HK1203493B

HK1203493B - Substituted azabicycles and use thereof

Info

Publication number: HK1203493B
Application number: HK15103934.6A
Authority: HK
Inventors: Markus Follmann; Johannes-Peter Stasch; Gorden Redlich; Alexandros Vakalopoulos; Dieter Lang; Frank Wunder; Walter Hübsch; Michael Hahn
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2012-03-06
Filing date: 2013-03-05
Publication date: 2018-02-15

Description

Substituted azabicycles and their use

The present application relates to novel substituted azabicycles, to methods for the production thereof, to the use thereof, alone or in combination, for the treatment and/or prophylaxis of diseases, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular diseases.

One of the most important cellular delivery systems in mammalian cells is cyclic guanosine monophosphate (cGMP). It forms the NO/cGMP system with Nitric Oxide (NO), which is released by the endothelium and transmits hormonal and mechanical signals. Guanylate cyclase catalyzes the biosynthesis of cGMP from Guanosine Triphosphate (GTP). The representatives of this family known to date can be divided into two groups according to structural features or ligand type: particulate guanylate cyclase excitable by natriuretic peptides, and soluble guanylate cyclase excitable by NO. Soluble guanylate cyclase consists of two subunits, and it is likely that each heterodimer contains one heme, which is part of the regulatory center. This is crucial for the activation mechanism. NO can bind to the iron atom in heme and thus significantly increase the activity of the enzyme. In contrast, heme-free preparations are not stimulated by NO. Carbon monoxide (CO) can also bind to the central iron atom of heme, but the excitation of CO is significantly less than that of NO.

By forming cGMP and due to the ensuing regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays an important role in a variety of physiological processes, particularly during relaxation and proliferation of smooth muscle cells, during platelet aggregation and platelet adhesion and during nerve signal transduction, and in diseases that are disrupted based on the foregoing processes. Under pathophysiological conditions, the NO/cGMP system can be inhibited, which may lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.

In view of the high efficiency and low levels of side effects that can be expected, a possible NO-independent treatment for such diseases, intended to influence the cGMP signalling pathway in organisms, is a promising approach.

To date, compounds such as organic nitrates, the action of which is based on NO, have been used exclusively for the therapeutic stimulation of soluble guanylate cyclase. NO is formed by biotransformation and activates soluble guanylate cyclase by acting on the central iron atom of heme. In addition to side effects, one of the key drawbacks of this mode of treatment is the development of tolerance.

In recent years, several substances have been described which directly stimulate soluble guanylate cyclase, i.e. which do not release NO beforehand, such as 3- (5 '-hydroxymethyl-2' -furyl) -1-benzylindazole [ YC-1; wu et al, Blood 84(1994), 4226; mulsch et al, brit.j.pharmacol.120(1997), 681), fatty acids [ Goldberg et al, j.biol.chem.252(1977), 1279], iodonium diphenylhexafluorophosphate [ Pettibone et al, eur.j.pharmacol.116(1985), 307], isoliquiritigenin [ Yu et al, brit.j.pharmacol.114(1995), 1587] and various substituted pyrazole derivatives (WO 98/16223).

As stimulators of soluble guanylate cyclase, WO 00/06569 discloses fused pyrazole derivatives and WO01/083490 discloses fused aminopyridine derivatives. WO 2010/065275 discloses pyrrolopyrimidinones as activators of soluble guanylate cyclase.

It is an object of the present invention to provide novel substances which are stimulators of soluble guanylate cyclase and which have the same or improved therapeutic properties compared to the compounds known from the prior art, for example with respect to their in vivo properties, such as their pharmacokinetic and pharmacodynamic behaviour and/or their metabolic properties and/or their dose-activity relationship.

The present invention provides compounds of general formula (I), and the N-oxides, salts, solvates, salts of said N-oxides and solvates of said N-oxides or salts thereof,

wherein

Ring Q represents an 8-or 9-membered heteroaryl group,

R¹represents fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl radicals, (C)₃-C₇) -cycloalkyl or (C)₁-C₄) -an alkoxy group,

n represents the number 0, 1 or 2,

R²represents trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₃-C₈) -cycloalkyl, phenyl or 5-or 6-membered heteroaryl,

wherein (C)₁-C₆) -alkyl is substituted with a substituent selected from difluoromethyl and trifluoromethyl,

wherein (C)₁-C₆) Alkyl may be substituted with 1 to 3 fluoro substituents,

wherein (C)₃-C₈) -cycloalkyl may be substituted with 1 or 2 substituents independently selected from fluoro, methyl and methoxy,

wherein the phenyl group is substituted with 1 to 3 fluoro substituents,

wherein phenyl may be substituted with 1 or 2 substituents independently selected from methyl and methoxy,

and

wherein the 5-and 6-membered heteroaryl groups may be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl and methyl,

R³represents a group of the formula

Wherein the content of the first and second substances,

# represents the point of attachment to loop Q,

l represents a group selected from the group consisting of CH and N,

m represents CR⁴Or the number of N is greater than the number of N,

wherein

R⁴represents-R⁵、-OR⁶or-NR⁷R⁸，

Wherein

R⁵Represents hydrogen, halogen, cyano, (C)₁-C₆) Alkyl radicals, (C)₂-C₄) -alkynyl, (C)₁-C₄) -alkylcarbonyl or (C)₁-C₄) -an alkoxycarbonyl group, a carbonyl group,

wherein (C)₁-C₆) -alkyl and (C)₂-C₄) -alkynyl can itself be independently selected by 1 or 2 from fluoro, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₃-C₆) -cycloalkyl, difluoromethoxy, trifluoromethoxy, oxo, - (C ═ O)_p-OR⁹、-C(＝O)_p-NR⁹R¹⁰、-NR⁹-(C＝O)-R¹⁰、-NR⁹-(C＝O)-OR¹⁰、-NR⁹-(C＝O)-NR¹⁰R¹¹、-NR⁹-SO₂-R¹⁰、-S(O)_q-R¹²and-SO₂-NR⁹R¹⁰The substituent (b) of (a) is substituted,

R⁶represents hydrogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, 4-to 7-membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl,

wherein (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, 4-to 7-membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₃-C₆) -cycloalkyl, difluoromethoxy, trifluoromethoxy, oxo, - (C ═ O)_p-OR⁹、-C(＝O)_p-NR⁹R¹⁰、-NR⁹-(C＝O)-R¹⁰、-NR⁹-(C＝O)-OR¹⁰、-NR⁹-(C＝O)-NR¹⁰R¹¹、-NR⁹-SO₂-R¹⁰、-S(O)_q-R¹²and-SO₂-NR⁹R¹⁰The substituent (b) of (a) is substituted,

R⁷represents hydrogen or (C)₁-C₄) -an alkyl group,

R⁸represents hydrogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, 4-to 7-membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl,

wherein (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, 4-to 7-membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, difluoromethoxy, trifluoromethoxy, oxo, - (C ═ O)_p-OR⁹、-(C＝O)_p-NR⁹R¹⁰、-NR⁹-(C＝O)-R¹⁰、-NR⁹-(C＝O)-OR¹⁰、-NR⁹-(C＝O)-NR¹⁰R¹¹、-NR⁹-SO₂-R¹⁰、-S(O)_q-R¹²、-SO₂-NR⁹R¹⁰Phenyl, 4-to 7-membered heterocyclyl and 5-or 6-membered heteroaryl,

wherein, in each case,

p represents the number 0 or 1 and,

q represents the number 0, 1 or 2,

R⁹、R¹⁰and R¹¹Each independently represents hydrogen or (C)₁-C₆) -alkyl or (C)₃-C₈) -a cycloalkyl group,

wherein (C)₁-C₆) -alkyl may itself be substituted by 1 or 2 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, hydroxy, (C)₁-C₆) -alkoxy, difluoromethoxy, trifluoromethoxy, (C)₁-C₆) Alkoxycarbonyl, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino and 4-to 7-membered heterocyclyl,

or

R⁹And R¹⁰Together with the atoms to which they are each attached form a 4-to 7-membered heterocyclic ring,

wherein the 4-to 7-membered heterocyclic ring may itself be substituted by 1 or 2 substituents independently selected from fluoro, cyano, trifluoromethyl, (C)₁-C₆) -alkyl, hydroxy, oxo, (C)₁-C₆) -alkoxy, trifluoromethoxy, (C)₁-C₆) Alkoxycarbonyl, amino, mono- (C)₁-C₆) Alkylamino and di- (C)₁-C₆) -a substituent of an alkylamino group,

or

R¹⁰And R¹¹Together with the atoms to which they are each attached form a 4-to 7-membered heterocyclic ring,

and wherein

R¹²Is represented by (C)₁-C₆) -alkyl or (C)₃-C₇) -a cycloalkyl group,

or therein

R⁷And R⁸Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclic ring or a 5-or 6-membered heteroaryl group,

wherein the 4-to 7-membered heterocycle and 5-or 6-membered heteroaryl may be substituted with 1 to 3 substituents independently selected from fluoro, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, hydroxy, oxo, (C)₁-C₆) -alkoxy, difluoromethoxy, trifluoromethoxy, (C)₁-C₆) Alkoxycarbonyl, amino, mono- (C)₁-C₆) Alkylamino and di- (C)₁-C₆) -a substituent of an alkylamino group,

and is

Wherein all of (C) above₁-C₄) Alkyl radicals, (C)₁-C₆) Alkyl radicals, (C)₃-C₈) -cycloalkyl and 4-to 7-membered heterocyclyl, each independently and, unless otherwise specified, may be independently selected from fluoro, difluoromethyl, trifluoromethyl, (C)₃-C₇) -cycloalkyl, hydroxy, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, hydroxycarbonyl, (C)₁-C₄) Alkoxycarbonyl, amino, phenyl, 4-to 7-membered heterocyclyl and 5-or 6-membered heteroaromatic compoundsThe substituent of the group is substituted,

ring P¹Represents a 5-to 7-membered heterocyclic group, a phenyl group or a 5-or 6-membered heteroaryl group,

wherein the 5-to 7-membered heterocyclyl, phenyl and 5-or 6-membered heteroaryl can be substituted with 1 to 3 substituents independently selected from halogen, cyano, difluoromethyl, trifluoromethyl, trideuteromethyl, (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₃-C₇) -cycloalkyl, oxo, difluoromethoxy, trifluoromethoxy, thio (thiooxo) and of formula-M-R¹³Is substituted with a substituent of the group (a),

wherein (C)₁-C₆) -alkyl may be independently selected from 1 to 3 fluorine, cyano, trifluoromethyl, (C)₃-C₇) -cycloalkyl, difluoromethoxy and trifluoromethoxy substituents,

ring P²Represents a 5-membered heteroaryl group, which is,

wherein the 5-membered heteroaryl group can be substituted with 1 to 3 substituents independently selected from halogen, cyano, difluoromethyl, trifluoromethyl, trideuteromethyl, (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₃-C₇) -cycloalkyl, oxo, difluoromethoxy, trifluoromethoxy, thio and of formula-M-R¹³Is substituted with a substituent of the group (a),

and wherein, in each case,

m represents a bond or (C)₁-C₄) -an alkylene group,

R¹³represents- (C ═ O)_r-OR¹⁴、-(C＝O)_r-NR¹⁴R¹⁵、-C(＝S)-NR¹⁴R¹⁵、-NR¹⁴-(C＝O)-R¹⁵、-NR¹⁴-(C＝O)-OR¹⁷、-NR¹⁴-(C＝O)-NR¹⁵R¹⁶、-NR¹⁴-SO₂-NR¹⁵R¹⁶、-NR¹⁴-SO₂-R¹⁷、-S(O)_s-R¹⁷、-SO₂-NR¹⁴R¹⁵4-to 7-membered heterocyclyl, phenyl, benzyl or 5-or 6-membered heteroaryl,

wherein

r represents the number 0 or 1 and,

s represents the number 0, 1 or 2,

R¹⁴、R¹⁵and R¹⁶Each independently represents hydrogen or (C)₁-C₆) Alkyl radicals, (C)₃-C₈) -cycloalkyl, 4-to 7-membered heterocyclyl, phenyl, benzyl or 5-or 6-membered heteroaryl,

or

R¹⁴And R¹⁵Together with the atoms to which they are each attached form a 4-to 7-membered heterocyclic ring,

wherein the 4-to 7-membered heterocyclic ring may itself be substituted by 1 or 2 substituents independently selected from cyano, trifluoromethyl, (C)₁-C₆) -alkyl, hydroxy, oxo, (C)₁-C₆) -alkoxy, trifluoromethoxy, (C)₁-C₆) Alkoxycarbonyl, amino, mono- (C)₁-C₆) Alkylamino and di- (C)₁-C₆) -a substituent of an alkylamino group,

or

wherein the 4-to 7-membered heterocyclic ring may itself be substituted by 1 or 2 substituents independently selected from cyano, trifluoromethyl, (C)₁-C₆) -alkyl, hydroxy, oxo, (C)₁-C₆) -alkoxy, trifluoromethoxy, (C)₁-C₆) Alkoxycarbonyl, amino, mono- (C)₁-C₆) -alkyl radicalAmino and di- (C)₁-C₆) -a substituent of an alkylamino group,

R¹⁷is represented by (C)₁-C₆) -alkyl or (C)₃-C₇) -a cycloalkyl group,

or

R¹⁴And R¹⁷Together with the atoms to which they are each attached form a 4-to 7-membered heterocyclic ring,

and is

Wherein the 4-to 7-membered heterocyclyl, phenyl, benzyl and 5-or 6-membered heteroaryl groups may themselves be substituted by 1 to 3 substituents independently selected from halogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, hydroxy, oxo, thio and (C)₁-C₄) -a substituent of an alkoxy group,

and is

Wherein above (C)₁-C₄) Alkyl radicals, (C)₁-C₆) Alkyl radicals, (C)₃-C₈) -cycloalkyl and 4-to 7-membered heterocyclyl, each independently and, unless otherwise specified, may be independently selected from fluoro, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, hydroxy, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, hydroxycarbonyl, (C)₁-C₄) -substituent substitutions of alkoxycarbonyl, amino, phenyl, 4-to 7-membered heterocyclyl and 5-or 6-membered heteroaryl,

with the exception of the following compounds:

2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -8-methyl-9H-purine,

2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -8-methyl-9H-purin-6-amine,

n-butyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -8-methyl-9H-purin-6-amine.

If the compounds of formula (I) comprise compounds which are not already salts, solvates and solvates of salts, the compounds of the invention are compounds of formula (I) and their salts, solvates and solvates of salts, the compounds of formula (I) comprise compounds of formula (I) which are mentioned below and their salts, solvates and solvates of salts, and the compounds of formula (I) comprise compounds which are mentioned below as working examples and their salts, solvates and solvates of salts.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds of the invention. Also included are salts which are not suitable per se for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example the salts of the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically acceptable salts of the compounds of the invention also include salts of customary bases, such as, for example and with preference, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, for example and with preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1, 2-ethylenediamine and N-methylpiperidine.

In the context of the present invention, a solvate refers to a complex formed by coordination of a compound of the present invention in a solid or liquid state with a solvent molecule. Hydrates are a particular form of solvates in which the water is coordinated. Preferred solvent compounds in the context of the present invention are hydrates.

Depending on their structure, the compounds of the invention may exist in the form of different stereoisomers, i.e. in the form of configurational isomers, or optionally also as conformational isomers (enantiomers and/or diastereomers, including the case of atropisomers). Thus, the present invention includes enantiomers and diastereomers and mixtures of each thereof. The stereoisomerically homogeneous components can be separated from the mixture of enantiomers and/or diastereomers in a known manner; chromatography is preferably used for this separation, in particular HPLC chromatography based on achiral or chiral phases.

When a compound of the present invention may exist in tautomeric forms, the present invention includes all tautomeric forms.

The present invention also includes all suitable isotopic variations of the compounds of the present invention. Isotopic variations of the compounds of the present invention are understood herein to mean compounds in which at least one atom is exchanged for another atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly present in nature. Examples of isotopes that can be incorporated into the compounds of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. compounds of the inventionCertain isotopic variations, for example, more specifically, those into which one or more radioisotopes have been introduced, may be advantageous, for example, for studying the mechanism of action or active substance distribution in vivo; due to relative ease of preparation and detection³H-isotope or¹⁴C-isotopically labelled compounds are particularly suitable for this purpose. Furthermore, the introduction of isotopes such as deuterium may afford particular therapeutic benefits due to increased metabolic stability of such compounds (e.g. longer half-life in vivo or reduced effective dosages required); thus, in certain instances, such modifications of the compounds of the invention may also constitute preferred embodiments of the invention. Isotopic variations of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example, by the methods described below and by the procedures described in the working examples, in which the respective reagents and/or the corresponding isotopic modifications of the starting compounds are employed.

In addition, the present invention also includes prodrugs of the compounds of the present invention. As used herein, the term "prodrug" means a compound that may be biologically active or inactive by itself but which may be converted (e.g., by metabolic means or by hydrolytic means) to the compound of the present invention during its residence in the body.

In the context of the present invention, unless otherwise indicated, the substituents are each as defined below:

in the context of the present invention,alkyl radicalRefers to a straight or branched chain alkyl group having the indicated number of carbon atoms in each case. For example and preferably the following groups may be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.

In the context of the present invention,cycloalkyl or carbocycleRefers to monocyclic saturated alkyl groups having the indicated number of carbon atoms in each case. For example and preferably the following groups may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the present invention,5-to 7-membered saturated or partially unsaturated carbocyclic ringRefers to saturated or partially unsaturated cyclic alkyl groups having in each case the indicated number of carbon atoms. For example and preferably the following groups may be mentioned: cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

In the context of the present invention,alkylene radicalRefers to a linear or branched divalent alkyl group having 1 to 4 carbon atoms. For example and preferably the following groups may be mentioned: methylene, ethane-1, 2-diyl, ethane-1, 1-diyl, propane-1, 3-diyl, propane-1, 1-diyl, propane-1, 2-diyl, propane-2, 2-diyl, butane-1, 4-diyl, butane-1, 2-diyl, butane-1, 3-diyl, and butane-2, 3-diyl. Preferably: methylene, ethane-1, 2-diyl, propane-1, 3-diyl and butane-1, 4-diyl.

In the context of the present invention,alkenyl radicalRefers to a straight or branched chain alkenyl group having 2 to 6 or 2 to 4 carbon atoms and a double bond. For example and preferably the following groups may be mentioned: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

In the context of the present invention,alkynyl radicalRefers to a straight or branched chain alkynyl group having 2 to 4 carbon atoms and one triple bond. For example and preferably the following groups may be mentioned: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl.

In the context of the present invention,alkoxy radicalRefers to a straight or branched chain alkoxy group having 1 to 6 or 1 to 4 carbon atoms. For example and preferably the following groups may be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy and n-hexoxy. Linear or branched alkoxy groups having 1 to 4 carbon atoms are preferred. For example and preferably mayThe following groups are mentioned: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.

In the context of the present invention,alkyl carbonylRefers to a straight or branched chain alkyl group having 1 to 6 or 1 to 4 carbon atoms and having a carbonyl group attached at the 1 position. For example and preferably the following groups may be mentioned: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl and tert-butylcarbonyl.

In the context of the present invention,alkoxycarbonyl radicalRefers to a straight or branched alkoxy group having 1 to 6 or 1 to 4 carbon atoms with a carbonyl group attached to the oxygen. For example and preferably the following groups may be mentioned: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

In the context of the present invention,monoalkylamino groupRefers to an amino group having a straight or branched alkyl substituent and having 1 to 6 carbon atoms. For example and preferably the following groups may be mentioned: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

In the context of the present invention,dialkylamino radicalRefers to an amino group having 2 identical or different straight or branched alkyl substituents each having 1 to 6 carbon atoms. For example and preferably the following groups may be mentioned: n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propylamino, N-isopropyl-N-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-N-pentylamino and N-N-hexyl-N-methylamino.

In the context of the present invention,5-to 7-membered saturated or partially unsaturated heterocyclic ringMeans having a total of 5 to 7 ring atoms and comprising one atom selected from N, O, S, SO and/or SO₂A saturated or partially unsaturated heterocyclic ring of a ring heteroatom of (a). For example and preferably the following groups may be mentioned: pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, dihydropyrrolyl, dihydropyridinyl.

In the context of the present invention,heterocyclic or heterocyclic ringMeans having a total of 4 to 7 ring atoms and containing one or two atoms selected from N, O, S, SO and/or SO₂Saturated heterocyclic ring of the ring heteroatom of (1). For example and preferably the following groups may be mentioned: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and thiomorpholinyl dioxide. Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl and morpholinyl.

In the context of the present invention,5-or 6-membered heteroarylRefers to monocyclic aromatic heterocycles (heteroaromatics) having a total of 5 or 6 ring atoms, which contain up to three identical or different ring heteroatoms from the group N, O and/or S and are connected via ring carbon atoms or optionally via ring nitrogen atoms. For example and preferably the following groups may be mentioned: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preferably: pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl.

In the context of the present invention,8-or 9-membered heteroarylRefers to a bicyclic aromatic or partially unsaturated heterocyclic ring having a total of 8 or 9 ring atoms and containing at least two nitrogen atoms and up to two other identical or different ring heteroatoms selected from N, O and/or S. For example, the following groups may be mentioned: dihydrothienopyrazolyl, thienopyrazolyl, pyrazolopyrazolyl, imidazothiazolyl, tetrahydrocyclopentapyrazolyl, dihydrocyclopentapyrazolyl, tetrahydroindazolyl, dihydroindazolyl, indazolyl, pyrazolopyridyl, tetrahydropyrazolopyridyl, pyrazolopyrimidinyl, imidazopyridinyl and imidazopyridazinyl.

In the context of the present invention,halogen elementMeans thatFluorine, chlorine, bromine and iodine. Fluorine and chlorine are preferred.

In the context of the present invention,oxo radicalRefers to an oxygen atom that is attached to a carbon atom via a double bond.

In the context of the present invention,thio groupRefers to a sulfur atom attached to a carbon atom via a double bond.

At Q or R³In the formula of the group which may be represented, the end points of the line marked by the symbols ＊, ＊＊ or # # do not represent carbon atoms or CH₂Group, and represents Q or R³A part of a bond to each atom.

When a group in a compound of the present invention is substituted, the group may be mono-or polysubstituted, unless otherwise specifically indicated. In the context of the present invention, all radicals occurring more than once are defined independently of one another. Preferably by 1,2 or 3 identical or different substituents.

In the context of the present invention, the term "treating" includes preventing, delaying, hindering, alleviating, attenuating, limiting, alleviating, inhibiting, combating or curing a disease, disorder, condition, injury or health problem, or the occurrence, course or progression of such a condition and/or symptoms of such a condition. The term "therapy" is to be understood herein as synonymous with the term "treatment".

In the context of the present invention, the terms "prevention", "prevention" or "prevention" are used synonymously and mean avoiding or reducing the following risks: an infection, a experiencing, suffering from, or having a disease, condition, disorder, injury, or health problem, or the occurrence or progression of such a condition and/or symptoms of such a condition.

The treatment or prevention of a disease, condition, disorder, injury, or health problem may be partial or complete.

In the context of the present invention, preference is given to compounds of the formula (I) and salts, solvates and solvates of the salts, where

Ring Q represents a group of the formula:

wherein

＊ represents a bond to-CH₂-R²The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

ring Q₁Together with the atoms to which they are attached form a 5-to 7-membered saturated or partially unsaturated carbocyclic ring or a 5-to 7-membered saturated or partially unsaturated heterocyclic ring,

R¹represents fluorine, chlorine, methyl, hydroxy or oxo,

R^1Arepresents hydrogen or a methyl group,

n represents the number 0, 1 or 2,

A¹、A²、A³and A⁴Each independently represents N, CH or CR¹，

With the proviso that A¹、A²、A³And A⁴No more than two of the radicals represent N,

R²represents trifluoromethyl, 2,2, 2-trifluoroethyl, 3,3, 3-trifluoroprop-1-yl, 2,2,3, 3-tetrafluoroprop-1-yl, 2,2,3,3, 3-pentafluoroprop-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,

wherein the phenyl group is substituted with 1 to 3 fluoro substituents,

and

wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridinyl, pyrimidinyl, pyrazinyl and

the pyridazinyl group may be substituted with 1 or 2 fluoro substituents,

R³represents a group of formula:

wherein the content of the first and second substances,

# represents the point of attachment to loop Q,

l represents a group selected from the group consisting of CH and N,

m represents CR⁴Or the number of N is greater than the number of N,

wherein

R⁴represents-R⁵、-OR⁶or-NR⁷R⁸，

Wherein

R⁵Represents hydrogen, chlorine, cyano, (C)₁-C₄) -alkyl or (C)₂-C₄) -alkynyl, wherein (C)₁-C₄) -alkyl and (C)₂-C₄) -alkynyl may itself be substituted by 1 or 2 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, - (C ═ O)_p-OR⁹and-C (═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 and p represents the number 0,

R⁹and R¹⁰Each independently represents hydrogen, methyl, ethyl, isopropyl,Trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,

or

R⁹And R¹⁰Together with the atoms to which they are each attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring,

wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl rings may themselves be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino,

R⁶is represented by (C)₁-C₆) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl,

wherein (C)₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, - (C ═ O)_p-OR⁹、-(C＝O)_p-NR⁹R¹⁰and-NR⁹-(C＝O)-R¹⁰The substituent (b) of (a) is substituted,

and is

Wherein cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, or pyrimidinyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, methyl, ethyl, isopropyl, cyclopropylAlkyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, oxo, - (C ═ O)_p-OR⁹And- (C ═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein in each of the cases of use,

p represents the number 0 or 1 and,

R⁹and R¹⁰Each independently of the others represents hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl, or

R⁹And R¹⁰Together with the atoms to which each is attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring,

R⁷represents hydrogen, a methyl group or an ethyl group,

R⁸represents hydrogen, (C)₁-C₆) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl,

wherein (C)₁-C₆) -alkyl, cyclopropyl, cyclobutyl and cyclopentyl are independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, - (C ═ O)_p-OR⁹、-(C＝O)_p-NR⁹R¹⁰、-NR⁹-(C＝O)-R¹⁰Substituted with substituents of oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl,

wherein

p represents the number 0 or 1 and,

R⁹and R¹⁰Each independently of the others represents hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,

or

R⁹And R¹⁰Together with the atoms to which each is attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring, wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl rings may themselves be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, and diethylamino,

and is

Wherein oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl may themselves be substituted with 1 or 2 substituents independently selected from fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo, difluoromethoxy, trifluoromethoxy, methoxy, and ethoxy,

and is

Wherein oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinylTetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, oxo, - (C ═ O)_p-OR⁹And- (C ═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 or 1 and,

or

R⁷And R⁸Together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl or triazolyl ring,

wherein the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl or triazolyl ring may be substituted with 1 or 2 substituents independently selected from fluoro, cyano, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, methyl, ethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy,

E¹represents O, S or NR¹⁸，

Wherein

R¹⁸Represents hydrogen, trifluoromethyl or (C)₁-C₄) -an alkyl group,

wherein (C)₁-C₄) The alkyl group may itself be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, hydroxy, methoxy and ethoxy,

E²represents N and a nitrogen-containing compound which is a nitrogen-containing compound,

E³represents N or CR¹⁹，

Wherein

R¹⁹Represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl or of formula-M-R¹³The group of (a) or (b),

wherein (C)₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently selected from fluoro, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy and trifluoromethoxy,

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl, R¹³Represents- (C ═ O)_r-OR¹⁴、-(C＝O)_r-NR¹⁴R¹⁵、-C(＝S)-NR¹⁴R¹⁵、-NR¹⁴-(C＝O)-OR¹⁷Oxadiazolonyl, oxadiazolonylthio, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl,

wherein

r represents the number 0 or 1 and,

R¹⁴and R¹⁵Each independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or pyridinyl, wherein methyl, ethyl and isopropyl may be additionally substituted by 1 or 2 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,

R¹⁷represents methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and

wherein the oxadiazolonyl, oxadiazolidinethionyl, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl and pyrazinyl groups may themselves be substituted by 1 or 2 substituents independently selected from fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, hydroxy, methoxy and ethoxy,

E⁴and E⁶Each independently represents N or CR²⁰，

Wherein

R²⁰Represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl or of formula-M-R¹³A group of (C) wherein₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently selected from fluoro, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy and trifluoromethoxy,

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl, R¹³Represents- (C ═ O)_r-OR¹⁴、-(C＝O)_r-NR¹⁴R¹⁵、

-C(＝S)-NR¹⁴R¹⁵、-NR¹⁴-(C＝O)-OR¹⁷Oxadiazolonyl, oxadiazolonylthionyl, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl,

wherein

r represents the number 0 or 1 and,

R¹⁴and R¹⁵Each independently of the others represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or pyridyl,

wherein methyl, ethyl and isopropyl may be additionally substituted with 1 or 2 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,

R¹⁷represents methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,

and is

E⁵represents NR²¹，

Wherein

R²¹Represents hydrogen or (C)₁-C₄) -an alkyl group,

G¹、G²、G³and G⁴Each independently represents N or CR²²，

Wherein

R²²Represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl or of formula-M-R¹³The group of (a) or (b),

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

R¹³represents- (C ═ O)_r-OR¹⁴、-(C＝O)_r-NR¹⁴R¹⁵、-C(＝S)-NR¹⁴R¹⁵、-NR¹⁴-(C＝O)-OR¹⁷Oxadiazolonyl, oxadiazolonylthionyl, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl,

wherein

r represents the number 0 or 1 and,

and is

provided that G is¹、G²、G³And G⁴No more than two of the radicals represent nitrogen,

and

provided that G is¹、G²、G³And G⁴At least one of the radicals represents CH,

u represents C-O, C-S or SO₂，

V represents O or NR²⁴，

Wherein

R²⁴Represents hydrogen, trideuteromethyl、(C₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₃-C₇) -cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl or benzyl,

wherein (C)₁-C₆) Alkyl may itself be substituted with 1 to 3 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl and morpholinyl,

wherein azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl and morpholinyl may themselves be substituted by 1 or 2 substituents independently selected from fluoro, trifluoromethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methyl and ethyl,

wherein azetidinyl, pyrrolidinyl and piperidinyl may themselves be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, methyl, ethyl, cyclopropyl and cyclobutyl,

wherein methyl and ethyl may themselves be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy and ethoxy,

and is

Wherein the benzyl group may itself be substituted by 1 or 2 fluoro, chloro, trifluoromethyl, methyl, ethyl, methylsulfonyl and ethylsulfonyl substituents,

w represents N or CR²⁵，

Wherein

R²⁵Represents a hydrogen or an oxo group,

R²³represents hydrogen, trideuteromethyl, (C)₁-C₆) -alkyl or (C)₂-C₆) -an alkenyl group,

wherein (C)₁-C₄) -alkyl can be substituted by 1 or 2 independently selected from fluoro, trifluoromethyl, cyclopropyl, cycloButyl, hydroxy, methoxy and ethoxy,

R²⁵represents a hydrogen or an oxo group,

R²⁷represents hydrogen, (C)₁-C₃) -an alkoxycarbonyl group or an aminosulfonyl group,

wherein (C)₁-C₃) Alkoxycarbonyl may be substituted by 1 or 2 substituents independently selected from fluoro, trifluoromethyl, hydroxy, methoxy and ethoxy,

R²⁸represents hydrogen, trifluoromethyl, (C)₁-C₄) Alkyl radicals, (C)₃-C₆) -a cycloalkyl group and a phenyl group,

wherein phenyl can be substituted by 1 or 2 groups independently selected from fluoro, chloro, trifluoromethyl, (C)₁-C₄) -alkyl, methoxy and ethoxy substituents,

R²⁹represents hydrogen, trifluoromethyl, (C)₁-C₄) Alkyl, cyclopropyl, cyclobutyl and phenyl,

wherein phenyl may be substituted with 1 or 2 substituents independently selected from fluoro, chloro, trifluoromethyl, methyl, ethyl, methoxy and ethoxy,

R³⁰represents hydrogen or (C)₁-C₆) -an alkyl group,

wherein (C)₁-C₆) -alkyl may be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy and ethoxy,

R³¹represents hydrogen or (C)₁-C₆) -an alkyl group,

wherein (C)₁-C₆) -alkyl may be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy and ethoxy.

In the context of the present invention, particular preference is given to compounds of the formula (I) and their salts, solvates and solvates of the salts, where

Ring Q represents a group of the formula:

wherein

＊ represents a bond to-CH₂-R²The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

R^1Arepresents hydrogen or a methyl group,

R^1Brepresents hydrogen or fluorine, and is selected from the group consisting of,

R^1Crepresents hydrogen or chlorine, and represents hydrogen or chlorine,

A¹represents N or CH, and is selected from the group consisting of,

R²represents 3,3, 3-trifluoroprop-1-yl, 2,3, 3-tetrafluoroprop-1-yl, 2,3,3, 3-pentafluoroprop-1-yl, phenyl or pyridyl,

wherein the phenyl group is substituted with 1 to 3 fluoro substituents,

and is

Wherein the pyridyl group may be substituted with 1 fluoro substituent,

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents N, and L represents N,

m represents CR⁴，

Wherein

R⁴represents-R⁵、-OR⁶or-NR⁷R⁸，

Wherein

R⁵Represents hydrogen or (C)₁-C₄) -an alkyl group,

wherein (C)₁-C₄) -alkyl may itself be substituted by 1 or 2 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, - (C ═ O)_p-OR⁹and-C (═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 and p represents the number 0,

R⁹and R¹⁰Each independently of the others represents hydrogen, methyl, ethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl or cyclobutyl,

R⁶is represented by (C)₁-C₆) -an alkyl group or a pyrazolyl group,

wherein (C)₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently selected from fluoro, trifluoromethyl, - (C ═ O)_p-OR⁹and-C (═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 or 1 and,

R⁹and R¹⁰Each independently of the other represents hydrogen or methyl,

or

R⁹And R¹⁰Together with the atoms to which each is attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring, wherein said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl rings may themselves be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methyl, trifluoromethyl, cyclohexyl, and cyclohexyl,Methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, and diethylamino,

and is

Wherein the pyrazolyl group can be substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, methyl, cyclopropyl, cyclobutyl and cyclopentyl,

R⁷represents hydrogen, a methyl group or an ethyl group,

R⁸represents hydrogen, (C)₁-C₆) -alkyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl,

wherein (C)₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethoxy, - (C ═ O)_p-OR⁹、-(C＝O)_p-NR⁹R¹⁰Tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl, imidazolyl, triazolyl, and pyridyl,

wherein

p represents the number 0 or 1 and,

and is

Wherein tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl may themselves be substituted by 1 or 2 substituents independently selected from fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, oxo, difluoromethoxy, trifluoromethoxy, methoxy and ethoxy,

and is

Wherein oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, and trifluoromethoxy,

E¹represents NR¹⁸，

Wherein

R¹⁸Represents hydrogen, and is selected from the group consisting of,

E³represents N or CR¹⁹，

Wherein

R¹⁹Represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl or of the formula-M-R¹³The group of (a) or (b),

wherein (C)₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl and cyclobutyl,

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

R¹³represents- (C ═ O)_r-OR¹⁴、-(C＝O)_r-NR¹⁴R¹⁵Phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl or pyrimidinyl,

wherein

r represents the number 0 or 1 and,

R¹⁴and R¹⁵Each independently of the others represents hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl or phenyl,

wherein methyl and ethyl may be additionally substituted with 1 or 2 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, trifluoromethoxy and methoxy,

and is

Wherein phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyrimidinyl may each in turn be substituted by 1 or 2 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl and cyclobutylmethyl,

u represents C (═ O),

v represents NR²⁴，

Wherein

R²⁴Represents a trideuteromethyl group, and (C)₁-C₆) -alkyl, cyclopropyl, cyclobutyl, azetidin-3-yl, pyrrolidin-3-yl or piperidin-4-yl,

wherein (C)₁-C₆) The alkyl group may itself be substituted with 1 to 3 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, oxetanyl and morpholin-4-yl,

and is

Wherein azetidin-3-yl, pyrrolidin-3-yl and piperidin-4-yl may themselves be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, cyclopropyl and cyclobutyl,

R²³represents hydrogen.

In the context of the present invention, preference is given to compounds of the formula (I) and their salts, solvates and solvates of the salts, where

Ring Q represents a group of the formula:

wherein

＊ represents a bond to-CH₂-R²The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

R^1Crepresents hydrogen or fluorine, and is selected from the group consisting of,

A²represents N or CH, and is selected from the group consisting of,

R²represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,

wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl may be substituted by 1 or 2 fluoro substituents,

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents a group selected from the group consisting of CH and N,

m represents CR⁴Or the number of N is greater than the number of N,

wherein

R⁴represents-R⁵、-OR⁶or-NR⁷R⁸，

Wherein

R⁵Represents hydrogen, chlorine, cyano, (C)₁-C₄) -alkyl or (C)₂-C₄) -an alkynyl group,

wherein (C)₁-C₄) -alkyl and (C)₂-C₄) -alkynyl may itself be substituted by 1 or 2 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, - (C ═ O)_p-OR⁹and-C (═ O)_p-NR⁹R¹⁰Is substituted with a substituent of (a),

wherein

p represents the number 0 and p represents the number 0,

or

wherein (C)₁-C₆) -alkyl can be independently selected from fluoro, diFluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, - (C ═ O)_p-OR⁹、-(C＝O)_p-NR⁹R¹⁰and-NR⁹-(C＝O)-R¹⁰The substituent (b) of (a) is substituted,

and is

Wherein cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, or pyrimidinyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, oxo, - (C ═ O)_p-OR⁹And (C ═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 or 1 and,

or

R⁷represents hydrogen, a methyl group or an ethyl group,

R⁸represents hydrogen, (C)₁-C₆) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl, wherein (C) is₁-C₆) -alkyl, cyclopropyl, cyclobutyl and cyclopentyl are independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, - (C ═ O)_p-OR⁹、-(C＝O)_p-NR⁹R¹⁰、-NR⁹-(C＝O)-R¹⁰Substituted with substituents of oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl,

wherein

p represents the number 0 or 1 and,

or

and is

Wherein oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, oxo, - (C ═ O)_p-OR⁹And- (C ═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 or 1 and,

or

R⁹And R¹⁰Together with the atoms to which they are each attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring, wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl rings themselves may be independently selected from fluoro, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methylSubstituted with oxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, and diethylamino groups,

or

E¹represents O, S or NR¹⁸，

Wherein

R¹⁸Represents hydrogen, trifluoromethyl or (C)₁-C₄) -an alkyl group,

E³represents N or CR¹⁹，

Wherein

wherein (C)₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently selected from fluoro, cyano, and the like,Trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy and trifluoromethoxy,

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

and is

E⁴and E⁶Each independently represents N or CR²⁰，

Wherein

R²⁰Represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl or of formula-M-R¹³The group of (a) or (b),

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

and is

E⁵represents NR²¹，

Wherein

R²¹Represents hydrogen or (C)₁-C₄) -an alkyl group,

wherein (C)₁-C₄) The alkyl group may itself be substituted with 1 or 2 substituents each independently selected from fluoro, trifluoromethyl, hydroxy, methoxy and ethoxy,

G¹、G²、G³and G⁴Each independently represents N or CR²²，

Wherein

wherein (C)₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently selected from fluoro, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy and trisThe substituent group of the fluorine methoxyl group is substituted,

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

and is

u represents C-O, C-S or SO₂，

V represents O or NR²⁴，

Wherein

R²⁴Represents hydrogen, trideuteromethyl, (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₃-C₇) -cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl or benzyl, wherein (C)₁-C₆) Alkyl may itself be substituted with 1 to 3 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl and morpholinyl,

and is

Wherein benzyl may itself be substituted by 1 or 2 substituents of fluoro, chloro, trifluoromethyl, methyl, ethyl, methylsulfonyl and ethylsulfonyl,

w represents N or CR²⁵，

Wherein

R²⁵Represents a hydrogen or an oxo group,

wherein (C)₁-C₄) -alkyl may be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy and ethoxy,

R²⁵represents a hydrogen or an oxo group,

R³⁰represents hydrogen or (C)₁-C₆) -an alkyl group,

R³¹represents hydrogen or (C)₁-C₆) -an alkyl group,

Ring Q represents a group of the formula:

wherein

＊ represents a bond to-CH₂-R₂The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

A²represents N or CH, and is selected from the group consisting of,

wherein the phenyl group is substituted with 1 to 3 fluoro substituents,

and is

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents a group selected from the group consisting of CH and N,

m represents CR⁴Or the number of N is greater than the number of N,

wherein

R⁴represents-R⁵、-OR⁶or-NR⁷R⁸，

Wherein

R⁵Represents trifluoromethyl or (C)₁-C₄) -an alkyl group,

wherein (C)₁-C₄) -alkyl may itself be substituted by 1 or 2 substituents independently selected from difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, - (C ═ O)_p-OR⁹and-C (═ O)_p-NR⁹R¹⁰Is substituted by a substituent of (1), wherein

p represents the number 0 and p represents the number 0,

R⁹and R¹⁰Each independently of the others represents methyl, ethyl, isopropyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,

or

R⁹And R¹⁰Together with the atoms to which they are each attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring, wherein the aza isThe cyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl rings may themselves be substituted by 1 or 2 substituents independently selected from fluoro, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino,

R⁶is represented by (C)₁-C₆) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl, wherein (C) is₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently selected from difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, - (C ═ O) -OR⁹、-(C＝O)-NR⁹R¹⁰and-NR⁹-(C＝O)-R¹⁰The substituent (b) of (a) is substituted,

wherein

or

and is

Wherein cyclopropyl, cyclobutyl, cyclopentyl, oxetanylAzetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, or pyrimidinyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, oxo, - (C ═ O)_p-OR⁹And- (C ═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein in each of the cases of use,

p represents the number 0 or 1 and,

or

R⁷represents hydrogen, a methyl group or an ethyl group,

R⁸is represented by (C)₁-C₆) -alkyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl, wherein (C) is₁-C₆) -alkyl, cyclopropyl, cyclobutyl and cyclopentyl are independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, - (C ═ O) -OR⁹、-(C＝O)-NR⁹R¹⁰、-NR⁹-(C＝O)-R¹⁰Substituted with substituents of oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl,

wherein

or

and is

wherein

p represents the number 0 or 1 and,

or

E¹represents O, S or NR¹⁸，

Wherein

R¹⁸Represents hydrogen, trifluoromethyl or (C)₁-C₄) -an alkyl group,

wherein (C)₁-C₄) The alkyl group itself may be independently selected from 1 or 2 fluorine, trifluoromethyl, hydroxy

Substituted by substituents of the group, methoxy and ethoxy,

E³represents N or CR¹⁹，

Wherein

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

and is

E⁴and E⁶Each independently represents N or CR²⁰，

Wherein

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

and is

E⁵represents NR²¹，

Wherein

R²¹Represents hydrogen or (C)₁-C₄) -an alkyl group,

G¹、G²、G³and G⁴Each independently represents N or CR²²，

Wherein

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

and is

u represents C-O, C-S or SO₂，

V represents O or NR²⁴，

Wherein

R²⁴Represents hydrogen, trideuteromethyl, (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₃-C₇) -cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl or benzyl,

and is

w represents N or CR²⁵，

Wherein

R²⁵Represents a hydrogen or an oxo group,

R²⁵represents a hydrogen or an oxo group,

R³⁰represents hydrogen or (C)₁-C₆) -an alkyl group,

R³¹represents hydrogen or (C)₁-C₆) -an alkyl group,

with the exception of the following compounds:

Ring Q represents a group of the formula

Wherein

＊ represents a bond to-CH₂-R²The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

R^1Crepresents hydrogen, fluorine or a methyl group,

A²represents a group of a compound represented by the formula CH,

R²represents a pyridyl or pyrimidyl group,

wherein the pyridyl and pyrimidinyl groups may be substituted with 1 fluoro substituent,

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents N, and L represents N,

m represents CR⁴，

Wherein

R⁴represents-R⁵、-OR⁶or-NR⁷R⁸，

Wherein

R⁵Represents hydrogen, trifluoromethyl or (C)₁-C₄) -an alkyl group,

wherein

p represents the number 0 and p represents the number 0,

R⁶is represented by (C)₁-C₆) -an alkyl group or a pyrazolyl group,

wherein

p represents the number 0 or 1 and,

R⁹and R¹⁰Each independently of the other represents hydrogen or methyl,

or

and is

R⁷represents hydrogen, a methyl group or an ethyl group,

wherein

p represents the number 0 or 1 and,

and is

E¹represents NR¹⁸，

Wherein

R¹⁸Represents hydrogen, and is selected from the group consisting of,

E³represents N or CR¹⁹，

Wherein

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

and is

u represents C (═ O),

v represents NR²⁴，

Wherein

and is

R²³represents hydrogen.

Ring Q represents a group of the formula:

wherein

＊ represents a bond to-CH₂-R²The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

A²represents a group of a compound represented by the formula CH,

R²represents a 3-fluoropyridin-2-yl group,

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents N, and L represents N,

m represents CR⁴，

Wherein

R⁴represents-R⁵or-NR⁷R⁸，

Wherein

R⁵Represents hydrogen, and is selected from the group consisting of,

R⁷represents hydrogen, and is selected from the group consisting of,

R⁸represents hydrogen or (C)₁-C₆) -an alkyl group,

wherein (C)₁-C₆) -alkyl is independently selected from 1 to 3 from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, - (C ═ O)_p-OR⁹and-C (═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 and p represents the number 0,

E¹represents NR¹⁸，

Wherein

R¹⁸Represents hydrogen, and is selected from the group consisting of,

E³represents CR¹⁹，

Wherein

R¹⁹Represents hydrogen, trifluoromethyl, (C)₁-C₄) -alkyl or of the formula-M-R¹³The group of (a) or (b),

and wherein

M represents a bond of a carbon atom,

R¹³represents- (C ═ O)_r-OR¹⁴Or- (C ═ O)_r-NR¹⁴R¹⁵，

Wherein

r represents the number 0 and r represents the number 0,

R¹⁴and R¹⁵Each independently of the others represents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl,

u represents C (═ O),

v represents NR²⁴，

Wherein

R²⁴Is represented by (C)₁-C₆) -an alkyl group,

wherein (C)₁-C₆) The alkyl group may itself be substituted with 1 to 3 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl and hydroxy,

R²³represents hydrogen.

Ring Q represents a group of the formula:

wherein

＊ represents a bond to-CH₂-R²The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

A²represents a group of a compound represented by the formula CH,

R²represents 3,3, 3-trifluoroprop-1-yl, 2,3, 3-tetrafluoroprop-1-yl, 2,3,3, 3-pentafluoroprop-1-yl, phenyl, pyridyl or pyrimidineThe base group is a group of a compound,

wherein the phenyl group is substituted with 1 to 3 fluoro substituents,

and is

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents N, and L represents N,

m represents CR⁴，

Wherein

R⁴represents-R⁵、-oR⁶or-NR⁷R⁸，

Wherein

R⁵Represents trifluoromethyl or (C)₁-C₄) -an alkyl group,

wherein (C)₁-C₄) -alkyl can be itself selected by 1 or 2, independently of one another, from trifluoromethyl, cyclopropyl, cyclobutyl, difluoromethoxy, trifluoromethoxy, - (C ═ o)_p-oR⁹and-C (═ o)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 and p represents the number 0,

R⁹and R¹⁰Each independently of the others represents methyl, ethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl or cyclobutyl,

or

R⁹And R¹⁰Together with the atoms to which they are each attached form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,

wherein the pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl rings may themselves be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino,

R⁶is represented by (C)₁-C₆) -an alkyl group or a pyrazolyl group,

wherein (C)₁-C₆) -alkyl can be chosen, independently of one another, from 1 to 3 trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, - (C ═ o) -oR⁹And- (C ═ o) -NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

and is

Wherein the pyrazolyl radical can be substituted by 1 to 3 substituents which are selected, independently of one another, from fluorine, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, methyl, cyclopropyl, cyclobutyl and cyclopentyl,

R⁷represents hydrogen, a methyl group or an ethyl group,

R⁸is represented by (C)₁-C₆) -alkyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl,

wherein (C)₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently selected from trifluoromethyl, cyclopropyl, cyclobutyl, trifluoromethoxy, (C)₁-C₄) -alkoxy, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl,

and is

Wherein oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl and pyrimidinyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, trifluoromethoxy and oxo,

E¹represents NR¹⁸，

Wherein

R¹⁸Represents hydrogen, and is selected from the group consisting of,

E³represents N or CR¹⁹，

Wherein

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

and is

u represents C (═ o),

v represents NR²⁴，

Wherein

and is

R²³represents hydrogen.

R³Represents a group of the formula

Wherein

# represents the point of attachment to loop Q,

l represents N, and L represents N,

m represents CR⁴，

Wherein

R⁴represents-R⁵or-NR⁷R⁸，

Wherein

R⁵Represents hydrogen, and is selected from the group consisting of,

R⁷represents hydrogen, and is selected from the group consisting of,

R⁸represents hydrogen or (C)₁-C₆) -an alkyl group,

wherein (C)₁-C₆) -alkyl is selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl, - (C ═ o) by 1 to 3 substituents independently of one another_p-oR⁹and-C (═ o)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 and p represents the number 0,

E¹represents NR¹⁸，

Wherein

R¹⁸Represents hydrogen, and is selected from the group consisting of,

E³represents CR¹⁹，

Wherein

wherein (C)₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently from each other selected from fluoro, trifluoromethyl, cyclopropyl and cyclobutyl,

and wherein

M represents a bond of a carbon atom,

R¹³represents- (C ═ o)_r-oR¹⁴Or- (C ═ o)_r-NR¹⁴R¹⁵，

Wherein

r represents the number 0 and r represents the number 0,

u represents C (═ o),

v represents NR²⁴，

Wherein

R²⁴Is represented by (C)₁-C₆) -an alkyl group,

wherein(C₁-C₆) The alkyl group may itself be substituted with 1 to 3 substituents independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl and hydroxy,

R²³represents hydrogen.

Ring Q represents a group of the formula:

wherein

＊ represents a bond to-CH₂-R²The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

A²represents CH.

R²Represents 3,3, 3-trifluoroprop-1-yl, 2,3, 3-tetrafluoroprop-1-yl, 2,3,3, 3-pentafluoroprop-1-yl, phenyl, pyridyl or pyrimidyl,

wherein the phenyl group is substituted with 1 to 3 fluoro substituents,

and is

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents N, and L represents N,

m represents CR⁴，

Wherein

R⁴represents-R⁵、-oR⁶or-NR⁷R⁸，

Wherein

R⁵Represents trifluoromethyl or (C)₁-C₄) -an alkyl group,

wherein (C)₁-C₄) -alkyl may itself be substituted by 1 or 2 substituents independently selected from trifluoromethyl, cyclopropyl, cyclobutyl, difluoromethoxy, trifluoromethoxy, - (C ═ o)_p-oR⁹and-C (═ o)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 and p represents the number 0,

or

R⁶is represented by (C)₁-C₆) -an alkyl group or a pyrazolyl group,

wherein (C)₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently selected from trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, - (C ═ o) -oR⁹And- (C ═ o) -NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

and is

Wherein the pyrazolyl group can be substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, methyl, cyclopropyl, cyclobutyl, and cyclopentyl,

R⁷represents hydrogen, a methyl group or an ethyl group,

R⁸is represented by (C)₁-C₆) -alkyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl or pyrimidinyl, wherein (C)₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently selected from trifluoromethyl, cyclopropyl, cyclobutyl, trifluoromethoxy, (C)₁-C₄) Alkoxy, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl,

and is

Wherein oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl may be substituted with 1 to 3 substituents independently selected from fluoro, difluoromethyl, trifluoromethyl, methyl, ethyl, trifluoromethoxy, and oxo,

E¹represents NR¹⁸，

Wherein

R¹⁸Represents hydrogen, and is selected from the group consisting of,

E³represents N or CR¹⁹，

Wherein

and wherein

M represents a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,

wherein

r represents the number 0 or 1 and,

R¹⁴and R¹⁵Each independently represents hydrogen, methyl, ethyl, cyclopropylA group selected from the group consisting of a cyclobutyl group and a phenyl group,

and is

u represents C (═ O),

v represents NR²⁴，

Wherein

and is

R²³represents hydrogen.

R²Is 3,3, 3-trifluoropropan-1-yl, 2,3, 3-tetrafluoropropane-1-yl, 2,3,3, 3-pentafluoropropan-1-yl, 2-fluorophenyl or 3-fluoropyridin-2-yl,

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents N, and L represents N,

m represents CR⁴，

Wherein

R⁴represents-NR⁷R⁸，

Wherein

R⁷Represents hydrogen or a methyl group,

R⁸is represented by (C)₁-C₆) -an alkyl group,

wherein (C)₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently selected from trifluoromethyl, cyclopropyl, cyclobutyl, trifluoromethoxy and (C)₁-C₄) -a substituent of an alkoxy group,

E¹represents NR¹⁸，

Wherein

R¹⁸Represents hydrogen, and is selected from the group consisting of,

E³represents CR¹⁹，

Wherein

and wherein

M represents a bond of a carbon atom,

R¹³represents- (C ═ O)_r-OR¹⁴Or- (C ═ O)_r-NR¹⁴R¹⁵，

Wherein

r represents the number 0 and r represents the number 0,

u represents C (═ O),

v represents NR²⁴，

Wherein

R²⁴Is represented by (C)₁-C₆) -an alkyl group,

R²³represents hydrogen.

The definitions of the individual radicals specified in a particular combination or preferred combination of radicals can also be replaced by definitions of radicals of other combinations, as desired, independently of the particular combination of radicals specified.

Combinations of two or more of the above-mentioned preferred ranges are particularly preferred.

The invention also provides a process for the preparation of a compound of formula (I) according to the invention,

[A] reacting a compound of formula (II) with a compound of formula (III-1) or (III-2) in an inert solvent in the presence of a suitable base to give a compound of formula (I-A-1) or (I-A-2),

wherein R is²Have the meanings given above, and

ring Q^ARepresents a group of formula:

wherein

＊ represents a bond to-CH₂-R²The point (c) of (a) is,

＊＊ represents a group linked to R³The point (c) of (a) is,

ring Q₁Together with the atoms to which it is attached form a 5-to 7-membered saturated or partially unsaturated carbocyclic ring or a 5-to 7-membered saturated or partially unsaturated heterocyclic ring,

R¹represents fluorine, chlorine, methyl, hydroxy or oxo,

n represents the number 0, 1 or 2,

A¹、A²、A³and A⁴Each independently represents N, CH or CR¹，

wherein G is¹、G²、G³、G⁴、E¹、E²And E³Each having the meaning given above,

wherein n and R¹、R²、G¹、G²、G³、G⁴、E¹、E²、E³And Q^AEach having the meaning given above,

or

[B] Reacting a compound of formula (I-B-1) or (I-B-2) with a suitable nitrite (nitrites) in an inert solvent to give a compound of formula (I-I-3) or (I-I-4),

wherein n, P¹、P²、R¹、R²And Q each have the meaning given above,

or

[C] Converting a compound of formula (I-B-1) or (I-B-2) into a compound of formula (IV-1) or (IV-2) in an inert solvent,

wherein n, P¹、P²、R¹、R²And Q each have the meaning given above, and

X²represents bromine, iodine or chlorine,

this compound is then reacted with a compound of formula (V) in an inert solvent, optionally in the presence of a suitable base, to obtain a compound of formula (I-C-1) or (I-C-2),

R^4A-H (V)

wherein

R⁴represents-OR⁶or-NR⁷R⁸，

Wherein R is⁶、R⁷And R⁸Each having the meaning given above,

wherein n, P¹、P²、R¹、R²、R^4AAnd Q each have the meaning given above,

or

[D] Reacting a compound of formula (VI) with a compound of formula (VII) in an inert solvent in the presence of a suitable base to give a compound of formula (VIII),

wherein n, Q, R¹And R²As defined above, and

T¹is represented by (C)₁-C₄) -alkyl radical

R^24A-X¹(VII)

Wherein

R^24ARepresents a trideuteromethyl group, and (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₃-C₇) -cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl or benzyl, wherein (C)₁-C₆) -alkyl, azetidinyl, pyrrolidinyl, piperidinyl and benzyl may be substituted within the ranges defined above,

and is

X¹Represents a suitable leaving group, for example halogen, in particular chlorine or bromine, a mesylate or tosylate group,

wherein n, Q, R¹、R²And R^24AEach having the meaning given above, which is then cyclized in an inert solvent in the presence of a suitable base to obtain the compound of formula (I-D),

wherein n, Q, R¹、R²And R^24AEach having the meaning given above, and isolating any protecting groups present by methods known to those skilled in the art, and the resulting compound of formula (I) is optionally converted to its solvates, salts and/or solvates of the salts, optionally with a suitable (I) solvent and/or (ii) acid or base.

Inert solvents for process steps (II) + (III-1) → (I-A-1) or (II) + (III-2) → (I-A-2) are, for example, halogenated hydrocarbons and hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), sulfolane or pyridine. Mixtures of the solvents mentioned may also be used. Preferably DMF is used.

Suitable bases for process steps (II) + (III-1) → (I-A-1) or (II) + (III-2) → (I-A-2) are customary inorganic or organic bases. It preferably comprises an alkali metal alkoxide such as sodium or potassium methoxide, ethoxide or tert-butoxide; alkali metal hydrides such as sodium hydride or potassium hydride; or amides such as sodium amide or lithium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide or lithium diisopropylamide. Preferably potassium tert-butoxide is used.

Process steps (II) + (III-1) → (I-A-1) or (II) + (III-2) → (I-A-2) are usually carried out in a temperature range from +100 ℃ to +200 ℃, preferably from +140 ℃ to +180 ℃, preferably in a microwave. The conversion reaction may be carried out at atmospheric pressure, under increased pressure or under reduced pressure (for example from 0.5 bar to 5 bar).

Suitable nitrites for the conversion reaction (I-B-1) or (I-B-2) → (I-B-3) or (I-B-4) are, for example, sodium nitrite, isoamyl nitrite or tert-butyl nitrite.

The inert solvent used for the conversion reaction (I-B-1) or (I-B-2) → (I-B-3) or (I-B-4) is, for example, an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, or another solvent such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. Mixtures of the above solvents may also be used. Tetrahydrofuran and DMF are preferred.

The reaction (I-B-1) or (I-B-2) → (I-B-3) or (I-B-4) is usually carried out at a temperature in the range of from 0 ℃ to +120 ℃, preferably from +40 ℃ to +80 ℃. The reaction may be carried out at atmospheric, elevated or reduced pressure (e.g. from 0.5 to 5 bar). The reaction is generally carried out under normal pressure.

Process steps (I-B-1) → (IV-1) or (I-B-2) → (IV-2) being carried out with or without a solvent. Suitable solvents are all organic solvents which are inert under the reaction conditions. The preferred solvent is dimethoxyethane.

The reaction (I-B-1) → (IV-1) or (I-B-2) → (IV-2) is usually carried out in a temperature range of +20 ℃ to +100 ℃, preferably +50 ℃ to +100 ℃, optionally in a microwave. The conversion reaction may be carried out at atmospheric pressure, under pressure or under reduced pressure (for example from 0.5 to 5 bar). The reaction is generally carried out under normal pressure.

Process steps (I-B-1) → (IV-1) or (I-B-2) → (IV-2) are usually carried out in the following molar ratios: 10 to 30mol of isoamyl nitrite and 10 to 30mol of iodine in an equivalent amount based on 1mol of the compound of the formula (I-B-1) or (I-B-2).

Suitable halogen sources in the conversion reaction (I-B-1) → (IV-1) or (I-B-2) → (IV-2) are, for example, diiodomethane, cesium iodide, iodine and mixtures of copper (I) iodide or copper (II) bromide, and also phosphorus oxychloride.

The inert solvents used in process step (I-B-1) → (I-B-3) or (I-B-2) → (I-B-4) are alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1, 2-ethanediol; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. Mixtures of the above-mentioned solvents may also be used. DMF is preferred.

The reduction reaction (I-B-1) → (I-B-3) or (I-B-2) → (I-B-4) is carried out using hydrogen and a transition metal catalyst such as palladium (10% on activated carbon), Raney nickel or palladium hydroxide.

The reaction (I-B-1) → (I-B-3) or (I-B-2) → (I-B-4) is usually carried out in a temperature range of +20 ℃ to +50 ℃. The conversion reaction may be carried out at atmospheric pressure or under elevated pressure (e.g. from 0.5 to 5 bar). The reaction is generally carried out under normal pressure.

Inert solvents for process steps (IV-1) or (IV-2) + (V) → (I-C-1) or (I-C-2) are, for example, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulfolane. Mixtures of the solvents mentioned may also be used. NMP is preferred.

At R^4A＝-OR⁶In the case of (2), the reaction (IV-1) or (IV-2) + (V) → (I-C-1) or (I-C-2) is preferably carried out in the absence of a solvent.

At R^4A＝-OR⁶In the case of (2), (IV-1) or (IV-2) + (V) → (I-C-1) or (I-C-2) being carried out in the presence of a suitable copper catalyst such as copper (I) iodide with addition of 3,4, 7, 8-tetramethyl-1, 10-phenanthroline and a suitable base such as an alkaline earth metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, preferably cesium carbonate.

Or, at R^4A＝-OR⁶In the case of (A), the compound of formula (I-C-1) or (I-C-2) can also be prepared under Mitsunobu conditions [ see: a) hughes, d.l. "The Mitsunobu Reaction," Organic Reactions; john Wiley&Sons，Ltd，1992，vol.42，p.335.b)Hughes，D.L.Org.Prep.Proceed.Int.1996，28，127.]Starting from a compound of formula (IX-1) or (IX-2),

wherein n, L, Q, P¹、P²、R¹And R²Each as defined above.

Herein, the Mitsunobu reaction is carried out using: triphenylphosphine or tri-N-butylphosphine, 1, 2-bis (diphenylphosphino) ethane (DPPE), diphenyl (2-pyridyl) phosphine (Ph2P-Py), (p-dimethylaminophenyl) diphenylphosphine (DAP-DP), Tris (4-dimethylaminophenyl) phosphine (Tris-DAP) and suitable dialkyl azodicarboxylates, for example diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, N, N, N ', N ' -Tetramethylazodicarboxamide (TMAD), 1 ' - (azodicarbonyl) dipiperidine (ADDP) or 4, 7-dimethyl-3, 5, 7-hexahydro-1, 2, 4, 7-tetraazaoctacin-3, 8-dione (DHTD). Preference is given to using triphenylphosphine and diisopropyl azodicarboxylate (DIAD), or a suitable azodicarbonamide, for example N, N, N ', N' -tetramethyldiazene-1, 2-dicarbonamide.

The inert solvent used in the Mitsunobu reaction (IV-1) or (IV-2) + (V) → (I-C-1) or (I-C-2) is, for example, an ether such as tetrahydrofuran, diethyl ether; hydrocarbons, such as benzene, toluene, xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane; or other solvents such as acetonitrile, DMF or NMP. Mixtures of the solvents mentioned may also be used. Preferably, THF is used.

The Mitsunobu reaction (IV-1) or (IV-2) + (V) → (I-C-1) or (I-C-2) is usually carried out at a temperature in the range of-78 ℃ to +180 ℃, preferably 0 ℃ to +50 ℃, optionally in the presence of microwaves. The conversion reaction may be carried out at atmospheric pressure, under increased pressure or under reduced pressure (e.g. 0.5 bar to 5 bar).

At R^4A＝-NR⁷R⁸In the case of (1), if R is⁷And R⁸Together with the nitrogen atom to which they are attached form a 5-or 6-membered heteroaryl group, which 5-or 6-membered heteroaryl group may be substituted within the meaning given above, the conversion reaction (IV-1) or (IV-2) + (V) → (I-C-1) or (I-C-2) is carried out in the presence of a suitable copper catalyst, for example copper (I) oxide with the addition of 2-hydroxybenzaldehyde oxime, and a suitable base, for example an alkaline earth metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, preferably carbonic acidAnd cesium.

The reaction (IV-1) or (IV-2) + (V) → (I-C-1) or (I-C-2) is usually carried out at a temperature in the range of +20 ℃ to +200 ℃, preferably +150 ℃ to +200 ℃, preferably in a microwave. The conversion reaction may be carried out at atmospheric pressure, under pressure or under reduced pressure (for example from 0.5 to 5 bar).

Suitable inert solvents for the cyclization reaction (VIII) → (I-D) are ethers, such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions; or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulfolane. Mixtures of the solvents mentioned may also be used. Tetrahydrofuran is preferred.

Suitable bases for the cyclization reaction (VIII) → (I-D) are customary inorganic or organic bases. It preferably includes an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; carbonates of alkali metals or alkaline earth metals, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, or cesium carbonate; alkali metal alkoxides, such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide; alkali metal hydrides such as sodium hydride or potassium hydride; amides, such as sodium or lithium bis (trimethylsilyl) amide, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide; or organic amines, e.g. triethylamine, N-methylmorpholine, N-methylpiperidine, N-diisopropylethylamine, pyridine, 1, 5-diazabicyclo [4.3.0 ]]Non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2]Octane. Sodium bis (trimethylsilyl) amide is preferably used.

The reaction (VIII) → (I-D) is usually carried out in a temperature range of-10 ℃ to +80 ℃, preferably +10 ℃ to +30 ℃. The conversion reaction may be carried out at atmospheric pressure, under pressure or under reduced pressure (for example from 0.5 to 5 bar). The reaction is generally carried out under normal pressure.

Inert solvents for (VI) + (VII) → (VIII) are ethers, such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions; or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulfolane. Mixtures of the solvents mentioned may also be used. Tetrahydrofuran is preferred.

Suitable bases for the reaction (VI) + (VII) → (VIII) are the customary inorganic or organic bases. It preferably includes an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; carbonates of alkali metals or alkaline earth metals such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, or cesium carbonate; alkali metal alkoxides, such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide; alkali metal hydrides such as sodium hydride or potassium hydride; amides, such as sodium or lithium bis (trimethylsilyl) amide, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide; or organic amines, e.g. triethylamine, N-methylmorpholine, N-methylpiperidine, N-diisopropylethylamine, pyridine, 1, 5-diazabicyclo [4.3.0 ]]Non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2]Octane. Sodium hydride is preferably used.

The reaction (VI) + (VII) → (VIII) is usually carried out in the range of-10 ℃ to +80 ℃, preferably +10 ℃ to +30 ℃. The conversion reaction may be carried out at atmospheric pressure, under pressure or under reduced pressure (for example from 0.5 to 5 bar). The reaction is generally carried out under normal pressure.

The inert solvent used for the conversion reaction (I-B-1) or (I-B-2) → (I-B-3) or (I-B-4) is, for example, an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. Mixtures of the solvents mentioned may also be used. Tetrahydrofuran or DMF is preferred.

The reaction (I-B-1) or (I-B-2) → (I-B-3) or (I-B-4) is usually carried out at a temperature in the range of from 0 ℃ to +120 ℃, preferably from +40 ℃ to +80 ℃. The conversion reaction may be carried out at atmospheric pressure, under pressure or under reduced pressure (for example from 0.5 to 5 bar). The reaction is generally carried out under normal pressure.

Examples of suitable iodine sources in conversion reaction (I-B-1) → (IV-1) or (I-B-2) → (IV-2) include methylene iodide, or a mixture of cesium iodide, iodine and copper (I) iodide.

The inert solvents used in process step (I-B-1) → (I-B-3) or (I-B-2) → (I-B-4) are alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1, 2-ethanediol; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. Mixtures of the solvents mentioned may also be used. DMF is preferred.

The above preparation method can be exemplified by the following synthetic schemes (schemes 1 and 2):

scheme 1:

[ potassium tert-butoxide, DMF, microwave, 160 ℃ C. ].

Scheme 2:

[ a): 3,3, 3-trifluoropropyl-1-amine hydrochloride, N, N-diisopropylethylamine, NMP, microwave, 150 ℃ C.

The compounds of the formulae (III-1), (III-2), (V) and (VII) are commercially available, known in the literature or can be prepared by methods analogous to the literature methods.

The compounds of the formulae (II), (I-B-1), (I-B-2), (IV-1), (IV-2) and (VI) are known from the literature and can be prepared by methods analogous to those known from the literature or those described in the experimental part of the invention.

The compounds of the invention are useful as potent stimulators of soluble guanylate cyclase, having valuable pharmacological properties and, for example, improved therapeutic properties in terms of their in vivo properties and/or their pharmacokinetic and/or metabolic profiles. They are therefore suitable for the treatment and/or prophylaxis of diseases in humans and animals.

The compounds of the invention cause vasodilation and inhibit platelet aggregation, and result in a decrease in blood pressure and an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. In addition, the compounds of the present invention potentiate the action of substances that increase cGMP levels, such as EDRF (endothelium-derived relaxation factor), NO donors, protoporphyrin IX, arachidonic acid, or phenylhydrazine derivatives.

The compounds of the invention are suitable for the treatment and/or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic diseases.

Thus, the compounds of the invention may be used in medicaments for the following uses: for the treatment and/or prophylaxis of cardiovascular diseases, such as hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina, peripheral and cardiovascular diseases, arrhythmias, atrial and ventricular arrhythmias and conduction disorders (e.g. I-III degree atrioventricular block (AB block I-III)), supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, torsades de pointes, atrial and ventricular junctional preshrinks, atrioventricular regional preshrinks, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, WolPak-Huai syndrome, Acute Coronary Syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvulitis, aortic inflammation, myocardial diseases), Shock (e.g., cardiogenic, septic and anaphylactic shock), aneurysm, boxer canine cardiomyopathy (premature ventricular contraction (PVC)); for the treatment and/or prophylaxis of thromboembolic disorders and ischemia, such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, coronary and peripheral arterial spasm, edema formation (such as pulmonary edema, cerebral edema, renal edema, or edema resulting from heart failure), impaired peripheral perfusion, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction; for the prevention of restenosis, e.g. following thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), coronary transluminal angioplasty (PTCA), heart transplantation and bypass surgery, as well as micro-and macrovascular injury (vasculitis), elevated fibrinogen and low density LDL levels, elevated concentrations of plasminogen activator inhibitor 1 (PAI-1); and for the treatment and/or prevention of erectile dysfunction and female sexual dysfunction.

In the context of the present invention, the term heart failure also includes more specific or related diseases, such as acute decompensated heart failure, right ventricular failure, left ventricular failure, total heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary insufficiency, mixed heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, myocardial storage (storage) disease, diastolic heart failure, and systolic heart failure.

In addition, the compounds of the present invention are useful for the treatment and/or prevention of arteriosclerosis, impaired lipid metabolism, hypolipidaemia, dyslipidaemia, hypertriglyceridaemia, hyperlipidaemia, hypercholesterolaemia, betalipoproteinaemia, sitosterolemia, xanthomatosis, dangill disease, obesity (adiposity), obesity (obesity) and mixed hyperlipidaemia and metabolic syndrome.

In addition, the compounds of the invention are also useful for the treatment and/or prevention of primary and secondary raynaud's phenomena, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathy, diabetic retinopathy, diabetic limb ulcers, gangrene, CREST syndrome, lupus erythematosus (erythrematosis), onychomycosis, rheumatic diseases, and for promoting wound healing.

Furthermore, the compounds of the invention are suitable for the treatment of urological disorders, such as Benign Prostate Syndrome (BPS), Benign Prostatic Hyperplasia (BPH), benign prostatic hypertrophy (BPE), Bladder Outlet Obstruction (BOO), lower urinary tract syndrome (LUTS, including Feline Urinary Syndrome (FUS)), urogenital disorders, including neurogenic bladder Overactivity (OAB) and (IC), Urinary Incontinence (UI) (e.g. mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUI)), pelvic pain, benign and malignant diseases of male and female urogenital organs.

Furthermore, the compounds of the invention are suitable for the treatment and/or prophylaxis of renal diseases, in particular acute and chronic renal insufficiency and acute and chronic renal failure. In the context of the present invention, the term renal insufficiency includes acute and chronic manifestations of renal insufficiency, and also includes potential or related renal diseases, such as hypoperfusion of the renal blood flow; dialysis-related hypotension (intradialytic hypotension); obstructive urinary tract disease; glomerulopathy; glomerulonephritis; acute glomerulonephritis; glomerulosclerosis; tubulointerstitial disease; nephropathy (nephropathic disease) (e.g., primary and congenital nephropathy); nephritis; immune kidney disease (e.g., kidney transplant rejection and immune complex-induced kidney disease); nephropathies induced by toxic substances; contrast-induced nephropathy; diabetic and non-diabetic nephropathy; pyelonephritis; renal cyst; nephrosclerosis; hypertensive nephrosclerosis and nephrotic syndrome, which can be diagnostically characterized by: abnormal reduction in, for example, creatinine and/or water drainage; an abnormal increase in blood concentration of urea, nitrogen, potassium and/or creatinine; altered activity of kidney enzymes (e.g., glutamyl synthetase); changes in urine osmolality or urine volume; increase in microalbuminuria, macroalbuminuria (macroalbuminuria); glomerular and arteriolar lesions; tubular dilation (tubular dilation); hyperphosphatemia and/or the need for dialysis. The invention also encompasses the use of the compounds according to the invention for the treatment and/or prevention of the sequelae of renal insufficiency, such as emphysema, heart failure, uremia, anemia, electrolyte disorders (e.g. hypercalcemia, hyponatremia) and disorders of bone and carbohydrate metabolism.

In addition, the compounds of the invention are also suitable for use in the treatment and/or prevention of wheezing disease, Pulmonary Arterial Hypertension (PAH) and other forms of Pulmonary Hypertension (PH) including left ventricular disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, Chronic Obstructive Pulmonary Disease (COPD), Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), alpha 1 antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema (e.g. emphysema induced by smoking), and Cystic Fibrosis (CF).

The compounds described in the present invention are also active substances for controlling diseases of the central nervous system which are characterized by disturbances of the NO/cGMP system. In particular, they are suitable for improving perception, enhancing attention-concentration, improving learning or memory after cognitive disorders such as those which are associated specifically with the following situations/diseases/syndromes: such as mild cognitive impairment, age-related learning and memory disorders, age-related memory loss, vascular dementia, craniocerebral injury, stroke, post-stroke dementia (post-stroke dementia), post-traumatic craniocerebral injury, global disorders of attention focus, disorders of attention focus in children with learning and memory problems, alzheimer's disease, lewy body dementia, dementia associated with frontal lobe degeneration (including pick's syndrome, parkinson's disease, progressive nuclear palsy), dementia associated with cortical basal degeneration, Amyotrophic Lateral Sclerosis (ALS), huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia associated with dementia or coxsackie's psychosis. They are also suitable for the treatment and/or prophylaxis of disorders of the central nervous system, such as anxiety states, stress and depression, CNS-related sexual dysfunctions and sleep disorders, and for the control of pathological eating disorders of foods, stimulants and addictive substances.

Furthermore, the compounds of the present invention are also suitable for regulating cerebral blood flow and are therefore effective agents for controlling migraine. They are also suitable for the prevention and control of the sequelae of cerebral infarctions (stroke) such as stroke, cerebral ischemia and craniocerebral injury. The compounds of the invention are also useful for controlling pain states and tinnitus.

Furthermore, the compounds of the invention have an anti-inflammatory effect and can therefore be used as anti-inflammatory agents for the treatment and/or prevention of the following diseases: sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disease, inflammatory skin diseases, and inflammatory eye diseases.

Furthermore, the compounds of the invention may also be useful for the treatment and/or prevention of autoimmune diseases.

Furthermore, the compounds of the invention are suitable for the treatment and/or prophylaxis of fibrotic diseases of internal organs, such as the lung, the heart, the kidney, the bone marrow and in particular the liver, and also of dermatological fibrosis and of the eye. In the context of the present invention, the term fibrotic disease specifically includes the following terms: liver fibrosis, cirrhosis, lung fibrosis, endomyocardial fibrosis, kidney disease, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage due to diabetes, myelofibrosis and similar fibrotic diseases, scleroderma, maculopathy, keloids, hypertrophic scars (also including hypertrophic scars after surgical operations), nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (e.g., sarcoidosis).

Furthermore, the compounds of the invention are suitable for controlling post-operative scars, such as those resulting from glaucoma surgery.

The compounds of the present invention are also cosmetically useful for aging and keratinizing skin.

Furthermore, the compounds of the invention are suitable for the treatment and/or prophylaxis of hepatitis, tumors, osteoporosis, glaucoma and gastroparesis.

The invention also relates to the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of the diseases mentioned above.

The invention also relates to the use of the compounds according to the invention for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic diseases, fibrous diseases and arteriosclerosis.

The invention also relates to the use of the compounds according to the invention in a method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic diseases, fibrous diseases and arteriosclerosis.

The invention also relates to the use of the compounds according to the invention for the production of medicaments for the treatment and/or prophylaxis of diseases, in particular of the diseases mentioned above.

The invention also relates to the use of the compounds according to the invention for producing medicaments for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic diseases, fibrous diseases and arteriosclerosis.

The invention also relates to a method for the treatment and/or prophylaxis of diseases, in particular the diseases mentioned above, using an effective amount of at least one compound according to the invention.

The invention also relates to a method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic diseases, fibrous diseases and arteriosclerosis, using an effective amount of at least one compound according to the invention.

The compounds of the invention can be used alone or, if desired, in combination with other active substances. The invention also relates to medicaments comprising at least one compound according to the invention and one or more further active substances, in particular for the treatment and/or prevention of the abovementioned diseases. Preferred examples of suitable active substance combinations include:

● organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine (molsidomine) or SIN-1, and inhaled NO;

● compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP), for example inhibitors of Phosphodiesterase (PDE)1, 2 and/or 5, in particular PDE-5 inhibitors such as sildenafil, vardenafil and tadalafil;

● an agent having antithrombotic activity, such as, and preferably, a platelet aggregation inhibitor, an anticoagulant or plasminogen (proteolytic cleavage);

● blood pressure lowering active compounds such as, and preferably, calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics; and/or

● active compounds which alter lipid metabolism, such as, and preferably, thyroid receptor agonists; cholesterol synthesis inhibitors, such as and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha agonists, PPAR-gamma agonists and/or PPAR-agonists; cholesterol absorption inhibitors; a lipase inhibitor; a polymerized bile acid adsorbent; a bile acid resorption inhibitor and a lipoprotein (a) antagonist.

An antithrombotic agent is preferably understood to be a compound selected from the group consisting of platelet aggregation inhibitors, anticoagulants or plasminogen substances.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with platelet aggregation inhibitors such as, and preferably, aspirin, clopidogrel (clopidogrel), ticlopidine (ticlopidine) or dipyridamole (dipyridamole).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, such as, and preferably, ximegatran (ximelagatran), dabigatran (dabigatran), melagatran (melagatran), bivalirudin (bivalirudin) or crexate (clexane).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a GPIIb/IIIa antagonist, such as, and preferably, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban (BAY59-7939), DU-176b, apixaban (apixaban), omixaban (otamixaxban), fidaxaban (fidaxaban), rizaxaban (fidaxaban), razaxaban (razaxaban), fondaparinux (fondaparinux), epidoparin (idraparinux), PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512, or SSR-128428.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or a Low Molecular Weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a vitamin K antagonist, such as, and preferably, coumarin.

A hypotensive agent should preferably be understood as a compound selected from the group consisting of: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist such as, and preferably, nifedipine (nifedipine), amlodipine (amlodipine), verapamil (verapamil) or diltiazem (diltiazem).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an α 1-receptor blocker, such as, and preferably, prazosin (prazosin).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-blocker, the beta-receptor blocker is for example and preferably propranolol (propranolol), atenolol (atenolol), timolol (timolol), pindolol (pindolol), alprenolol (alprenolol), oxprenolol (oxprenolol), penbutolol (penbutolol), blanolol (bunolol), metipranolol (metipranolol), nadolol (nadolol), mepindolol (mepinnolol), caramolol (carazalol), sotalol (sotalol), metoprolol (metoprolol), betaxolol (betaxolol), celiprolol (celolol), bisoprolol (bisoprolol), carteolol (carteolol), esmolol (momolol), labetalol (labetalol), carvedilol (carindiolol), cardiolol (cardiolol), adapalolol (celandiolol), landiolol (anetholol), or anetholol (nebiolol).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an angiotensin AII antagonist such as, and preferably, losartan (losartan), candesartan (candisartan), valsartan (valsartan), telmisartan (telmisartan) or embsartan (embursatan).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACE inhibitor, such as, and preferably, enalapril (enalapril), captopril (captopril), lisinopril (lisinopril), ramipril (ramipril), delapril (delapril), fosinopril (fosinopril), quinapril (quinopril), perindopril (perindopril) or quadolapril (trandopril).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist such as, and preferably, bosentan (bosentan), darussentan (daursentan), ambrisentan (ambrisentan) or sitaxsentan (sitaxsentan).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as, and preferably, aliskiren (aliskiren), SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist such as, and preferably, spironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with: loop diuretics such as furosemide (furosemide), torasemide (torasemide), bumetanide (bumetanide) and piretanide (piretanide); potassium sparing diuretics such as amiloride (amiloride) and triamterene (triamterene); aldosterone antagonists such as spironolactone (spironolactone), potassium canrenoate (potassium canrenoate), and eplerenone (eplerenone); and thiazide diuretics such as hydrochlorothiazide (hydrochlorothiazide), chlorthalidone (chlorothalidone), xipamide (xipamide), and indapamide (indapamide).

Lipid metabolism regulator is preferably understood to mean a compound selected from the group consisting of: a CETP inhibitor; a thyroid receptor agonist; cholesterol synthesis inhibitors, such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha agonists, PPAR-gamma agonists and/or PPAR-agonists; cholesterol absorption inhibitors; a polymerized bile acid adsorbent; bile acid resorption inhibitors; lipase inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor, such as, and preferably, Dacetrapib (dalcetrapib), BAY60-5521, Anacetrapib (anacetrapib) or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, and preferably, D-thyroxine, 3, 5, 3' -triiodothyronine (T3), CGS23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a statin HMG-CoA reductase inhibitor, such as, and preferably, lovastatin (lovastatin), simvastatin (simvastatin), pravastatin (pravastatin), fluvastatin (fluvastatin), atorvastatin (atorvastatin), rosuvastatin (rosuvastatin) or pitavastatin (pitavastatin).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthesis inhibitor, such as and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACAT inhibitor such as, and preferably, avasimibe (avasimibe), melinamide (melinamide), patiticum (pactimibe), ibrutinib (eflucimibe) or SMP-797.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an MTP inhibitor, such as, and preferably, Enptapide (impliptatide), BMS-201038, R-103757, or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, and preferably, pioglitazone (pioglitazone) or rosiglitazone (rosiglitazone).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-agonist, such as, and preferably, GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterol absorption inhibitor, such as, and preferably, ezetimibe (ezetimibe), tiquinane (tiqueside) or pamabrin (pamaquide).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipase inhibitor, such as, and preferably, orlistat (orlistat).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, and preferably, cholestyramine (cholestyramine), colestipol (colestipol), colesevol (colesevivam), colestyrol (CholestaGel) or colestipol (colestimide).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a bile acid resorption inhibitor, such as, and preferably, an ASBT (═ IBAT) inhibitor, e.g. AZD-7806, S-8921, AK-105, baii-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist, such as, and preferably, calcium gemcabene (calcium) (CI-1027) or niacin.

The invention also relates to a medicament comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to the use of said medicament for the above-mentioned purposes.

The compounds of the invention may act systemically and/or locally. For this purpose, it can be administered in a suitable manner, for example by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic administration, or as an implant or stent.

The compounds of the present invention may be administered in a form of administration suitable for these routes of administration.

Administration forms which act according to the prior art, release the compounds according to the invention rapidly and/or in a modified manner and which contain the compounds according to the invention in crystalline and/or amorphous and/or dissolved form are suitable for oral administration, for example tablets (uncoated or coated tablets, such as tablets with enteric coatings or coatings which delay dissolution or insolubility and control the release of the compounds according to the invention), tablets or films/wafers (tablets) which disintegrate rapidly in the oral cavity, films/lyophilizates or capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may bypass the absorption step (e.g., intravenous, intra-arterial, intracardiac, intravertebral or intravertebral) or involve absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Administration forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration, suitable examples are inhalation pharmaceutical forms (including powder inhalants, sprays); nasal drops; a solution or mist; tablets, films/wafers or capsules for lingual, sublingual or buccal administration; suppositories; ear or eye preparations; vaginal capsules; aqueous suspending agents (lotions, shaking mixes); a lipophilic suspending agent; an ointment; cream (cream); transdermal therapeutic systems (e.g., patches); an emulsion; a paste; a foaming agent; sprinkling powder (springlingpowder); an implant or a stent.

Oral or parenteral administration, in particular oral administration, is preferred.

The compounds of the invention can be converted into the administration forms mentioned. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. Such excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifying and dispersing agents or wetting agents (e.g., sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), colorants (e.g., inorganic pigments such as iron oxides), and taste and/or odor agents.

Generally, for parenteral administration, it has been found advantageous to administer an amount of about 0.001 to 1mg/kg body weight, preferably about 0.01 to 0.5mg/kg body weight, to achieve effective results. For oral administration, the dose is about 0.001-2mg/kg body weight, preferably about 0.001-1mg/kg body weight.

However, if appropriate, it may be necessary to deviate from the stated amounts, in particular with respect to body weight, route of administration, individual response to the active substance, nature of the preparation and time or interval of administration. Thus, in some cases, it may be sufficient to fall below the minimum amount, while in other cases the upper limit is exceeded. When larger amounts are administered, it may be advisable to divide these amounts into several individual doses during the day.

The following working examples serve to illustrate the invention. The present invention is not limited to these examples.

Unless otherwise indicated, the percentages in the following tests and examples are percentages by weight; the parts are parts by weight. The solvent ratio, dilution ratio and concentration for the liquid/liquid type solution are all by volume.

A. Examples of the embodiments

Abbreviations and acronyms：

aq. aqueous solution

calc. calculated

DCI direct chemical ionization (in MS)

DMF dimethyl formamide

DMSO dimethyl sulfoxide

eq. equivalent

ESI electrospray ionization (in MS)

Et Ethyl group

h hours

HPLC high pressure high performance liquid chromatography

HRMS high resolution mass spectrum

conc. concentrated

LC/MS and liquid chromatogram combined mass spectrum

LiHMDS lithium hexamethyldisilazide

Me methyl group

min for

MS Mass Spectrometry

NMR nuclear magnetic resonance spectrum

Pd/C on activated carbon (10%)

Ph phenyl

RT Room temperature

R_tRetention time (in HPLC)

t-Bu tert-butyl

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrum

Ratio of v/v (of solution) by volume

XPHOS dicyclohexyl- (2 ', 4 ', 6 ' -triisopropylbiphenyl-2-yl) -phosphine

HPLC and LC/MS methods:

method 1 (LC-MS):

the instrument comprises the following steps: waters ACQUITY SQD UPLC system; column: waters acquisition UPLC HSS T31.8 μ 50x1 mm; mobile phase A: 1l of water +0.25ml of 99% strength formic acid, mobile phase B: 1l acetonitrile +0.25ml 99% strength formic acid; gradient: 0.0min 90% a → 1.2min 5% a → 2.0min 5% a, oven temperature: 50 ℃; flow rate: 0.40 ml/min; and (4) UV detection: 210-400 nm.

Method 2 (LC-MS):

the instrument comprises the following steps: waters ACQUITY SQD UPLC system; column: waters acquisition UPLC HSS T31.8 μ 30x2 mm; mobile phase A: 1l of water +0.25ml of 99% strength formic acid, mobile phase B: 1l acetonitrile +0.25ml 99% strength formic acid; gradient: 0.0min 90% a → 1.2min 5% a → 2.0min 5% a, oven temperature: 50 ℃; flow rate: 0.60 ml/min; and (4) UV detection: 208-400 nm.

Method 3 (LC-MS):

the instrument comprises the following steps: micromass Quattro Premier equipped with Waters UPLC Acquity; column: ThermoHypersil GOLD 1.9 μ 50mm x1 mm; mobile phase A: 1l of water +0.5ml of 50% strength formic acid, mobile phase B: 1l acetonitrile +0.5ml 50% strength formic acid; gradient: 0.0min 90% A → 0.1min 90% A → 1.5min 10% A → 2.2min 10% A; flow rate: 0.33 ml/min; furnace temperature: 50 ℃; and (4) UV detection: 210 nm.

General procedure:

general procedure 1:

in a microwave vessel with magnetic stirring apparatus, 1.0 equivalent of example 2A (100mg, 0.369mmol) is dissolved in dimethylformamide (2.5ml) together with 1.0 equivalent of the appropriate aminonitrile and 1.0 equivalent of potassium tert-butoxide, the vessel is sealed and heated at 160 ℃ for 2h under microwave irradiation. The reaction analysis was then performed. In the case of incomplete conversion, a further 0.5 equivalent of potassium tert-butoxide is added and the mixture is heated again at 160 ℃ under microwave irradiation until complete conversion. The reaction mixture was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.05% formic acid, gradient).

General procedure 2:

in a microwave vessel with magnetic stirring apparatus, 1.0 equivalent of example 2A (100mg, 0.32mmol) is dissolved in dimethylformamide (2ml) together with 1.0 equivalent of the appropriate aminonitrile and 1.0 equivalent of potassium tert-butoxide, the vessel is sealed and heated at 160 ℃ for 2h under microwave irradiation.

The reaction analysis was then performed. If desired (see, examples), further reagents are added and the mixture is again heated under microwave irradiation. The reaction mixture was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.01% formic acid, gradient).

Starting materials and intermediates:

example 1A

5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -3-iodo-1H-pyrazolo [3,4-b ] pyridine

First, 6.291g (23.921mmol) of 5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine (described in WO2011/147809, example 1, page 42) and 8.573g (26.313mmol) of cesium carbonate were added to DMF (10ml), followed by dropwise addition of 5.00g (26.313mmol) of 2- (bromomethyl) -3-fluoropyridine dissolved in DMF (20 ml). The mixture was stirred at RT overnight. The mixture was then cooled and poured into 200ml of water. The precipitate was filtered off with suction, washed with water and dried overnight under vacuum. 6.28g (70% of theory) of the title compound are obtained.

LC-MS (method 3): r_t＝2.17min

MS(ESIpos)：m/z＝373(M+H)⁺

¹H NMR(400MHz；DMSO-d₆)：＝5.88(s，2H)，7.42-7.46(m，1H)，7.77(dd，1H)，7.93(dd，1H)，8.27(d，1H)，8.67(t，1H)。

Example 2A

5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile

First, 6.280g (16.876mmol) of copper (I) cyanide from example 1A and 1.663g (18.564mmol) were added to DMSO (100ml) and stirred at 150 ℃ for 3 h. After cooling, the reaction mixture was filtered through Celite (Celite), and the filter cake was washed with ethyl acetate. The filtrate was extracted four times with saturated aqueous ammonium chloride and concentrated aqueous ammonia (3: 1v/v) and the organic phase was separated. The organic phase was subsequently washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. 3.97g (86% of theory) of the title compound are obtained.

LC-MS (method 1): r_t＝0.92min

MS(ESIpos)：m/z＝272(M+H)⁺

¹H NMR(400MHz；DMSO-d₆)：＝6.04(s，2H)，7.44-7.48(m，1H)，7.61(t，1H)，8.26(d，1H)，8.52(dd，1H)，8.83(dd，1H)。

Example 3A

{4, 6-diamino-2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] pyrimidin-5-yl } (2,2, 2-trifluoroethyl) carbamic acid methyl ester

The synthesis of this compound is described in WO2011/147809, example 3, page 44.

Example 4A

6-amino-2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one

5.005g (6.458mmol) of the compound from example 3A are dissolved in 355ml of tetrahydrofuran under an argon atmosphere and cooled to 0 ℃ and 16.145ml (16.145mmol) of a 1N solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran are added dropwise. The mixture was stirred at 0 ℃ for 2h and then at RT for 16 h. 16.145ml (16.145mmol) of 1N hydrochloric acid were added and the mixture was concentrated on a rotary evaporator. The residue is taken up in ethyl acetate and the organic phase is washed twice with water, dried over sodium sulfate and concentrated on a rotary evaporator. 6.13g of the title compound are obtained (purity 61% by HPLC). 500mg of the residue are purified by preparative HPLC (mobile phase: methanol/water, gradient 30: 70 → 90: 10). 93mg of the title compound (36% of theory) are obtained.

LC-MS (method 1): r_t＝1.01min；MS(EIpos)：m/z＝477[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝4.91(q，2H)，5.80(s，2H)，7.01(s br，2H)，7.13-7.18(m，1H)，7.21-7.26(m，2H)，7.34-7.40(m，1H)，8.70(dd，1H)，8.87(dd，1H)，11.96(s，1H)。

Example 5A

2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6-iodo-7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one

4.650g (5.954mmol) of the compound from example 4A were dissolved in 12ml of diiodomethane and 12.76ml (95.270mmol) of isoamyl nitrite were added. The reaction mixture was heated at 85 ℃ for 16h, cooled and concentrated on a rotary evaporator. 5g of crude product (purity 54%) are obtained. 1.2g of the residue are purified by preparative HPLC (mobile phase: acetonitrile/water with 0.05% formic acid, gradient 40: 60 → 95: 5). 128mg of the title compound (15% of theory) are obtained.

LC-MS (method 1): r_t＝1.23min；MS(EIpos)：m/z＝588[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝4.95(q，2H)，5.86(s，2H)，7.14-7.18(m，1H)，7.21-7.27(m，2H)，7.35-7.41(m，1H)，8.47(dd，1H)，8.76(dd，1H)，12.79(s，1H)。

Example 6A

6-chloro-2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one

262mg (0.446mmol) of the compound from example 5A are heated in 4ml of phosphorus oxychloride at 85 ℃ for 2 hours. The reaction mixture was then poured into warm water and stirred for 1 hour. The solid formed was filtered off and washed with a little water. After drying in vacuo, 198mg of the title compound (89% of theory) are obtained.

LC-MS (method 1): r_t＝1.29min；MS(EIpos)：m/z＝496[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝4.86(q，2H)，5.86(s，2H)，7.15-7.19(m，1H)，7.21-7.30(m，2H)，7.35-7.41(m，1H)，8.49(dd，1H)，8.77(dd，1H)，12.95(s，1H)。

Example 7A

2- (2-fluorophenyl) -N- [ (6-oxo-1, 4, 5, 6-tetrahydropyridazin-3-yl) methyl ] acetamide

First, 200.00g (1.101mol) of methyl 5-amino-4-oxopentanoate hydrochloride were added to ethanol (3500ml), 64.28ml (1.321mol) of hydrazine hydrate were added, and the mixture was heated at reflux for 45 min. After cooling, triethylamine (152ml) was added and the mixture was evaporated to dryness. To the residue was added water (500ml) and the mixture was concentrated. Ethanol (500ml) was then added and the mixture was concentrated, then toluene (500ml) was added twice and evaporated to dryness after each toluene addition. The residue (140g) was dissolved in acetonitrile (500ml), and 307.85g (1.784mol) of (2-fluorophenyl) acetyl chloride (preparation: Journal of Organic Chemistry; 22; 1957; 879) and 304.86ml (2.202mol) of triethylamine in acetonitrile (1500ml) and molecular sieves were slowly added at 0 ℃. The mixture was stirred at 20 ℃ for 3 days. The mixture was then filtered, and the precipitate was washed with tert-butyl methyl ether and then dried. 458g of the expected compound (90% of theory) are obtained.

LC-MS (method 1): r_t＝0.57min；MS(EIpos)：m/z＝264[M+H]⁺。

Example 8A

2- (2-fluorophenyl) -N- [ (6-oxo-1, 6-dihydropyridazin-3-yl) methyl ] acetamide

First, 458g (1.740mol) of the compound obtained in example 7A was added to acetic acid (2250ml), and the mixture was warmed to 50 ℃. At this temperature, 98.16ml (1.914mol) of bromine are added dropwise with vigorous stirring and stirring is then continued for 3h at 50 ℃. After cooling, the reaction mixture was concentrated to dryness. The residue was stirred with saturated aqueous sodium bicarbonate (4800 ml). The mixture was then filtered and the precipitate was washed with a small amount of water. The filtrate was extracted twice with ethyl acetate. The organic phases were combined, dried and concentrated. 117g of the expected compound (25% of theory) are obtained.

LC-MS (method 1): r_t＝0.56min；MS(EIpos)：m/z＝262[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝3.54(s，2H)，4.16(d，2H)，6.86(d，1H)，7.12-7.16(m，2H)，7.27-7.35(m，3H)，8.62(t，1H)，12.88(s，1H)。

Example 9A

2-chloro-7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazine

First, 65.00g (248.79mmol) of the compound obtained in example 8A was added to sulfolane (780ml), 185.52ml (1.990mol) of phosphorus oxychloride was added, and the mixture was heated to 100 ℃ for 3 hours. Excess phosphorus oxychloride was then distilled off under high vacuum, and the residue was dissolved with ethyl acetate and added to saturated aqueous sodium bicarbonate solution. The mixture was diluted with water and then extracted with ethyl acetate. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (mobile phase: dichloromethane/methanol 20: 1 → 5: 1(v/v)), then washed with water and purified by chromatography on silica gel (mobile phase: dichloromethane/methanol 100: 1 v/v). 23.6g of the expected compound (36% of theory) are obtained.

LC-MS (method 1): r_t＝1.00min；MS(EIpos)：m/z＝262[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝4.40(s，2H)，6.84(d，1H)，7.10-7.33(m，4H)，7.55(s，1H)，8.19(d，1H)。

Example 10A

7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazine

Under argon, first 2.004g of palladium on carbon (5%) and then 20.04g (76.58mmol) of the compound obtained in example 9A in ethyl acetate (750ml) were added. 21.348ml (153.159mmol) of triethylamine are then added and the reaction mixture is hydrogenated for 16 hours under standard hydrogen pressure at 20 ℃. The same amount of catalyst as indicated above was then added and the reaction mixture was then hydrogenated again overnight at standard hydrogen pressure and 20 ℃. The mixture is then filtered through celite, the filter cake is washed with ethanol, the filtrate is concentrated and dried under high vacuum. 22.79g of the expected compound (about 100% of theory, contaminated with triethylamine) are obtained.

LC-MS (method 1): r_t＝0.77min；MS(EIpos)：m/z＝228[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝4.44(s，2H)，6.70(dd，1H)，7.08-7.31(m，4H)，7.45(s，1H)，8.09(dd，1H)，8.28(dd，1H)。

Example 11A

5-bromo-7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazine

First, 22.46g (98.837mmol) of the compound obtained in example 10A was added to methylene chloride (400ml), and 17.591g (98.837mmol) of N-bromosuccinimide was added. The mixture was then stirred at 20 ℃ for 10 min. Then, water was added to the reaction mixture, the phases were separated, and the organic phase was washed with water. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 22.78g of the expected compound (75% of theory) are obtained.

LC-MS (method 1): r_t1.05 min; ms (eipos): 306, 308[ M + H, bromo-mode]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝4.45(s，2H)，6.81(dd，1H)，7.12-7.34(m，4H)，7.94(dd，1H)，8.28(dd，1H)。

Example 12A

7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazine-5-carbonitrile

First, 1.00g (3.266mmol) of the compound obtained in example 11A was added to dry DMSO (25ml), 1.170g (13.066mmol) of copper (I) cyanide was added, and the mixture was heated at 170 ℃ for 3.5h with stirring. The mixture was filtered through celite and the filter cake was washed with ethyl acetate and tetrahydrofuran. The filtrate was then extracted four times with a mixture of saturated aqueous ammonium chloride/aqueous ammonia (33%) (3: 1, v/v) and washed once with saturated aqueous sodium chloride. The phases were separated and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated with ethanol in an ultrasonic bath, then water was added. The precipitate formed is filtered off, washed with ethanol and then dried under high vacuum. 586mg of the expected compound (71% of theory) are obtained.

LC-MS (method 1): r_t＝0.95min；MS(EIpos)：m/z＝253[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝4.49(s，2H)，7.13-7.35(m，5H)，8.40(d，1H)，8.61(d，1H)。

Example 13A

5-fluoro-3-iodo-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine

First, 5.0g (19.010mmol) of 5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine was added to DMF (100ml), followed by 20.83g (76.042mmol) of 1,1, 1,2, 2-pentafluoro-4-iodobutane and 14.86g (45.65mmol) of cesium carbonate and 0.63g (3.802mmol) of potassium iodide. The mixture was stirred at 140 ℃ overnight. The mixture was then cooled and combined with a previous experiment using 200mg of 5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine in a similar manner. The solid is filtered off with suction and washed with DMF, and the filtrate is then concentrated under high vacuum. The residue was purified by preparative HPLC (methanol: water, gradient). 4.34g (52% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝1.30min

MS(ESIpos)：m/z＝410(M+H)⁺

¹H NMR(400MHz；DMSO-d₆)：＝2.84-3.00(m，2H)，4.79(t，2H)，7.93(dd，1H)，8.71(dd，1H)。

Example 14A

5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile

First, 4.34g (10.609mmol) of the suspension from example 13A and 1.045g (11.670mmol) of copper (I) cyanide are added to DMSO (30ml) and stirred at 150 ℃ for 2 h. After cooling, the mixture was filtered through celite, the filter cake was washed with ethyl acetate and THF, and the filtrate was extracted four times with a solution of saturated aqueous ammonium chloride and concentrated aqueous ammonia (3: 1 v/v). . The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure.

Yield: 3.19g (97% of theory)

¹H NMR(400MHz；DMSO-d₆)：＝2.94-3.09(m，2H)，4.93(t，2H)，8.54(dd，1H)，8.88(dd，1H)。

Working examples are as follows:

example 1

6- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -1H-pyrazolo [3,4-b ] pyridin-3-yl } -3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine

Following general procedure 1, 100mg (0.369mmol) of example 2A were reacted with 5-amino-3-methyl-1H-pyrazole-4-carbonitrile.

Yield: 14mg (10% of theory)

LC-MS (method 1): r_t＝0.71min；MS(EIpos)：m/z＝394[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]Methyl, 3H is likely to be under the DMSO signal, 5.96(s, 2H), 7.42-7.46(m, 1H), 7.76(t, 1H), 8.28(d, 1H), 8.67(s br, 1H), 8.90(dd, 1H), 12.97(s br, 1H).

Example 2

N³，N³-diethyl-6- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl]-1H-pyrazolo [3,4-b]Pyridin-3-yl } -1H-pyrazolo [3,4-d]Pyrimidine-3, 4-diamines

Following general procedure 1, 100mg (0.369mmol) of example 2A were reacted with 5-amino-3- (diethylamino) -1H-pyrazole-4-carbonitrile.

Yield: 37mg (22% of theory)

LC-MS (method 1): r_t＝0.93min；MS(EIpos)：m/z＝451[M+H]⁺.

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝1.04(t，6H)，3.22(q，4H)，5.96(s，2H)，7.42-7.46(m，1H)，7.75-7.80(m，1H)，8.27-8.29(m，1H)，8.66(dd，1H)，8.90(dd，1H)，12.55(sbr，1H).

Example 3

2- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -1H-pyrazolo [3,4-b ] pyridin-3-yl } pyrido [2,3-d ] pyrimidin-4-amine

Following general procedure 1, 100mg (0.369mmol) of example 2A were reacted with 2-aminopyridinecarbonitrile.

Yield: 19mg (13% of theory)

LC-MS (method 1): r_t＝0.71min；MS(EIpos)：m/z＝391[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝6.01(s，2H)，7.43-7.47(m，1H)，7.52(dd，1H)，(7.76-7.81(m，1H)，8.28-8.30(m，1H)，8.33(s br，2H)，8.67-8.70(m，2H)，8.90(dd，1H)，9.01(dd，1H)。

Example 4

6- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -1H-pyrazolo [3,4-b ] pyridin-3-yl } -3-methoxy-1H-pyrazolo [3,4-d ] pyrimidin-4-amine

Following general procedure 1, 100mg (0.369mmol) of example 2A were reacted with 5-amino-3-methoxy-1H-pyrazole-4-carbonitrile.

Yield: 18mg (12% of theory)

LC-MS (method 1): r_t＝0.79min；MS(EIpos)：m/z＝410[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝3.98(s，3H)，5.96(s，2H)，7.42-7.46(m，1H)，7.75-7.80(m，1H)，8.27-8.29(m，1H)，8.66(dd，1H)，8.88(dd，1H)，12.41(s br，1H)。

Example 5

6- [ (cyclopropylmethyl) amino ] -2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one

In a microwave vessel with a magnetic stirring device, 90mg (0.182mmol) of example 6A were dissolved in 2ml of NMP, aminomethylcyclopropane (0.5ml) was added, and the mixture was heated at 150 ℃ for 3h under microwave irradiation. The reaction mixture was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.05% formic acid, gradient).

Yield: 18mg (18% of theory)

LC-MS (method 1): r_t＝1.26min；MS(EIpos)：m/z＝531[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝0.32-0.35(m，2H)，0.43-0.48(m，2H)，1.23-1.28(m，1H)，3.51(dd，2H)，4.96(q，2H)，5.82(s，2H)，6.91(t，1H)，7.13-7.17(m，1H)，7.20-7.27(m，2H)，7.35-7.40(m，1H)，8.57(dd，1H)，8.72(dd，1H)，11.99(s，1H)。

Example 6

2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -7- (2,2, 2-trifluoroethyl) -6- [ (3,3, 3-trifluoropropyl) amino ] -7, 9-dihydro-8H-purin-8-one

In a microwave vessel with magnetic stirring means 90mg (0.182mmol) of example 6A are dissolved in 2ml of NMP, 122mg (0.817mmol) of 3,3, 3-trifluoropropyl-1-amine hydrochloride and 0.164ml (0.944mmol) of N, N-diisopropylethylamine are added, and the mixture is then heated at 150 ℃ for 3h under microwave irradiation. The reaction mixture was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.05% formic acid, gradient). 54mg of material still containing starting material were isolated. Then, 44mg of this mixture was dissolved in 1ml of NMP in a microwave vessel equipped with a magnetic stirring apparatus, 60mg (0.405mmol) of 3,3, 3-trifluoropropyl-1-amine hydrochloride and 81. mu.l (0.468mmol) of N, N-diisopropylethylamine were added, and then the mixture was heated at 150 ℃ under microwave irradiation for 6 hours. The reaction mixture was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.05% formic acid, gradient).

Yield: 34mg (33% of theory)

LC-MS (method 1): r_t＝1.22min；MS(EIpos)：m/z＝573[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝2.65-2.72(m，2H)，3.85-3.90(q，2H)，4.90-4.97(q，2H)，5.82(s，2H)，6.97(t，1H)，7.16(t，1H)，7.20-7.29(m，2H)，7.34-7.40(m，1H)，8.46(dd，1H)，8.72(dd，1H)，12.09(s，1H)。

Example 7

6- [7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazin-5-yl ] -3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine

Following general procedure 1, 100mg (0.369mmol) of example 12A are reacted with 5-amino-3-methyl-1H-pyrazole-4-carbonitrile at 200 ℃.

Yield: 19mg (13% of theory)

LC-MS (method 1): r_t＝0.77min；MS(EIpos)：m/z＝375[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]Methyl, 3H is likely to be under the DMSO signal, 4.50(s, 2H), 6.95(dd, 1H), 7.12-7.23(m, 2H), 7.29-7.34(m, 2H), 8.41(dd, 1H), 9.11(dd, 1H), 12.80(sbr, 1H).

Example 8

6- [ 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine

Following general procedure 2, 200mg (0.65mmol) of example 14A, 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile were reacted with 5-amino-3-methyl-1H-pyrazole-4-carbonitrile.

Yield: 6.6mg (2% of theory)

LC-MS (method 1): r_t＝0.92min；MS(EIpos)：m/z＝431[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝2.57(s，3H)，2.90-3.12(m，2H)，4.88(t，2H)，7.50(br.s，2H)，8.68-8.74(m，1H)，8.94(dd，1H)，13.03(br.s，1H)。

Example 9

N3, N3-diethyl-6- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -1H-pyrazolo [3,4-b ] pyridin-3-yl } -1H-pyrazolo [3,4-d ] pyrimidine-3, 4-diamine

Following general procedure 2, 100mg (0.32mmol) of example 14A, 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile were reacted with 5-amino-3- (diethylamino) -1H-pyrazole-4-carbonitrile. The mixture was then heated at 200 ℃ for a further 2h and finally at 160 ℃ for 10h under microwave irradiation.

Yield: 5.2mg (3% of theory)

LC-MS (method 1): r_t＝1.09min；MS(EIpos)：m/z＝488[M+H]⁺。

¹H NMR(400MHz；DMSO-d₆)：[ppm]＝1.05(t，6H)，2.86-3.13(m，3H)，3.22(q，4H)，4.88(t，2H)，7.22(br.s，2H)，8.70(dd，1H)，8.95(dd，1H)，12.61(s，1H)。

Example 10

2- [ 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] pyrido [2,3-d ] pyrimidin-4-amine

Following general procedure 2, 200mg (0.65mmol) of example 14A, 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile were reacted with 2-aminopyridinecarbonitrile. The mixture was then heated at 180 ℃ for a further 3h under microwave irradiation. Finally, 80mg (0.67mmol) of 2-aminopyridinecarbonitrile and 73mg (0.65mmol) of potassium tert-butoxide are added and the mixture is heated at 180 ℃ for 3h under microwave irradiation.

Yield: 6.6mg (2% of theory)

LC-MS (method 1): r_t＝0.89min；MS(EIpos)：m/z＝428[M+H]⁺。

¹H NMR(400MHz，DMSO-d₆)：[ppm]＝2.94-3.12(m，2H)，4.93(t，2H)，7.50-7.59(m，1H)，8.37(br.s.，1H)，8.70(d，1H)，8.75(br.s.，1H)，8.91(dd，1H)，9.04(br.s.，1H)

B.Pharmacological efficacy assessment

The pharmacological effects of the compounds of the invention can be shown in the following assays:

B-1.in vitro vasodilatory action

Rabbits were stunned by neck pounding and exsanguinated. The aorta was removed, the adherent tissue peeled off and divided into 1.5mM wide rings, which were individually placed under initial tension in a 5ml organ bath containing a 37 ℃ Krebs-Henseleit solution aerated with carbopol gas, the solution having the following composition (in each case in mM): sodium chloride: 119; potassium chloride: 4.8; calcium chloride dihydrate: 1; magnesium sulfate heptahydrate: 1.4; potassium dihydrogen phosphate: 1.2; sodium bicarbonate: 25; glucose: 10. the contractile force was measured with Statham UC2 cells, amplified and digitized using an A/D converter (DAS-1802HC, Keithley Instruments Munich), and then recorded in parallel in a strip recorder (linerecorder). Phenylephrine is added cumulatively to the bath at increasing concentrations in order to produce contractions. After several control cycles, the substance to be investigated is added in increasing doses in each subsequent cycle and the height of contraction reached is compared with the height of contraction reached in the immediately preceding cycle. This was used to calculate the concentration required to reduce the level of the control value by 50% (I)C₅₀Value). The standard administration volume was 5 μ l; and the DMSO content in the bath solution corresponded to 0.1%.

B-2.Effect on recombinant guanylate cyclase reporter cell lines

The cellular activity of the compounds of the invention was determined using a recombinant guanylate cyclase reporter cell line, as described in f.wunder et al, anal.biochem.339, 104-112 (2005).

Representative values (MEC ═ minimum effective concentration) for the compounds of the invention are shown in the following table (table 2):

table 2:

examples	MEC[μM]
		1	0.3
2	0.1
		3	10
4	0.3
		5	0.3
7	0.01

Examples	MEC[μM]
		8	0.1
9	0.03
		10	0.3

B-3.Radio telemetry measurement of blood pressure in conscious, spontaneously hypertensive rats

Blood pressure measurements were performed on conscious rats described below using a commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA.

The system consists of 3 main components:

an implantable emitter (Remote measuring emitter

A receiver (a)Receiver) connected to the receiver through a multiplexer (DSI Data Exchange Matrix)

-a data acquisition computer.

The telemetry system allows continuous recording of blood pressure, heart rate and body movements of a conscious animal in its general living space.

Animal material

The study was carried out in adult female spontaneously hypertensive rats (SHR Okamoto) weighing > 200 g. SHR/NCrl from Okamoto Kyoto School of Medicine (1963) is a cross-breed of male Wistar Kyoto rats with greatly elevated blood pressure and female rats with slightly elevated blood pressure and was shipped to the national Institutes of Health (U.S. national Institutes of Health) at F13.

After implantation of the emitter, the test animals were housed individually in Makrolon type 3 cages. They can freely ingest standard feed and water.

In the test laboratory, the day/night regulation was regulated by adjusting the day/night schedule at 6: 00 and 19 in the evening: 00 are changed for room lighting.

Emitter implantation

At least 14 days prior to the first experimental use, the TA11 PA-C40 telemetry transmitter used was surgically implanted in the test animals under sterile conditions. Animals equipped with the apparatus in this manner can be reused after wound healing and implant incorporation.

For implantation, fasted animals were anesthetized with pentobarbital (Nembutal, Sanofi: 50mg/kg intraperitoneal) and then shaved and disinfected over a large area of their abdomen. After opening the abdominal cavity along the albedo line, the liquid-filled measuring catheter of the system is inserted cranially into the descending aorta above the bifurcation point and cemented with tissue glue (VetBond D)^TMAnd 3M) fixing. The transmitter housing is secured to the abdominal wall muscles within the abdominal cavity and the wound is closed layer by layer.

After surgery, antibiotics (Tardomyocel COMP, Bayer, 1ml/kg, administered subcutaneously) were administered to prevent infection.

Substances and solutions

Unless otherwise stated, the substances to be investigated were each administered orally to a group of animals via a gastric tube (n-6). The test substance is dissolved in a suitable solvent mixture or suspended in Tylose at a concentration of 0.5%, suitable for an administration volume of 5ml/kg body weight.

A group of animals treated with solvent was used as a control.

Test procedure

The telemetric measuring device of the present invention was configured for 24 animals. Each experiment is recorded with the experiment number (V years, months, days).

Each rat equipped with instrumentation living in the system was assigned a separate receiving antenna (1010Receiver, DSI).

The implanted transmitter can be activated externally by a built-in magnetic switch and switched to a transmitting state at the start of the experiment. The transmitted signal may be passed through a data acquisition system (Dataquest)^TMFor WINDOWS, DSI) and processed accordingly. The data are each stored in a folder created for this purpose, with the experiment number.

In the standard procedure, the following criteria were measured in each case for 10 seconds:

-systolic pressure (SBP)

Diastolic pressure (DBP)

Mean Arterial Pressure (MAP)

Heart Rate (HR)

-Activity (ACT).

The acquisition of the measured values was repeated under computer control at 5 minute intervals. The source data obtained as absolute values are corrected in the diagram with the currently measured air pressure (ambient pressure reference monitor; APR-1) and stored as separate data. Further technical details are described in a large number of documents of the manufacturing company (DSI).

Unless otherwise stated, test substances were tested at 9 am on the day of the experiment: 00 is administered. After administration, the above parameters were measured over 24 hours.

Evaluation of

At the end of the experiment, the individual data collected were sorted using analytical software (DATAQUEST. TM. A.R.T.TMANALYSIS). The 2 hour pre-dose time was set to blank values, so the data set selected included the data from 7 am of the day of the experiment: time 00 until the following day 9 am: a period of 00.

The data were smoothed over a preset time by mean value determination (15 minute average) and transferred to storage media as a text folder. The measurements pre-classified and compressed in this way were transferred into Excel templates and presented as a table. The data obtained were stored in a special folder with the experiment number for each experiment day. The results and test protocol are filed in paper form sorted by number.

Literature reference

Klaus Witte，Kai Hu，Johanna Swiatek，Claudia Müssig，Georg Ertl andLemmer：Experimental heart failure in rats：effects on cardiovascularcircadian rhythms and on myocardialβ-adrenergic signaling.Cardiovasc Res 47(2)：203-405，2000；Kozo Okamoto：Spontaneous hypertension in rats.Int Rev ExpPathol 7：227-270，1969；Maarten van den Buuse：Circadian Rhythms of BloodPressure，Heart Rate，and Locomotor Activity in Spontaneously Hypertensive Ratsas Measured With Radio-Telemetry.Physiology&Behavior 55(4)：783-787，1994。

B-4.Determination of pharmacokinetic parameters after intravenous and oral administration

Pharmacokinetic parameters of the compounds of the invention were determined in male CD-1 mice, male Wistar rats and/or female beagle dogs. Intravenous administration was achieved by species-specific plasma/DMSO formulations for mice and rats, and by water/PEG 400/ethanol formulations for dogs. For all species, oral administration of the dissolved substance was performed by gavage, based on a water/PEG 400/ethanol formulation. Removal of blood from the rat is simplified by inserting a silicone catheter into the right external jugular vein prior to administration of the substance. Surgery was performed at least one day prior to the experiment using isoflurane anesthesia and administering the analgesic (0.1 ml subcutaneous administration of atropine/ibuprofen (3/1)). Blood was collected over a time window of at least 24 to maximum 72 hours (typically over 10 time points) after administration of the substance, including the endpoint time points. Blood was transferred to heparinized tubes. Then obtaining plasma by centrifugation; if desired, it can be stored at-20 ℃ until further processing.

An internal standard, which may also be a chemically unrelated substance, is added to the samples of the compounds of the present invention, calibration samples and qualifiers (qualifier) and protein precipitation is carried out using an excess of acetonitrile. Buffer solution matching the LC conditions was added followed by vortexing and then centrifugation at 1000 g. The supernatant was analyzed by LC-MS/MS using a C18 reverse phase column and variable mobile phase mixture. The species is quantified by peak height or peak area in the extracted ion chromatogram of a particular selected ion monitoring experiment.

Using validated pharmacokinetic calculation program, pharmacokinetic parameters such as AUC, C are calculated using the determined plasma concentration/time curves_max、t_1/2(terminal half-life), MRT (mean residence time) and CL (clearance).

Since the mass spectrometry is carried out in plasma, the blood/plasma distribution of the substance must be determined in order to be able to adjust the pharmacokinetic parameters accordingly. For this purpose, defined amounts of substances are introduced into the heparinized holo-material of the species in question in a roller mixer (tumbling roller mixer)Incubate in blood for 20 minutes. After centrifugation at 1000g, measured (by LC-MS/MS; see above) and calculated by C_{Blood, blood-enriching agent and method for producing the same}/C_{Blood plasma}The ratio of values to determine plasma concentration.

B-5.Metabolic studies

To determine the metabolic properties of the compounds of the invention, they were incubated with recombinant human Cytochrome P450(CPY) enzyme, liver microsomes, or primary fresh hepatocytes from various animal species (e.g., rat, dog) and human sources to obtain and compare substantially more complete information on phase I and phase II liver metabolism and information on enzymes involved in the metabolism.

The compounds of the invention are incubated at a concentration of about 0.1-10. mu.M. For this purpose, an acetonitrile stock solution of the compound of the invention at a concentration of 0.01-1mM is prepared and then pipetted into the incubation mixture at a dilution of 1: 100. The liver microsomes and the recombinant enzyme were incubated at 37 ℃ in 50mM potassium phosphate buffer (pH 7.4) with or without 1mM NADP⁺An NADPH-producing system consisting of 10mM glucose-6-phosphate and 1 unit of glucose-6-phosphate dehydrogenase. Primary hepatocytes were incubated in suspension in Williams E medium, also at 37 ℃. After 0-4 hours of incubation, the incubation mixture was stopped with acetonitrile (final concentration of about 30%) and the protein was centrifuged off at about 15000 xg. The samples thus terminated were either directly analysed or stored at-20 ℃ until analysis.

The analysis was performed by high performance liquid chromatography (HPLC-UV-MS/MS) with UV and mass spectrometric detection. For this purpose, the supernatant of the incubated sample was chromatographed using a suitable C18 reverse phase column and a variable mobile phase mixture (acetonitrile and 10mM aqueous ammonium formate or 0.05% formic acid). The UV chromatograms are used together with mass spectral data for identification, structural analysis and quantitative determination of metabolites, and for the assessment of quantitative metabolic reduction of the compounds of the invention in the incubation mixtures.

C.Working examples of pharmaceutical compositions

The compounds of the invention can be converted into pharmaceutical preparations as follows:

and (3) tablet preparation:

consists of the following components:

100mg of a compound of the invention, 50mg of lactose (monohydrate), 50mg of corn starch (native), 10mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

The tablet has the weight of 212mg, the diameter of 8mm and the curvature radius of 12 mm.

Preparation of：

A mixture of the compound of the invention, lactose and starch was granulated with a 5% (w/w) aqueous solution of PVP. The granules were dried and mixed with magnesium stearate for 5 minutes. The mixture is compressed using a conventional tablet press (tablet size see above). The guiding value for tabletting was 15kN pressure.

Orally administrable suspension：

Composition of：

1000mg of a compound of the invention, 1000mg of ethanol (96%), 400mg(xanthan gum available from FMC, Pennsylvania, USA) and 99g water.

A single dose of 100mg of a compound of the invention corresponds to 10ml of an oral suspension.

Preparation of：

Rhodigel is suspended in ethanol and the compound of the invention is added to the suspension. Water was added with stirring. The mixture was stirred for about 6h until the Rhodigel swelling was complete.

Orally administrable solutions:

consists of the following components:

500mg of a compound of the invention, 2.5g of polysorbate and 97g of polyethylene glycol 400. A single dose of 100mg of a compound of the invention corresponds to 20g of an oral solution.

Preparation of：

The compounds of the invention are suspended in a mixture of polyethylene glycol and polysorbate under agitation. The stirring operation is continued until the compound of the present invention is completely dissolved.

Intravenous solution:

the compounds of the invention are dissolved in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and/or 30% PEG400 solution) at a concentration below the saturation solubility. The solution was sterile filtered and dispensed into sterile and pyrogen-free injection containers.

Claims

1. A compound of formula (I) and salts thereof, wherein

Ring Q represents a group of the formula:

wherein

Represents a connection to-CH₂-R²The point (c) of (a) is,

represents a connection to R³The point (c) of (a) is,

A²represents a group of a compound represented by the formula CH,

R¹represents fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, C₁-C₄Alkyl radical, C₃-C₇-cycloalkyl or C₁-C₄-an alkoxy group,

n represents the number 0, 1 or 2,

wherein the phenyl group is substituted with 1 to 3 fluoro substituents,

and is

R³represents a group of formula:

wherein

# represents the point of attachment to loop Q,

l represents N, and L represents N,

m represents CR⁴，

Wherein

R⁴represents-R⁵or-NR⁷R⁸，

Wherein

R⁵Represents hydrogen, and is selected from the group consisting of,

R⁷represents hydrogen, and is selected from the group consisting of,

R⁸represents hydrogen or C₁-C₆-an alkyl group,

wherein C is₁-C₆-alkyl is independently selected from 1 to 3 from fluoro, trifluoromethyl, cyclopropyl, cycloButyl, - (C ═ O)_p-OR⁹And- (C ═ O)_p-NR⁹R¹⁰The substituent (b) of (a) is substituted,

wherein

p represents the number 0 and p represents the number 0,

E¹represents NR¹⁸，

Wherein

R¹⁸Represents hydrogen, and is selected from the group consisting of,

E³represents CR¹⁹，

Wherein

R¹⁹Represents hydrogen, trifluoromethyl, C₁-C₄-alkyl or of the formula-J-R¹³The group of (a) or (b),

wherein C is₁-C₄-alkyl may be substituted with 1 to 3 substituents each independently selected from fluoro, trifluoromethyl, cyclopropyl and cyclobutyl,

and wherein

J represents a bond of one of the groups,

R¹³represents- (C ═ O)_r-OR¹⁴Or- (C ═ O)_r-NR¹⁴R¹⁵，

Wherein

r represents the number 0 and r represents the number 0,

u represents C ═ O,

v represents NR²⁴，

Wherein

R²⁴Represents C₁-C₆-an alkyl group,

wherein C is₁-C₆The alkyl group may itself be substituted with 1 to 3 substituents each independently selected from fluoro, trifluoromethyl, cyclopropyl, cyclobutyl and hydroxy,

R²³represents hydrogen, and is selected from the group consisting of,

with the exception of the following compounds:

2. A compound of formula (I) according to claim 1 and salts thereof, wherein

Ring Q represents a group of the formula:

wherein

Represents a connection to-CH₂-R²The point (c) of (a) is,

represents a connection to R³The point (c) of (a) is,

A²represents a group of a compound represented by the formula CH,

wherein the phenyl group is substituted with 1 to 3 fluoro substituents,

and is

Wherein the pyridyl and pyrimidinyl groups may be substituted with 1 fluoro substituent.

3. A compound of formula (I) according to claim 1 or 2 and salts thereof selected from:

6- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -1H-pyrazolo [3,4-b ] pyridin-3-yl } -3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine,

N³,N³-diethyl-6- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl]-1H-pyrazolo [3,4-b]Pyridin-3-yl } -1H-pyrazolo [3,4-d]Pyrimidine-3, 4-diamine, 6- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl]-1H-pyrazolo [3,4-b]Pyridin-3-yl } -3-methoxy-1H-pyrazolo [3,4-d]A pyrimidine-4-amine, a salt thereof,

6- [ (cyclopropylmethyl) amino ] -2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one,

2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -7- (2,2, 2-trifluoroethyl) -6- [ (3,3, 3-trifluoropropyl) amino ] -7, 9-dihydro-8H-purin-8-one, 6- [ 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine, and

n3, N3-diethyl-6- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -1H-pyrazolo [3,4-b ] pyridin-3-yl } -1H-pyrazolo [3,4-d ] pyrimidine-3, 4-diamine.

4. A compound selected from the group consisting of,

2- { 5-fluoro-1- [ (3-fluoropyridin-2-yl) methyl ] -1H-pyrazolo [3,4-b ] pyridin-3-yl } pyrido [2,3-d ] pyrimidin-4-amine,

6- [7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazin-5-yl ] -3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine, and

2- [ 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] pyrido [2,3-d ] pyrimidin-4-amine.

5. A process for the preparation of a compound of formula (I) as defined in claims 1 to 3,

wherein n, Q, R¹And R²Each having the meaning given in any one of claims 1 to 3, and

T¹represents C₁-C₄-an alkyl group,

R^24A-X¹(VII)

wherein

R^24AHaving the features given in any of claims 1 to 3R of (A) to (B)²⁴The meaning of (a) is given,

and is

X¹Represents a suitable leaving group which is, for example,

wherein n, Q, R¹And R²Each having the meaning given in any one of claims 1 to 3, and R^24AHaving R as given in any of claims 1 to 3²⁴The meaning of (a);

this compound is then cyclized in an inert solvent in the presence of a suitable base to give the compound of formula (I-D),

the resulting compounds of formula (I) are optionally converted to their salts with suitable acids or bases.

6. The method of claim 5, wherein X¹Represents halogen, a mesylate or a tosylate group.

7. The method of claim 6, wherein X¹Represents chlorine or bromine.

8. Use of a compound as defined in any of claims 1 to 4 for the preparation of a medicament for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, vascular diseases, renal insufficiency and fibrotic diseases.

9. The use according to claim 8, wherein the medicament is for the treatment and/or prophylaxis of pulmonary hypertension, ischemia, thromboembolic diseases, and arteriosclerosis.

10. A medicament comprising a compound as defined in any one of claims 1 to 4 and an inert, non-toxic, pharmaceutically suitable excipient.

11. A medicament comprising a compound as defined in any one of claims 1 to 4 and a further active compound selected from organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modulators.