point of attachment;
T is CH, CR 17 or N;
Y is CH, CR 17 or N;
wherein one or both of T and Y is CH or CR 17 ;

and
R 1 and R 2 are independently from each other hydrogen or halogen;
each R 3 is independently 1-3C-alkoxy;
and

n is 0, 1, 2, or 3;
or

R 3 is -(1-4C-alkylene)-S—R 14 , -(1-4C-alkylene)-S(O)—R 14 , -(1-4C-alkylene)-S(O) 2 —R 14 , -(1-4C-alkylene)-S(═O)(═NR 15 )R 14 , —O-(1-4C-alkylene)-S—R 14 , —O-(1-4C-alkylene)-S(O)—R 14 , —O-(1-4C-alkylene)-S(O) 2 —R 14 , or —O-(1-4C-alkylene)-S(═O)(═NR 15 )R 14 ;
and

n is 1;
R 4 is independently from each other
(a) hydrogen,
(b) hydroxy,
(c) 1-4C-alkoxy optionally substituted with
(c1) 1 or 2 hydroxy,
(c2) —NR 9 R 10 ,
(c3) —S—R 14 ,
(c4) —S(O)—R 14 ,
(c5) —S(O) 2 —R 14 ,
(c6) —S(═O)(═NR 15 )R 14 , or
(c7) —S(O) 2 NR 9 R 10 ,

(f) cyano, or
(g) —S(O) 2 -(1-4C-alkyl);

R 5 is hydrogen;
each R 6 is independently halogen, cyano, —C(O)NR 11 R 12 , or —C(O)OR 13 ;
m is 0, 1, or 2;
R 7 is hydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl, 1-3C-alkoxy, 1-3C-haloalkoxy, 3-6C-cycloalkyl, —C(O)NR 11 R 12 or —NR 9 R 10 ;
R 8 is hydrogen, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl, 1-3C-alkoxy, 1-3C-haloalkoxy, 3-6C-cycloalkyl or —NR 9 R 10 ;
R 9 and R 10 are independently from each other hydrogen or 1-3C-alkyl;
or

R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclic ring optionally containing one further heteroatom selected from the group consisting of O, S and N;
R 11 and R 12 are independently from each other hydrogen, 1-3C-alkyl, or 2-3C-hydroxyalkyl;
each R 13 is independently hydrogen or 1-3C-alkyl;
each R 14 is independently a group selected from 1-3C-alkyl, and 3-7C-cycloalkyl;
each R 15 is independently hydrogen, cyano, or —C(O)R 16 ;
R 16 is methyl or trifluoromethyl;
each R 17 is independently halogen, cyano, —C(O)NR 11 R 12 , or —C(O)OR 13 ;
R 18 is
(a) hydrogen,
(b) 1-4C-alkyl optionally substituted with
(b1) 1 or 2 hydroxy,
(b2) 1-3C-alkoxy,
(b3) —C(O)OR 13 ,
(b4) —C(O)NR 11 R 12 ,
(b5) —NR 9 R 10 ,
(b6) —S—R 14 ,
(b7) —S(O)—R 14 ,
(b8) —S(O) 2 —R 14 ,
(b9) —S(═O)(═NR 15 )R 14 , or

Assignees

• Bayer Pharma AG

Inventors

• Mengel Anne
• Richter Anja
• Hitchcock Marion
• Briem Hans
• Siemeister Gerhard
• Bone Wilhelm
• Fernandez-Montalvan Amaury Ernesto
• SCHRÖDER Jens
• Holton Simon
• Preuβe Cornelia
• Mönning Ursula

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title