Heteroaryl substituted pyrazoles

Patent metadata

Field	Value
Publication number	US-2016145238-A1
Application number	US-201414900548-A
Country	US
Kind code	A1
Filing date	Jun 17, 2014
Priority date	Jun 21, 2013
Publication date	May 26, 2016
Grant date	—

Abstract

Compounds of formula (I), which are inhibitors of Bub1 kinase, processes for their production and their use as pharmaceuticals.

First claim

1 . A compound of formula (I)

wherein
T is CH, CR 17 or N,
Y is CH, CR 17 or N,
whereby one or both of T and Y represent CH or CR 17 ,

R 2 is heteroaryl, which is optionally substituted independently one or more times with hydroxy, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl, 2-6C-alkynyl, 1-6C-haloalkyl, 1-6C-hydroxyalkyl, 1-6C-alkoxy, 1-6C-haloalkoxy, —NR 9 R 10 , —C(O)OR 13 , —C(O)-(1-6C-alkyl), —C(O)NR 11 R 12 , 3-6C-cycloalkyl, —S(O) 2 NH-(3-6C-cycloalkyl), or —S(O) 2 NR 9 R 10 ,
R 3 is
(a) hydrogen,
(b) NR 9 R 10 , or
(c)

whereby the * is the point of attachment;
R 4 is
(a) hydrogen,
(b) hydroxy,
(c) 1-6C-alkoxy optionally substituted with
(c1) 1 or 2 hydroxy groups,
(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 ,
(c7) —S(O) 2 NR 9 R 10 ,

(d)

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

whereby 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)

whereby 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),
R 6 is independently from each other halogen, cyano, —C(O)NR 11 R 12 , —C(O)OR 13 , or —C(O)NHOH,
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 ,
m is 0, 1, 2 or 3,
R 9 , R 10 are independently from each other hydrogen or 1-6C-alkyl,
R 11 , R 12 are independently from each other hydrogen, 1-6C-alkyl, 2-6C-hydroxyalkyl, or (1-4C-alkyl)-S(O) 2 -(1-4C-alkyl),
R 13 is hydrogen, or 1-6C-alkyl,
R 14 is a group selected from 1-6C-alkyl, 3-6C-cycloalkyl, phenyl, or benzyl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group of hydroxy, halogen, or —NR 9 R 10 ,
R 15 is hydrogen, cyano, or —C(O)R 16 ,
R 16 is 1-6C-alkyl, or 1-6C-haloalkyl,
R 17 is independently from each other halogen, cyano, —C(O)NR 11 R 12 or —C(O)OR 13 ,
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 of formula (I) according to claim 1 ,
wherein T is CH, CR 17 or N, Y is CH, CR 17 or N,
whereby one or both of T and Y represent CH or CR 17 ,
R 2 is heteroaryl, which is optionally substituted independently one or more times with hydroxy, halogen, cyano, 1-3C-alkyl, 2-3C-alkenyl, 2-3C-alkynyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, 1-3C-haloalkoxy, —NR 9 R 10 , —C(O)OR 13 , —C(O)-(1-3C-alkyl), —C(O)NR 11 R 12 , 3-6C-cycloalkyl, —S(O) 2 NH-(3-6C-cycloalkyl), or —S(O) 2 NR 9 R 10 , R 3 is
(a) hydrogen,
(b) —NR 9 R 10 , or
(c)

whereby the * is the point of attachment;
R 4 is
(a) hydrogen,
(b) hydroxy,
(c) 1-4C-alkoxy optionally substituted with
(c1) 1 or 2 hydroxy groups,
(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 ,
(c7) —S(O) 2 NR 9 R 10 ,

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

R 5 is hydrogen,
R 6 is independently from each other halogen, cyano, —C(O)NR 11 R 12 , or —C(O)OR 13 ,
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 ,
m is 0, 1, 2 or 3,
R 9 , R 10 are independently from each other hydrogen or 1-3C-alkyl,
R 11 , R 12 are independently from each other hydrogen, 1-3C-alkyl, or 2-3C-hydroxyalkyl,
R 13 is hydrogen, or 1-3C-alkyl,
R 14 is a group selected from methyl, or cyclopropyl,
R 15 is hydrogen, cyano, or —C(O)R 16 ,
R 16 is methyl, or trifluoromethyl,
R 17 is independently from each other halogen, cyano, —C(O)NR 11 R 12 or —C(O)OR 13 ,
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

3 . The compound of formula (I) according to claim 1 or 2 ,
wherein
T is CH or CR 17 ,
Y is CH or CR 17 ,
R 2 is heteroaryl, which is optionally substituted independently one or more times with hydroxy, halogen, cyano, or 1-3C-alkyl,
R 3 is hydrogen,
R 4 is
(a) hydrogen,
(b) hydroxy,
(c) 1-4C-alkoxy optionally substituted with
(c1) hydroxy,
(c3) —S—R 14 ,
(c4) —S(O)—R 14 ,
(c5) —S(O) 2 —R 14 ,
(c6) —S(═O)(═NR 15 )R 14 ,

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

R 5 is hydrogen,
R 6 is halogen, cyano, —C(O)NR 11 R 12 , or —C(O)OR 13 ,
R 7 is 1-3C-alkyl, or 3-6C-cycloalkyl,
R 8 is 1-3C-alkyl,
m is 0 or 1,
R 11 , R 12 are independently from each other hydrogen, or 1-3C-alkyl,
R 13 is hydrogen or 1-3C-alkyl,
R 14 is a group selected from methyl or cyclopropyl,
R 15 is hydrogen,
R 17 is independently from each other halogen, cyano, —C(O)NR 11 R 12 or —C(O)OR 13 ,
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

4 . The compound of formula (I) according to any of claims 1 to 3 ,
wherein
T is CH,
Y is CH,
R 2 is heteroaryl, which is optionally substituted independently one or more times with chloro, or methyl,
R 3 is hydrogen,
R 4 is methoxy,
R 5 is hydrogen,
R 6 is —C(O)NR 11 R 12 , or —C(O)OR 13 ,
R 7 is cyclopropyl,
R 8 is methyl,
m is 0 or 1,
R 11 , R 12 are hydrogen,
R 13 is hydrogen, or ethyl,
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

5 . Compounds of formula (I) according to any of claims 1 to 4 , which is selected from the group consisting of:
2-{1-[(4-chloro-1-methyl-1H-pyrazol-5-yl)methyl]-5-cyclopropyl-4-methyl-1H-pyrazol-3-yl}-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine,
4-[(2-{5-cyclopropyl-1-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-4-methyl-1H-pyrazol-3-yl}-5-methoxypyrimidin-4-yl)amino]nicotinamide,
4-[(2-{5-cyclopropyl-1-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-4-methyl-1H-pyrazol-3-yl}-5-methoxypyrimidin-4-yl)amino]nicotinic acid,
4-[(2-{5-cyclopropyl-1-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-4-methyl-1H-pyrazol-3-yl}-5-methoxypyrimidin-4-yl)amino]nicotinate,
ethyl 4-[(2-{5-cyclopropyl-4-methyl-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1H-pyrazol-3-yl}-5-methoxypyrimidin-4-yl)amino]pyridine-3-carboxylate, and
4-[(2-{5-cyclopropyl-4-methyl-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-H-pyrazol-3-yl}-5-methoxypyrimidin-4-yl)amino]pyridine-3-carboxamide,
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

6 . Use of a compound of general formula (I) according to any of claims 1 to 5 for the treatment or prophylaxis of a disease.

7 . Use of a compound of general formul

Assignees

• Bayer Pharma AG

Inventors

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

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

• A61P15/00

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