Benzyl substituted indazoles as bub1 kinase inhibitors

Patent metadata

Field	Value
Publication number	US-2017305882-A1
Application number	US-201515512473-A
Country	US
Kind code	A1
Filing date	Sep 17, 2015
Priority date	Sep 19, 2014
Publication date	Oct 26, 2017
Grant date	—

Abstract

Compounds of formula (I) and their use as pharmaceuticals.

First claim

1 : A compound of formula (I)

in which
V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 ,
or,

V represents N, and W, Y and Z independently of each other represent CH or CR 2 ,
or,

V and Y represent N, and W and Z independently of each other represent CH or CR 2 ,
R 1 represents a group selected from:
C 2 -C 6 -hydroxyalkyl, and R 4 ,
wherein said C 2 -C 6 -hydroxyalkyl group is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,

R 2 represents, independently of each other, halogen or a group selected from:
C 1 -C 3 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, —N(H)C(═O)—(C 1 -C 3 -alkyl),
—N(H)C(═O)H, —N(H)C(═O)—(C 1 -C 3 -hydroxyalkyl), —N(H)C(═O)—(C 1 -C 3 -alkyl)-(C 1 -C 3 -alkoxy), —N(H)C(═O)-phenyl, —N(H)C(═O)—(C 3 -C 4 -cycloalkyl), —N(H)C(═O)—(C 1 -C 3 -alkyl)-(C 3 -C 4 -cycloalkyl), and —N(H)C(═O)N(H)R 8 ,
said —N(H)C(═O)-phenyl being optionally substituted at the phenyl ring, one, two or three times, identically or differently, with a substituent selected from:
halogen, hydroxy, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 4 -cycloalkyl, and C 3 -C 4 -cycloalkyloxy,
said —N(H)C(═O)—(C 3 -C 4 -cycloalkyl) being optionally substituted at the C 3 -C 4 -cycloalkyl ring with a substituent selected from:
fluorine, chlorine, trifluoromethyl, and methoxy,

R 3 represents a group selected from:
C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, (C 1 -C 3 -alkoxy)-(C 1 -C 3 -alkyl)-, (C 3 -C 6 -cycloalkyl)-(C 1 -C 3 -alkyl)-, C 1 -C 6 -alkoxy, (C 2 -C 6 -hydroxyalkyl)-O—, C 1 -C 6 -haloalkoxy, C 3 -C 6 -cycloalkyloxy, (C 1 -C 3 -alkoxy)-(C 2 -C 3 -alkoxy)-, and (C 3 -C 6 -cycloalkyl)-(C 1 -C 3 -alkoxy)-,
wherein said C 2 -C 6 -hydroxyalkyl group is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,

R 4 represents —(C 2 -C 6 -alkyl)-OC(═O)—C(H)(R 5 )—N(H)C(═O)—C(H)(R 7 )—NH 2 ,
in which C 2 -C 6 -alkyl is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,

R 5 and R 7 independently of each other represent hydrogen (glycine) or a group selected from:
—CH 3 (alanine), —C(H)(CH 3 ) 2 (valine), —(CH 2 ) 2 CH 3 (norvaline), —CH 2 C(H)(CH 3 ) 2 (leucine), —C(H)(CH 3 )CH 2 CH 3 (isoleucine), —(CH 2 ) 3 CH 3 (norleucine), —C(CH 3 ) 3 (2-tert-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), —(CH 2 ) 3 NH 2 (ornithine), —(CH 2 ) 4 NH 2 (lysine), —(CH 2 ) 2 C(H)(OH)CH 2 NH 2 (hydroxylysine), —CH 2 OH (serine), —(CH 2 ) 2 OH (homoserine), —C(H)(OH)CH 3 (threonine), —(CH 2 ) 3 N(H)C(═NH)NH 2 (arginine), —(CH 2 ) 3 N(H)C(═O)NH 2 (citrulline), —CH 2 C(═O)NH 2 (asparagine), —CH 2 C(═O)OH (aspartic acid), —(CH 2 ) 2 C(═O)OH (glutamic acid), —(CH 2 ) 2 C(═O)NH 2 (glutamine), —CH 2 SH (cysteine), —(CH 2 ) 2 SH (homocysteine), —(CH 2 ) 2 SCH 3 (methionine), —CH 2 SCH 3 (S-methylcysteine), (1H-imidazol-4-yl)methyl-(histidine), (1H-indol-3-yl)methyl-(thryptophan), —CH 2 NH 2 (2,3-diaminopropanoic acid), and —(CH 2 ) 2 NH 2 (2,4-diaminobutanoic acid), and

R 8 represents hydrogen or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl, (C 3 -C 4 -cycloalkyl)-(C 1 -C 3 -alkyl)-, and (C 1 -C 3 -alkoxy)-(C 2 -C 3 -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 of formula (I) according to claim 1 , wherein
V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 ,
or,
V represents N, and W, Y and Z independently of each other represent CH or CR 2 , R 1 represents a group selected from:
C 2 -C 6 -hydroxyalkyl, and R 4 ,
wherein said C 2 -C 6 -hydroxyalkyl group is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,

R 2 represents, independently of each other, halogen or a group selected from:
C 1 -C 3 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, —N(H)C(═O)—(C 1 -C 3 -alkyl), —N(H)C(═O)H,
—N(H)C(═O)—(C 1 -C 3 -hydroxyalkyl), —N(H)C(═O)—(C 1 -C 3 -alkyl)-(C 1 -C 3 -alkoxy), —N(H)C(═O)-phenyl, —N(H)C(═O)—(C 3 -C 4 -cycloalkyl), —N(H)C(═O)—(C 1 -C 3 -alkyl)-(C 3 -C 4 -cycloalkyl), and —N(H)C(═O)N(H)R 8 ,
said —N(H)C(═O)-phenyl being optionally substituted at the phenyl ring, one, two or three times, identically or differently, with a substituent selected from:
halogen, hydroxy, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 4 -cycloalkyl, and C 3 -C 4 -cycloalkyloxy,
said —N(H)C(═O)—(C 3 -C 4 -cycloalkyl) being optionally substituted at the C 3 -C 4 -cycloalkyl ring with a substituent selected from:
fluorine, chlorine, trifluoromethyl, and methoxy,

R 3 represents a group selected from:
C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy, (C 2 -C 6 -hydroxyalkyl)-O—, C 1 -C 6 -haloalkoxy, and (C 3 -C 6 -cycloalkyl)-(C 1 -C 3 -alkoxy)-,
wherein said C 2 -C 6 -hydroxyalkyl group is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,

R 4 represents —(C 2 -C 6 -alkyl)-OC(═O)—C(H)(R 5 )—N(H)C(═O)—C(H)(R 7 )—NH 2 ,
in which C 2 -C 6 -alkyl is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,
R 5 and R 7 independently of each other represent a group selected from:
—CH 3 (alanine), —C(H)(CH 3 ) 2 (valine), —(CH 2 ) 2 CH 3 (norvaline), —(CH 2 ) 3 NH 2 (ornithine), —(CH 2 ) 4 NH 2 (lysine), and —(CH 2 ) 3 N(H)C(═NH)NH 2 (arginine), and
R 8 represents hydrogen or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl, (C 3 -C 4 -cycloalkyl)-(C 1 -C 3 -alkyl)-, and (C 1 -C 3 -alkoxy)-(C 2 -C 3 -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.

3 : The compound of formula (I) according to claim 1 , wherein
V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 ,
or,
V represents N, and W, Y and Z independently of each other represent CH or CR 2 , R 1 represents a group selected from:
C 2 -C 6 -hydroxyalkyl, and R 4 ,
R 2 represents, independently of each other, halogen or a group selected from:
C 1 -C 3 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 3 -haloalkyl, and —N(H)C(═O)—(C 1 -C 3 -alkyl),
R 3 represents a group selected from:
C 1 -C 6 -alkoxy, and (C 3 -C 6 -cycloalkyl)-(C 1 -C 3 -alkoxy)-,
R 4 represents —(C 2 -C 6 -alkyl)-OC(═O)—C(H)(R 5 )—N(H)C(═O)—C(H)(R 7 )—NH 2 , and R 5 and R 7 independently of each other represent a group selected from:
—CH 3 (alanine), —(CH 2 ) 4 NH 2 (lysine), and —(CH 2 ) 3 N(H)C(═NH)NH 2 (arginine),

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 claim 1 ,
wherein V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 ,
or,
V represents N, and W, Y and Z independently of each other represent CH or CR 2 , R 1 represents a group selected from:
—(CH 2 ) 3 OH, and R 4 ,
R 2 represents, independently of each other, fluorine, chlorine or a group selected from:
methyl

Assignees

• Bayer Pharma AG

Inventors

• Mengel Anne
• Lerchen Hans-Georg
• Müller Thomas
• Bärfacker Lars
• Hitchcock Marion
• Cleve Arwed
• Briem Hans
• Siemeister Gerhard
• Bone Wilhelm
• FERNÁNDEZ-MONTÁLVAN Amaury Ernesto
• SCHRÖDER Jens
• Mönning Ursula
• Holton Simon

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/04

  specific for metastasis · 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

• A61P15/08

  for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis · CPC title