Piperidinylpyrazolopyrimidinones and their use

Patent metadata

Field	Value
Publication number	US-10118930-B2
Application number	US-201515523954-A
Country	US
Kind code	B2
Filing date	Oct 30, 2015
Priority date	Nov 3, 2014
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

The present application relates to novel substituted piperidinylpyrazolopyrimidinones, to processes for their preparation, the compounds for use alone or in combinations in a method for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, hemorrhagic cystitis, gastrointestinal hemorrhage, trauma, surgery, transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis and cartilage damage following hemarthrosis.

First claim

The invention claimed is:

1. Compound of formula (I-A)

in which
R 1 is selected from the group consisting of hydrogen and C 1 -C 5 alkyl;
R 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, carboxyl, C 1 -C 4 alkylester, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, halogen, methylsulfanyl, phenyl, the phenyl being optionally substituted with halogen, and 5 membered heteroaryl;
R 3 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl, the alkyl being optionally substituted with di-C 1 -C 4 alkylamino, C 1 -C 4 alkenyl, C 1 -C 4 alkylester, the C 1 -C 4 alkylester being optionally substituted with one, two, three, four, or five halogen substituents, C 3 -C 4 cycloalkylester, C 3 -C 4 cycloalkyl, carboxyl, carboxamide, benzylester, —NH—CO-phenyl, —CS—NH 2 ,
phenylsulfonyl, the phenylsulfonyl being optionally substituted with one, two, or three halogen substituents,
phenyl,
the phenyl being optionally substituted with one, two, or three substituents selected from the group consisting of halogen and C 1 -C 4 alkoxy, where two adjacent methoxy groups may optionally form a dioxane ring,
or the phenyl being optionally substituted with one or two substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, cyano, benzyloxy, methylsulfonyl, and phenyl, the phenyl being optionally substituted with C 1 -C 4 haloalkyl,

5-6 membered heterocyclyl-C 1 -C 4 alkyl, the 5-6 membered heterocyclyl-moiety being optionally substituted with one, two, or three substituents selected from the group consisting of C 1 -C 4 alkyl and oxo,
5-6 membered heteroaryl,
the 5-6 membered heteroaryl being optionally substituted with one, two, or three substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylester, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, cyano, hydroxyl, carboxyl, C 1 -C 4 alkyl-SO 2 —C 1 -C 4 alkyl, and —CO—NH 2 ,
or the 5-6 membered heteroaryl being optionally substituted with one C 3 -C 6 cycloalkyl substituent, the C 3 -C 6 cycloalkyl optionally being substituted with one, two, or three halogen or methyl substituents, or with phenyl, the phenyl being optionally substituted with C 1 -C 4 alkoxy or halogen,
or the 5-6 membered heteroaryl being optionally substituted with one substituent selected from the group consisting of fused or bridged C 5 -C 12 bi- or tricycloalkyl, C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl-C 1 -C 4 alkenyl,
phenyl, the phenyl optionally being substituted with one, two, or three substituents selected from the group consisting of C 1 -C 4 alkyl, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 -alkylester, nitro, amino, di-C 1 -C 4 alkylamine, and cyano,
phenyl-C 1 -C 4 alkyl,
 the phenyl moiety optionally being substituted with one, two, or three substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and hydroxyl,
 the alkyl moiety optionally being substituted with one or two substituents selected from the group consisting of C 1 -C 4 alkyl and hydroxyl,
5-6 membered heterocycloalkyl, the 5-6 membered heterocycloalkyl being optionally substituted with C 3 -C 6 cycloalkyl or C 1 -C 4 alkyl,
5-6 membered heterocycloalkyl-C 1 -C 4 alkyl,
 the 5-6 membered heterocycloalkyl moiety being optionally substituted with C 1 -C 4 alkyl or oxo,
 the C 1 -C 4 alkyl moiety being optionally substituted with C 1 -C 4 alkyl,
5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted with one, two, or three substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl,
and 5-6 membered heteroaryl-C 1 -C 4 alkyl,
 the 5-6 membered heteroaryl-moiety being optionally substituted with one or two substituents selected from the group consisting of C 1 -C 4 alkoxy and C 1 -C 4 alkyl,
 the C 1 -C 4 alkyl-moiety being optionally substituted with one or two methyl substituents,

—CO—R 4 , with R 4 being selected from the group consisting of C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with one or two methyl, and C 3 -C 6 cycloalkyl,
—CO—N(R 5 R 7 ), with
R 5 being selected from the group consisting of hydrogen and C 1 -C 4 alkyl,
R 7 being selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 alkyl, amino-oxo-C 1 -C 4 alkyl, naphthyl,
C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl being optionally substituted with one or two C 1 -C 4 alkyl substituents,
C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl,
5-6 membered heterocyclyl,
oxazolidinyl-C 1 -C 4 alkyl,
benzyl,
 the phenyl moiety of the benzyl being optionally substituted with one, two, or three C 1 -C 4 alkyl substituents,
 the methyl moiety of the benzyl optionally being substituted with C 1 -C 4 alkyl,
benzyl-C 3 -C 6 cycloalkyl,
imidazolyl-C 1 -C 4 alkyl, the imidazolyl-C 1 -C 4 alkyl being optionally substituted with one, two, or three C 1 -C 4 alkyl substituents,
oxazolyl-C 1 -C 4 alkyl, the oxazolyl-C 1 -C 4 alkyl being optionally substituted with one, two, or three C 1 -C 4 alkyl substituents,
oxazolidinone-C 1 -C 4 alkyl,
pyridinyl-C 1 -C 4 alkyl,
and phenyl, the phenyl being optionally substituted with one, two, or three substituents selected from the group consisting of C 1 -C 4 alkyl, halogen, and C 1 -C 4 alkoxy,

or —N(R 5 R 7 ) being selected from the group consisting of 5-7 membered cyclic amines which contain one or two ring nitrogen atoms, zero or one ring oxygen atom, and zero or one ring sulfur atom, and are attached via a ring nitrogen atom, the 5 to 7 membered cyclic amines being optionally substituted with one, two, or three substituents selected from the group consisting of C 1 -C 4 alkoxy, C 1 -C 4 alkoxy C 1 -C 4 alkyl, oxo, hydroxyl, halogen, and C 1 -C 4 alkyl,
or —N(R 5 R 7 ) being selected from the group consisting of two annelated, aromatic, partially saturated or saturated rings which are each 5-7 membered and each contain one or two ring nitrogen atoms and are attached via a ring nitrogen atom,
and —N(R 5 R 7 ) being selected from the group consisting of bicyclic azaspiro compounds, the azaspiro compounds being optionally substituted with oxo;

or R 2 and R 3 together form a C 5 -C 6 cycloalkyl ring;

or a salt of the compound, or a solvate of the compound, or a solvate of the salt thereof.

2. Compound of formula (I-B)

in which
R 1 is selected from the group consisting of hydrogen, and C 1 -C 5 alkyl;
R 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, carboxyl, C 1 -C 4 alkylester, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, halogen, methylsulfanyl, phenyl, the phenyl being optionally substituted with halogen, and 5 membered heteroaryl;
R 3 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl, the alkyl being optionally substituted with di-C 1 -C 4 alkylamino, C 1 -C 4 alkenyl, C 1 -C 4 alkylester, the C 1 -C 4 alkylester being optionally substituted with one, two, three, four, or five halogen substituents, C 3 -C 4 cycloalkylester, C 3 -C 4 cycloalkyl, carboxyl, carboxamide, benzylester, —NH—CO-phenyl, —CS—NH 2 ,
phenylsulfonyl, the phenylsulfonyl being optionally substituted with one, two, or three halogen substi

Assignees

• Bayer Pharma AG

Inventors

• Ellermann Manuel
• Valot Gaelle
• Cancho Grande Yolanda
• Hassfeld Jorma
• Kinzel Tom
• Köbberling Johannes
• Beyer Kristin
• Röhrig Susanne
• Sperzel Michael
• Stampfuss Jan
• Meyer Imke
• Köllnberger Maria
• Burkhardt Nils
• Schlemmer Karl-Heinz
• Stegmann Christian
• Schuhmacher Joachim
• Werner Matthias
• HEIERMANN Jörg
• Hengeveld Willem Jan

Classifications

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P43/00

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

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title