Diaminoheteroaryl substituted pyrazoles

Patent metadata

Field	Value
Publication number	US-2016145239-A1
Application number	US-201414900599-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), and their use as pharmaceuticals.

First claim

1 . A compound of formula (I)

in which
R 1 /R 2 are independently from each other hydrogen, halogen or phenyl-S—,
R 3 is independently from each other 1-6C-alkyl, 1-6C-alkoxy, halogen, 2-6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy or —C(O)OH,
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,

R 4 is
(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 ,
(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 ,
with the proviso that when R 8 is hydrogen or 1-6C-alkyl,
R 7 is not hydrogen, 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-6C-cycloalkyl, or —NR 9 R 10 ,

m is 0, 1, 2, 3 or 4,
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 1-4C-alkyl,
R 14 is a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, phenyl, benzyl, wherein said group is optionally substituted with one or 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,
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 R 1 /R 2 are independently from each other hydrogen, or halogen, R 3 is independently from each other 1-3C-alkoxy, 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
(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 ,
(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 ,
with the proviso that when R 8 is hydrogen or 1-3C-alkyl,
R 7 is not hydrogen, 1-3C-alkyl, 2-3C-alkenyl, 1-3C-alkoxy, 3-6C-cycloalkyl, or —NR 9 R 10 ,
m is 0, 1, 2, 3 or 4, 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, 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
R 1 /R 2 are independently from each other hydrogen, or halogen,
R 3 is 1-3C-alkoxy,
n is 0 or 1,
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 —C(O)NR 11 R 12 or —O(O)OR 13 ,
R 7 is hydrogen, halogen, cyano, 1-3C-alkyl, 3-6C-cycloalkyl,
R 8 is halogen, cyano, 1-3C-alkyl, or —NR 9 R 10 ,
with the proviso that when R 8 is 1-3C-alkyl,
R 7 is not hydrogen, 1-3C-alkyl, or 3-6C-cycloalkyl,

m is 0 or 1,
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
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
R 1 /R 2 are fluoro,
R 3 is ethoxy,
n is 1,
R 4 is
(a) hydrogen, or
(c) methoxy,

R 5 is hydrogen,
R 6 is —C(O)NR 11 R 12 or —C(O)OR 13 ,
R 7 is hydrogen, bromo, cyano, methyl, or cyclopropyl,
R 8 is fluoro, chloro, bromo, cyano, methyl, or —NR 9 R 10 ,
with the proviso that when R 8 is methyl,
R 7 is not hydrogen, methyl, or cyclopropyl,

m is 0 or 1,
R 9 , R 10 are methyl,
R 11 is hydrogen,
R 12 is hydrogen, methyl or 2-hydroxyethyl,
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 . The compound of formula (I) according to any of claims 1 to 4 , which is selected from the group consisting of:
4-({2-[4-chloro-5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-1H-pyrazol-3-yl]pyrimidin-4-yl}amino)-N-methylnicotinamide,
4-({2-[4-chloro-5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-1H-pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinamide,
2-[4-chloro-5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-1H-pyrazol-3-yl]-N-(pyridin-4-yl)pyrimidin-4-amine,
ethyl 4-({2-[4-chloro-5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-1H-pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinate,
2-[4-chloro-1-(4-ethoxy-2,6-difluorobenzyl)-5-methyl-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine,
2-[4-bromo-1-(4-ethoxy-2,6-difluorobenzyl)-5-methyl-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine,
2-[4-chloro-1-(4-ethoxy-2,6-difluorobenzyl)-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine,
2-[1-(4-ethoxy-2,6-difluorobenzyl)-4-fluoro-5-methyl-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine,
ethyl 4-({2-[4-chloro-1-(4-ethoxy-2,6-difluoro

Assignees

• Bayer Pharma AG

Inventors

• Hilger Christoph-Stephan
• Hitchcock Marion
• Briem Hans
• Siemeister Gerhard
• Fernandez-Montalvan Amaury Ernesto
• SCHRÖDER Jens
• Holton Simon
• Preusse Comelia
• Denner Karsten

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P15/00

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title