HK1190710B

HK1190710B - Fluoroalkyl-substituted pyrazolopyridines and use thereof

Info

Publication number: HK1190710B
Application number: HK14103778.6A
Authority: HK
Inventors: Markus Follmann; Johannes-Peter Stasch; Gorden Redlich; Nils Griebenow; Frank Wunder; Volkhart Min-Jian Li; Dieter Lang
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2011-04-21
Filing date: 2012-04-20
Publication date: 2017-08-11

Description

Fluoroalkyl-substituted pyrazolopyridines and use thereof

The present application relates to novel fluoroalkyl-substituted pyrazolopyridines, processes for their preparation, their use (alone or in combination) for the treatment and/or prophylaxis of diseases, and their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular for the prophylaxis and/or treatment 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 the formation of 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, atherosclerosis, 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.

The therapeutic stimulatory action of soluble guanylate cyclase has been achieved today 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-benzylindazole [ YC-1; wuet 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 diphenylhexafluorophosphate [ Pettibone et al, eur.j.pharmacol.116(1985), 307], isoliquiritigenin [ Yu et al, brit.j.pharmacol.114(1995), 1587] and various substituted pyrazole derivatives (WO 98/16223).

As stimulators of soluble guanylate cyclase, WO 00/06569 discloses fused pyrazole derivatives and WO 03/095451 discloses carbamate substituted 3-pyrimidinyl pyrazolopyridines. WO 2010/065275 and WO 2011/149921 disclose substituted pyrrolo and dihydropyridopyrimidines 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 with respect to 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 having the general formula (I), and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides or salts thereof

Wherein

A is nitrogen or CR³，

Wherein

R³Is hydrogen, deuterium, halogen, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, (C)₂-C₄) Alkynyl, cyclopropyl, cyclobutyl, hydroxy, phenyl or 5-or 6-membered heteroaryl,

wherein (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, (C)₂-C₄) The alkynyl, phenyl and 5-or 6-membered heteroaryl groups may be substituted with 1 to 3 substituents independently from each other selected from the group consisting of fluoro, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkoxycarbonyl, cyclopropyl and cyclobutyl,

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0, 1 or 2,

R^4Ais hydrogen, fluorine, (C)₁-C₄) An alkyl group, a hydroxyl group or an amino group,

wherein (C)₁-C₄) Alkyl may be substituted with 1 to 3 substituents independently selected from fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl, (C)₁-C₄) An alkoxycarbonyl group and an amino group, and a pharmaceutically acceptable salt thereof,

R^4Bis hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl, (C)₁-C₄) Alkoxycarbonylamino group, cyano group, (C)₃-C₇) Cycloalkyl, difluoromethoxy, trifluoromethoxy, phenyl or of the formula-M-R⁸The group of (a) or (b),

wherein (C)₁-C₆) Alkyl may be substituted with 1-3 substituents independently selected 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 a pharmaceutically acceptable salt thereof,

and wherein the one or more of the one,

m is a bond or (C)₁-C₄) An alkylene group (alkanediyl group),

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-NR⁹R¹⁰4-7 membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl

The base group is a group of a compound,

wherein the content of the first and second substances,

r is a number 0 or 1 and,

s is the number 0, 1 or 2,

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

or

R⁹And R¹⁰Together with the atoms to which they are attached form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring may itself be substituted with 1 or 2 substituents independently selected from cyano, trifluoromethyl, (C)₁-C₆) Alkyl, hydroxy, oxo, (C)₁-C₆) Alkoxy, trifluoromethoxy and (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 attached form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring may itself be substituted with 1 or 2 substituents independently selected from cyano, trifluoromethyl, (C)₁-C₆) Alkyl, hydroxy, oxo, (C)₁-C₆) Alkoxy, trifluoromethoxy and (C)₁-C₆) Alkoxycarbonyl, amino, mono- (C)₁-C₆) Alkylamino and di- (C)₁-C₆) Alkyl ammoniaThe base group is a group of a compound,

R¹²is (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group,

or

R⁹And R¹²Together with the atoms to which they are attached form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring may itself be substituted with 1 or 2 substituents independently selected from cyano, trifluoromethyl, (C)₁-C₆) Alkyl, hydroxy, oxo, (C)₁-C₆) Alkoxy, trifluoromethoxy and (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 independently of one another selected from the group consisting of halogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl, hydroxy, oxo, thio and (C)₁-C₄) An alkoxy group,

and is

Wherein (C) is as described above, unless otherwise indicated₁-C₄) Alkyl, (C)₁-C₆) Alkyl, (C)₃-C₈) The cycloalkyl and the 4-7 membered heterocyclyl can each, independently of one another, be additionally substituted by 1 to 3 substituents which are selected, independently of one another, from fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl, (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^4BWith carbon atoms to which they are attachedTogether form (C)₂-C₄) Alkenyl, oxo, 3-6 membered carbocyclic ring or 4-7 membered heterocyclic ring,

wherein said 3-6 membered carbocycle and 4-7 membered heterocycle may be substituted with 1 or 2 substituents independently selected from fluoro and (C)₁-C₄) An alkyl group, a carboxyl group,

R^5Ais hydrogen, fluorine, (C)₁-C₄) An alkyl group or a hydroxyl group, and a carboxyl group,

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

R¹is hydrogen, halogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl or (C)₃-C₇) A cycloalkyl group,

R²is of the formula: - (CR)^6AR^6B)_qCHF₂、*-(CR^6AR^6B)_qCF₃Or: - (CR)^6AR^6B)_q-(C₃-C₇) The radical of a cycloalkyl group,

wherein

Is a point of attachment to the pyrazolopyridine,

q is the number 1, 2 or 3,

R^6Ais hydrogen or fluorine, and can be used as the active ingredient,

R^6Bis hydrogen or fluorine, and can be used as the active ingredient,

and is

Wherein (C)₃-C₇) Cycloalkyl can be substituted with 1 to 3 substituents independently selected from fluorine and (C)₁-C₄) An alkyl group, a carboxyl group,

R^7Ais hydrogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl or (C)₃-C₇) A cycloalkyl group,

R^7Bis hydrogen, cyano, difluoromethyl, trifluoromethylBase, (C)₁-C₄) Alkyl or (C)₃-C₇) A cycloalkyl group.

The compound of the present invention is a compound of the formula (I) and a salt, a solvate and a solvate of the salt, a compound having the following formula and a salt, a solvate and a solvate of the salt included in the formula (I), and a compound mentioned below as a working example and a salt, a solvate and a solvate of the salt included in the formula (I), provided that the following compound included in the formula (I) is not already a salt, a solvate and a solvate of the salt.

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.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds of the invention. Salts which are not suitable per se for pharmaceutical applications but which can be used, for example, for isolating or purifying the compounds of the invention are also encompassed.

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

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

Solvates in the context of the present invention refer to those forms of the compounds of the invention which form complexes by coordination with solvent molecules, either in the solid or liquid state. A hydrate is a specific form of solvate in which coordination occurs with water. Preferred solvates in the context of the present invention are hydrates.

Depending on the structure of the compounds of the invention, they may exist in different stereoisomeric forms, i.e. in the form of configurational isomers or optionally also in the form of conformational isomers (enantiomers and/or diastereomers, including the case of atropisomers). Thus, the present invention includes enantiomers and diastereomers, as well as individual mixtures thereof. The stereoisomerically homogeneous components can be separated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatographic methods are preferably used for this purpose, in particular HPLC chromatography on achiral or chiral phases.

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

The invention also includes all suitable isotopic variations of the compounds of the invention. Isotopic variations of the compounds of the present invention are understood herein to mean compounds in which at least one atom in the compounds of the present invention has been exchanged for another atom having the same atomic number, but an atomic weight different from the atomic weight usually or predominantly present in its natural state. Examples of isotopes that can be incorporated into the compounds of the invention are 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, more specifically, those into which one or more radioactive isotopes have been incorporated are useful, for example, in the study of the mechanism of action or in vivo active compoundsThe study of the distribution of the substance may be advantageous; due to the relative ease of preparation and detectability, in particular³H or¹⁴C-isotopically labeled compounds are suitable for this purpose. Furthermore, the inclusion of isotopes such as deuterium can result in specific therapeutic benefits due to greater metabolic stability of the compounds (e.g. increased half-life in vivo or reduced active doses required); such modifications of the compounds of the invention therefore also constitute preferred embodiments of the invention in some cases. 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 respective reagents and/or the corresponding isotopic modifications of the starting compounds.

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

In the presence of L or R²In the formula (a), the ends of the lines marked with #, # # or #do not represent carbon atoms or CH₂Radicals, but instead of L or R²A portion of the bond to which the bonded atom is attached.

Unless otherwise specifically indicated, in the context of the present invention, the substituents each have the following meaning:

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

Cycloalkyl or carbocycleIn the context of the present invention, monocyclic saturated alkyl radicals having in each case the specified number of carbon atoms are meant. For example and preferably the following groups may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkylene radicalIn the context of the present invention represents a linear divalent alkyl radical having from 1 to 4 carbon atoms. For example and preferably the following groups may be mentioned: methylene, ethane-1, 2-diyl, ethane-1, 1-diyl, propane-1, 3-diyl, propane-1, 1-diyl, propane-1, 2-diyl, propane-2, 2-diyl, butane-1, 4-diyl, butane-1, 2-diyl, butane-1, 3-diyl, and butane-2, 3-diyl.

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

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

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

Alkoxycarbonyl radicalIn the context of the present invention means a straight or branched alkoxy group having 1 to 4 carbon atoms and a carbonyl group attached to an oxygen. For example and preferablyThe following groups may be mentioned: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Alkoxycarbonyl amino groupIn the context of the present invention refers to an amino group having a straight or branched alkoxycarbonyl substituent having from 1 to 4 carbon atoms in the alkyl chain and being linked to the nitrogen atom via the carbonyl group. For example and preferably the following groups may be mentioned: methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino and tert-butoxycarbonylamino.

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

Dialkylamino radicalIn the context of the present invention, amino groups having 2 identical or different straight-chain or branched alkyl substituents, each of which has from 1 to 6 carbon atoms, are meant. For example and preferably the following groups may be mentioned: n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propylamino, N-isopropyl-N-N-propylamino, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-N-pentylamino and N-N-hexyl-N-methylamino.

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

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

Halogen elementIn the context of the present invention, fluorine, chlorine, bromine and iodine are meant. Bromine and iodine are preferred.

Oxo radicalIn the context of the present invention means an oxygen atom which is bonded to a carbon atom by a double bond.

Thio groupIn the context of the present invention refers to a sulfur atom which is bonded to a carbon atom by 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 preventing, delaying, hindering, alleviating, attenuating, limiting, alleviating, inhibiting, combating or curing a disease, disorder, condition, injury or health problem, or the occurrence, course or progression of such a condition and/or symptoms of such a condition. The term "therapy" is to be understood herein as synonymous with the term "treatment".

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

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

Compounds of formula (I-1) form a subclass of compounds of formula (I) of the invention, wherein R^7AAnd R^7BIs hydrogen.

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

A is nitrogen or CR³，

Wherein

R³Is hydrogen, deuterium, fluorine, iodine, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl, 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 of each other selected from methyl, cyclopropyl and cyclobutyl,

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 or 1 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-M-R⁸The group of (a) or (b),

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

and wherein the one or more of the one,

m 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 the content of the first and second substances,

r is a number 0 or 1 and,

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,

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

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 by 1 or 2 substituents independently selected from fluoro and methyl,

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

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

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R²is of the formula: - (CR)^6AR^6B)_qCHF₂、*-(CR^6AR^6B)_qCF₃Cyclobutylmethyl group

Or a group of a cyclopentylmethyl group,

wherein

Is a point of attachment to the pyrazolopyridine,

q is the number 2 or 3,

R^6Ais hydrogen or fluorine, and can be used as the active ingredient,

R^6Bis hydrogen or fluorine, and can be used as the active ingredient,

and is

Wherein the cyclobutylmethyl and cyclopentylmethyl groups may be substituted with 1 or 2 fluoro substituents,

R^7Ais hydrogen or a methyl group,

R^7Bis hydrogen.

A is nitrogen or CR³，

Wherein

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

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 or 1 and,

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

R^4Bis hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, methoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl or of the formula-M-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,

m is a bond of the silicon-oxygen compound,

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

wherein the content of the first and second substances,

r is a number 1 and r is a number,

R⁹and R¹⁰Each independently of the others, 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

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

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

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R²is 3,3, 3-trifluoroprop-1-yl, 4,4, 4-trifluorobut-1-yl, 3,3,4, 4-tetrafluorobut-1-yl, 3,3,4,4, 4-pentafluorobut-1-yl, cyclobutylmethyl or cyclopentylmethyl, wherein the cyclobutylmethyl and cyclopentylmethyl groups may be substituted with 1 or 2 fluoro substituents,

R^7Ais hydrogen or a methyl group,

R^7Bis hydrogen.

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

A is nitrogen or CR³，

Wherein

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

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

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

R^4Bis hydrogen, fluorine, trifluoromethyl, 2, 2, 2-trifluoroethyl, methyl or of the formula-M-R⁸The group of (a) or (b),

wherein the content of the first and second substances,

m is a bond of the silicon-oxygen compound,

R⁸is- (C = O)_r-NR⁹R¹⁰，

Wherein the content of the first and second substances,

r is a number 1 and r is a number,

R⁹and R¹⁰Each independently of the others, hydrogen or cyclopropyl,

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R²is 4,4, 4-trifluorobut-1-yl, 3,4, 4-tetrafluorobut-1-yl, 3,4,4, 4-pentafluorobut-1-yl, cyclobutylmethyl or cyclopentylmethyl,

R^7Ais hydrogen or a methyl group,

R^7Bis hydrogen.

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

A is nitrogen or CR³，

Wherein

R³Is hydrogen, deuterium, fluorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) An alkyl group, a cyclopropyl group or a cyclobutyl group,

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0, 1 or 2,

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 selected from fluorine, 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 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring,

wherein said 3-6 membered carbocycle and 4-6 membered heterocycle may be substituted with 1 or 2 substituents independently selected from fluoro and (C)₁-C₄) An alkyl group, a carboxyl group,

or

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

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R²is of the formula: - (CR)^6AR^6B)_qCF₃The group of (a) or (b),

wherein

Is a point of attachment to the pyrazolopyridine,

q is the number 1, 2 or 3,

R^6Ais hydrogen or fluorine, and can be used as the active ingredient,

R^6Bis hydrogen or fluorine.

A is nitrogen or CR³，

Wherein

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

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 or 1 and,

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 which are 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,

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R²is 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)_pA group of the form- ###,

wherein

# is the point of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine ring,

p is a number 0 which is the number,

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

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R²is 3,3,4,4, 4-pentafluorobutan-1-yl.

A is nitrogen, and the content of A is,

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

wherein

# is the point of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is the number 0 and p is the number 0,

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

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

or

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R²is 3,3,4,4, 4-pentafluorobutan-1-yl.

Also preferred in the context of the present invention are compounds of formula (I) and formula (I-1), and salts, solvates and solvates of said salts, wherein R is¹Is H.

Also preferred in the context of the present invention are compounds of formula (I) and formula (I-1), and salts, solvates and solvates of said salts, wherein R is¹Is fluorine.

Also preferred in the context of the present invention are compounds of formula (I) and formula (I-1), and salts, solvates and solvates of said salts, wherein A is N or CH.

Also preferred in the context of the present invention are compounds of formula (I) and formula (I-1), and salts, solvates and solvates of said salts, wherein A is CH.

Also preferred in the context of the present invention are compounds of formula (I) and formula (I-1), and salts, solvates and solvates of said salts, wherein a is N.

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

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

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.

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

R^4Aand R^4BTogether with the carbon atom to which they are attached form an azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring.

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

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

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

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

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

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)_pA group of the form- ###,

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

R^4Ais a hydroxyl group or an amino group,

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

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

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

R^4Bis methyl.

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

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

R²Is 3,3,4,4, 4-pentafluorobutan-1-yl.

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

A is nitrogen, and the content of A is,

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

wherein

# is the point of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is the number 0 and p is the number 0,

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)_pA group of the form- ###,

wherein

# is the point of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine ring,

p is the number 0 and p is the number 0,

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)_pA group of the form- ###,

wherein

# is the point of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine ring,

p is the number 0 and p is the number 0,

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

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

wherein the content of the first and second substances,

m is a bond of the silicon-oxygen compound,

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

Wherein the content of the first and second substances,

r is a number 0 and r is a number,

R⁹and R¹⁰Independently of one another, are each hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or pyridinyl,

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)_pA group of the form- ###,

wherein

# is the point of attachment to the carbonyl group,

# is the point of attachment to the triazine ring,

p is the number 0 and p is the number 0,

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

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

wherein the content of the first and second substances,

m is a bond of the silicon-oxygen compound,

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 0 and r is a number,

and is

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

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

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

Wherein R is¹、R²、R^7AAnd R^7BEach having the meaning given above,

[A] reacting a compound of formula (II) with a compound of formula (III) in an inert solvent in the presence of a suitable base to obtain a compound of formula (IV)

Wherein L has the meaning given above, and

T¹is (C)₁-C₄) An alkyl group, a carboxyl group,

l, R therein¹、R²、R^7AAnd R^7BEach having the meaning given above,

the compound of formula (IV) is then converted to the compound of formula (V) using isoamyl nitrite and a halogen equivalent

L, R therein¹、R²、R^7AAnd R^7BEach having the meaning given above, and X²Is the bromine or the iodine, and the iodine,

then reacting the compound of formula (V) in an inert solvent in the presence of a suitable transition metal catalyst to obtain the compound of formula (I-A),

l, R therein¹、R²、R^7AAnd R^7BEach having the meaning given above, or

[B] Reacting a compound of formula (II) with hydrazine hydrate in the presence of a suitable base in an inert solvent to obtain a compound of formula (VI)

Wherein R is¹、R²、R^7AAnd R^7BEach having the meaning given above,

then reacting the compound of formula (VI) with a compound of formula (VII) in an inert solvent to obtain a compound of formula (VIII)

Wherein L has the meaning given above, and

T⁴is (C)₁-C₄) An alkyl group, a carboxyl group,

l, R therein¹、R²、R^7A、R^7BAnd T⁴Each having the meaning given above,

the compound of formula (VIII) is then converted with phosphorus oxychloride to the compound of formula (IX)

L, R therein¹、R²、R^7A、R^7BAnd T⁴Each having the meaning given above,

and reacting the compound of formula (IX) directly with ammonia to obtain the compound of formula (X)

L, R therein¹、R²、R^7A、R^7BAnd T⁴Each having the meaning given above,

and finally cyclizing the compound of formula (X) in an inert solvent, optionally in the presence of a suitable base, to obtain the compound of formula (I-B)

L, R therein¹、R²、R^7AAnd R^7BEach having the meaning given above,

and, where appropriate, converting the obtained compounds of formulae (I-a) and (I-B) into their solvates, salts and/or solvates of said salts with a suitable (I) solvent and/or (ii) acid or base.

Said compounds of formula (I-A) and (I-B) together form the group of compounds of formula (I) of the present invention.

Inert solvents used in steps (II) + (III) of the process 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, acetonitrile, sulfolane or water. Mixtures of the solvents mentioned may also be used. Tert-butanol or methanol are preferred.

Suitable bases for steps (II) + (III) of the process are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal hydrogencarbonates such as sodium or potassium hydrogencarbonate, alkali metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium 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 or sodium methoxide are preferred.

The reactions (II) + (III) are generally carried out at a temperature in the range from +20 ℃ to +150 ℃, preferably from +75 ℃ to +100 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure, under elevated or reduced pressure (e.g. from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Process step (IV) → (V) is 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) → (V) is usually carried out in a temperature range of +20 ℃ to +100 ℃, preferably in a temperature range of +50 ℃ to +100 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure, under elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Suitable halogen sources in the reaction (IV) → (V) are, for example, diiodomethane, cesium iodide, iodine and copper (I) or copper (II) iodide.

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

Inert solvents used in step (V) → (I-a) of the process are alcohols such as methanol, ethanol, N-propanol, isopropanol, N-butanol, tert-butanol or 1, 2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diglyme, 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 (V) → (I-a) is carried out with hydrogen gas and a transition metal catalyst such as palladium (10% supported on activated carbon), raney nickel or palladium hydroxide.

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

The reaction (VIII) → (IX) may be carried out in a solvent which is inert under the reaction conditions, or may be carried out without a solvent. The preferred solvent is sulfolane.

The reaction (VIII) → (IX) is usually carried out in a temperature range of +70 ℃ to +150 ℃, preferably +80 ℃ to +130 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure or under elevated pressure (e.g. in the range from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

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

The process step (IX) → (X) being carried out in a solvent which is inert under the reaction conditions. 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 (IX) → (X) is usually carried out in a temperature range of +20 ℃ to +100 ℃, preferably +40 ℃ to +70 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure or under elevated pressure (e.g. in the range from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

The cyclization reaction (X) → (I-B) is 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 t-butanol, an ether such as diethyl ether, dioxane, dimethoxyethane, Tetrahydrofuran (THF), ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, a hydrocarbon such as benzene, xylene, toluene, hexane, cyclohexane or a mineral oil fraction, 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 (X) → (I-B) 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 (X) → (I-B) 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 under elevated pressure (e.g. in the range from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Preferably, the cyclisation reaction to obtain (I-B) is carried out directly during the reaction (IX) → (X), without the addition of further reagents.

In an alternative step of process [ B ], the conversion (VI) + (VII) → (VIII) → (IX) → (X) → (IB) is carried out without isolation of intermediates.

Preferably, the reaction (VIII) → (IX) → (X) → (IB) is carried out without isolating the intermediates.

Inert solvents (VI) + (VII) → (VIII) used in the process steps 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 (VI) + (VII) → (VIII) is typically 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 elevated pressure (e.g. in the range from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Inert solvents used in step (II) → (VI) of the process 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) → (VI) 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). Triethylamine is preferred.

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

The preparation can be illustrated by the following synthetic schemes (schemes 1 and 2):

scheme 1

[ a): hydrazine hydrate, NEt₃、EtOH；b)：EtOH；c)：1.POCl₃2, concentrated NH3, acetonitrile]。

Scheme 2

[ a): KOt-Bu, tert-butanol; b) the method comprises the following steps Diiodomethane, isoamyl nitrite; c) the method comprises the following steps Pd/C, hydrogen, DMF ].

In an alternative process, the preparation of the compounds of formula (I) according to the invention can be carried out by: the order of the reaction steps is reversed chemically using protecting groups, as shown, for example, in the following synthetic scheme (scheme 6):

scheme 6

[ a): 2- (trimethylsilyl) ethoxymethyl chloride, Cs₂CO₃DMF; b) the method comprises the following steps Ammonium cerium (IV) nitrate, acetonitrile, water; c) the method comprises the following steps Cs₂CO₃DMF; d) the method comprises the following steps 1) TFA, dichloromethane, 2) HCl, ethanol]。

Other compounds of the invention may also optionally be prepared by: conversion of the functional groups of the various substituents of the compounds of formula (I) obtained by the above-mentioned process, in particular with respect to L and R³Those listed. These transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal catalyzed coupling reactions, eliminations, alkylations, amination, esterification, ester cleavage, etherification, ether cleavage, carbonamide (carbonamide) formation, and the introduction and removal of temporary protecting groups.

The compounds of formula (II) may be prepared by: cyclizing the compound of formula (IX) with hydrazine hydrate in an inert solvent to obtain the compound of formula (XII)

WhereinR¹、R^7AAnd R^7BEach having the meaning given above,

wherein R is¹、R^7AAnd R^7BEach having the meaning given above,

the compound of formula (XII) is then first reacted with isoamyl nitrite in an inert solvent in the presence of a suitable Lewis acid to obtain the corresponding diazonium salt, which is then converted directly with sodium iodide to the compound of formula (XIII)

Wherein R is¹、R^7AAnd R^7BEach having the meaning given above,

subsequently, the compound of formula (XIII) is converted to the compound of formula (XV) with the compound of formula (XIV) in an inert solvent in the presence of a suitable base

R²-X¹(XIV)

Wherein R is²Has the meaning given above and X¹Suitable leaving groups, such as halogen, tosylate or mesylate,

wherein R is¹、R²、R^7AAnd R^7BEach having the meaning given above,

the compound of formula (XV) is then reacted with cuprous cyanide in an inert solvent to obtain the compound of formula (XVI)

Wherein R is¹、R²、R^7AAnd R^7BEach having the meaning given above,

and finally reacting the compound of formula (XVI) under acidic conditions with an ammonia equivalent.

Inert solvents used in step (XI) → (XII) of the process are alcohols such as methanol, ethanol, N-propanol, isopropanol, N-butanol, tert-butanol or 1, 2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diglyme, 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. 1, 2-ethanediol is preferred.

The reaction (XI) → (XII) is usually carried out in a temperature range of +60 ℃ to +200 ℃, preferably +120 ℃ to +180 ℃. The reaction may be carried out at atmospheric pressure, under elevated or reduced pressure (e.g. from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Inert solvents for the reaction (XII) → (XIII) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diglyme, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. DMF is preferred.

Suitable lewis acids for the process step (XII) → (XIII) are boron trifluoride/diethyl ether complex, cerium (IV) ammonium nitrate (CAN), stannous (II) chloride, lithium perchlorate, zinc (II) chloride, indium (III) chloride or indium (III) bromide. Boron trifluoride/diethyl ether complexes are preferred.

The reaction (XII) → (XIII) is usually carried out in a temperature range of-78 ℃ to +40 ℃, preferably 0 ℃ to +20 ℃. The reaction may be carried out at atmospheric pressure, under elevated or reduced pressure (e.g. from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Inert solvents for the reaction (XIII) + (XIV) → (XV) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethylene or chlorobenzene, 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. DMF is preferred.

Suitable bases for step (XIII) + (XIV) → (XV) of the process are alkali metal hydrides, such as potassium hydride or sodium hydride, 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 ethoxide, or potassium tert-butoxide, amides, such as sodium amide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds, such as butyllithium or phenyllithium, or an organic amine 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). Cesium carbonate is preferred.

The reaction (XIII) + (XIV) → (XV) is usually carried out in a temperature range of from 0 ℃ to +60 ℃, preferably from +10 ℃ to +25 ℃. The reaction may be carried out at atmospheric pressure, under elevated or reduced pressure (e.g. from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Inert solvents for the process step (XV) → (XVI) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diglyme, 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 in a temperature range of +20 ℃ to +180 ℃, preferably +100 ℃ to +160 ℃, optionally in microwaves. The reaction may be carried out at atmospheric pressure, under elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

The reaction (XVI) → (II) is carried out in a two-step process using methods known to those skilled in the art, starting with the formation of the imidate ester using sodium methoxide in methanol at 0 ℃ to +40 ℃, followed by nucleophilic addition of an ammonia equivalent (e.g. ammonia or ammonium chloride) in a suitable acid and formation of the amidine (III) at +50 ℃ to +150 ℃.

Suitable acids for the formation of amidines (II) are inorganic acids such as hydrogen chloride/hydrochloric acid, sulfuric acid, polyphosphoric acid or phosphoric acid, or organic acids such as acetic acid, trifluoroacetic acid or formic acid. Hydrochloric acid or acetic acid is preferably used.

The preparation can be illustrated by the following synthetic scheme (scheme 3):

scheme 3

[ a): hydrazine hydrate, 1, 2-ethanediol; b) the method comprises the following steps Isoamyl nitrite, NaI and THF; c) the method comprises the following steps 1, 1, 1, 2, 2-pentafluoro-4-iodobutane, Cs₂CO₃、DMF；d)：CuCN、DMSO；e)：1)NaOMe、MeOH，2)NH₄Cl, acetic acid]。

Alternatively, the preparation of the compound of formula (II) is carried out as shown in the following synthetic scheme (scheme 4):

scheme 4

[ a): THF, dioxane; b) the method comprises the following steps NH (NH)₃(ii) a c) The method comprises the following steps Trifluoroacetic anhydride]。

Said compounds of formula (XI) are described in the literature [ see, for example, Winn m., j.med.chem.1993, 36, 2676-; EP 634413-A1; CN 1613849-A; EP 1626045-A1; WO 2009/018415 ], or can be prepared in analogy to the methods described in said documents, or can be prepared as shown in the following synthetic scheme (scheme 5):

scheme 5

[ a): sulfuric acid; b) the method comprises the following steps Zinc, methanol, glacial acetic acid; c) the method comprises the following steps Trifluoroacetic anhydride, dichloromethane ].

The compounds of the formulae (III) and (VII) are commercially available and are described in the literature or can be prepared by methods analogous to those described in the literature.

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 with respect to 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 intracellular cGMP increase. In addition, the compounds of the present invention potentiate the action of substances that can increase cGMP levels, such as EDRF (endothelial cell-derived relaxation factor), NO donors, protoporphyrin IX, arachidonic acid, or phenylhydrazine derivatives.

The compounds of the invention are suitable for the treatment and/or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic 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, betalipoproteinaemia, sitosterolemia, xanthomatosis, dangill 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-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 according to the invention for the treatment and/or prevention of the sequelae of renal insufficiency, such as emphysema, heart failure, uremia, anemia, electrolyte disorders (e.g. hypercalcemia, hyponatremia), and disorders of bone and carbohydrate metabolism.

In addition, the compounds of the invention are also suitable for use in the treatment and/or prevention of Pulmonary Arterial Hypertension (PAH) and other forms of Pulmonary Hypertension (PH), including pulmonary hypertension associated with left ventricular 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 in the central nervous system which are characterized by disturbances 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 focus, disorders of attention focus in children with learning and memory difficulties, alzheimer's disease, lewy body dementia, dementia associated with frontal lobe degeneration (including pick's syndrome, parkinson's disease, progressive nuclear palsy), dementia associated with corticobasal degeneration, Amyotrophic Lateral Sclerosis (ALS), huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia associated with dementia or coxsackhaki'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, CNS-related sexual dysfunction and sleep disorders, and of pathological disorders in which food intake, stimulants and addictive drugs are controlled.

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 after surgical procedures), 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, 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 insufficiency, 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 insufficiency, 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 insufficiency, thromboembolic disorders, fibrous disorders, and arteriosclerosis, using an effective amount 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 fibrinolytics (proteolytic substance);

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

Active compounds which alter lipid metabolism, such as, and preferably, thyroid receptor agonists, cholesterol synthesis inhibitors, such as, and preferably, HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, 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 substance 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 (rivaroxaban, BAY59-7939), DU-176b, apixaban (apixaban), omixaban (otamixaxban), fidaxaban (fidaxaban), rizaxaban (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.

The blood pressure lowering agent is preferably understood to mean a compound selected from the group consisting of: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an alpha-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 sartan (embursatan).

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

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

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

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

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

Modulators of lipid metabolism are preferably understood to mean compounds 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 acitirome (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 (impliptatide), BMS-201038, R-103757, or JTT-130.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-agonist, such as, and preferably, GW501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe (ezetimibe), tiquinane (tiqueside) or 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), colesevol (colesevolvam), colestyril (CholestaGel) or colestipol (colestimide).

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

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

The invention also provides a medicament comprising at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable adjuvants, and to the use thereof 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 administration forms suitable for these routes of administration.

Suitable administration forms for oral administration are those which function according to the prior art, release the compounds of the invention rapidly and/or in a gentle manner and contain the compounds of 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 juices or coatings which delay dissolution and which control the release of the compounds of the invention), tablets which disintegrate rapidly in the oral cavity or films/tablets (oplate), films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out while avoiding absorption steps (e.g., intravenous, intra-arterial, intracardiac, intravertebral or lumbar intramedullary) or including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal routes). Administration forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration, suitable examples are inhalation dosage 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, foams, sprinkles (sprinking powers), 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. Such adjuvants include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifying and dispersing agents or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, e.g. ascorbic acid), colorants (e.g. inorganic pigments, e.g. iron oxides) and flavouring and/or flavoring agents.

In general, it has been found advantageous to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg body weight for parenteral administration to achieve effective results. For oral administration, the dose is about 0.001 to 2 mg/kg, preferably 0.001 to 1 mg/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 the point in time or interval at which 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 parts by weight. The solvent ratio, dilution ratio and concentration values of the liquid/liquid solution are each based on volume.

A.Examples

Abbreviations and acronyms:

LC/MS method:

method 1 (LC-MS):

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

Method 2 (LC-MS):

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

Method 3(LC-MS)：

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

Starting materials and intermediates：

Example 1A

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

The synthesis is described in example 4 of WO 2006/130673.

Example 2A

2, 6-dichloro-5-fluoronicotinamide

A suspension of 25g (130.90mmol)2, 6-dichloro-5-fluoro-3-cyanopyridine in concentrated sulfuric acid (125ml) was stirred at 60-65 ℃ for 1 hour. After cooling to RT, the contents of the flask were poured into ice water and extracted three times with ethyl acetate (100ml each). The combined organic phases were washed with water (100ml) and then with saturated aqueous sodium bicarbonate solution (100ml), dried and concentrated on a rotary evaporator. The resulting material was dried under high vacuum.

Yield: 24.5g (90% of theory)

¹H-NMR(400MHz，DMSO-d₆)：=7.95(br s，1H)，8.11(br s，1H)，8.24(d，1H)。

Example 3A

2-chloro-5-fluoronicotinamide

44g (210.58mmol) of 2, 6-dichloro-5-fluoronicotinamide were added at RT to a suspension of 21.9g (335.35mmol) of zinc in methanol (207 ml). Acetic acid (18.5ml) was then added and the resulting mixture was heated under reflux with stirring for 24 hours. The contents of the flask were then poured out, separated from the zinc, ethyl acetate (414ml) and saturated aqueous sodium bicarbonate solution (414ml) were added and the extraction was then stirred vigorously. Subsequently, the resulting reaction mixture was filtered by suction through celite (kieselguhr), and the resulting filter cake was washed three times with ethyl acetate (517 ml each). The organic phase was removed and the aqueous phase was washed with ethyl acetate (258 ml). The combined organic phases were washed once with saturated aqueous sodium bicarbonate (414ml), dried and concentrated under reduced pressure. To the solid obtained in the manner described was added dichloromethane (388ml), and extraction was performed by stirring for 20 minutes. The mixture was again filtered with suction, and the resulting filter cake was then washed with diethyl ether and drained.

Yield: 20.2g (53% of theory)

¹H-NMR(400MHz，DMSO-d₆)：=7.87(br s，1H)，7.99(dd，1H)，8.10(br s，1H)，8.52(d，1H)。

Example 4A

2-chloro-5-fluoronicotinonitrile

81.2ml (582.25mmol) of triethylamine were added to a suspension of 46.2g (264.66mmol) of 2-chloro-5-fluoronicotinamide in dichloromethane (783ml), and the resulting mixture was cooled to 0 ℃. 41.12ml (291.13mmol) of trifluoroacetic anhydride are slowly added dropwise with stirring, and the mixture is then stirred at 0 ℃ for 1.5 hours. The reaction solution was subsequently washed twice with saturated aqueous sodium bicarbonate solution (391 ml each), dried and concentrated under reduced pressure.

Yield: 42.1g (90% of theory)

¹H-NMR(400MHz，DMSO-d₆)：=8.66(dd，1H)，8.82(d，1H)。

Example 5A

5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-amines

A suspension of 38.5g (245.93mmol) of 2-chloro-5-fluoronicotinonitrile was first added to 1, 2-ethanediol (380ml) and then hydrazine hydrate (119.6 ml). The resulting mixture was heated to reflux for 4 hours with stirring. Cooling resulted in precipitation of the resulting solid, which was mixed with water (380ml) and extracted by stirring at RT for 10 min. The suspension was then filtered with suction through a glass funnel (frat) and the filter cake was washed with water (200ml) and-10 ℃ THF (200 ml). The resulting solid was dried under high vacuum with phosphorus pentoxide.

Yield: 22.8g (61% of theory)

¹H-NMR(400MHz，DMSO-d₆)：=5.54(s，2H)，7.96(dd，1H)，8.38(m，1H)，12.07(m，1H)。

Example 6A

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

10g (65.75mmol) of 5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-amine are initially taken up in THF (329ml) and the resulting mixture is cooled to 0 ℃. Then 16.65ml (131.46mmol) of boron trifluoride/diethyl ether complex were slowly added. The resulting reaction mixture was further cooled to-10 ℃. A solution of 10.01g (85.45mmol) of isoamyl nitrite in THF (24.39ml) was then slowly added, and the resulting mixture was then stirred for an additional 30 minutes. The resulting mixture was diluted with cold diethyl ether (329ml) and the resulting solid was filtered off. The diazonium salt prepared in this way was added in small portions at 0 ℃ to a solution of 12.81g (85.45mmol) of sodium iodide in acetone (329ml) and the resulting mixture was stirred at RT for 30 minutes. The resulting reaction mixture was poured into ice water (1.8l) and extracted twice with ethyl acetate (487 ml each time). The collected organic phases were washed with saturated aqueous sodium chloride (244ml), dried, filtered and concentrated. 12.1g of the title compound are obtained in the form of a solid (purity 86%, 60% of theory).

LC-MS (method 2): r_t=1.68min

MS(ESIpos)：m／z＝264(M+H)⁺。

Example 7A

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

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

LC-MS (method 2): r_t=1.30min

MS(ESIpos)：m／z=410(M+H)^＋

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

Example 8A

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

A suspension of 4.34g (10.609mmol) of example 7A and 1.045g (11.670mmol) of copper (I) cyanide is initially introduced into DMSO (30ml) and stirred at 150 ℃ for 2 hours. After cooling, the resulting mixture was filtered through Celite (Celite), the resulting filter cake was washed with ethyl acetate and THF, and the resulting filtrate was extracted four times with a solution of saturated aqueous ammonium chloride and concentrated aqueous ammonia (3: 1 v/v). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure.

Yield: 3.19g (97% of theory)

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

Example 9A

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

3.19g (10.351mmol) of example 8A are added to 0.559g (10.351mmol) of sodium methoxide dissolved in methanol (25ml) and the mixture is stirred at RT for 2 hours. Then 0.664g (12.421mmol) of ammonium chloride and acetic acid (2.31ml) were added, and the resulting mixture was heated under reflux overnight. The resulting mixture was then concentrated to dryness, and the resulting residue was mixed with ethyl acetate and 1N sodium hydroxide solution. The phases were separated. The resulting aqueous phase was extracted once more with ethyl acetate. The combined organic phases were combined and concentrated. The resulting crude product can be reacted further without further purification.

Yield: 2.67g (37% of theory, purity about 56%)

LC-MS (method 2): r_t=0.68min

MS(ESIpos)：m／z＝326(M+H)⁺。

Example 10A

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

In THF (91ml), 3g (45.411mmol) of malononitrile were slowly added to 1.816g (45.411mmol) of sodium hydride (60% in mineral oil). Subsequently, 5.876ml (45.411mmol) of methyl 2-bromo-2-methylpropionate were added, and the resulting mixture was stirred at room temperature overnight. Thereafter an additional 5.876ml (45.411mmol) methyl 2-bromo-2-methylpropionate were added and the resulting mixture was heated at 50 ℃ overnight. Then another 1.762ml (13.623mmol) of methyl 2-bromo-2-methylpropionate were added and the resulting mixture was heated at 50 ℃ for another 4 hours. Then, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction, and the resulting 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 11A

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

10.00g (40.813mmol) of example 1A were initially taken in DMF (170ml) and 12.30g (44.894mmol) of 1, 1, 1, 2, 2-pentafluoro-4-iodobutane and 14.628g (44.894mmol) of cesium carbonate dissolved in DMF (30ml) were then added. The resulting mixture was stirred at RT for 2 days. Subsequently, another 12.30g (44.894mmol) of 1, 1, 1, 2, 2-pentafluoro-4-iodobutane and 14.628g (44.894mmol) of cesium carbonate were added and the resulting mixture was stirred at RT for 2 days. Thereafter, 3.485g (12.720mmol)1, 1, 1, 2, 2-pentafluoro-4-iodobutane and 4.145g (12.720mmol) cesium carbonate were added and the resulting mixture was stirred at RT overnight. After this period, 5.00g (18.250mmol) of 1, 1, 1, 2, 2-pentafluoro-4-iodobutane and 5.946g (18.250mmol) of cesium carbonate were added and the resulting mixture was stirred at room temperature for 6 days. The resulting mixture was then stirred at 70 ℃ for 2 days. The solid was filtered off with suction and washed with DMF, and the resulting liquid was then concentrated under high vacuum. The resulting residue was purified by preparative HPLC (methanol: water (with 0.1% formic acid) gradient). This gives 5.48g of the title compound (34% of theory).

LC-MS (method 1): r_t=1.23min

MS(ESIpos)：m／z＝392(M+H)^＋

¹H-NMR(400MHz，DMSO-d₆)：=2.87-3.00(m，2H)，4.81(t，2H)，7.33(dd，1H)，7.97(dd，1H)，8.65(dd，1H).

Example 12A

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

A suspension of 5.480g (14.012mmol) of cuprous cyanide from example 11A and 1.380g (15.414mmol) was initially added to DMSO (50ml) and stirred at 150 ℃ for 3 hours.

After cooling, the resulting mixture was filtered through celite, and the resulting filter cake was washed with ethyl acetate and THF. It was then washed four times with a solution of saturated aqueous ammonium chloride and concentrated aqueous ammonia (3: 1, v/v) and then with saturated aqueous sodium chloride. The resulting organic phase was dried over sodium sulfate, filtered and concentrated, then dried under high vacuum.

Yield: 3.59g (88% of theory)

LC-MS (method 2): r_t=1.04min

MS(ESIpos)：m／z=291(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：=2.97-3.10(m，2H)，4.94(t，2H)，7.55(dd，1H)，8.51(dd，1H)，8.81(dd，1H).

Example 13A

1- (3, 3,4,4, 4-Pentafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridine-3-carboxamidine acetate

3.59g (12.371mmol) of example 12A in methanol (20ml) are added to 0.668g (12.371mmol) of sodium methoxide in methanol (40ml) and the resulting mixture is stirred at RT for 2 hours, then 0.794g (14.845mmol) of ammonium chloride and acetic acid (2.762ml) are added and the resulting mixture is heated under reflux overnight. Thereafter, the resulting mixture was concentrated to dryness, and the resulting residue was mixed with ethyl acetate and 1N sodium hydroxide solution. The resulting mixture was stirred vigorously at RT for about 1 hour. The resulting solid was filtered off with suction and washed with ethyl acetate and water. The resulting residue was dried under high vacuum. This gives 0.507g of product (11% of theory). The phases of the combined filtrates were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, then dried under high vacuum. This gives in turn 2.76g (43% of theory, purity approx. 70%).

LC-MS (method 2): r_t=0.58min

MS(ESIpos)：m／z=308(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：=1.84(s，3H)，2.95-3.08(m，2H)，4.85(t，2H)，7.39(dd，1H)，8.63-8.67(m，2H).

Example 14A

1- (3, 3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridine-3-carboximidoyl hydrazide

0.6g (approx. 1.144mmol) of the compound from example 13A are dissolved in 10ml of ethanol and 462mg (4.574mmol) of triethylamine and 71mg (1.144mmol) of hydrazine hydrate (80% strength in water) are added at 0 ℃. The resulting mixture was stirred at RT overnight and then concentrated on a rotary evaporator. 689mg of the title compound (purity about 60%) were obtained.

LC-MS (method 2): r_t=0.57min；MS(ESIpos)：m／z=323(M+H)⁺

Example 15A

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

0.62g (0.901mmol) of the compound from example 9A (purity approx. 56%) are dissolved in 10.3ml of ethanol, and 456mg (4.506mmol) of triethylamine and 70mg (1.126mmol) 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. This gives the crude compound which can be reacted further directly.

LC-MS (method 1): r_t=0.61min；MS(ESIpos)：m／z=341(M+H)⁺

Example 16A

2- { 5-hydroxy-3- [1- (3, 3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -1, 2, 4-triazin-6-yl } -2-methylpropionic acid methyl ester

The crude material from example 14A (about 1.144mmol) was dissolved in 15ml of ethanol and 430mg (2.288mmol) of dimethyl 2, 2-dimethyl-3-oxosuccinate (described in J.Am.chem.Soc.124(14), 3680-3691; 2002) were added. The resulting mixture was stirred at RT overnight and then heated to reflux for 1 h. After cooling, the resulting solid is filtered off with suction and washed with ethanol, and the resulting filtrate is concentrated. To the residue obtained, diethyl ether was added and the precipitate formed was filtered off and washed with diethyl ether. The resulting filtrate was concentrated, and the resulting residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). This gave 264mg of the title compound (50% of theory).

LC-MS (method 2): r_t=1.03min；MS(ESIpos)：m／z=461(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.46(s，6H)，3.06-3.17(m，2H)，3.57(s，3H)，4.95(t，2H)，7.51(dd，1H)，8.70(dd，1H)，8.75(dd，1H)，14.52(s，1H).

Example 17A

2- {3- [ 5-fluoro-1- (3, 3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-hydroxy-1, 2, 4-triazin-6-yl } -2-methylpropanoic acid methyl ester

The crude material from example 15A (ca. 0.845mmol) was dissolved in 10ml of ethanol, and 318mg (1.689mmol) of dimethyl 2, 2-dimethyl-3-oxosuccinate (described in J.Am.chem.Soc.124(14), 3680-3691; 2002) were added. The mixture was stirred at RT overnight and then heated to reflux for 6 h. After cooling, the resulting filtrate was concentrated and the residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). This gave 291mg of the title compound (72% of theory).

LC-MS (method 2): rt =1.04 min; ms (esipos): m/z =479(M + H)⁺

¹H-NMR(400MHz.DMSO-d₆)：[ppm]=1.46(s，6H)，3.07-3.14(m，2H)，3.56(s，3H)，4.94(t，2H)，8.40(d，1H)，8.85(br s，1H)，14.56(s，1H).

Example 18A

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

500mg (1.361mmol) of example 13A are initially introduced into tert-butanol (7.5ml) and 183mg (1.361mmol) of potassium tert-butoxide are added. 226mg (1.361mmol) of example 10A in tert-butanol (2.5ml) are subsequently added dropwise and the mixture is heated to reflux overnight. After cooling, ethyl acetate and water were added, the phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue obtained is stirred with methanol and the solid is filtered off with suction. The resulting solid was vigorously stirred with methanol, and the combined filtrates were concentrated and then purified using preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). This gave 127mg of the title compound (21% of theory).

LC-MS (method 2): r_t=0.93min；MS(ESIpos)：m／z=442(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.36(s，6H)，2.91-3.04(m，2H)，4.88(t，2H)，6.83(brs，2H)，7.38(dd，1H)，8.63(dd，1H)，9.02(dd，1H)，11.01(br s，1H).

Example 19A

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

520mg (1.350mmol) of example 9A are initially introduced into tert-butanol (10ml) and 181mg (1.620mmol) of potassium tert-butoxide are added. Subsequently, 224mg (1.350mmol) of example 10A dissolved in tert-butanol (2.5ml) were added and the resulting mixture was heated under reflux overnight. Then an additional 112mg (0.675mmol) of example 10A were added and the resulting mixture heated to reflux for an additional 7.5 h. After cooling, water and ethanol were added and the reaction mixture was treated in an ultrasonic bath for 1 h. The precipitate formed is filtered off with suction and washed with water. The filter cake obtained is stirred with a small amount of ethanol (2-3ml) and filtered off with suction once more. The resulting solid was dried under high vacuum. This gave 212mg of the title compound (34% of theory).

LC-MS (method 1): r_t=1.01min；MS(ESIpos)：m／z=460(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.36(s，6H)，2.92-3.04(m，2H)，4.87(t，2H)，6.88(brs，2H)，8.71(br s，1H)，8.85(dd，1H)，1].01(br s，1H).

Example 20A

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

155mg (0.351mmol) of example 18A were first added to isoamyl nitrite (1.017ml) and diiodomethane (2.655ml) and heated at 85 ℃ for 2 days. After cooling, the solid was filtered off and washed with cyclohexane, and the resulting solid was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). This gave 39mg of the title compound (20% of theory).

LC-MS (method 2): r_t=1.21min；MS(ESIpos)：m／z=553(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.44(s，6H)，2.96-3.06(m，2H)，4.94(t，2H)，7.48(dd，1H)，8.69(dd，1H)，8.79(dd，1H)，11.80(br s，1H).

Example 21A

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

142mg (0.310mmol) of example 19A were first added to isoamyl nitrite (0.90ml) and diiodomethane (2.4ml) and heated at 85 ℃ overnight. More isoamyl nitrite (1ml) was then added and the resulting mixture heated at 85 ℃ for an additional 22 h. More isoamyl nitrite (1ml) was then added and the resulting mixture heated at 85 ℃ for an additional 12 h. After cooling, the resulting solid was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). This gave 71mg of the title compound (40% of theory).

LC-MS (method 2): r_t=1.28min；MS(ESIpos)：m／z=571(M+H)⁺

Example 22A

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

10.000g (38.021mmol) of 5-fluoro-3-iodo-1H-pyrazolo [3, 4-b ] pyridine and 13.627g (41.823) of cesium carbonate were initially introduced into 270ml of DMF and 8.785g (41.823mmol) of (iodomethyl) cyclopentane were added. The reaction mixture was stirred at RT overnight, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. This gave 6.370g of the expected compound (purity 83%, 49% of theory) which were reacted further as crude product.

LC-MS (method 2): r_t=1.37min；MS(ESIpos)：m／z=346(M+H)⁺

Example 23A

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

6.370g (purity 83%, 15.447mmol)1- (cyclopentylmethyl) -5-fluoro-3-iodo-1H-pyrazolo [3, 4-b ] pyridine and 1.522g (16.992mmol) copper (I) cyanide were initially introduced into 45ml pure DMSO under an argon atmosphere and the resulting mixture was heated at 150 ℃ for 1.5H. After cooling, the reaction was diluted with methanol and filtered through Celite (Celite). The organic phase is washed twice with a mixture of 25% strength aqueous ammonia solution and saturated aqueous ammonium chloride solution (v/v = 1: 3), then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. This gives 3.670g of the expected compound (purity 86%, 97% of theory).

LC-MS (method 1): r_t=2.56min；MS(ESIpos)：m／z=245(M+H)⁺

Example 24A

1- (Cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridine-3-carboxamidine acetate

296mg (12.861mmol) of sodium are stirred in small portions into methanol under an argon atmosphere. After the sodium had been consumed 3.670g (purity 86%, ca. 12.861mmol) of 1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridine-3-carbonitrile were added in small portions at a time, and the resulting mixture was stirred at RT for 2H. Then 3.004g (50.021mmol) of acetic acid and 825mg (15.433mmol) of ammonium chloride were added and the resulting mixture was boiled under reflux overnight. The reaction mixture obtained is concentrated, the residue obtained is triturated with 1N sodium hydroxide solution and the precipitate obtained is filtered off with suction and dried under high vacuum. This gives 2.840g (98% pure, 83% of theory) of the target compound.

LC-MS (method 2): r_t=0.67min；MS(ESIpos)：m／z=262(M+N)⁺

Example 25A

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

30ml of tert-butanol, 1.068g (6.429mmol) of methyl 3, 3-dicyano-2, 2-dimethylpropionate and 901mg (8.037mmol) of potassium tert-butoxide dissolved in 15ml of tert-butanol were added to 1.400g (5.358mmol) of 1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridine-3-carboxamidine and the resulting mixture was heated under reflux for 24H. The reaction mixture obtained is concentrated on a rotary evaporator, triturated with 60ml of water/ethanol (v/v = 5: 1), filtered off with suction and dried under high vacuum. This gives 1.296g (57% of theory) of the target compound.

LC-MS (method 1): r_t=1.04min；MS(ESIpos)：m／z=396(M+H)⁺

Example 26A

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

40.549g (151.398mmol) diiodomethane and 4.420g (37.738mmol) isoamyl nitrite were added to 711mg (1.799mmol) 4-amino-2- [1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2, 3-d ] pyrimidin-6-one. The resulting mixture was heated at 85 ℃ for 8 h. After cooling, the resulting mixture was filtered, and the resulting filtrate was diluted with cyclohexane and filtered with suction through silica gel. The silica gel was washed with cyclohexane and the resulting product was eluted with dichloromethane/methanol (v/v = 50: 2). The collected fractions were concentrated on a rotary evaporator, added to 20ml ethyl acetate and 5ml isopropanol, filtered and concentrated again. The residue obtained is triturated with 5ml of isopropanol. The resulting solid is filtered off with suction and dried under high vacuum. This gives 230mg of the target compound (purity 92%, 23% of theory).

LC-MS (method 1): r_t=1.41min；MS(ESIpos)：m／z=507(M+H)⁺

Example 27A

1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridine-3-carboximidoyl hydrazide

1.400g (5.358mmol) of 1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridine-3-carboxamidine are initially taken up in 26ml of ethanol and the resulting mixture is cooled to 0 ℃. 2.169g (21.431mmol) triethylamine and 335mg (5.358mmol) 80% strength hydrazine hydrate are added and the resulting mixture is stirred at room temperature for 18 h. The resulting mixture was concentrated on a rotary evaporator, dissolved in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, concentrated on a rotary evaporator and dried under high vacuum. This gives 1.070g of the target compound (purity 77%, 56% of theory).

LC-MS (method 2): r_t=0.67min；MS(ESIpos)：m／z=277(M+H)⁺

Example 28A

2- {3- [1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-hydroxy-1, 2, 4-triazin-6-yl } -2-methylpropionic acid methyl ester

841mg (4.473mmol) of dimethyl 2, 2-dimethyl-3-oxosuccinate were first added to 20ml of ethanol, and the resulting mixture was heated under reflux. Subsequently, 1.070g (2.982mmol)1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridine-3-carboximidoyl hydrazide suspended in 26ml ethanol are added and the resulting mixture is boiled under reflux overnight. After cooling, the resulting mixture was concentrated, dissolved with acetonitrile and filtered. The resulting filtrate was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient: 30: 70 → 100: 0). This gives 396mg of the target compound (32% of theory).

LC-MS (method 2): rt =1.15 min; ms (esipos): m/z =415(M + H)⁺

Example 29A

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

In a manner analogous to that of example 22A, 10.00g (38.021mmol) of example 6A are reacted with 4-methoxybenzyl chloride. Chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate mixture) gave 8.94g of the title compound (61% of theory).

LC-MS (method 2): r_t=1.25min

MS(ESIpos)：m／z＝384(M+H)^＋。

Example 30A

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

8.94g (23.332mmol) of example 29A were reacted in a similar manner to the process of example 23A. The crude product obtained in this way was reacted without further purification.

Yield: 6.52g (99% of theory)

LC-MS (method 2): r_t=1.11min

MS(ESIpos)：m／z＝283(M+H)⁺。

Example 31A

5-fluoro-1- (4-methoxybenzyl) -1H-pyrazolo [3, 4-b ] pyridine-3-carboxamidine acetate

6.52g (23.098mmol) of example 30A were reacted in a similar manner to the process of example 13A.

Yield: 6.16g (74% of theory)

LC-MS (method 1): r_t=0.55min

MS(ESIpos)：m／z=300(M+H)⁺

Example 32A

5-fluoro-1- (4-methoxybenzyl) -1H-pyrazolo [3, 4-b ] pyridine-3-carboximidoyl hydrazide

6.16g (17.141mmol) of example 31A were reacted in a similar manner to the process of example 27A. This gives 4.90g of the title compound (90% of theory).

LC-MS (method 1): r_t=0.57min；MS(ESIpos)：m／z=315(M+H)⁺

Example 33A

2- {3- [ 5-fluoro-1- (4-methoxybenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-hydroxy-1, 2, 4-triazin-6-yl } -2-methylpropionic acid methyl ester

In a manner analogous to the process of example 28A, 4.89g (15.557mmol) of the compound from example 32A are reacted with 4.391mg (23.336mmol) of dimethyl 2, 2-dimethyl-3-oxosuccinate (described in J.Am.chem.Soc.124(14), 3680-3691; 2002). After the reaction has been completed, the solid is filtered off, washed with ethanol and then dried under high vacuum. This gives 6.04g of the title compound (85% of theory).

LC-MS (method 1): r_t=1.05min；MS(ESIpos)：m／z=453(M+H)⁺

Example 34A

3- [ 5-fluoro-1- (4-methoxybenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -7, 7-dimethyl-5, 7-dihydro-6H-pyrrolo [2, 3-e ] [1, 2, 4] triazin-6-one

6.04g (13.350mmol) of the compound from example 33A were reacted in a similar manner to the process of example 1. After drying under high vacuum, this gives 1.27g of the title compound (22% of theory).

LC-MS (method 2): r_t=1.02min；MS(EIpos)：m／z=420[M+H]⁺

¹H-NMR(400MHz，DMSO-d₆，)：[ppm]=1.45(s，6H)，3.70(s，3H)，5.75(s，2H)，6.88(d，2H)，7.29(d，2H)，8.53(dd，1H)，8.78(dd，1H)，12.18(s br，1H).

Example 35A

3- [ 5-fluoro-1- (4-methoxybenzyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -7, 7-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5, 7-dihydro-6H-pyrrolo [2, 3-e ] [1, 2, 4] triazin-6-one

2.067g (6.345mmol) of cesium carbonate in DMF (30ml) were added to 2.45g (5.768mmol) of the compound from example 34A. Then 1.221ml (6.922mmol) of 2- (trimethylsilyl) ethoxymethyl chloride were added and the resulting mixture was stirred at room temperature for 1 h. The resulting solid was then filtered off and washed with DMF, the resulting filtrate was concentrated, and the resulting residue was dried under high vacuum. This gave 4.45g of crude product, which was used in the next step without further purification.

LC-MS (method 2): r_t=1.43min；MS(EIpos)：m／z=550[M+H]⁺

Example 36A

3- [ 5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -7, 7-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5, 7-dihydro-6H-pyrrolo [2, 3-e ] [1, 2, 4] triazin-6-one

4.148g (7.546mmol) of the compound from example 35A were dissolved in acetonitrile (110ml) and water (55ml), 12.411g (22.638mmol) of ammonium cerium (IV) nitrate were added, and the resulting mixture was stirred at room temperature for 20 min. Then a large amount of water was added and the precipitate was filtered off. The solid was washed with water and then with a small amount of diethyl ether. After drying under high vacuum, this gives 1.53g of the title compound (47% of theory).

LC-MS (method 2): r_t=1.14min；MS(EIpos)：m／z=430[M+H]⁺

Example 37A

3- [ 5-fluoro-1- (3, 3,4, 4-tetrafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -7, 7-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5, 7-dihydro-6H-pyrrolo [2, 3-e ] [1, 2, 4] triazin-6-one

In a manner analogous to that of example 7A, 0.150g (0.349mmol) of the compound from example 36A were reacted with 1-bromo-3, 3,4, 4-tetrafluorobutane. In this case, potassium iodide was not added. After filtration, the resulting product was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). This gave 97mg of the title compound (N1/N2-alkylated in a ratio of 3.2: 1) (50% of theory) as a mixture of isomers.

LC-MS (method 2): r_t=1.36min (N2) and 1.38min (N1); ms (eipos): m/z =558[ M + H ]]⁺

Example 38A

3- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl } -7, 7-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5, 7-dihydro-6H-pyrrolo [2, 3-e ] [1, 2, 4] triazin-6-one

In a flask, 137mg (0.524mmol) of triphenylphosphine were dissolved in 4ml of tetrahydrofuran, and the resulting mixture was cooled to 0 ℃. Then 101. mu.l (0.524mmol) of diisopropyl azodicarboxylate were added and the resulting solution was stirred at 0 ℃ for 1h (solution 1). In another flask, 0.150g (0.349mmol) of the compound from example 36A and 64mg (0.542mmol) of 3, 3-difluorocyclobutylmethanol were dissolved in tetrahydrofuran (6ml) and the resulting mixture was cooled to 0 ℃ (solution 2). Then, solution 1 was added to this solution 2, and the resulting mixture was stirred at room temperature overnight. Subsequently, solution 1 was prepared again as described above using 274mg (1.048mmol) of triphenylphosphine and 203. mu.l (1.048mmol) of diisopropyl azodicarboxylate, and added to the reaction system at 0 ℃ together with 127mg (1.048mmol) of 3, 3-difluorocyclobutylmethanol and dichloromethane (5 ml). After stirring at room temperature overnight, the resulting product was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). This gave 102mg of the title compound as an isomer mixture (N1/N2-alkylated in a ratio of 1.4: 1) (55% of theory).

LC-MS (method 2): r_t=1.38min (N2) and 1.41 min (N1); ms (eipos): m/z =558[ M + H ]]⁺

Example 39A

(Dicyanomethyl) (methyl) malonic acid diethyl ester

19.156g (75.686mmol) diethyl 2-bromo-2-methylmalonate and 5g (75.686mmol) malononitrile were first added to THF (120ml) and then 8.493g (75.686mmol) potassium tert-butoxide were added. The resulting mixture was then heated to reflux overnight. Ethyl acetate and saturated ammonium chloride solution were then added to the reaction system, and the phases were separated. The aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. This gives the crude product which is purified by chromatography on a gel (cyclohexane/ethyl acetate 9: 1).

Yield: 5.94g (32% of theory)

¹H-NMR(400MHz，CDCl₃)：[ppm]=1.32(t，6H)，1.80(s，3H)，4.28-4.37(m，4H)，4.53(s，1H).

Example 40A

4-amino-5-methyl-6-oxo-2- [1- (3, 3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -6, 7-dihydro-5H-pyrrolo [2, 3-d ] pyrimidine-5-carboxylic acid ethyl ester

0.5g (1.361mmol) of example 13A (70% pure) are initially taken in tert-butanol (10ml) and 272mg (2.723mmol) of potassium hydrogencarbonate are added. 372mg (1.566mmol) of example 39A were then added and the resulting mixture was heated under reflux for 5 h. After cooling, water was added, the resulting mixture was stirred for 30 minutes, and then the precipitate was filtered off. The precipitate was washed with a small amount of water and diethyl ether and dried under high vacuum overnight. This gave 0.458g of the title compound with a purity of 94% (63% of theory).

LC-MS (method 2): r_t=1.00min；MS(ESIpos)：m／z=500(M+H)⁺

Example 41A

4-bromo-5-methyl-6-oxo-2- [1- (3, 3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -6, 7-dihydro-5H-pyrrolo [2, 3-d ] pyrimidine-5-carboxylic acid ethyl ester

437mg (0.875mmol) of example 40A were initially charged with 1, 2-dichloroethane (14.2ml) and 0.176ml (1.313mmol) of isoamyl nitrite and 234mg (1.050mmol) of copper (II) bromide were added. The resulting compound was then heated at 65 ℃ for 10 h. After cooling, water and dichloromethane were added and the phases were separated. The aqueous phase is extracted once with ethyl acetate, and the combined organic phases are dried over sodium sulfate and concentrated, and the residue is purified by preparative chromatography on silica gel (mobile phase: dichloromethane/methanol 66: 1). This gave 0.393g of the title compound with a purity of about 90% (89% of theory).

LC-MS (method 2): r_t=1.23min；MS(ESIpos)：m／z=563(⁷⁹Br)，565(⁸¹Br)(M+H)⁺

Working examples are as follows:

example 1

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

4ml of phosphorus oxychloride were added to 263mg (0.571mmol) of the compound from example 16A and the resulting mixture was stirred at RT overnight. The resulting reaction mixture was dissolved in 38ml of acetonitrile and stirred into 24ml of a concentrated aqueous ammonia solution (concentration 33%) with ice cooling. The resulting mixture was stirred at RT for 2 days. Then, the resulting reaction mixture was 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 ethanol. The residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). This gave 119mg of the title compound (49% of theory).

LC-MS (method 2): r_t=0.98min；MS(EIpos)：m／z=428[M+H]⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.47(s，6H)，2.96-3.07(m，2H)，4.95(t，2H)，7.48(dd，1H)，8.71(dd，1H)，8.85(dd，1H)，12.21(br s，1H).

Example 2

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

4.172ml of phosphorus oxychloride were added to 290mg (0.606mmol) of the compound from example 17A and the resulting mixture was stirred at RT overnight. The resulting reaction mixture was dissolved in 40ml of acetonitrile and stirred into 27ml of a concentrated aqueous ammonia solution (concentration 33%) with ice cooling. The resulting mixture was stirred at room temperature for 2 days. Then, the resulting reaction mixture was concentrated. The residue obtained is added to water and ethanol and treated in an ultrasonic bath. A precipitate formed which was filtered off with suction and washed with water, ethanol and then with diethyl ether. DMF is added to the residue, acetonitrile and water are added, and the mixture is filtered off with suction again. The resulting precipitate was washed with acetonitrile and water and then dried under high vacuum. This gave 149mg of the title compound (52% of theory, purity 94%).

LC-MS (method 2): r_t=1.05min；MS(EIpos)：m／z=446[M+H]⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.47(s，6H)，2.96-3.07(m，2H)，4.95(t，2H)，8.56(dd，1H)，8.80(br s，1H)，12.21(br s，1H).

Example 3

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

39mg (0.071mmol) of example 20A were dissolved in DMF (4ml) and added to 20mg palladium on carbon (10%) dissolved in 1ml of DMF and the resulting mixture was hydrogenated at standard pressure for 12 h. The resulting mixture was then filtered through Celite (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). This gave 22mg of the title compound (74% of theory).

LC-MS (method 2): r_t=1.02min；MS(ESIpos)：m／z=427(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.39(s，6H)，2.96-3.06(m，2H)，4.92(t，2H)，7.43(dd，1H)，8.66-8.69(m，2H)，8.86(dd，1H)，11.61(br s，1H).

Example 4

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

39mg (0.068mmol) of example 21A are dissolved in DMF (5ml), 20mg of palladium on carbon (10%) are added and the resulting mixture is hydrogenated under standard pressure for 12 h. The resulting mixture was then filtered through Celite (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). This gave 8mg of the title compound (74% of theory).

LC-MS (method 2): r_t=1.10min；MS(ESIpos)：m／z=445(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.39(s，6H)，2.96-3.06(m，2H)，4.91(t，2H)，8.59(dd，1H)，8.65(m，1H)，8.76(dd，1H)，11.60(br s，1H).

Example 5

2- [1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2, 3-d ] pyrimidin-6-one

230mg (0.454mmol) of 2- [1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -4-iodo-5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2, 3-d ] pyrimidin-6-one are dissolved in 8ml of pure DMF, 150mg of 10% palladium on charcoal are added and the resulting mixture is hydrogenated with hydrogen under standard pressure for 3 hours. The resulting mixture was filtered through Celite (Celite) and concentrated. The residue obtained is triturated with 4ml of acetonitrile, filtered off with suction and dried under high vacuum. This gives 123mg of the expected compound (purity 94%, 67% of theory).

LC-MS (method 1): r_t=1.18min；MS(ESIpos)：m／z=381(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.30-1.65(m，14H)，2.56-2.63(m，1H)，4.50(d，2H)，8.57(dd，1H)，8.65(s，1H)，8.71(dd，1H)，11.64(s br，1H).

Example 6

3- [1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -7, 7-dimethyl-5, 7-dihydro-6H-pyrrolo [2, 3-e ] [1, 2, 4] triazin-6-one

5ml (53.642mmol) of phosphorus oxychloride were added to 376mg (0.863mmol) of methyl 2- {3- [1- (cyclopentylmethyl) -5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -5-hydroxy-1, 2, 4-triazin-6-yl } -2-methylpropionate, and the resulting mixture was stirred at room temperature overnight. The resulting reaction solution was diluted with 20ml of dry acetonitrile and 83ml of 25% strength aqueous ammonia solution was slowly added dropwise with ice cooling, and the resulting mixture was stirred at RT overnight. The resulting reaction mixture was concentrated on a rotary evaporator and the resulting precipitate was filtered off. The residue obtained is triturated with DMF/methanol, filtered off with suction and dried under high vacuum. This gives 84mg of the target compound (24% of theory).

LC-MS (method 1): r_t=1.12min；MS(EIpos)：m／z=382[M+H]⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.30-1.65(m，14H)，2.57-2.63(m，1H)，4.53(d，2H)，8.54(dd，1H)，8.74(dd，1H).

Example 7

3- [ 5-fluoro-1- (3, 3,4,4, -tetrafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -7, 7-dimethyl-5, 7-dihydro-6H-pyrrolo [2, 3-e ] [1, 2, 4] triazin-6-one

96mg (0.173mmol) of the compound from example 37A are stirred in dichloromethane (4ml) and trifluoroacetic acid (1ml) for 4.5 h at room temperature. The resulting mixture was then concentrated to dryness. The residue was stirred in ethanol/2N hydrochloric acid (4: 1, 15ml) at 45 ℃ for 3 hours. Then concentrated to dryness. Purification by preparative HPLC (methanol: water (+ 1% trifluoroacetic acid) gradient) gives 31mg of the title compound (42% of theory).

LC-MS (method 2): r_t=0.95min；MS(EIpos)：m／z=428[M+H]⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.47(s，6H)，2.76-2.87(m，2H)，4.89(t，2H)，6.39-6.62(m，1H)，8.55(dd，1H)，8.78(dd，1H)，12.17(s br，1H).

Example 8

3- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -5-fluoro-1H-pyrazolo [3, 4-b ] pyridin-3-yl } -7, 7-dimethyl-5, 7-dihydro-6H-pyrrolo [2, 3-e ] [1, 2, 4] triazin-6-one

In a manner analogous to the method of example 7, 100mg (0.189mmol) of the compound from example 38A are reacted. Purification by preparative HPLC (acetonitrile: water (+ 1% trifluoroacetic acid) gradient) gives 15mg of the title compound (19% of theory).

LC-MS (method 1): r_t=1.00min；MS(EIpos)：m／z=404[M+H]⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=1.47(s，6H)，2.47-2.54(m，2H，von Solventüberlagert)，2.64-2.73(m，2H)，2.78-2.86(m，1H)，4.75(d，2H)，8.54(dd，1H)，8.76(dd，1H)，12.14(s br，1H).

Example 9

5-methyl-6-oxo-2- [1- (3, 3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -6, 7-dihydro-5H-pyrrolo [2, 3-d ] pyrimidine-5-carboxylic acid ethyl ester

In a manner analogous to the process of example 3, 190mg (0.304mmol, approx. 90% purity) of example 41A are hydrogenated. This gave 36mg of the title compound (18% of theory) in a purity of 77%.

LC-MS (method 2): r_t=1.08min；MS(ESIpos)：m／z=485(M+H)⁺

Example 10

N-cyclopropyl-5-methyl-6-oxo-2- [1- (3, 3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3, 4-b ] pyridin-3-yl ] -6, 7-dihydro-5H-pyrrolo [2, 3-d ] pyrimidine-5-carboxamide (racemic compound)

34mg (0.054mmol, 77% purity) of example 9 are dissolved in methanol (0.5ml) and 30mg (0.540mmol) of cyclopropylamine are added. The resulting mixture was then treated in a microwave at 80 ℃ for 1 day. Purification by preparative HPLC (acetonitrile: water (+ 0.1% formic acid) gradient) gives 13mg of the title compound (50% of theory).

LC-MS (method 2): r_t=0.99min；MS(EIpos)：m／z=496[M+H]⁺

¹H-NMR(400MHz，DMSO-d₆)：[ppm]=0.41-0.46(m，2H)，0.59-0.61(m，2H)，1.61(s，3H)，2.62-2.66(m，1H)，2.95-3.08(m，2H)，4.93(t，2H)，7.44(dd，1H)，7.75(d，1H)，8.58(s，1H)，8.68(dd，1H)，8.87(dd，1H)，11.79(s，1H).

B.Pharmacological efficacy assessment

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

B-1.in vitro vasodilatory action

Rabbits were stunned by neck pounding and exsanguinated. The aorta was removed, the adherent tissue removed, and divided into 1.5mm wide sectionsRings, which were placed individually under preload in a 5ml organ bath containing a 37 ℃ Krebs-Henseleit solution aerated with carbopol gas, the solution having the following composition (in mM in each case): 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. contractile force was recorded with Statham UC2 cells, amplified and digitized using an A/D converter (DAS-1802HC, Keithley instruments Munich), and then recorded in parallel in a strip recorder (line recorder). To produce contraction, phenylephrine is added incrementally to the bath at increasing concentrations. After several control cycles, the substance to be investigated is added in increasing doses in each subsequent cycle and the height of contraction reached is compared with the height of contraction reached in the immediately preceding cycle. This was used to calculate the concentration required to reduce the level of the control value by 50% (IC)₅₀Value). The standard administration volume was 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]
		1	263
2	129
		3	46
4	101
		5	23
6	102

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

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

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

TABLE 2：

Example numbering	MEC[μM]
		1	0.3
2	0.1
		3	0.03
4	0.03
		5	0.1
6	0.1

Example numbering	MEC[μM]
		7	0.3
8	3.0

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 Inc.

The system consists of 3 main components:

-an implantable emitter(s) (ii)Remote measuring emitter

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

-a data acquisition computer.

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

Animal material

The study was carried out in adult female spontaneously hypertensive rats (SHROkamoto) with a body weight >200 g. SHR/NCrl from Okamoto Kyoto School of Medicine (1963) is a hybrid of male Wistar Kyoto rats with greatly elevated blood pressure and female rats with slightly elevated blood pressure and was delivered at F13 to the national Institutes of Health (u.s.national Institutes of Health).

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

The day/night rhythm was changed in the test laboratory by indoor lighting at 6:00 in the morning and 19:00 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 are treated with pentobarbital (Nembutal), Sanofi: 50 mg-kg administered intraperitoneally) anesthetized, then shaved and disinfected over a large area of its abdomen. After opening the abdominal cavity along the albedo line, the liquid-filled measuring catheter of the system is inserted cranially into the descending aorta above the bifurcation point and cemented with tissue glue (VetBond D)^TMAnd 3M) fixing. The transmitter housing is secured to the abdominal wall muscles within the abdominal cavity, and the wound is closed layer by layer.

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

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 substances are dissolved in a suitable solvent mixture or suspended in Tylose at a concentration of 0.5%, suitable for an administration volume of 5 ml/kg body weight.

Animals of the solvent-treated group were used as controls.

Test method

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

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

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

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

-systolic pressure (SBP)

Diastolic pressure (DBP)

Mean Arterial Pressure (MAP)

Heart Rate (HR)

-Activity (ACT).

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

Unless otherwise 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)^TMTm Analysis) classification. The 2 hours prior to dosing was set as a blank value, so the data set selected included the period from 7.00 am the day of the experiment to 9.00 am the following day.

The data was smoothed by measuring the average (15 minute average) 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 into Excel templates and presented as a table. The data obtained were stored in a special file with the experimental number for each experimental day. The results and test protocol are filed in paper form sorted by number.

Literature reference

Klaus Witte，Kai Hu，Johanna Swiatek，Claudia Müssig，GeorgErtl andLemmer：Experimental heart failure in rats：effects oncardiovascular circadian rhythms and on myocardial β-adrenergicsignaling.Cardiovasc Res47(2)：203-405，2000；Kozo Okamoto：Spontaneous hypertension in rats.Int Rev Exp Pathol7：227-270，1969；Maarten van den Buuse：Circadian Rhythms of Blood Pressure，HeartRate，and Locomotor Activity in Spontaneously Hypertensive Rats asMeasured 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 are determined in male CD-1 mice, male Wistar rats and/or female beagle dogs. Intravenous administration was via species-specific plasma/DMSO formulations for mice and rats and via water/PEG 400/ethanol formulations for dogs. For all species, oral administration of the dissolved substance was performed by gavage, based on a water/PEG 400/ethanol formulation. Blood sampling of rats is simplified by: prior to administration of the substance, a silicone catheter was inserted into the right external jugular vein. Surgery was performed at least one day prior to the experiment using isoflurane anesthesia and administering the analgesic (0.1 ml subcutaneous administration of atropine/carboprofen (3/1)). Blood was collected over a time window including a final time point of at least 24 to at most 72 hours after administration of the substance (typically more than 10 time points). Blood was transferred to heparinized tubes. Then obtaining plasma by centrifugation; if desired, it can be stored at-20 ℃ until further processing

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

Validated pharmacokinetic meters using determined plasma concentration/time curvesCalculation program calculation of pharmacokinetic parameters such as AUC, C_max、t_1／2(terminal half-life), MRT (mean residence time) and CL (clearance).

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

B-5.Metabolic studies

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

The compounds of the invention are incubated at a concentration of about 0.1-10. mu.M. For this purpose, an acetonitrile stock solution of the compound of the invention at a concentration of 0.01-1mM is prepared and then pipetted into the incubation mixture at a dilution of 1: 100. Incubating the liver microsomes and the recombinant enzyme in 50mM potassium phosphate buffer (pH7.4) with or without 1mM NADP 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 Williams E 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 off at about 15000 xg. The samples thus terminated were either directly analysed or stored at-20 ℃ until analysis.

The analysis was performed by high performance liquid chromatography 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 are used for identification, structural analysis and quantitative determination of the metabolites, and for quantitative metabolic assessment 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 the following pharmaceutical preparations:

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 (PVP25) (BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

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

Preparation:

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 in a conventional tablet press (see above for tablet size). The guide value for compression is a pressure of 15 kN.

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 added to the suspension. Water was added with stirring. The mixture was stirred for about 6h until the Rhodigel was fully expanded.

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 agitation. 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 and pyrogen-free injection containers.

Claims

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

wherein

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-##The radical(s) is (are),

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

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

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

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R^7Ais a hydrogen atom, and is,

R^7Bis hydrogen.

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

A is nitrogen or CR³，

Wherein

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

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

wherein

# is the point of attachment to the carbonyl group,

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

p is the number 0 and p is the number 0,

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

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

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R^7Ais a hydrogen atom, and is,

R^7Bis hydrogen.

3. Process for the preparation of a compound of formula (I) as defined in claim 1 or 2, characterized in that the compound of formula (II)

Wherein R is¹、R²、R^7AAnd R^7BEach having the meaning given in claim 1 or 2,

[A] reacting a compound of formula (II) with a compound of formula (III) in an inert solvent in the presence of an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal alkoxide or organic amine to obtain a compound of formula (IV)

Wherein L has the meaning given in claim 1 or 2, and

T¹is (C)₁-C₄) An alkyl group, a carboxyl group,

l, R therein¹、R²、R^7AAnd R^7BEach having the meaning given in claim 1 or 2,

L, R therein¹、R²、R^7AAnd R^7BEach having the meaning given in claim 1 or 2, and

X²is the bromine or the iodine, and the iodine,

or

[B] Reacting a compound of formula (II) with hydrazine hydrate in the presence of an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal alkoxide or organic amine in an inert solvent to obtain a compound of formula (VI)

Wherein L has the meaning given in claim 1 or 2, and

T⁴is (C)₁-C₄) An alkyl group, a carboxyl group,

l, R therein¹、R²、R^7A、R^7BAnd T⁴Each having the meaning given above,

L, R therein¹、R²、R^7A、R^7BAnd T⁴Each having the meaning given above,

and finally cyclizing the compound of formula (X) in an inert solvent, optionally in the presence of an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal alkoxide or organic amine, to obtain the compound of formula (I-B)

and optionally converting the obtained compounds of formulae (I-A) and (I-B) into their salts with an acid or a base.

4. Use of a compound of formula (I) as defined in any of claims 1-2 for the preparation of a medicament for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis.

5. A medicament comprising a compound of formula (I) as defined in any one of claims 1-2 together with inert, non-toxic and pharmaceutically suitable excipients.

6. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 2 together with another active compound selected from organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modulators.

7. The medicament as claimed in claim 5 or 6 for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis.