Factor xia-inhibiting pyridobenzazepine and pyridobenzazocine derivatives

Patent metadata

Field	Value
Publication number	US-10138236-B2
Application number	US-201515514276-A
Country	US
Kind code	B2
Filing date	Sep 22, 2015
Priority date	Sep 24, 2014
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The invention relates to substituted pyridobenzazepine and pyridobenzazocine derivatives and to processes for preparation thereof, and also to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
A is a bond or —CH 2 —,
R 1 is hydrogen or methyl,
where methyl may be substituted by a fluorine substituent,

R 2 is hydrogen or methyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a cyclopropyl ring,
R 3 is hydrogen, C 1 -C 5 -alkyl, C 1 -C 4 -alkoxy, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 3,3,3-trifluoro-2-hydroxyprop-1-yl, 3,3,3-trifluoro-2-methoxyprop-1-yl, 3,3,3-trifluoro-2-ethoxyprop-1-yl, prop-2-yn-1-yl, cyclopropyloxy or cyclobutyloxy,
where alkyl may be substituted by a substituent selected from the group consisting of fluorine, cyano, hydroxyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered oxoheterocyclyl, 1,4-dioxanyl, oxazolyl, phenyl and pyridyl,
in which cycloalkyl may be substituted by 1 to 2 substituents selected independently from the group consisting of fluorine, hydroxyl, methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy,
and
in which the 4- to 6-membered oxoheterocyclyl is a monocyclic saturated ring having 3-5 carbons and an oxygen,

R 4 is hydrogen,
R 5 is a group of the formula

where # is the attachment point to the nitrogen atom,
R 8 is carboxyl, aminocarbonyl or 5-membered heterocyclyl,
where the heterocyclyl is a monocyclic saturated, partly saturated or aromatic ring having 1, 2, 3 or 4 heteroatoms selected independently from the group consisting of sulfur, oxygen and nitrogen,
and
where the heterocyclyl may be substituted by 1 to 2 substituents selected independently from the group consisting of oxo, hydroxyl, thioxo, sulphanyl, methyl, difluoromethyl, trifluoromethyl, 2-carboxyl-1,1,2,2-tetrafluoroethyl and 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,
in which methyl may be substituted by a methoxy substituent,

R 9 is hydrogen, chlorine, fluorine or methyl,
R 10 and R 11 together with the carbon atoms to which they are bonded form a 5-membered heterocycle,
where the heterocycle is a monocyclic saturated, partly saturated or aromatic ring having 1 or 2 heteroatoms selected independently from the group consisting of sulfur, oxygen and nitrogen,
and
where the heterocycle may be substituted by 1 to 2 substituents selected independently from the group consisting of oxo, chlorine, hydroxyl, carboxyl, methyl, difluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl, 2-carboxyl-1,1,2,2-tetrafluoroethyl and 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,

R 12 is hydrogen, chlorine, fluorine, methyl or methoxy,
Y 1 is a nitrogen atom or C—R 15
in which

R 15 is hydrogen, chlorine, hydroxyl, methoxy or C 1 -C 3 alkoxycarbonyl,
Y 2 is a nitrogen atom or C—R 16
in which

R 16 is hydrogen, chlorine, hydroxyl or methoxy,
R 13 is hydrogen, carboxyl, carboxylmethyl or phenyl,
where phenyl may be substituted by 1 to 2 fluorine substituents,

R 14 is hydrogen, chlorine, fluorine or methyl,
Y 3 is a nitrogen atom or C—R 19
in which

R 19 is hydrogen, chlorine, hydroxyl or methoxy,
Y 4 is a nitrogen atom or C—R 20
in which

R 20 is hydrogen, chlorine, hydroxyl or methoxy,
R 17 is hydrogen, carboxyl, carboxylmethyl, C 1 -C 3 -alkoxycarbonyl or aminocarbonyl,
R 18 is hydrogen, chlorine, fluorine or methyl,
R 21 is hydrogen, chlorine, hydroxy, C 1 -C 4 -alkyl, methoxy, C 1 -C 3 -alkylaminomethyl or morpholinylmethyl,
R 22 is hydrogen, chlorine, fluorine or methyl,
R 23 is hydrogen, chlorine, hydroxyl or methoxy,
R 24 is hydrogen, chlorine, fluorine or methyl,
R 25 is hydrogen, carboxyl or carboxylmethyl,
R 26 is hydrogen, chlorine, fluorine or methyl,
R 27 is carboxyl, aminocarbonyl, C 1 -C 3 -alkoxycarbonyl or C 1 -C 3 -alkylaminocarbonyl,
where alkylaminocarbonyl may be substituted by a substituent selected from the group consisting of hydroxyl, trifluoromethyl, methoxy and trifluoromethoxy,

R 28 is hydrogen, chlorine, fluorine or methyl,
R 31 is hydrogen or fluorine,
R 32 is hydroxyl or —NHR 33 ,
in which
R 33 is hydrogen, methyl or ethyl,

R 34 is hydrogen or fluorine,
R 35 is hydroxyl or —NHR 36 ,
in which
R 36 is hydrogen, methyl or ethyl,

R 37 is hydrogen or fluorine,
R 38 is hydroxyl or —NHR 39 ,
in which
R 39 is hydrogen, methyl or ethyl,

R 40 is hydrogen or fluorine,
R 41 is hydroxyl or —NHR 42 ,
in which
R 42 is hydrogen, methyl or ethyl,

R 6 is bromine, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,
R 7 is hydrogen, chlorine or fluorine,
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein
A is a bond or —CH 2 —,
R 1 is hydrogen or methyl,
R 2 is hydrogen or methyl,
or
R 1 and R 2 together with the carbon atom to which they are bonded form a cyclopropyl ring,
R 3 is hydrogen, methyl, ethyl, n-propyl, 2-methylprop-1-yl, n-butyl or ethoxy,
where methyl may be substituted by a substituent selected from the group consisting of difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl and 1,4-dioxanyl,
where cyclopropyl, cyclobutyl, cyclohexyl and oxetanyl may be substituted by 1 to 2 substituents selected independently from the group consisting of fluorine, hydroxyl, methyl, ethyl and methoxy,
and
where ethyl, n-propyl and n-butyl may be substituted by a substituent selected from the group consisting of fluorine, methoxy and trifluoromethoxy,

R 4 is hydrogen,
R 5 is a group of the formula

where # is the attachment point to the nitrogen atom,
R 8 is carboxyl, aminocarbonyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl or dihydrooxazolyl,
where oxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl and dihydrooxazolyl may be substituted by 1 to 2 substituents selected independently from the group consisting of oxo, hydroxyl, thioxo, sulphanyl, methyl, trifluoromethyl and 2-carboxyl-1,1,2,2-tetrafluoroethyl,
in which methyl may be substituted by a methoxy substituent,

R 9 is hydrogen, chlorine, fluorine or methyl,
Y 1 is a nitrogen atom or C—R 15
in which
R 15 is hydrogen, chlorine, hydroxyl or methoxy,

Y 2 is a nitrogen atom or C—R 16
in which
R 16 is hydrogen, chlorine, hydroxyl or methoxy,

R 13 is hydrogen or carboxyl,
R 14 is hydrogen or fluorine,
Y 3 is a nitrogen atom or C—R 19
in which
R 19 is hydrogen, chlorine, hydroxyl or methoxy,

Y 4 is a nitrogen atom or C—R 20
in which
R 20 is hydrogen, chlorine, hydroxyl or methoxy,

R 17 is hydrogen or carboxyl,
R 18 is hydrogen or fluorine,
R 31 is hydrogen,

R 32 is hydroxyl or —NHR 33 ,
in which
R 33 is hydrogen,

R 34 is hydrogen,
R 35 is hydroxyl,
or
R 5 is 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl, 2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-y

Assignees

• Bayer Pharma AG

Inventors

• Röhrig Susanne
• Hillisch Alexander
• Heitmeier Stefan
• Schmidt Martina Victoria
• Schlemmer Karl-Heinz
• Tersteegen Adrian
• Schäfer Martina
• Teller Henrik
• Jimènez Nùnez Eloisa

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P27/02

  Ophthalmic agents · CPC title