HK1190403B

HK1190403B - Substituted imidazopyridines and imidazopyridazines and the use thereof

Info

Publication number: HK1190403B
Application number: HK14103646.6A
Authority: HK
Inventors: Markus Follmann; Johannes-Peter Stasch; Gorden Redlich; Nils Griebenow; Dieter Lang; Frank Wunder; Volkhart Min-Jian Li
Original assignee: Bayer Intellectual Property Gmbh; Bayer Pharma Aktiengesellschaft
Priority date: 2011-05-06
Filing date: 2012-05-02
Publication date: 2018-04-27

Description

Substituted imidazopyridines and imidazopyridazines and their use

The present invention relates to novel substituted imidazopyridines and imidazopyridazines, to a process for their preparation, to their use alone or in combination for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.

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 according to ligand type: particulate guanylate cyclase excitable by natriuretic peptides and soluble guanylate cyclase excitable by NO. The soluble guanylate cyclase is composed of two subunits, and it is highly likely that each heterodimer contains one heme, which is part of the regulatory site. This is extremely important for the activation mechanism. NO is able to bind to the iron atom of 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 resulting modulation of phosphodiesterases, iron channels and protein kinases, guanylate cyclase plays an important role in a variety of physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, in platelet aggregation and platelet adhesion and in neuronal signaling, and in disorders based on interruptions to the above processes. Under pathophysiological conditions, the NO/cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.

The possible NO-independent treatment for such disorders (by targeting the effects of the cGMP signaling pathway in the organism) is a promising approach due to the high efficiency and low levels of side effects that can be expected.

Therapeutic stimulation of soluble guanylate cyclase has been achieved currently exclusively using compounds such as organic nitrates, the action of which is based on NO. NO is formed by biotransformation and activates soluble guanylate cyclase by attacking the central iron atom of heme. In addition to the side effects mentioned, the development of tolerance is one of the key disadvantages of this mode of treatment.

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-benzyl indazole [ YC-1; Wu et al, Blood84(1994),4226; Mulsch et al, Brit.J.Pharmacol.120(1997),681], fatty acids [ Goldberg et al, J.biol.Chem.252(1977),1279], iodonium diphenyl hexafluorophosphate [ Pettidione 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, WO00/06569 discloses fused pyrazole derivatives and WO03/095451 discloses carbamate substituted 3-pyrimidinyl pyrazolopyridines. WO2008/031513 describes, for example, substituted imidazopyridines and imidazopyrimidines as stimulators of soluble guanylate cyclase. WO2010/065275 and WO2011/149921 disclose 4-amino-5, 5-dimethyl-5, 7, dihydro-6H-pyrrolo [2,3-d ] pyrimidinones containing imidazopyridine and imidazopyrimidine substituents as sGC activators.

It is an object of the present invention to provide novel substances which can act as 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 in terms of their in vivo properties, such as their pharmacokinetic and pharmacodynamic profile and/or their metabolic profile 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 and salts,

wherein

A is nitrogen or CR³，

Wherein

R³Is hydrogen, deuterium, halogen, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl radicals, (C)₂-C₄) -alkenyl, (C)₂-C₄) -alkynyl, cyclopropyl, cyclobutyl, hydroxy, phenyl or 5-or 6-membered heteroaryl, wherein (C)₁-C₄) Alkyl radicals, (C)₂-C₄) -alkenyl, (C)₂-C₄) -alkynyl, phenyl and 5-or 6-membered heteroaryl groups may be substituted with 1 to 3 substituents independently from each other selected from fluoro, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, (C)₁-C₄) Alkoxycarbonyl, cyclopropyl and cyclobutyl,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is 0, 1 or 2,

R^4Ais hydrogen, fluorine, (C)₁-C₄) -alkyl, hydroxy or amino, wherein (C)₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently from each other selected from fluoro, trifluoromethyl, hydroxy, hydroxycarbonyl, (C1-C4) -alkoxycarbonyl and amino,

R^4Bis hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₁-C₄) -alkoxycarbonylamino, cyano, (C)₃-C₇) -cycloalkyl, difluoromethoxy, trifluoromethoxy, phenyl or of formula-Q-R⁸A group of (C) wherein₁-C₆) -alkyl may be substituted with 1 to 3 substituents independently chosen from fluoro, cyano, trifluoromethyl, (C)₃-C₇) -cycloalkyl, hydroxy, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, hydroxycarbonyl, (C)₁-C₄) -an alkoxycarbonyl group and an amino group,

and wherein

Q is a bond or (C1-C4) -alkylene,

R⁸is- (C = O)_r-OR⁹、-(C=O)_r-NR⁹R¹⁰、-C(=S)-NR⁹R¹⁰、-NR⁹-(C=O)-R¹²、-NR⁹-(C=O)-NR¹⁰R¹¹、-NR⁹-SO₂-NR¹⁰R¹¹、-NR⁹-SO₂-R¹²、-S(O)_s-R¹²、-SO₂-NR⁹R¹⁰4-to 7-membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl,

wherein

r is a number of 0 or 1,

s is 0, 1 or 2,

R⁹、R¹⁰and R¹¹Independently of one another, are each hydrogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₈) -cycloalkyl, 4-to 7-membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl,

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 cyano, trifluoromethyl, (C)₁-C₆) -alkyl, hydroxy, oxo (oxo), (C)₁-C₆) -alkoxy, trifluoromethoxy, (C)₁-C₆) Alkoxycarbonyl, amino, mono- (C)₁-C₆) Alkylamino and di- (C)₁-C₆) -an alkylamino group,

or

R¹⁰And R¹¹Together 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) -an alkylamino group,

R¹²is (C)₁-C₆) -alkyl or (C)₃-C₇) -a cycloalkyl group,

or

R⁹And R¹²Together 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) -an alkylamino group,

and is

Wherein the 4-to 7-membered heterocyclyl, phenyl and 5-or 6-membered heteroaryl can themselves be substituted by 1 to 3 substituents which are selected independently of one another from halogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, hydroxy, oxo, thio (thioxo) and (C)₁-C₄) -an alkoxy group,

and wherein (C) above, unless otherwise indicated₁-C₄) Alkyl radicals, (C)₁-C₆) Alkyl radicals, (C)₃-C₈) -cycloalkyl and 4-to 7-membered heterocyclyl may each, independently of each other, be substituted with 1 to 3 substituents independently of each other 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) Alkoxycarbonyl, amino, phenyl, 4-to 7-membered heterocyclyl and 5-or 6-membered heteroaryl,

or

R^4AAnd R^4BTogether with the carbon atom to which they are attached form (C)₂-C₄) -alkenyl, oxo, 3-to 6-membered carbocycle or 4-to 7-membered heterocycle,

wherein the 3-to 6-membered carbocyclic ring and the 4-to 7-membered heterocyclic ring may be substituted with 1 or 2 substituentsThe substituents are independently of each other selected from fluorine and (C)₁-C₄) -an alkyl group,

R^5Ais hydrogen, fluorine, (C)₁-C₄) Alkyl radicals, (C)₁-C₄) -an alkoxycarbonyl group or a hydroxyl group,

R^5Bis hydrogen, fluorine, (C)₁-C₄) -an alkyl group or a trifluoromethyl group,

m is a group selected from the group consisting of CH and N,

R¹is (C)₁-C₆) Alkyl radicals, (C)₃-C₈) -cycloalkylmethyl, benzyl or 5-or 6-membered heteroarylmethyl,

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) -cycloalkylmethyl may be substituted with 1 or 2 substituents independently from each other selected from fluoro, methyl and methoxy,

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

and is

Wherein the 5-and 6-membered heteroarylmethyl groups may be substituted with 1 or 2 fluoro substituents,

R²is hydrogen, cyano, halogen, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl or (C)₃-C₇) -a cycloalkyl group,

R⁶is hydrogen, cyano, halogen, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl or (C)₃-C₇) -a cycloalkyl group,

R⁷is hydrogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl or (C)₃-C₇) -a cycloalkyl group.

The compounds of the present invention are compounds of formula (I) and salts, solvates and solvates of said salts, compounds encompassed by formula (I) of the following formula and salts, solvates and solvates of said salts, and compounds encompassed by formula (I) mentioned below as embodiments and salts, solvates and solvates of said salts, with the proviso that said compounds encompassed by formula (I) are not already salts, solvates and solvates of said salts.

The compounds of the invention may also be the N-oxides of the compounds of formula (I) and the salts, solvates and solvates of said salts.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of the invention. Also included are salts which are not only suitable per se for pharmaceutical use but also useful, for example, in 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 and sulfonic acids) such as hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, naphthalenedisulfonate, formate, acetate, trifluoroacetate, propionate, lactate, tartrate, malate, citrate, fumarate, maleate and benzoate.

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 ammonium salts 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, ethylenediamine and N-methylpiperidine.

In the context of the present invention, a solvate refers to the following form of a compound of the present invention: which (solid or liquid) form complexes by coordination with solvent molecules. Hydrates are a particular form of solvate that coordinates to water. In the context of the present invention, preferred solvates are hydrates.

The compounds of the invention may, depending on their structure, exist in different stereoisomeric forms, 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, as well as mixtures of each thereof. The stereoisomerically homogeneous components can be separated from the mixture of enantiomers and/or diastereomers in a known manner; for this purpose, preference is given to using chromatography, in particular HPLC chromatography on achiral or chiral phase.

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

The invention also includes all suitable isotopic variations of the compounds of the invention. In this context, isotopic variations of the compounds of the present invention are understood to mean the following compounds: wherein at least one atom within a compound of the invention is exchanged for another atom having the same atomic number, but a different atomic mass than that which normally or predominantly occurs in nature. Examples of isotopes that can be incorporated into the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. particular isotopic variations of the compounds of the present invention, for example, those in which one or more radioisotopes have been incorporated, among others, may be beneficial, for example, in research effortsWith the active compound distribution either mechanically or in vivo; due to the relative ease of preparation and detection, use³H or¹⁴C-isotopically labelled compounds are particularly suitable for this purpose. Furthermore, the inclusion of isotopes (e.g., deuterium), due to the greater metabolic stability of the resulting compounds, may produce specific therapeutic benefits, such as increased in vivo half-life or a reduction in the active dose required; thus, in some cases, such modifications to the compounds of the invention 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 in the working examples, by employing the corresponding isotopic modifications of the respective reactants and/or starting compounds.

In addition, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" herein denotes a compound as follows: which may or may not be biologically active per se, but which may be converted (e.g. by metabolism or hydrolysis) to a compound of the invention during in vivo residence.

In the formula of the group which may represent L, the end points of the line marked by the symbol # or # # do not represent a carbon atom or CH₂A group, but is part of a bond to each atom to which L is attached.

The compounds of formula (I-1) constitute a subgroup of the compounds of formula (I) wherein R⁶And R⁷Is hydrogen.

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

in the context of the present invention it is,alkyl radicalRepresents a straight-chain or branched alkyl group having in each case the indicated number of carbon atoms. The following groups may be mentioned by way of example and preferably: 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-methylpentyl4-methylpentyl, 3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.

In the context of the present inventionCycloalkyl or carbocycleAre monocyclic saturated alkyl groups having in each case the specified number of carbon atoms. The following groups may be mentioned by way of example and preferably: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the inventionAlkylene radicalIs a linear or branched divalent alkyl group having 1 to 4 carbon atoms. The following groups may be mentioned by way of example and preferably: 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.

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

In the context of the present inventionAlkynyl radicalIs a straight or branched chain alkynyl group having 2 to 4 carbon atoms and one triple bond. The following groups may be mentioned by way of example and preferably: 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 inventionAlkoxy radicalIs a straight or branched chain alkoxy group having 1 to 6 carbon atoms or 1 to 4 carbon atoms. The following groups may be mentioned by way of example: 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. Preference is given to linear or branched alkoxy groups having from 1 to 4 carbon atoms. The following groups may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy.

In the context of the present inventionAlkoxycarbonyl radicalIs a straight or branched alkoxy group having 1 to 6 or 1 to 4 carbon atoms and one carbonyl group attached to oxygen. The following groups may be mentioned by way of example and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

In the context of the present inventionAlkoxycarbonyl amino groupIs an amino group having a straight or branched alkoxycarbonyl substituent containing from 1 to 4 carbon atoms in the alkyl chain and attached to the nitrogen atom via a carbonyl group. The following groups may be mentioned by way of example and preferably: methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino and tert-butoxycarbonylamino.

In the context of the present inventionMonoalkylamino groupIs an amino group having a straight or branched alkyl substituent containing 1 to 6 carbon atoms. The following groups may be mentioned by way of example and preferably: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

In the context of the present inventionDialkylamino radicalIs an amino group having two identical or different straight or branched alkyl substituents each having from 1 to 6 carbon atoms. The following groups may be mentioned by way of example and preferably: 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 inventionHeterocyclic or heterocyclic ringIs a saturated heterocyclic ring having a total of 4 to 7 ring atoms and containing 1 or 2 ring heteroatoms selected from N, O, S, SO and SO 2. The following groups may be mentioned by way of example: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolinyl, imidazolinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and thiomorpholinyl dioxideA quinoline group. Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl and morpholinyl.

In the context of the present invention5-or 6-membered heteroarylIs a monocyclic aromatic heterocycle (heteroaromatic) having a total of 5 or 6 ring atoms, containing up to 3 identical or different ring heteroatoms from the group consisting of N, O and S and being linked via a ring carbon atom or optionally via a ring nitrogen atom. The following groups may be exemplified and preferred: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl and pyrimidyl are preferred.

In the context of the present inventionHalogen elementFluorine, chlorine, bromine and iodine. Bromine and iodine are preferred.

In the context of the present inventionOxo radicalIs an oxygen atom attached to a carbon atom through a double bond.

In the context of the present inventionThio groupIs a sulfur atom attached to a carbon atom through a double bond.

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. Preference is given to substitution of 1,2 or 3 identical or different substituents.

In the context of the present invention, the term "treating" includes inhibiting, delaying, hindering, alleviating, attenuating, limiting, alleviating, preventing, 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 said salts, where

A is nitrogen or CR³，

Wherein

R³Is hydrogen, deuterium, fluorine, iodine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -an alkyl group,

Vinyl, allyl, ethynyl, cyclopropyl, cyclobutyl, hydroxy, pyrazolyl or pyridyl,

wherein (C)₁-C₄) -alkyl, vinyl, allyl, ethynyl and pyridyl may be substituted by 1 or 2 substituents independently from each other selected from methyl, cyclopropyl and cyclobutyl,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is 0 or 1, and p is,

R^4Ais hydrogen, fluorine, methyl, ethyl, hydroxyl or amino,

R^4Bis hydrogen,Fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, methoxycarbonylamino, cyano, cyclopropyl, cyclobutyl, cyclopentyl, phenyl or of formula-Q-R⁸The group of (a) or (b),

wherein (C)₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently from each other selected from fluoro, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,

and wherein

Q is a bond or a methylene group,

R⁸is- (C = O)_r-NR⁹R¹⁰、-C(=S)-NR⁹R¹⁰Oxadiazolonyl, oxadiazolidinyl, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl,

wherein

r is a number of 0 or 1,

R⁹and R¹⁰Each, independently of the others, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or pyridyl,

wherein the methyl, ethyl and isopropyl radicals may additionally be substituted by 1 or 2 substituents which are selected, independently of one another, from the group consisting of fluorine, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,

and is

Wherein oxadiazolonyl, oxadiazolthioketo, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl may themselves be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, hydroxy, methoxy and ethoxy,

or

R^4AAnd R^4BTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl or tetrahydropyranyl ring, wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl and tetrahydropyranyl rings may be substituted with 1 or 2 substituents independently of each other selected from fluoro and methyl,

R^5Ais hydrogen, fluorine, methyl, ethyl or hydroxyl,

R^5Bis hydrogen, fluorine, methyl, ethyl or trifluoromethyl,

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

R¹is 3,3, 3-trifluoropropan-1-yl, 2,3,3, 3-pentafluoropropan-1-yl, 4,4, 4-trifluorobutan-1-yl, 3,3,4, 4-tetrafluorobutan-1-yl, 3,3,4,4, 4-pentafluorobutan-1-yl, (C)₃-C₆) -cycloalkylmethyl, benzyl, thienylmethyl, pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl or pyridazinylmethyl,

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

and is

Wherein (C)₃-C₆) Cycloalkylmethyl, thienylmethyl, pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl and pyridazinylmethyl groups may be substituted with 1 or 2 fluoro substituents,

R²is hydrogen, fluorine or chlorine,

R⁶is hydrogen, fluorine, chlorine or methyl,

R⁷is hydrogen or methyl.

A is nitrogen or CR³，

Wherein

R³Is a hydrogen atom, and is,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R4A is hydrogen, fluoro, methyl, ethyl, hydroxy or amino,

R^4Bis hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, methoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl or of the formula-Q-R⁸The group of (a) or (b),

wherein methyl and ethyl groups may be substituted with 1 to 3 substituents independently selected from fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,

and wherein

Q is a bond of the alkyl group,

R⁸is- (C = O)_r-NR⁹R¹⁰Phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl or pyrimidinyl,

wherein

r is a number of 1, and r is,

R⁹and R¹⁰Independently of one another, are each hydrogen or cyclopropyl,

and is

Wherein the phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyrimidinyl radicals may themselves be substituted by 1 or 2 substituents which are, independently of one another, selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl and cyclobutylmethyl,

or

m is a group selected from the group consisting of CH and N,

R¹is 4,4, 4-trifluorobutan-1-yl, 3,4, 4-tetrafluorobutan-1-yl, 3,4,4, 4-pentafluorobutan-1-

A radical or a benzyl radical,

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

R²fluorine or chlorine, with the proviso that M is CH,

or

R²Is hydrogen, provided that M is N,

R⁶is a hydrogen atom, and is,

R⁷represents hydrogen.

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

A is nitrogen or CR³，

Wherein

R³Represents hydrogen, and is selected from the group consisting of,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl or hydroxyl,

R^4Bis hydrogen, fluorine, trifluoromethyl, 2,2, 2-trifluoroethyl or methyl,

m is a group selected from the group consisting of CH and N,

R¹is 4,4, 4-trifluorobut-1-yl, 3,4, 4-tetrafluorobut-1-yl, 3,4,4, 4-pentafluorobut-1-yl or benzyl,

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

R²fluorine or chlorine, with the proviso that M is CH,

or

R²Is hydrogen, provided that M is N,

R⁶is a hydrogen atom, and is,

R⁷represents hydrogen.

In the context of the present invention, preference is given to compounds of the formula (I-1) and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof, where

Wherein

A is nitrogen or CR³，

Wherein

R³Hydrogen, deuterium, fluorine, difluoromethyl, trifluoromethyl, (C1-C4) -alkyl, cyclopropyl or cyclobutyl,

l is # -CR^4AR^4B-(CR^5AR^5B)_pA group of the form- ###,

wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is 0, 1 or 2,

R^4Ais hydrogen, fluorine, (C1-C4) -alkyl, hydroxyl or amino,

R^4Bis hydrogen, fluorine, (C)₁-C₄) -alkyl, trifluoromethyl, (C)₁-C₄) -an alkoxycarbonylamino group or a phenyl group,

wherein (C)₁-C₄) -alkyl may be substituted with 1 to 3 substituents independently from each other selected from fluoro, trifluoromethyl, hydroxy, hydroxycarbonyl and (C)₁-C₄) -an alkoxycarbonyl group, a carbonyl group,

or

R^4AAnd R^4BTogether with the carbon atom to which they are attached form an oxo group, a 3-to 6-membered carbocyclic ring or a 4-to 6-membered heterocyclic ring,

wherein the 3-to 6-membered carbocycle and the 4-to 6-membered heterocycle may be substituted with 1 or 2 substituents independently selected from fluorine and (C)₁-C₄) -an alkyl group,

or

R^4AAnd R^4BTogether with the carbon atom to which they are attached form (C)₂-C₄) -an alkenyl group,

R^5Ais hydrogen, fluorine, (C1-C4) -alkyl or hydroxy,

R^5Bis hydrogen, fluorine, (C1-C4) -alkyl or trifluoromethyl,

m is a group selected from the group consisting of CH and N,

R¹is represented by (C)₁-C₆) -an alkyl group or a benzyl group,

wherein (C)₁-C₆) -alkyl is substituted with one trifluoromethyl substituent,

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

and is

Wherein the benzyl group is substituted with 1 to 3 fluoro substituents,

R²is hydrogen, fluorine or chlorine.

In the context of the present invention, preference is given to compounds of the formula (I-1) below and to salts, solvates and solvates of said salts, where

A is nitrogen or CR³，

Wherein

R³Is hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl or cyclopropyl,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is 0 or 1, and p is,

R^4Ais hydrogen, fluorine, methyl, ethyl or hydroxyl,

R^4Bis hydrogen, fluorine, methyl, ethyl, trifluoromethyl, methoxycarbonylamino or phenyl,

wherein methyl and ethyl can be substituted with 1 to 3 substituents independently of one another selected from fluorine, trifluoromethyl and hydroxyl,

or

R^4AAnd R^4BTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring,

wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl and tetrahydropyranyl rings may be substituted by 1 or 2 substituents independently of each other selected from fluoro and methyl,

R^5Ais hydrogen, fluorine, methyl, ethyl or hydroxyl,

R^5Bis hydrogen, fluorine, methyl, ethyl or trifluoromethyl,

m is a group of a nitrogen atom,

R¹is 2,2, 2-trifluoroethyl, 3,3, 3-trifluoropropan-1-yl, 4,4, 4-trifluorobutan-1-yl, 3,3,4,4, 4-pentafluorobutan-1-yl or benzyl,

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

R²is fluorine or chlorine.

A is nitrogen or CR³，

Wherein

R³Is hydrogen, fluorine, difluoromethyl, trifluoromethyl, methylAn ethyl group or a cyclopropyl group, or a salt thereof,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is 0 or 1, and p is,

R^4Ais hydrogen, fluorine, methyl, ethyl or hydroxyl,

or

R^5Ais hydrogen, fluorine, methyl, ethyl or hydroxyl,

R^5Bis hydrogen, fluorine, methyl, ethyl or trifluoromethyl,

m is the number of N atoms,

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

R²is hydrogen.

In the context of the present invention, particular preference is given to the following compounds of the formula (I-1) and to their salts, solvates and solvates of said salts, where

A is nitrogen or CR³，

Wherein

R³Represents hydrogen, and is selected from the group consisting of,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl or hydroxyl,

R^4Bis hydrogen, fluorine, methyl or trifluoromethyl,

or

R^4AAnd R^4BTogether with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl and cyclobutyl ring may be substituted by 1 or 2 substituents independently of each other selected from fluoro and methyl,

m is a group of a nitrogen atom,

R¹is 3,3,4,4, 4-pentafluorobutan-1-yl, 2-fluorobenzyl or 2,3, 6-trifluorobenzyl,

R²is fluorine or chlorine.

A is nitrogen or CR³，

Wherein

R³Represents hydrogen, and is selected from the group consisting of,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl or hydroxyl,

R^4Bis hydrogen, fluorine, methyl or trifluoromethyl,

or

R^4AAnd R^4BTogether with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl ring,

wherein the cyclopropyl and cyclobutyl rings may be substituted by 1 or 2 substituents independently of each other selected from fluoro and methyl,

m is the number of N atoms,

R²is hydrogen.

In the context of the present invention, preference is given to the following compounds of the formulae (I) and (I-1) and to their salts, solvates and solvates of the salts, where

A is nitrogen.

Also preferred in the context of the present invention are the compounds of the formulae (I) and (I-1) below and the salts, solvates and solvates of said salts, wherein

A is CR³，

Wherein

R³Represents hydrogen.

M is the number of N atoms,

R²is hydrogen.

M is a group of a nitrogen atom,

R²is fluorine or chlorine.

L is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl or hydroxyl,

R^4Bis hydrogen, fluorine, methyl or trifluoromethyl.

L is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl or hydroxyl,

R^4Bis hydrogen, fluorine, methyl, trifluoromethyl, 2,2, 2-trifluoroethyl or 1,1,2,2, 2-pentafluoroethyl.

L is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl or hydroxyl,

R^4Bis trifluoromethyl, 2,2, 2-trifluoroethyl or 1,1,2,2, 2-pentafluoroethyl.

L is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Ais a methyl group, and the compound is,

R^4Bis methyl.

L is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Aand R^4BThe carbon atom to which they are attached forms a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring.

Also preferred in the context of the present invention are compounds of formula (I) below and salts, solvates and solvates of said salts, wherein

L is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring,

p is a number of 0 and,

R^4Aand R^4BThe carbon atom to which it is attached forms an azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring.

R¹Is a benzyl group, and the benzyl group,

wherein the benzyl group is substituted with 1 to 3 fluoro substituents.

R¹Is 2-fluorobenzyl, 2, 3-difluorobenzyl or 2,3, 6-trifluorobenzyl.

R¹Is 2,2, 2-trifluoroethyl, 3,3, 3-trifluoropropan-1-yl, 4,4, 4-trifluorobutan-1-yl or 3,3,4,4, 4-pentafluorobutan-1-yl.

A is CR³，

Wherein

R³Represents hydrogen, and is selected from the group consisting of,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl, ethyl, hydroxyl or amino,

R^4Bis hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl radicalMethoxycarbonylamino, cyano, cyclopropyl, cyclobutyl, cyclopentyl, phenyl or of formula-Q-R⁸The group of (a) or (b),

and wherein

Q is a bond or a methylene group,

R⁸is- (C = O)_r-NR⁹R¹⁰、-C(=S)-NR⁹R¹⁰Oxadiazolonyl, oxadiazolthioketo, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl,

wherein

r is a number of 0 or 1,

wherein methyl, ethyl and isopropyl may additionally be substituted by 1 or 2 substituents which are independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,

and is

Wherein oxadiazolonyl, oxadiazolthioketo, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl may themselves be substituted by 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2, 2-trifluoroethyl, 1,2,2, 2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, hydroxy, methoxy and ethoxy.

A is N, and the content of the N,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl, ethyl, hydroxyl or amino,

R^4Bis hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, methoxycarbonylamino, cyano, cyclopropyl, cyclobutyl, cyclopentyl, phenyl or of formula-Q-R⁸The group of (a) or (b),

and wherein

Q is a bond or a methylene group,

wherein

r is a number of 0 or 1,

and is

A is CR³，

Wherein

R³Represents hydrogen, and is selected from the group consisting of,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl or hydroxyl,

R^4Bis hydrogen, fluorine, trifluoromethyl, 2,2, 2-trifluoroethyl or methyl.

A is nitrogen, and the content of A is,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl or hydroxyl,

R^4Bis hydrogen, fluorine, trifluoromethyl, 2,2, 2-trifluoroethyl or methyl.

A is CR³，

Wherein

R³Represents hydrogen, and is selected from the group consisting of,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl, ethyl, hydroxyl or amino,

R^4Bis of the formula-Q-R⁸The group of (a) or (b),

wherein

Q is a bond of the alkyl group,

wherein

r is a number of 0, and r is,

wherein the methyl, ethyl and isopropyl radicals may themselves be substituted by 1 or 2 substituents which are selected, independently of one another, from the group consisting of fluorine, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,

and is

A is N, and the content of the N,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is a number of 0 and,

R^4Ais hydrogen, fluorine, methyl, ethyl, hydroxyl or amino,

R^4Bis of the formula-Q-R⁸The group of (a) or (b),

wherein

Q is a bond of the alkyl group,

wherein

r is a number of 0, and r is,

R⁹and R¹⁰Each independently of the others hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,Azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or pyridinyl,

and is

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

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

The invention also provides a process for preparing the compounds of the formula (I) according to the invention, characterized in that

[A] Reacting a compound of formula (II)

M, R therein¹、R²、R⁶And R⁷Each having the meaning given above,

a cyclisation reaction with a compound of formula (III) in an inert solvent and in the presence of a suitable base to give a compound of formula (IV)

Wherein L has the meaning given above and

T¹is (C)₁-C₄) -alkyl radical

M, L, R therein¹,、R²、R⁶And R⁷Each having the meaning given above,

the compound of formula (IV) is then converted to a compound of formula (I-A) using isoamyl nitrite and a halogen equivalent in an inert solvent

M, L, R therein¹、R²、R⁶And R⁷Each having the meaning given above,

or

[B] Reacting a compound of formula (I-A) in an inert solvent and in the presence of a suitable transition metal catalyst to give a compound of formula (I-B)

M, L, R therein¹、R²、R⁶And R⁷Each having the meaning given above,

or

[C] Reacting a compound of formula (II) with a compound of formula (V) in an inert solvent and in the presence of a suitable base to give a compound of formula (VI)

Wherein L has the meaning given above,

R^3Ais hydrogen, halogen, (C)₁-C₄) -alkyl or hydroxy and

T²is (C)₁-C₄) -an alkyl group,

m, L, R therein¹、R²、R^3A、R⁶、R⁷And T²Each having the meaning given above,

the compound of formula (VI) is then converted to the compound of formula (VII) using phosphorus oxychloride

subsequently, the compound of formula (VII) is converted in an inert solvent into the corresponding azide which is directly reduced to the compound of formula (VIII)

then, the compound of formula (VIII) is reacted in an inert solvent and in the presence of a suitable base to give the compound of formula (I-C)

M, L, R therein¹、R²And R^3A、R⁶、R⁷Each having the meaning given above,

or

[D] Reacting a compound of formula (II) with hydrazine hydrate in an inert solvent and in the presence of a suitable base to give a compound of formula (IX)

M, R therein¹、R²、R⁶And R⁷Each having the meaning given above,

then, the compound of formula (IX) is reacted with the compound of formula (X) in an inert solvent to obtain the compound of formula (XI)

Wherein L has the meaning given above and

T³is (C)₁-C₄) -alkyl radical

M, L, R therein¹、R²、R⁶、R⁷And T³Each having the meaning given above, and then converting the compound of formula (XI) into a compound of formula (XII)

M, L, R therein¹、R²、R⁶、R⁷And T³Each having the meaning given above, and then reacting the compound of formula (XII) with ammonia directly to give the compound of formula (XIII)

M, L, R therein¹、R²、R⁶、R⁷And T³Each having the meaning given above,

finally, cyclisation of the compound of formula (XIII) in an inert solvent and optionally in the presence of a suitable base to give the compound of formula (I-D)

M, L, R therein¹、R²、R⁶And R⁷Each having the meaning given above,

the resulting compounds of the formulae (I-A), (I-B), (I-C) and (I-D) are then, if appropriate, converted into their solvates, salts and/or solvates of the salts with suitable (I) solvents and/or (ii) acids or bases.

The compounds of formulae (I-A), (I-B), (I-C) and (I-D) together form the group of compounds of formula (I) according to the invention.

Inert solvents used in process step (II) + (III) → (IV) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; ethers such as diethyl ether, dioxane (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, sulfolane or water. Mixtures of the solvents mentioned may also be used. Tert-butanol or methanol are preferred.

Suitable bases for step (II) + (III) → (IV) of the process are alkali metal hydroxides (e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g. lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate or potassium hydrogencarbonate), alkali metal alkoxides (e.g. sodium methoxide or potassium methoxide, sodium ethoxide or potassium tert-butoxide), or organic amines (e.g. triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)). Potassium tert-butoxide or sodium methoxide are preferred.

The reaction (II) + (III) → (IV) is usually carried out in a temperature range of +20 ℃ to +150 ℃, preferably +75 ℃ to +100 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure, elevated pressure or reduced pressure (e.g. 0.5 to 5 bar). The reaction is usually carried out at atmospheric pressure.

The process step (IV) → (I-a) being carried out in the presence or absence of a solvent. Suitable solvents are all organic solvents which are inert under the reaction conditions. The preferred solvent is dimethoxyethane.

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

Suitable halogen sources for the reaction (IV) → (I-a) are, for example, diiodomethane or cesium iodide, iodine and copper (I) iodide or ketone (II) bromide.

In the case of diiodomethane as halogen source, the process step (IV) → (I-a) is generally carried out using the following molar proportions: 10 to 30mol of isoamyl nitrite and 10 to 30mol of iodine equivalent based on 1mol of the compound of the formula (IV).

The inert solvent used in process step (I-a) → (I-B) is an alcohol 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), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or water. Mixtures of the solvents mentioned may also be used. DMF is preferred.

The reduction reaction (I-a) → (I-B) is carried out using hydrogen gas in combination with a transition metal catalyst such as palladium (10% on activated carbon), raney nickel or palladium hydroxide.

The reaction (I-a) → (I-B) is usually carried out in a temperature range of +20 ℃ to +50 ℃. The reaction may be carried out at atmospheric pressure or under pressure, for example in the range of 0.5 to 5 bar. The reaction is usually carried out at atmospheric pressure.

Inert solvents used in process step (II) + (V) → (VI) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; 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 or acetonitrile. Mixtures of the solvents mentioned may also be used. Methanol or ethanol is preferred.

Suitable bases for step (II) + (V) → (VI) of the process are alkali metal hydroxides (e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g. lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate or potassium hydrogencarbonate), alkali metal alkoxides (e.g. sodium methoxide or potassium methoxide, sodium ethoxide or potassium tert-butoxide), or organic amines (e.g. triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)). Sodium methoxide or sodium ethoxide is preferred.

The reaction (II) + (V) → (VI) is usually carried out in a temperature range of +50 ℃ to +120 ℃, preferably +50 ℃ to +100 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure or under pressure, for example in the range of 0.5 to 5 bar. The reaction is usually carried out at atmospheric pressure.

The conversions (VI) → (VII) and (XI) → (XII) may be carried out in a solvent which is inert under the reaction conditions, or in the absence of a solvent. The preferred solvent is sulfolane.

The reactions (VI) → (VII) and (XI) → (XII) are usually carried out at a temperature in the range of +70 ℃ to +150 ℃, preferably in the range of +80 ℃ to +130 ℃, optionally in microwaves. The conversion may be carried out at atmospheric pressure or at elevated pressure, for example in the range of from 0.5 to 5 bar. The reaction is usually carried out at atmospheric pressure.

Particularly preferably, the conversion (XI) → (XII) is carried out in the absence of a solvent at a temperature in the range from 0 ℃ to +50 ℃ and under atmospheric pressure.

The process step (VII) → (VIII) is carried out by reaction with sodium azide, an intermediate formation accompanied by an azide derivative which is directly further reduced to give the corresponding amine. Inert solvents for azide formation 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. DMF is preferred.

The azide formation is generally carried out at atmospheric pressure at a temperature in the range of from +50 ℃ to +100 ℃, preferably from +60 ℃ to +80 ℃.

The reduction reaction is carried out in an inert solvent, for example, an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol or 1, 2-ethylene glycol; 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 reduction is carried out at +10 ℃ to +30 ℃ using hydrogen in combination with a transition metal catalyst, such as palladium (10% on activated carbon), platinum dioxide or palladium hydroxide, or using stannous (II) chloride and hydrochloric acid instead of hydrogen.

Alternatively, the reaction (VII) → (VIII) can also be carried out in one step analogously to process steps (XII) → (XIII).

The cyclization reactions (VIII) → (I-C) and (XIII) → (I-D) are carried out in a solvent which is inert under the reaction conditions, for example, an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; ethers such as diethyl ether, dioxane, dimethoxyethane, Tetrahydrofuran (THF), 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. THF is preferred.

Suitable bases for the process steps (VIII) → (I-C) and (XIII) → (I-D) are alkali metal hydroxides (e.g. lithium, sodium or potassium hydroxide), alkali metal carbonates (e.g. lithium, sodium, potassium or cesium carbonate), alkali metal bicarbonates (e.g. sodium or potassium bicarbonate), alkali metal alkoxides (e.g. sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide), or organic amines (e.g. triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)). Potassium tert-butoxide is preferred.

The reactions (VIII) → (I-C) and (XIII) → (I-D) are usually carried out at a temperature in the range of from 0 ℃ to +50 ℃, preferably from +10 ℃ to +30 ℃, optionally in a microwave. The conversion may be carried out at atmospheric pressure or under pressure, for example in the range of from 0.5 to 5 bar. The reaction is usually carried out at atmospheric pressure.

Preferably, the cyclization reaction to (I-C) or (I-D) is carried out directly during the reduction of the azide to the corresponding amine (VIII) or during reaction (XII) → (XIII) without addition of further reagents.

In alternative steps of processes [ C ] and [ D ], the conversion (VII) → (VIII) → (I-C) or (IX) + (X) → (XI) → (XII) → (XIII) → (I-D) is carried out to isolate the intermediate.

Inert solvents used in process step (II) → (IX) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; 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 or acetonitrile. Mixtures of the solvents mentioned may also be used. Ethanol is preferred.

Suitable bases for step (II) → (IX) of the process are alkali metal hydroxides (e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g. lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate or potassium hydrogencarbonate), alkali metal alkoxides (e.g. sodium methoxide or potassium methoxide, sodium ethoxide or potassium tert-butoxide), or organic amines (e.g. triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)). Triethylamine is preferred.

The reaction (II) → (IX) is usually carried out in a temperature range of from 0 ℃ to +60 ℃, preferably from +10 ℃ to +30 ℃. The conversion may be carried out at atmospheric pressure or under pressure, for example in the range of from 0.5 to 5 bar. The reaction is usually carried out at atmospheric pressure.

Inert solvents used in process step (IX) + (X) → (XI) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; 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 or acetonitrile. Mixtures of the solvents mentioned may also be used. Methanol or ethanol is preferred.

The reaction (IX) + (X) → (XI) is usually carried out in a temperature range of +50 ℃ to +120 ℃, preferably +50 ℃ to +100 ℃, optionally in microwaves. The conversion may be carried out at atmospheric pressure or under pressure, for example in the range of from 0.5 to 5 bar. The reaction is generally carried out at atmospheric pressure.

The conversion (XI) → (XII) can be carried out in a solvent in which the reaction conditions are inert, or in the absence of a solvent. The preferred solvent is sulfolane.

The reaction (XI) → (XII) is usually carried out in a temperature range of +70 ℃ to +150 ℃, preferably +80 ℃ to +130 ℃, optionally in microwaves. The conversion may be carried out at atmospheric pressure or under pressure, for example in the range of from 0.5 to 5 bar. The reaction is usually carried out at atmospheric pressure.

Particularly preferably, the conversion (XI) → (XII) is carried out in the absence of solvent at a temperature in the range from 0 ℃ to +50 ℃ and under atmospheric pressure.

The process step (XII) → (XIII) being carried out in a solvent in which the reaction conditions are inert. Suitable solvents are, for example, 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. Acetonitrile is preferred.

The reaction (XII) → (XIII) is usually carried out at a temperature in the range of +20 ℃ to +100 ℃, preferably in the range of +40 ℃ to +70 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure or under pressure, for example in the range of 0.5 to 5 bar. Generally, the reaction is carried out at atmospheric pressure.

The cyclization reaction (XIII) → (I-D) is carried out in a solvent which is inert to the reaction conditions, for example, an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol; ethers such as diethyl ether, dioxane, dimethoxyethane, Tetrahydrofuran (THF), 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. THF is preferred.

Suitable bases for step (XIII) → (I-D) of the process are alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate or potassium hydrogencarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Potassium tert-butoxide is preferred.

The reaction (XIII) → (I-D) is usually carried out in a temperature range of from 0 ℃ to +50 ℃, preferably from +10 ℃ to +30 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure or at elevated pressure, for example in the range of from 0.5 to 5 bar. Generally, the reaction is carried out at atmospheric pressure.

The reaction (XI) → (XII) → (XIII) → (I-D) is preferably carried out simultaneously in a one-pot reaction without isolating the intermediates.

The preparation can be illustrated in an exemplary manner by the following synthetic schemes (schemes 1 to 3):

scheme 1:

refluxing potassium tert-butoxide and tert-butanol; b is isoamyl nitrite, diiodomethane, 85 deg.C, C is Pd-C (10%), hydrogen and DMF.

Scheme 2

[a):NaOMe,MeOH;b):POCl₃Sulfolane, c) NaN₃,DMF;d):Pd/C,H₂,DMF;e)KOt-Bu,THF]。

Scheme 3

[ a ] hydrazine hydrate, NEt3, EtOH b) EtOH c) POCl₃D) concentrated NH₃]。

The compounds of the formulae (III), (V) and (X) are commercially available, known from the literature or can be prepared by methods analogous to the literature methods.

The compounds of formula (II) are known from the literature (see, for example, WO 2010/065275) or can be prepared by the following steps: converting a compound of formula (XIV) to a compound of formula (XV) in an inert solvent and in the presence of a suitable halogenating agent

M, R therein¹、R²、R⁶And R⁷Each having the meaning given above,

m, R therein¹、R²、R⁶And R⁷Each having the meaning given above and X¹Is a halogen, in particular bromine or iodine,

then reacting the compound of formula (XV) in an inert solvent to obtain the compound of formula (XVI)

M, R therein¹、R²、R⁶And R⁷Each having the meaning given above,

subsequently, the compound of formula (XVI) is converted in an inert solvent into a compound of formula (II)

M, R therein¹、R²、R⁶And R⁷Each having the meaning given above.

Suitable inert solvents for the halogenation reaction (XIV) → (XV) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene or chlorobenzene; 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. Dichloromethane is preferred.

Suitable brominating agents for process step (XIV) → (XV) are elemental bromine and acetic acid, 1,3-dibromo-5,5-dimethylhydantoin (1, 3-dibromo-5, 5-dimethylhydantoin) and-in particular-N-bromosuccinimide (NBS).

A particularly suitable iodinating agent for process step (XIV) → (XV) is N-iodosuccinimide (NIS).

The halogenation reaction (XIV) → (XV) is usually carried out at a temperature in the range of-10 ℃ to +50 ℃, preferably 0 ℃ to +30 ℃. The conversion may be carried out at atmospheric pressure, elevated pressure or reduced pressure, for example in the range of from 0.5 to 5 bar. The reaction is usually carried out at atmospheric pressure.

Inert solvents used in process step (XV) → (XVI) are, for example, 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), N-methylpyrrolidone (NMP), pyridine or acetonitrile. Mixtures of the solvents mentioned may also be used. DMSO is preferred.

The reaction (XV) → (XVI) is usually carried out at a temperature in the range of +20 ℃ to +180 ℃, preferably in the range of +100 ℃ to +160 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure, elevated pressure or reduced pressure (e.g. in the range of 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

The reaction (XVI) → (II) is carried out in a two-stage process using methods known to the person skilled in the art: the amidine (VII) is formed by first formation of the iminoester(s) with sodium methoxide in methanol at 0 ℃ to +40 ℃ followed by nucleophilic addition of an ammonia equivalent (e.g. aqueous ammonia or ammonium chloride) in acetic acid at +50 ℃ to +150 ℃.

The preparation can be illustrated in an exemplary manner by the following synthetic scheme (scheme 4):

scheme 4:

n-bromosuccinimide and dichloromethane; b) copper (I) cyanide, DMSO,170 ℃, C) 1 sodium methoxide, methanol, 2 NH₄Cl, acetic acid, reflux]。

The compound of formula (XIV) may be prepared by the following steps: cyclizing the compound of formula (XVII) with hydrazine hydrate in an inert solvent and in the presence of a suitable base to give the compound of formula (XVIII)

Wherein

T⁵Is (C)₁-C₄) -alkyl radical

The compound of formula (XVIII) is then reacted with a compound of formula (XIX) in an inert solvent and in the presence of a suitable base to give a compound of formula (XX)

Wherein R is¹Have the meanings given above and

X²is a halogen, in particular chlorine or bromine,

wherein R is¹Having the meaning given above, the inventors have found that,

then oxidizing the compound of formula (XX) to obtain a compound of formula (XXI)

Wherein R is¹Having the meaning given above, the inventors have found that,

furthermore, cyclisation of a compound of formula (XXI) with phosphorus oxychloride in the absence of a solvent or in an inert solvent gives a compound of formula (XXII)

Wherein R is¹Having the meaning given above, the inventors have found that,

finally, the compound of formula (XXII) is hydrogenated in an inert solvent and in the presence of a suitable base.

The compounds of the formulae (XVII) and (XVIII) are commercially available, known from the literature or can be prepared analogously to literature methods.

The inert solvent used in process step (XVII) → (XVIII) is an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; 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), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. Mixtures of the solvents mentioned may also be used. Ethanol is preferred.

Suitable bases for step (XVII) → (XVIII) of the process are alkali metal hydroxides (e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g. lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate or potassium hydrogencarbonate), alkali metal alkoxides (e.g. sodium methoxide or potassium methoxide, sodium ethoxide or potassium tert-butoxide), or organic amines (e.g. triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)). Triethylamine is preferred.

The reaction (XVII) → (XVIII) is usually carried out at a temperature in the range of +20 ℃ to +150 ℃, preferably in the range of +80 ℃ to +120 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure, elevated pressure or reduced pressure (e.g. in the range of 0.5 to 5 bar). The reaction is usually carried out at atmospheric pressure.

The inert solvents used in process step (XVIII) + (XIX) → (XX) are ethers such as diethyl ether, dioxane, tetrahydrofuran, glyme or diglyme; hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene or chlorobenzene; 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. Acetonitrile is preferred.

Suitable bases for step (XVIII) + (XIX) → (XX) of the process are alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate, or organic amines, such as triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Triethylamine is preferred.

The reaction (XVIII) + (XIX) → (XX) is usually carried out in a temperature range of-20 ℃ to +40 ℃, preferably 0 ℃ to +20 ℃. The reaction may be carried out at atmospheric pressure, elevated pressure or reduced pressure (e.g. in the range of 0.5 to 5 bar). The reaction is usually carried out at atmospheric pressure.

The oxidation reaction (XX) → (XXI) is preferably carried out in an organic acid (e.g. formic acid or acetic acid) and in the presence of elemental bromine at a temperature of +40 ℃ to +100 ℃.

The cyclization reaction (XXI) → (XXII) is carried out in the absence of a solvent or in a solvent in which the reaction conditions are inert. Suitable solvents are, for example, 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, sulfolane or acetonitrile. Sulfolane is preferably used.

The cyclization reaction (XXI) → (XXII) is usually carried out in a temperature range of +50 ℃ to +140 ℃, preferably +80 ℃ to +120 ℃. The reaction may be carried out at atmospheric pressure, elevated pressure or reduced pressure (e.g. in the range of 0.5 to 5 bar). The reaction is usually carried out at atmospheric pressure.

The process step (XXII) → (XIV) being carried out in a solvent which is inert to the reaction conditions, for example, an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; 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 ethyl acetate, Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, sulfolane or acetonitrile. Preferably, ethyl acetate is used.

Suitable bases for the process step (XXII) → (XIV) are organic amines, for example triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Triethylamine is preferred.

The cyclization reaction (XXII) → (XIV) is usually carried out at a temperature in the range of from 0 ℃ to +60 ℃, preferably from +10 ℃ to +30 ℃.

The following scheme (scheme 5) shows the above preparation method in an exemplary manner:

scheme 5

Refluxing hydrazine hydrate, triethylamine and ethanol; b) the catalyst comprises (2-fluorophenyl) acetyl chloride, triethylamine and acetonitrile, C) bromine, acetic acid, 50 ℃, d) phosphoryl chloride, sulfolane, 100 ℃, e) palladium carbon (5 percent), triethylamine, hydrogen and ethyl acetate.

The group of compounds of the invention can be used as potent stimulators of soluble guanylate cyclase and have the same or improved therapeutic properties compared to the compounds known from the prior art, for example in terms of their in vivo properties, such as their pharmacokinetic and pharmacodynamic profile and/or their dose-activity relationship and/or their safety profile. 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 increased intracellular cGMP. In addition, the compound of the present invention enhances the effect of a substance which can increase the cGMP level, such as EDRF (endothelial cell derived relaxation factor), NO donor, protoporphyrin ix, arachidonic acid, or phenylhydrazine derivative.

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

Thus, the compounds of the present invention may be used in medicaments for the following uses: for the treatment and/or prophylaxis of cardiovascular disorders, 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 disease (pericarditis, endocarditis, valvulitis, aortic inflammation, myocardial disease), 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 disorders, coronary and peripheral arterial spasm, edema formation (e.g., 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 acute and chronic forms of heart failure, and more specific or related types of disease, such as acute decompensated heart failure, right heart failure, left heart failure, total heart failure (global failure), ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart failure 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 toxic cardiomyopathy, heart storage disease (cardiac disease), Diastolic heart failure and systolic heart failure, as well as the acute exacerbation phase of existing chronic heart failure (exacerbated heart failure).

In addition, the compounds of the present invention are useful in the treatment and/or prevention of arteriosclerosis, impaired lipid metabolism, hypolipidaemia, dyslipidaemia, hypertriglyceridaemia, hyperlipidaemia, hypercholesterolaemia, abetalipoproteinemia, sitosterolemia, xanthomatosis, Dangill's disease, 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 extremity ulcers, gangrene, CREST syndrome, systemic lupus erythematosus (erythrematosis), onychomycosis, rheumatism, 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 diseases, including neurogenic overactive bladder (OAB) and (IC), incontinence (UI), such as mixed, urge, stress or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant disorders 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" encompasses acute and chronic manifestations of renal insufficiency, and also encompasses potential or related renal diseases, such as insufficient renal blood flow perfusion, dialysis-related hypotension (intrarenal hypertension), obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, renal disorders (neuropathic disorders) such as primary and congenital renal diseases, nephritis, immune renal diseases (such as renal transplant rejection and immune complex-induced nephropathy, toxic substance-induced nephropathy, contrast agent-induced nephropathy), diabetic and non-diabetic renal diseases, pyelonephritis, renal cysts, renal sclerosis, hypertensive nephrosclerosis, and nephrotic syndromes 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 of 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 Pulmonary Arterial Hypertension (PAH) and other forms of Pulmonary Hypertension (PH), including pulmonary hypertension associated with left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or pulmonary fibrosis, Chronic Obstructive Pulmonary Disease (COPD), Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), alpha 1 antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema, e.g. 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 a disturbance of the NO/cGMP system. More specifically, they are suitable for improving perception, attention-focusing ability, learning ability or memory after cognitive disorders such as those occurring in particular in the following conditions/diseases/syndromes: such as mild cognitive impairment, age-related learning and memory disorders, age-related memory loss, vascular dementia, craniocerebral injury, stroke, dementia that occurs after stroke (post-stroke dementia), post-traumatic craniocerebral injury, global disorders of attention concentration, disorders of attention concentration in children with learning and memory difficulties, alzheimer's disease, lewy body dementia, dementia with degeneration of the frontal lobe (including pick's syndrome, parkinson's disease, progressive nuclear palsy), dementia with degeneration of the basal ganglia, amyotrophic lateral sclerosis (amyoplaral sclerosis, ALS), huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or korsakoff's psychosis. They are also suitable for the treatment and/or prevention of disorders of the central nervous system, such as anxiety, stress and depression states, CNS-related sexual dysfunctions and sleep disorders, and of pathological disorders which control the intake of food, stimulants and addictive drugs.

Furthermore, the compounds of the present invention are also suitable for modulating cerebral blood flow and are therefore effective agents for controlling migraine. They are also suitable for the prevention and control of sequelae of cerebral infarction (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 according to the invention are suitable for the treatment and/or prophylaxis of fibrotic disorders of internal organs, such as the lung, the heart, the kidney, the bone marrow and in particular the liver, and of dermatological fibrosis and of the eye. In the context of the present invention, the term "fibrotic disorder" specifically encompasses 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 disorders, scleroderma, maculopathy, keloids, hypertrophic scars (including post-surgical hypertrophic scars), nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorders (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 may also be used cosmetically for aging and keratinizing skin.

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

The present invention also provides the use of a compound of the invention for the treatment and/or prevention of diseases, in particular the disorders mentioned above.

The invention also provides the use of a compound of the invention for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal insufficiency, thromboembolic disorders, fibrous disorders and arteriosclerosis.

The invention also provides the use of a compound of the invention in a method of treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal failure, thromboembolic disorders, fibrous disorders, and arteriosclerosis.

The invention also provides the use of a compound of the invention for the preparation of a medicament for the treatment and/or prevention of diseases, in particular the disorders mentioned above.

The invention also provides the use of a compound of the invention for the preparation of a medicament for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal failure, thromboembolic disorders, fibrous disorders and arteriosclerosis.

The invention also provides methods of treating and/or preventing diseases, in particular the above-mentioned conditions, using an effective dose of at least one compound of the invention.

The invention also provides methods of treating and/or preventing heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal failure, thromboembolic disorders, fibrous disorders, and arteriosclerosis, using an effective dose of at least one compound of the invention.

The compounds of the invention can be used alone or, if desired, in combination with other active substances. The invention also provides medicaments comprising at least one compound according to the invention and one or more further active substances, in particular active substances for the treatment and/or prophylaxis of the abovementioned conditions. Preferred examples of suitable active compound 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;

antithrombotic agents, such as and preferably platelet aggregation inhibitors, anticoagulants or fibrinolysins (proteolytic substances);

hypotensive 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, PPAR-gamma and/or PPAR-agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid resorption inhibitors and lipoprotein (a) antagonists.

An antithrombotic agent should preferably be understood as meaning a compound selected from platelet aggregation inhibitors, anticoagulants or fibrinolytics.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a platelet aggregation inhibitor, 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), melagatran (melagatran), bivalirudin (bivalirudin) or clexase (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 (BAY 59-7939), 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, DX9065a, DPC906, JTV803, 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.

Hypotensive agents are preferably understood to mean compounds 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 (bunanol), 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 (caridiolol), cardenolol (cardiolol), adapalolol (celandiolol), landiolol (anetholol), or anetholol (anetholol).

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 emblosartan (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), SPP600 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).

A regulating agent of lipid metabolism is preferably understood to mean a compound selected from the group consisting of: CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, 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, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or 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), paratubib (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, implitapide (impliptaide), BMS201038, R103757 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, GW501516 or BAY 685042.

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 pamaquide (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), colestipol (colesevivam), cholestel (colestigel) 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, for example AZD7806, S8921, AK105, bali 1741, SC435 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 gemcabenecacalcium (CI 1027) or niacin.

The present invention also provides a pharmaceutical product comprising at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and its use for the purposes mentioned above.

The compounds of the invention may have systemic and/or local effects. For this purpose, it can be administered in a suitable manner, for example by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as a graft or stent.

The compounds of the invention may be administered in forms of administration suitable for these routes of administration.

Suitable administration forms for oral administration are those which function according to the prior art, release the compounds according to the invention rapidly and/or in a gentle manner and contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example with coatings resistant to gastric juice or coatings which delay dissolution or are insoluble and control the release of the compounds according to the invention), tablets which disintegrate rapidly in the oral cavity or films/tablets (oblate), films/lyophilisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out while avoiding an absorption step (e.g., by intravenous, intraarterial, intracardiac, intraspinal or lumbar intramedullary routes) or involving absorption (e.g., by intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal routes). Formulations suitable for parenteral administration include preparations for injection and infusion 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, solutions or sprays; tablets, films/slabs or capsules for lingual, sublingual or buccal administration; suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking suspensions), lipophilic suspensions, ointments, creams (creams), transdermal therapeutic systems (e.g. patches), milks, pastes, foaming agents, sprinkles (sprinklingpowder), implants or stents.

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

The compounds of the invention can be converted into the administration forms mentioned above. This can be carried out in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable auxiliaries. These include, inter alia, carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants 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, e.g. ascorbic acid), dyes (e.g. inorganic pigments, e.g. iron oxides) and also flavourings and/or flavours.

In general, it has been found advantageous to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5mg/kg body weight for parenteral administration to achieve effective results. For oral administration, the dosage is about 0.001 to 2mg/kg, preferably about 0.001 to 1mg/kg body weight.

However, where appropriate, it may be necessary to deviate from the stated dosage, in particular with regard to body weight, route of administration, individual response to the active compound, nature of the preparation and time or interval over which the administration takes place. For example, in some cases it may be sufficient to fall below the minimum amount mentioned above, while in other cases the upper limit must be exceeded. When relatively large amounts are administered, it is advisable to divide these doses into several individual doses during the day.

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

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

A.Examples

Abbreviations and acronyms:

aq. aqueous solution

calc calculated value

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 spectrometry

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 spectroscopy

Pd₂dba₃Tris (dibenzylideneacetone) dipalladium

Ph phenyl

RT Room temperature

R_tRetention time (in HPLC)

THF tetrahydrofuran

UV ultraviolet spectrum

volume ratio v/v (of solution)

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

LC/MS method:

method 1(LC-MS):

the instrument comprises the following steps: waters ACQUITY SQD UPLC system; column: waters Acquity UPLC HSS T31.8 μ 50x1 mm; mobile phase a1 liter of water +0.25ml of 99% strength formic acid, mobile phase B:1 l of acetonitrile +0.25ml of 99% strength formic acid; gradient: 0.0 min 90% a → 1.2 min 5% a → 2.0 min 5% a; the temperature of the oven is 50 ℃; flow rate: 0.40 ml/min; and (4) UV detection: 210-400 nm.

Method 2(LC-MS):

the instrument comprises the following steps: micromass Quattro Premier equipped with Waters UPLC Acquity; column: ThermoHypersil GOLD1.9 μ 50mm x1 mm; mobile phase A is 1 liter of water and 0.5ml of 50 percent formic acid, and mobile phase B is 1 liter of acetonitrile and 0.5ml of 50 percent formic acid; gradient: 0.0 min 97% a → 0.5 min 97% a → 3.2 min 5% a → 4.0 min 5% a; oven temperature: 50 ℃; flow rate: 0.3 ml/min; and (4) UV detection: 210 nm.

Method 3 (LC-MS):

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

Raw materials and intermediates:

example 1A

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

200.00g (1.101mol) of methyl 5-amino-4-oxopentanoate hydrochloride were initially taken in ethanol (3500ml), 64.28ml (1.321mol) of hydrazine hydrate were added, and the mixture was heated under reflux for 45 minutes. After cooling, triethylamine (152ml) was added and the resulting mixture was evaporated to dryness. Water (500ml) was added to the residue and the resulting mixture was concentrated. Ethanol (500ml) was then added and the resulting mixture was concentrated, followed by the addition of toluene (500ml) twice, each time followed by evaporation to dryness. The resulting residue (140g) was dissolved in acetonitrile (500ml), which was then slowly added to a solution of 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 at 0 ℃. The resulting mixture was stirred at 20 ℃ for 3 days. The resulting mixture was then filtered and the resulting 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=0.57 min, MS (EIpos) M/z =264[ M + H =]⁺。

Example 2A

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

458g (1.740mol) of the compound obtained in example 1A were initially introduced into acetic acid (2250ml), and the mixture was heated to 50 ℃. At this temperature, 98.16ml (1.914mol) of bromine were added dropwise with vigorous stirring, and stirring was then continued at 50 ℃ for 3 hours. After cooling, the resulting reaction mixture was concentrated to dryness. The resulting residue was stirred with a saturated aqueous solution of sodium bicarbonate (4800 ml). The resulting mixture was then filtered and the resulting precipitate was washed with a small amount of water. The resulting filtrate was extracted twice with ethyl acetate. The resulting organic phases were combined, dried and concentrated. 117g of the expected compound (25% of theory) are obtained.

LC-MS (method 1) R_t=0.56 min, 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 3A

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

65.00g (248.79mmol) of the compound obtained in example 2A were initially introduced into sulfolane (780ml), 185.52ml (1.990mol) of phosphorus oxychloride were added and the mixture was heated to 100 ℃ for 3 hours. Excess phosphorus oxychloride was then distilled off under high vacuum, and the resulting residue was dissolved with ethyl acetate and added to saturated aqueous sodium bicarbonate solution. The resulting mixture was diluted with water and then extracted with ethyl acetate. The resulting organic phases were combined, washed with water, dried over sodium sulfate and concentrated. The resulting residue was chromatographed over silica gel (mobile phase: dichloromethane/methanol 20:1 → 5:1 (v/v)), then washed with water and chromatographed over 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=1.00 min, 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 4A

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

2.004g of palladium on carbon (5%) are initially introduced under argon, followed by 20.04g (76.58mmol) of the compound obtained in example 3A dissolved in ethyl acetate (750 ml). 21.348ml (153.159mmol) of triethylamine are then added and the resulting reaction mixture is hydrogenated under standard hydrogen pressure at 20 ℃ for 16 hours. The catalyst was then added in the same amount as above and the resulting reaction mixture was then hydrogenated at 20 ℃ overnight under standard hydrogen pressure. The resulting mixture was then filtered through Celite (Celite), the resulting filter cake was washed with ethanol, and the resulting filtrate was concentrated and dried under high vacuum. 22.79g of the expected compound (about 100% of theory, contamination with triethylamine) are obtained.

LC-MS (method 1) R_t=0.77 min, 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 5A

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

22.46g (98.837mmol) of the compound obtained in example 4A were initially taken in dichloromethane (400ml) and 17.591g (98.837mmol) of N-bromosuccinimide were then added. The resulting mixture was then stirred at 20 ℃ for 10 minutes. Water was then added to the resulting reaction mixture, the phases were separated and the resulting organic phase was washed with water. The resulting 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_t=1.05 min, MS (EIpos) M/z =306,308[ M + H, bromo form]⁺。

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 6A

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

1.00g (3.266mmol) of the compound obtained in example 5A were initially introduced into dry DMSO (25ml), 1.170g (13.066mmol) of copper (I) cyanide were added and the mixture was heated at 170 ℃ for 3.5 h with stirring. The resulting mixture was filtered through celite, and the resulting filter cake was then washed with ethyl acetate and tetrahydrofuran. The filtrate was then extracted four times with a mixture (3:1, v/v) of saturated aqueous ammonium chloride/aqueous ammonia (33%) and washed once with saturated aqueous sodium chloride. The phases were separated and the resulting organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated with ethanol in an ultrasonic bath, and 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=0.95 min, 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 7A

7- (2-Fluorobenzyl) imidazo [1,5-b ] pyridazine-5-carboxamidine acetate

584mg (2.315mmol) of the compound prepared in example 6A was added to 125mg (2.315mmol) of sodium methoxide dissolved in methanol (10ml), and the resulting mixture was stirred at 20 ℃ for 16 hours. Then 148mg (2.778mmol) of ammonium chloride and acetic acid (0.517ml) were added and the resulting mixture was heated under reflux for 8 hours. The resulting reaction mixture was then concentrated to dryness, and the resulting residue was dissolved with water and ethyl acetate and a 1N aqueous solution of sodium hydroxide were added. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, concentrated and then dried under high vacuum. 543mg of the expected compound (71% of theory) are obtained.

LC-MS (method 1) R_t=0.63 min, MS (EIpos) M/z =270[ M + H [ ]]⁺。

Example 8A

3, 3-dicyano-2, 2-dimethylpropionic acid methyl ester

3g (45.411mmol) of malononitrile dissolved in THF (91ml) were slowly added to 1.816g (45.411mmol) of sodium hydride (60% in mineral oil). Subsequently, 5.876ml (45.411mmol) methyl 2-bromo-2-methylpropionate were added, and the resulting mixture was stirred at 20 ℃ for 16 hours. An additional 5.876ml (45.411mmol) methyl 2-bromo-2-methylpropionate were then added and the resulting mixture was heated at 50 ℃ for 16 hours. A further 1.762ml (13.623mmol) of methyl 2-bromo-2-methylpropionate were then added and the mixture was heated at 50 ℃ for a further 4 hours. Saturated aqueous sodium bicarbonate was then added and the resulting reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. 8.9g of crude product are obtained, which is purified by chromatography on silica gel (cyclohexane-ethyl acetate 4: 1).

Yield 6.47g (85% of theory)

1H NMR(400MHz,DMSO-d6):[ppm]=1.40(s,6H),3.74(s,3H),5.27(s,1H)。

Example 9A

4-amino-2- [7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazin-5-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

543mg (1.649mmol) of example 7A are initially introduced into tert-butanol (30ml) and 222mg (1.979mmol) of potassium tert-butoxide are added. Subsequently, 301mg (1.979mmol) of example 8A dissolved in tert-butanol (20ml) were added dropwise and the resulting mixture was heated at reflux for 2 hours. After cooling, water was added and the resulting mixture was extracted three times with ethyl acetate. The combined organic phases were concentrated and a small amount of ethyl acetate and a few drops of ethanol were added to the residue. Then diethyl ether was added. A precipitate formed. The precipitate was filtered off. Drying under high vacuum results in 290mg of the expected compound (43% of theory).

LC-MS (method 1) R_t=0.85 min, MS (EIpos) M/z =404[ M + H]⁺。

¹H NMR(400MHz,DMSO-d6):[ppm]=1.32(s,6H),4.49(s,2H),6.66(s br,2H),6.95(dd,1H),7.12-7.22(m,2H),7.24-7.33(m,2H),8.41(dd,1H),8.98(dd,1H),10.86(sbr,1H)。

Example 10A

7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazin-5-ylmethylether hydrazide

1.600g (4.858mmol) of example 7A are dissolved in 40ml of ethanol, and 1.966g (19.433mmol) of triethylamine and 304mg (4.858mmol) of hydrazine hydrate (80% strength in water) are added at 0 ℃. The resulting mixture was stirred at room temperature overnight and then concentrated. The resulting residue was used in the next step without further purification. 1.63g (73% of theory, purity 62%) of the title compound are obtained.

LC-MS (method 2) R_t=1.43 min, MS (ESIpos) M/z =285(M + H)⁺

Example 11A

2- {3- [7- (2-Fluorobenzyl) imidazo [1,5-b ] pyridazin-5-yl ] -5-hydroxy-1, 2, 4-triazin-6-yl } -2-methylpropionic acid methyl ester

1.010g (5.366mmol) dimethyl 2, 2-dimethyl-3-oxosuccinate (described in J.Am.chem.Soc.124(14),3680-3691;2002) are initially taken up in 30ml of ethanol and heated to reflux. 1.630g (approx. 3.577mmol) of the compound obtained in example 10A are added slowly dropwise in the form of a suspension in 30ml of ethanol. The resulting mixture was heated to reflux overnight. After concentration, the resulting residue was used in the next step without further purification. 2.00g (40% of theory, purity 30%) of the title compound are obtained.

LC-MS (method 1) R_t=1.01 min, MS (ESIpos): M/z =423(M + H)⁺

Example 12A

6-chloro-1-iodo-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridine

The title compound was prepared using procedures analogous to those in WO2010/065275, example 58, pages 46-48.

LC-MS (method 1) R_t=1.24 min, MS (ESIpos) M/z =423(M + H)⁺

Example 13A

6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridine-1-carbonitrile

10.00g (23.664mmol) of example 12A and 2.331g (26.031mmol) of copper (I) cyanide are stirred in DMSO at 150 ℃ for 5 hours. The resulting mixture was filtered through celite, the resulting cake was washed with ethyl acetate, and the resulting filtrate was extracted four times with a 3:1 mixture of saturated aqueous ammonium chloride and concentrated aqueous ammonia (33%). The resulting mixture was then washed with saturated aqueous sodium chloride solution, the phases were separated and the organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was dried under high vacuum overnight. 7.30g of the title compound (95% of theory) are obtained.

LC-MS (method 3) R_t=1.09 min, MS (ESIpos) M/z =322(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]=4.56(s,2H),7.18-7.24(m,1H),7.36(d,1H),7.48-7.57(m,1H),7.87(d,1H),9.00(s,1H)。

Example 14A

6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridine-1-carboxamidine

3.98g (12.372mmol) of example 13A were reacted in a similar procedure to that of step H of WO2010/065275, example 58, page 49. 3.54g of the title compound (84% of theory) are obtained.

LC-MS (method 1) R_t=0.66 min, MS (ESIpos) M/z =339(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]=4.61(s,2H),7.18-7.24(m,1H),7.47-7.57(m,2H),8.08(d,1H),8.79(br d,3H),9.03(s,1H)。

Practice ofExample 15A

4-amino-2- [ 6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridin-1-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

This compound is described in WO2010/065275, example 59, page 52. From 500mg of example 14A 607mg of the title compound are obtained (86% of theory).

LC-MS (method 2) R_t=1.95 min, MS (ESIpos): M/z =473(M + H)⁺

Example 16A

6-fluoro-1-iodo-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridine

The title compound was prepared using procedures analogous to those of example 12A.

LC-MS (method 3) R_t=1.24 min, MS (ESIpos) M/z =409(M + H)⁺

Example 17A

6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridine-1-carbonitrile

10.00g (24.505mmol) of example 16A were reacted in a similar procedure to that of example 13A. 6.98g of the title compound (92% of theory) are obtained.

LC-MS (method 3) R_t=1.07 min, MS (ESIpos) M/z =308(M + H)⁺

Example 18A

6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridine-1-carboxamidine

3.810g (12.402mmol) of example 17A were reacted in a similar procedure to that of example 14A. 2.95g of the title compound (73% of theory) are obtained.

LC-MS (method 1) R_t=0.64 min, MS (ESIpos) M/z =325(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]2.83-2.97(m,2H),2H presumes 7.53-7.58(m,1H),8.16(dd,1H),8.85(s br,3H),8.92(dd,1H) under the water signal.

Example 19A

4-amino-2- [ 6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridin-1-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

This compound is described in WO2010/065275, example 109, page 64. This compound was prepared using a procedure analogous to that of example 15A.

LC-MS (method 2) R_t=1.92 min, MS (ESIpos) M/z =459(M + H)⁺

Example 20A

6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridine-1-carboxamidine hydrazide

1.700g (5.019mmol) of the compound from example 14A are dissolved in 35ml of ethanol and 2.031g (20.075mmol) of triethylamine and 0.314g (5.019mmol) of hydrazine hydrate (80% strength in water) are added at 0 ℃. The resulting mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. Crude compound (2.08g, 86% of theory, purity 73%) was obtained, which was directly subjected to further reaction.

LC-MS (method 3) R_t=0.65 min, MS (ESIpos) M/z =354(M + H)⁺

Example 21A

2- {3- [ 6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridin-1-yl ] -5-hydroxy-1, 2, 4-triazin-6-yl } -2-methylpropionic acid methyl ester

1.222g (6.492mmol) of dimethyl 2, 2-dimethyl-3-oxosuccinate (described in J.Am.chem.Soc.124(14),3680-3691;2002) dissolved in 30ml of ethanol are heated to reflux. The crude substrate from example 20A (about 4.328mmol) was then dissolved in 20ml ethanol and added dropwise. The resulting mixture was heated at reflux overnight. After cooling, the solid is filtered off with suction and washed with ethanol, and the filtrate obtained is concentrated. The residue obtained is treated with diethyl ether for 30 minutes with stirring, and the precipitate formed is then filtered off and washed with diethyl ether. The solid was dried under high vacuum overnight. 1.67g of the title compound (55% of theory, purity 71%) are obtained.

LC-MS (method 1) R_t=1.07 min, MS (ESIpos): M/z =492(M + H)⁺

Example 22A

6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridine-1-carboxamidine hydrazide

1.400g (4.318mmol) of the compound from example 18A are dissolved in 30ml of ethanol and then 1.748g (17.272mmol) triethylamine and 0.270g (4.318mmol) hydrazine hydrate (80% strength in water) are added at 0 ℃. The resulting mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. Crude compound (1.70g, 86% of theory, purity 74%) was obtained, which was directly subjected to further reaction.

LC-MS (method 3) R_t=0.65 min, MS (ESIpos) M/z =340(M + H)⁺

Example 23A

2- {3- [ 6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridin-1-yl ] -5-hydroxy-1, 2, 4-triazin-6-yl } -2-methylpropionic acid methyl ester

1.047g (5.562mmol) of dimethyl 2, 2-dimethyl-3-oxosuccinate (described in J.Am.chem.Soc.124(14),3680-3691;2002) dissolved in 20ml of ethanol are heated to reflux. The crude substrate from example 22A (about 3.708mmol) was then suspended in 20ml of ethanol and added dropwise. The resulting mixture was heated at reflux overnight, then concentrated after cooling. The residue obtained is treated with diethyl ether for 30 minutes with stirring, and the precipitate formed is filtered off and washed with diethyl ether. The solid was dried under high vacuum overnight. 1.49g of the title compound (54% of theory, purity 64%) are obtained.

LC-MS (method 3) R_t=1.10 min, MS (ESIpos) M/z =478(M + H)⁺

Working examples

Example 1

2- [7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazin-5-yl ] -4-iodo-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

215mg (0.535mmol) of example 9A were initially added to isoamyl nitrite (1.548ml) and diiodomethane (4.045ml), and the resulting mixture was heated to 85 ℃ for 3 hours. After cooling, the resulting reaction mixture was concentrated, and the resulting residue was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 79mg (28% of theory) of the title compound and 20mg of example 2 are obtained.

LC-MS (method 1) R_t=1.11 min, MS (EIpos) M/z =515[ M + H]⁺。

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.40(s,6H),4.52(s,2H),6.95(dd,1H),7.12-7.33(m,5H),8.51(dd,1H),8.72(dd,1H),11.64(sbr,1H)。

Example 2

2- [7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazin-5-yl ] -4-hydroxy-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

215mg (0.535mmol) of example 9A were initially added to isoamyl nitrite (1.548ml) and diiodomethane (4.045ml), and the resulting mixture was heated to 85 ℃ for 3 hours. After cooling, the resulting reaction mixture was concentrated, and the resulting residue was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 20mg (9% of theory) of the title compound and 79mg of example 1 are obtained.

LC-MS (method 1) R_t=0.90 min, MS (EIpos) M/z =405[ M + H [ ]]⁺。

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.31(s,6H),4.55(s,2H),7.12(t,1H),7.18-7.23(m,2H),7.30-7.36(m,2H),8.58(dd,1H),8.63(d,1H),10.95(s br,1H),11.52(s br,1H)。

Example 3

2- [7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazin-5-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

32mg of palladium on carbon (10%) are added to 75mg (0.146mmol) of example 1 dissolved in dimethylformamide (10ml), and the resulting mixture is then hydrogenated under standard hydrogen pressure at 20 ℃ for 4 hours. After filtration through celite, the resulting product was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 30mg of the expected compound (53% of theory) are obtained.

LC-MS (method 1) R_t=0.86 min, MS (EIpos) M/z =389[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.35(s,6H),4.51(s,2H),7.04(dd,1H),7.12-7.23(m,2H),7.28-7.35(m,2H),8.46(dd,1H),8.51(s,1H),8.88(dd,1H),11.45(s br,1H)。

Example 4

3- [7- (2-fluorobenzyl) imidazo [1,5-b ] pyridazin-5-yl ] -7, 7-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-e ] [1,2,4] triazin-6-one

4.991ml of phosphorus oxychloride were added to 1.00g (0.733mmol) of the compound of example 12A, and the resulting mixture was stirred at room temperature overnight. The resulting reaction mixture was added to 48ml of acetonitrile, and then added dropwise to 30.29ml of a concentrated aqueous ammonia solution (33% concentration) under ice-cooling. The resulting mixture was stirred at room temperature for 3 days. The resulting mixture was then concentrated to dryness. The residue obtained is triturated with ethanol, filtered off with suction and washed with ethanol. The filtrate was then concentrated to dryness. The resulting residue was added to water and ethyl acetate, and the phases were separated. The organic phase was washed four times with water and then once with saturated aqueous sodium chloride solution, and then concentrated. The resulting residue was then purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 153mg of the expected compound (51% of theory) are obtained.

LC-MS (method 3) R_t=0.90 min, MS (EIpos) M/z =390[ M + H [ ]]⁺。

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.43(s,6H),4.54(s,2H),7.09-7.23(m,3H),7.26-7.35(m,2H),8.52(dd,1H),8.78(dd,1H),12.04(s br,1H)。

Example 5

2- [ 6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridin-1-yl ] -4-iodo-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

556mg (1.176mmol) of example 15A were initially introduced into 1, 2-dimethoxyethane (14ml), and 305mg (1.176mmol) of cesium iodide, 149mg (0.588mmol) of iodine and 67mg (0.353mmol) of copper (I) iodide were then added at room temperature. Isoamyl nitrite (0.933ml) was then added and the resulting mixture was heated at 60 ℃ overnight. The next day, 305mg (1.176mmol) of cesium iodide, 149mg (0.588mmol) of iodine, 67mg (0.353mmol) of copper (I) iodide and isoamyl nitrite (0.933ml) were further added, and the resulting mixture was heated at 60 ℃ for 3 days. After cooling, the resulting mixture was combined with a smaller batch (starting from 50mg of example 15A). The resulting mixture was extracted with ethyl acetate and saturated aqueous sodium thiosulfate solution, and the phases were separated. The organic phase was extracted more than twice with saturated aqueous sodium thiosulfate. The organic phase was then washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the resulting residue was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 236mg of the title compound (31% of theory) are obtained.

LC-MS (method 1) R_t=1.28 min, MS (ESIpos) M/z =584(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.37(s,6H),4.57(s,2H),7.19-7.25(m,1H),7.30(dd,1H),7.48-7.56(m,1H),8.43(d,1H),8.87(s,1H),11.58(s,1H)。

In addition to the title compound, 27mg (5% of theory, 90% pure) of 2- [ 6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridin-1-yl ] -4-hydroxy-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one are obtained (example 6).

Example 6

2- [ 6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridin-1-yl ] -4-hydroxy-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

Formed as a byproduct of example 5. Yield: 27mg (5% of theory, purity 90%).

LC-MS (method 1) R_t=0.97 min, MS (ESIpos) M/z =474(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.28(s,6H),4.59(s,2H),7.18-7.20(m,1H),7.41(d,1H),7.48-7.55(m,1H),8.31(d,1H),8.95(s,1H),10.93(s,1H),11.04(s,1H)。

Example 7

2- [ 6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridin-1-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

100mg (0.171mmol) of example 5 in DMF (9ml) was added to 41.1mg palladium on carbon (10%) in DMF (1ml) and the resulting mixture was hydrogenated under standard hydrogen pressure overnight. The resulting mixture was then filtered through celite, the resulting filter cake was washed with DMF and the resulting filtrate was concentrated to dryness. The resulting residue was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 27mg of the title compound (34% of theory, 96% purity) are obtained.

LC-MS (method 2) R_t=2.17 min, MS (ESIpos) M/z =458(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.33(s,6H),4.56(s,2H),7.17-7.25(m,2H),7.48-7.56(m,1H),8.46(s,1H),8.51(dd,1H),8.83(s,1H),11.38(s,1H)。

Example 8

2- [ 6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridin-1-yl ] -4-iodo-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

585mg (1.276mmol) of example 19A were reacted in a similar procedure to that of example 5. After purification by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient), 209mg of the title compound (28% of theory) are obtained.

LC-MS (method 1) R_t=1.22 min, MS (ESIpos) M/z =570(M + H)⁺

¹H NMR(400MHz,DMSO-d6):[ppm]=1.40(s,6H),2.80-2.96(m,2H),2H presumes 7.34(t,1H),8.46(dd,1H),8.73(d,1H),11.62(s,1H) under the water signal.

In addition to the title compound, 89mg (15% of theory, purity 87%) of 2- [ 6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridin-1-yl ] -4-hydroxy-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one are obtained (example 9).

Example 9

2- [ 6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridin-1-yl ] -4-hydroxy-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

Formed as a byproduct of example 8. Yield: 89mg (15% of theory, purity 87%).

LC-MS (method 1) R_t=0.96 min, MS (ESIpos) M/z =460(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.31(s,6H),2.88-3.07(m,2H),2H presumes 7.45(t,1H),8.32(dd,1H),8.81(d,1H),10.91(s,1H),11.56(s,1H) under the water signal.

Example 10

2- [ 6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridin-1-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

100mg (0.176mmol) of example 8 are hydrogenated in a manner analogous to that of example 7. 24mg of the title compound (30% of theory) are obtained.

LC-MS (method 3) R_t=0.95 min, MS (ESIpos) M/z =444(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.36(s,6H),2.84-2.95(m,2H),2H presumes 7.20-7.25(m,1H),8.50(s,1H),8.55(dd,1H),8.68(dd,1H),11.43(s, 1H) under the water signal.

Example 11

3- [ 6-chloro-3- (2,3, 6-trifluorobenzyl) imidazo [1,5-a ] pyridin-1-yl ] -7, 7-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-e ] [1,2,4] triazin-6-one

16ml of phosphorus oxychloride were added to 1.665g (approx. 2.407mmol, 71% purity) of the compound from example 21A, and the mixture was stirred at room temperature overnight. The resulting reaction mixture was dissolved in 160ml of acetonitrile, and then stirred into 100ml of a concentrated aqueous ammonia solution (33% concentration) under ice-cooling. The resulting mixture was stirred at room temperature for 3 days. The resulting reaction mixture was then concentrated. The resulting residue was added to water and ethanol, and stirred at room temperature for 1 hour. The precipitate formed is filtered off with suction and washed with water and a little ethanol. After drying under high vacuum, 899mg of the title compound (63% of theory, purity 78%) are obtained. 700mg of the product was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 212mg of the title compound (19% of theory) are obtained.

LC-MS (method 3) R_t=1.03 min, MS (EIpos) M/z =459[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.40(s,6H),4.58(s,2H),7.20-7.29(m,2H),7.48-7.56(m,1H),8.47(d,1H),8.88(s,1H),11.96(br s,1H)。

Example 12

3- [ 6-fluoro-3- (3,3,4,4, 4-pentafluorobutyl) imidazo [1,5-a ] pyridin-1-yl ] -7, 7-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-e ] [1,2,4] triazin-6-one

13ml of phosphorus oxychloride were added to 1.490g (about 2.026mmol, 65% purity) of the compound of example 23A and the resulting mixture was stirred at room temperature overnight. The resulting reaction mixture was dissolved in 130ml of acetonitrile, and then stirred into 85ml of a concentrated aqueous ammonia solution (33% concentration) under ice-cooling. The resulting mixture was stirred at room temperature for 3 days. The resulting reaction mixture was then concentrated. The resulting residue was taken up in water and ethanol and stirred at room temperature for 1 hour. The precipitate formed is filtered off with suction and washed with water and a little ethanol. After drying under high vacuum, 839mg of the title compound are obtained (62% of theory, purity 67%). 200mg of the product was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 71mg of the title compound (7% of theory) are obtained.

LC-MS (method 1) R_t=0.95 min, MS (EIpos) M/z =445[ M + H ]]⁺。

¹H NMR(400MHz,DMSO-d₆):[ppm]=1.43(s,6H),2.83-2.96(m,2H),2H presumes 7.29-7.34(m,1H),8.51(dd,1H),8.74(dd,1H),12.01(br s,1H) under the water signal.

B.Evaluation of pharmacological Activity

The pharmacological effects of the compounds of the invention can be demonstrated in the following tests:

B-1.in vitro vascular relaxation

Rabbits were stunned from the neck and then exsanguinated. The aorta was removed from the adherent tissue and divided into 1.5mm wide rings. The rings were placed individually under initial tension (initial tension) in a 5-ml organ bath (organbath) containing a Krebs-henselit solution aerated with carbopol gas, which had the following composition (mM in each case) at 37 ℃: 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 determined using StathamUC2 cells, amplified and digitized using an A/D converter (DAS-1802 HC, Keithley Instruments Munich), and then recorded in parallel in a strip recorder (line recorder). 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 run and the height of the achieved contractions is compared with the height of the contractions obtained in the previous run. This was used to calculate the concentration required to reduce the amplitude of the control value by 50% (IC)₅₀Value). The standard dosing volume is 5 μ l; and the DMSO content in the bath solution corresponded to 0.1%.

Representative IC's for the Compounds of the invention₅₀The values are shown in the following table (table 1):

table 1:

example numbering	IC₅₀[nM]
		3	72
4	42
		11	30
12	276

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.wunderetal, anal.biochem.339,104-112(2005)。

Representative values (MEC = lowest effective concentration) of the compounds of the invention are shown in the following table (table 2):

table 2:

example numbering	MEC[μM]
		1	0.1
3	0.03
		4	0.03
7	0.01
		11	0.03

Example numbering	MEC[μM]
		12	1.0

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(s) (ii)Remote measuring emitter

A receiver (a)A receiver) connected to the DSI DataExchange Matrix via a multiplexer (DSI)

-a data acquisition computer.

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

Animal material

The study was performed in adult female spontaneous 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 sent to the national Institutes of Health at F13 (U.S. national Institutes of Health).

After emitter implantation, the test animals were housed individually in Makrolon type 3 cages. It can be freely ingested with standard feed and water.

The day/night rhythm was varied in the test laboratory by indoor lighting at 6:00 in the morning and 7:00 in the evening.

Emitter implantation

At least 14 days prior to the first experimental use, the TA11PA-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 housing of the transmitter is secured within the abdominal cavity to the abdominal wall musculature and the wound is closed layer by layer.

After surgery, antibiotics were given to prevent infection (Tardomyocel COMP, Bayer,1ml/kg, subcutaneous injection).

Substances and solutions

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

The solvent-treated animal group was used as a control group.

Test method

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

Instrumented rats living in the system are each assigned a separate receive antenna (1010 Receiver, DSI).

The implanted transmitter can be activated externally by a built-in magnetic switch and switched to transmit at the start of the experiment. The transmitted signal may be passed through a data acquisition system (Dataquest)^TMFor WINDOWS, DSI) are recorded online and processed in an appropriate manner. 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 graph with the currently measured air pressure (ambient pressure reference monitor; APR-1) and stored as separate data. Other technical details can be found in the large number of documents of the manufacturing company (DSI).

Unless otherwise indicated, the test substance was administered at 9.00 am on the day of the experiment. After dosing, the above parameters were measured over 24 hours.

Evaluation of

At the end of the experiment, the individual data collected were analyzed using analytical software (DATAQUEST)^TMTmanalysis). The values from 2 hours prior to dosing were used as blank values so that the data set selected included the period from 7.00 am on the day of the experiment to 9.00 am on the following day.

The resulting data are smoothed by mean value measurement (mean 15 minutes) for a presettable time and transferred as a text document to a storage medium. The measurements pre-classified and compressed in this way were transferred to an Excel template and presented as a table. The data obtained on each experimental day is stored in a special folder with the experimental number. The results and test protocol are archived in paper form, sorted by number.

Literature reference

Klaus Witte,Kai Hu,Johanna Swiatek,Claudia Müssig,GeorgErtl andLemmer:Experimental heart failure in rats:effects oncardiovascularcircadian rhythms and on myocardialβ-adrenergicsignaling.Cardiovasc Res47(2):203-405,2000;Kozo Okamoto:Spontaneous hypertension in rats.Int Rev ExpPathol7:227-270,1969;Maarten van den Buuse:Circadian Rhythms of BloodPressure,HeartRate,and Locomotor Activity in Spontaneously Hypertensive RatsasMeasured With Radio-Telemetry.Physiology&Behavior55(4):783-787,1994。

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

The pharmacokinetic parameters of the compounds of formula (I) of the invention were determined in male Wistar rats. The administration volume was 5 ml/kg. Intravenous administration was via species-specific plasma/DMSO (99/1) formulations. A silicone catheter was inserted into the rat's right external jugular vein prior to administration of the substance to more easily collect blood from the rat. Surgical intervention was performed one day prior to the experiment using isoflurane anesthesia and the administration of an analgesic (0.1 ml subcutaneous administration of atropine/ibuprofen (3/1)). The substance administration is performed as an intravenous bolus. Blood was removed from rats after 0.033, 0.083, 0.17, 0.5, 1,2, 3,4, 6, 8, 24 and 27 hours. The resulting 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 (ZK 228859) was added to the samples of the compound of formula (I) of the present invention, the calibration sample and QC, and the protein was precipitated using excess acetonitrile. After addition of ammonium acetate buffer (0.01M, pH 6.8) and subsequent vortexing, the resulting mixture was centrifuged at 1000g and the resulting supernatant was detected by LC-MS/MS (API 4000, ABSciex). Chromatographic separation was performed on an Agilent 1100-HPLC. The injection volume was 20. mu.l. The separation column used was phenomenex gemini5 μ C18110a50x3mm, adjusted to a temperature of 40 ℃. A binary mobile phase gradient of 500. mu.l/min (A: 0.01M ammonium acetate buffer pH6.8, B: 0.1% formic acid in acetonitrile) was used: 0 min (90% A), 1 min (90% A), 3 min (10% A), 4 min (10% A), 4.50 min (90% A), 6 min (90% A). The temperature of the TurboV ion source was 400 ℃. The following MS instrument parameters were used: 15 units of curtain gas, 4.8kV of ion spray voltage, 150 units of gas, 240 units of gas and 8 units of CAD gas. The species were quantified by peak height or area using extracted ion chromatography for a particular MRM experiment.

Calculation of pharmacokinetic parameters, e.g. AUC, C, using the determined plasma concentration/time curves by the validated pharmacokinetic calculation program KinEx (version 3)_max、t_1/2(terminal half-life), MRT (mean residence time) and CL (clearance).

Since the quantification of the substance 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 the substances are incubated for 20 minutes in heparinized whole blood of the species of interest in a roller mixer (rolling roller mixer). After centrifugation at 1000g, the plasma concentration was measured (see above) and calculated by calculating C_Blood-C_{Blood plasma}The quotient (quotient) of the values.

The data listed in Table 3 were obtained after intravenous administration of 0.3mg/kg of a representative compound of the invention in rats:

table 3:

examples	11	12
			CL_{Blood, blood-enriching agent and method for producing the same}[l/h/kg]	0.03	0.16
Terminal half-life [ h]	7.2	5.2
			Average residence time [ h]	9.4	4.6

B-5.Metabolic studies

To determine the metabolic profile of the compounds of the invention, they were incubated with: recombinant human cytochrome P450(CYP) enzyme, liver microsomes or primary fresh hepatocytes from different animal species (e.g., rat, dog) and human origin, to obtain and compare information on: mainly the intact liver stage I and stage II metabolism, and the enzymes involved in said 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. Incubating the liver microsomes and the recombinant enzyme in 50mM potassium phosphate buffer (pH 7.4) with or without 1mM ADP at 37 deg.C⁺An NADPH-producing system consisting of 10mM glucose-6-phosphate and 1 unit of glucose-6-phosphate dehydrogenase. Primary hepatocytes were also incubated in suspension in WilliamsE medium at 37 ℃. After 0-4 hours of incubation, the incubation reaction was stopped with acetonitrile (final concentration of about 30%) and the protein was centrifuged out at about 15000x g. The samples thus terminated were either directly analyzed or stored at-20 ℃ until analysis.

The analysis was performed by high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS/MS). For this purpose, the supernatant of the incubation 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). UV chromatogram and mass spectrometry data were used for identification, structural analysis and quantitative evaluation of the metabolites, and for quantitative metabolic acceptance (metabiolacceptance) 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 in the following manner:

and (3) tablet preparation:

consists of the following components:

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

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

Preparation:

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 then mixed with magnesium stearate for 5 minutes. The mixture is compressed with a conventional tablet press (for tablet formats, see above). Compression with a guideline value of 15kN for compression; force.

Orally administrable suspension formulations:

consists of the following components:

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:

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

Orally administrable solutions:

consists of the following components:

500mg of a compound according to 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:

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

Intravenous administration 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 pyrogen-free injection containers.

Claims

1. Compounds of formula (I) and salts thereof,

wherein

A is nitrogen, and the content of A is,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is a number of 0 and,

R^4Ais (C)₁-C₄) -an alkyl group,

R^4Bis (C)₁-C₆) -an alkyl group,

m is a group selected from the group consisting of CH and N,

R¹is (C)₁-C₆) -an alkyl group or a benzyl group,

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

R²is a hydrogen or a halogen, and the halogen,

R⁶is a hydrogen atom, and is,

R⁷is hydrogen.

2. A compound of formula (I) as claimed in claim 1 and salts thereof, wherein

A is nitrogen, and the content of A is,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is a number of 0 and,

R^4Ais a methyl group or an ethyl group,

R^4Bis (C)₁-C₄) -an alkyl group,

m is a group selected from the group consisting of CH and N,

R¹is 3,3,4,4, 4-pentafluorobutan-1-yl or benzyl,

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

R²is hydrogen, fluorine or chlorine,

R⁶is a hydrogen atom, and is,

R⁷represents hydrogen.

3. A compound of formula (I) as claimed in claim 1 or 2 and salts thereof, wherein

A is nitrogen, and the content of A is,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is a number of 0 and,

R^4Ais a methyl group or an ethyl group,

R^4Bis a methyl group or an ethyl group,

m is a group selected from the group consisting of CH and N,

R¹is 3,3,4,4, 4-pentafluorobutan-1-yl or benzyl,

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

R²fluorine or chlorine, with the proviso that M is CH,

or

R²Is hydrogen, provided that M is N,

R⁶is a hydrogen atom, and is,

R⁷represents hydrogen.

4. A compound of formula (I) as claimed in claim 1 or 2 and salts thereof, wherein

A is nitrogen, and the content of A is,

l is # -CR^4AR^4B-(CR^5AR^5B)_p- # # radical

Wherein

# is the site of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is a number of 0 and,

R^4Ais a methyl group, and the compound is,

R^4Bis a methyl group, and the compound is,

m is a group selected from the group consisting of CH and N,

r1 is 3,3,4,4, 4-pentafluorobutan-1-yl or benzyl,

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

R²fluorine or chlorine, with the proviso that M is CH,

or

R²Is hydrogen, provided thatThe result is that M is N,

R⁶is a hydrogen atom, and is,

R⁷represents hydrogen.

5. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 4, characterized in that

Reacting a compound of formula (II)

M, R therein¹、R²、R⁶And R⁷Each having the meaning given in any one of claims 1 to 4,

reaction with hydrazine hydrate in an inert solvent and in the presence of a suitable base to give the compound of formula (IX)

then reacting the compound of formula (IX) with a compound of formula (X) in an inert solvent to give a compound of formula (XI)

Wherein L has the meaning given in any one of claims 1 to 4 and

T³is (C)₁-C₄) -alkyl radical

M, L, R therein¹、R²、R⁶And R⁷Each having the meaning given in any one of claims 1 to 4, and T³Is (C)₁-C₄) -an alkyl group,

the compound of formula (XI) is then converted to a compound of formula (XII)

the compound of formula (XII) is then reacted directly with ammonia to give the compound of formula (XIII)

finally cyclizing the compound of formula (XIII) in an inert solvent and optionally in the presence of a suitable base to give the compound of formula (I-D)

M, L, R therein¹、R²、R⁶And R⁷Each having the meaning given in any one of claims 1 to 4,

the resulting compounds of the formula (I-D) are, if appropriate, converted into their salts with suitable acids or bases.

6. Use of a compound of formula (I) as defined in any one of claims 1 to 4 for the preparation of a medicament for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal failure, thromboembolic disorders, fibrotic disorders and arteriosclerosis.

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

8. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 4 and a further active compound selected from: organic nitrate, NO donor, cGMP-PDE inhibitor, antithrombotic agent, hypotensive agent and lipid metabolism regulating agent.