HK1199641B

HK1199641B - Substituted triazine derivatives and use thereof as stimulators of soluble guanylate cyclase

Info

Publication number: HK1199641B
Application number: HK15100007.4A
Authority: HK
Inventors: Markus Follmann; Johannes-Peter Stasch; Gorden Redlich; Nils Griebenow; Frank Wunder; Dieter Lang
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2012-01-11
Filing date: 2013-01-08
Publication date: 2018-03-02

Description

Substituted triazine derivatives and their use as activators of soluble guanylate cyclase

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

One of the most important cellular delivery systems in mammalian cells is cyclic guanosine monophosphate (cGMP). Cycloguanylic acid forms the NO/cGMP system together 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 most likely includes one heme per heterodimer, which is part of the regulatory center. This is very important for the activation mechanism. NO can bind to the iron atom of heme and thus significantly increase the activity of the enzyme. In contrast, the heme-free formulation is not excited by NO. Carbon monoxide (CO) can also bind to the central iron atom of heme, but the excitation of CO is much smaller than that of NO.

By forming cGMP, and due to the resulting regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays an important role in a variety of physiological processes, particularly in relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, and in nerve signal transduction, as well as in diseases based on disruption of these 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 diseases, by targeting the effects of the cGMP signaling pathway in the organism, is a promising approach due to the expected high efficiency and low levels of side effects.

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

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

As activators of soluble guanylate cyclase, WO00/06568 and WO00/06569 disclose fused pyrazole derivatives, and WO03/095451 discloses carbamate-substituted 3-pyrimidinyl pyrazolopyridines. 3-pyrimidinyl pyrazolopyridines with benzamide substituents are described in e.m. becker et al, BMC Pharmacology 1(13), 2001. WO2004/009590 describes pyrazolopyridines with substituted 4-aminopyrimidines for the treatment of CNS disorders. WO2010/065275 discloses substituted pyrrolopyrimidines and dihydropyridopyrimidines as sGC activators.

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

The present invention provides compounds having the general formula (I)

Wherein

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

R¹is halogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl, hydroxy, oxo or (C)₁-C₄) An alkoxy group,

n is a number 0, 1 or 2,

R²is trifluoromethyl, (C)₁-C₆) Alkyl, (C)₃-C₈) Cycloalkyl, phenyl or 5-or 6-membered heteroaryl,

wherein (C)₁-C₆) The alkyl group is substituted with a substituent selected from the group consisting of difluoromethyl and trifluoromethyl,

wherein (C)₁-C₆) The alkyl group may be substituted with 1-3 fluoro substituents,

wherein (C)₃-C₈) Cycloalkyl can be substituted by 1 or 2 substituents which are independently of one another selected from fluorine, methyl and methoxy,

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

wherein the phenyl group may be substituted by 1 or 2 substituents which are independently of one another selected from methyl and methoxy,

and

wherein the 5-and 6-membered heteroaryl groups may be substituted by 1 or 2 substituents independently of each other selected from fluorine and methyl,

R³is difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₁-C₆) Alkylsulfonylamino group, (C)₁-C₆) Alkoxycarbonylamino, phenyl or 5-or 6-membered heteroaryl,

wherein (C)₁-C₆) The alkyl, phenyl and 5-or 6-membered heteroaryl groups may be substituted with 1 to 3 substituents independently from each other selected from halogen, trifluoromethyl, (C)₁-C₄) Alkyl, (C)₃-C₇) Cycloalkyl, difluoromethoxy, trifluoromethoxy and (C)₁-C₆) An alkoxy group,

R⁴is a hydroxyl group or an amino group,

and N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides or salts thereof.

The compounds of the present invention are compounds of formula (I) and salts, solvates and solvates of said salts, the compounds of formula (I) in the formulae mentioned below and salts, solvates and solvates of said salts, and the compounds of formula (I) and salts, solvates and solvates of said salts mentioned below as working examples if the compounds of formula (I) mentioned below are not already salts, solvates and solvates of salts.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of the invention. Also included is a salt which is not suitable per se for pharmaceutical applications but which can be used, for example, for isolating or purifying the compounds of the invention.

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

Physiologically acceptable salts of the compounds of the invention also include salts of customary bases, such as, for example and with preference, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as 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 with preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the present invention, a solvate is a term used to refer to a form of a compound of the present invention which coordinates in a solid or liquid state to a solvent molecule to form a complex. Hydrates are a particular form of solvates in which water is coordinated. Preferred solvates in the context of the present invention are hydrates.

The compounds of the invention may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or optionally as conformers (enantiomers and/or diastereomers, including atropisomers). Thus, the present invention encompasses enantiomers and diastereomers, and mixtures of each thereof. The stereoisomerically homogeneous constituents can be separated in a known manner from the abovementioned mixtures of enantiomers and/or diastereomers; chromatographic methods are preferably used for this separation, in particular HPLC chromatography on achiral or chiral phases.

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

The invention also encompasses all suitable isotopic variants (isotopic variants) of the compounds of the invention. An isotopic variation of a compound of the present invention is understood herein to be a substitution of at least one atom in the compound of the present invention with another atom having the same atomic number, but an atomic weight different from the atomic weight usually or predominantly found in nature. Isotopologues which can incorporate the compounds of the inventionExamples of elements are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. particular isotopic variations of the compounds of the present invention, particularly those into which one or more radioactive isotopes have been incorporated, can be beneficial, for example, in assessing the mechanism of action or the distribution of active ingredients in vivo; due to its relatively simple preparation and detection properties³H or¹⁴C-isotopically labelled compounds are particularly suitable for this purpose. In addition, the inclusion of isotopes such as deuterium can afford specific therapeutic advantages resulting from greater metabolic stability of the corresponding compounds, e.g., increased in vivo half-life or reduced effective dosages as required; such modifications of the compounds of the invention may therefore, in some cases, also constitute preferred embodiments of the invention. Isotopic variations of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example by the methods described below and in the working examples, by employing the respective isotopic modifications of the reagents and/or starting compounds.

In addition, the present invention also includes prodrugs of the compounds of the present invention. As used herein, the term "prodrug" refers to a compound that may be biologically active or biologically inactive by itself, but which may be converted (e.g., by metabolism or hydrolysis) to the compounds of the present invention over time in vivo.

In the context of the present invention, substituents, unless otherwise specified, each have the following meaning:

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

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

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

Alkoxy radicalIn the context of the present invention are linear or branched alkoxy groups having 1 to 6 or 1 to 4 carbon atoms. The following groups may be mentioned, for example and preferably: 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. Preferred are linear or branched alkoxy groups having 1 to 4 carbon atoms. The following groups may be mentioned, for example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy.

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

Alkylsulfonylamino groupIn the context of the present invention is an amino group having a straight or branched chain alkylsulfonyl substituent, said alkylsulfonyl group having from 1 to 6 carbon atoms and being linked to the nitrogen atom via a sulfonyl group. The following groups may be mentioned, for example and preferably: methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.

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

5-or 6-membered heteroarylIn the context of the present invention are monocyclic aromatic heterocycles (heteroaromatics) having a total of 5 or 6 ring atoms, comprising up to 3 identical or different ring atoms from the group N, O and/or S and being bonded via a ring carbon atom or optionally via a ring nitrogen atom. The following groups may be mentioned, for example and preferably: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preferably, the following components are adopted: pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.

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

Halogen elementIn the context of the present invention are fluorine, chlorine, bromine and iodine. Preferred are bromine and iodine.

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

In the formulae of the groups which may represent Q, the end points of the lines marked with the symbol or symbol do not represent a carbon atom or CH₂A group, but is part of a bond to the respectively indicated atom bound to Q.

If a group in a compound of the present invention is substituted, the group may be mono-or polysubstituted unless otherwise specifically stated. In the context of the present invention, the meanings are independent of one another for all radicals which occur more than once. Preferably by one, two or three identical or different substituents.

In the context of the present invention, the term "treating" includes preventing, delaying, terminating, alleviating, limiting, reducing, inhibiting, combating or curing a disease, disorder, 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 are meant to avoid or reduce the following risks: an infection, a experiencing, suffering from, or having a disease, condition, disorder, injury, or health problem, or the occurrence or progression of such a condition and/or symptoms of such a condition.

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

In the context of the present invention, preference is given to compounds of the formula (I) in which

Ring Q is a group of the formula

Wherein

Is and-CH₂-R²The attachment site(s) of (a),

is a site of attachment to the triazine ring,

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

R¹is fluorine, chlorine or methyl, and is,

n is a number 0, 1 or 2,

A¹、A²、A³、A⁴each independently is N, CH or CR¹，

With the proviso that A¹、A²、A³、A⁴No more than two of the groups are N,

R²is trifluoromethyl, 2,2, 2-trifluoroethyl, 3,3, 3-trifluoropropan-1-yl, 2,2,3,3, 3-pentafluoropropan-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,

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

and is

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

R³is difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, methylsulfonylamino, methoxycarbonylamino, phenyl, pyrazolyl, oxazolyl or pyridyl,

wherein (C)₁-C₆) The alkyl group may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, methoxy and ethoxy,

and is

Wherein phenyl, pyrazolyl, oxazolyl and pyridyl may be substituted by 1 or 2 substituents which are independently from each other selected from the group consisting of fluorine, chlorine, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethoxy, methoxy and ethoxy,

R⁴is a hydroxyl group or an amino group,

and salts, solvates and solvates of said salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which

Ring Q is a group of the formula

Wherein

Is and-CH₂-R²The attachment site(s) of (a),

is a site of attachment to the triazine ring,

R^1ais hydrogen or a methyl group,

R^1bis hydrogen or fluorine, and can be used as the active ingredient,

R^1cis hydrogen or chlorine, and is selected from the group consisting of,

A¹is N or CH, and is a nitrogen atom,

A³is N, CH or C-F, and has the following characteristics,

R²is 3,3, 3-trifluoropropan-1-yl, 2,3, 3-tetrafluoropropan-1-yl, 2,3,3, 3-pentafluoropropan-1-yl, phenyl or pyridyl,

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

and is

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

and is

R⁴is a hydroxyl group or an amino group,

and salts, solvates and solvates of said salts.

Ring Q is a group of the formula

Wherein

Is and-CH₂-R²The attachment site(s) of (a),

is a site of attachment to the triazine ring,

R^1ais hydrogen or fluorine, and can be used as the active ingredient,

R^1bis hydrogen or a methyl group,

and salts, solvates and solvates of said salts.

R²Is 2-fluorophenyl, 2, 3-difluorophenyl or 2,3, 6-trifluorophenyl,

and salts, solvates and solvates of said salts.

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

Particularly preferred are combinations of two or more of the above-mentioned preferred ranges.

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

[A] A compound of formula (II)

Wherein n, Q, R¹And R²Each having the meaning given above, are,

with a compound of formula (III) in an inert solvent in the presence of a suitable transition metal catalyst

Reaction of the compounds

Wherein

R^3AIs phenyl or 5-or 6-membered heteroaryl,

wherein phenyl and 5-or 6-membered heteroaryl can be substituted by 1 to 3 substituents independently selected from halogen, trifluoromethyl, (C)₁-C₄) Alkyl, (C)₃-C₇) Cycloalkyl, difluoromethoxy, trifluoromethoxy and (C)₁-C₆) An alkoxy group,

and

T¹is hydrogen or (C)₁-C₄) Alkyl, or two T¹The radicals together forming

-C(CH₃)₂-C(CH₃)₂-a bridge for connecting the bridge to the ground,

to give a compound of the formula (I-A)

Wherein n, Q, R¹、R²And R^3AEach of which has the above-mentioned meaning,

or

[B] A compound of formula (IV)

Wherein n, Q, R¹And R²Each of which has the above-mentioned meaning,

with a compound of formula (V) in an inert solvent

Wherein

R^3BIs difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group,

wherein (C)₁-C₆) The alkyl group may be substituted with 1 to 3 substituents independently selected from halogen, trifluoromethyl, (C)₁-C₄) Alkyl, (C)₃-C₇) Cycloalkyl, difluoromethoxy, trifluoromethoxy and (C)₁-C₆) An alkoxy group,

and is

T²Is (C)₁-C₄) An alkyl group, a carboxyl group,

to give a compound of the formula (I-B)

Wherein n, Q, R¹、R²And R^3BEach of which has the above-mentioned meaning,

or

[C] Conversion of a Compound of formula (I-B) to a Compound of formula (VI) with phosphorus oxychloride

Wherein n, Q, R¹、R²And R^3BEach of which has the above-mentioned meaning,

reacting the compound directly with ammonia to obtain a compound of formula (I-C)

Wherein n, Q, R¹、R²And R^3BEach of which has the above-mentioned meaning,

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

Process step (II) + (III) → (I-a) 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.

Optionally, the conversion of (II) + (III) → (I-a) may be carried out in the presence of a suitable palladium and/or copper catalyst. Suitable palladium catalysts are, for example, palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride and [1,1 '-bis (diphenylphosphino) ferrocene ] palladium (II) dichloride and the corresponding dichloromethane complexes, optionally together with additional phosphine ligands, such as [ (2-biphenyl) di-tert-butylphosphine ], dicyclohexyl [2',4',6' -tris (1-methylethyl) biphenyl-2-yl ] phosphine (XPHOS), bis (2-phenylphosphinophenyl) ether (DPEphos) or 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (xanthes) [ see, for example, Hassan j.et al, chem.rev.102,1359-1469(2002) ]. Suitable copper catalysts are, for example, bronze (copper bronze), copper (I) oxide, copper (I) iodide or copper (I) bromide.

The conversion of (II) + (III) → (I-A) is carried out in the presence of a suitable base. Is suitable for the transformationThe base is a common inorganic or organic base. These preferably include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N-diisopropylethylamine, pyridine, 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2]OctanePreferably, sodium hydride or cesium carbonate is used.

The reaction (II) + (III) → (I-a) is usually carried out in a temperature range of 0 ℃ to +200 ℃, preferably +10 ℃ to +150 ℃. The conversion may be carried out under atmospheric, pressurized or depressurized conditions (e.g. 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

If R is^3AThe group is unsaturated and the group may subsequently be fully or partially saturated. The reduction reaction is carried out with hydrogen and a transition metal catalyst, such as palladium (10% on activated carbon), raney nickel or palladium hydroxide. The reduction reaction is generally carried out at a temperature in the range of +20 ℃ to +50 ℃. The reaction may be carried out at atmospheric pressure or under increased pressure (e.g. in the range of 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Inert solvents for process step (IV) + (V) → (I-B) 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' -Dimethylpropylurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. Mixtures of the solvents mentioned may also be used. Preferably methanol or ethanol.

The reaction (IV) + (V) → (I-B) is typically carried out in a temperature range of +50 ℃ to +120 ℃, preferably in a range of +50 ℃ to +100 ℃, optionally in a microwave oven. The conversion may be carried out at atmospheric pressure or under increased pressure, for example in the range from 0.5 to 5 bar. The reaction is generally carried out at atmospheric pressure.

The reaction (I-B) → (VI) may be carried out in a solvent which is inert under the reaction conditions, or a solvent may not be required. A preferred solvent is sulfolane (sulfolane).

The reaction (I-B) → (VI) is typically carried out in a temperature range of +70 ℃ to +150 ℃, preferably in a range of +80 ℃ to +130 ℃, optionally in a microwave oven. The conversion can be carried out at atmospheric pressure or under increased pressure (for example in the range from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

Particularly preferably, the conversion (I-B) → (VI) is carried out in the solvent-free, temperature range from 0 ℃ to +50 ℃ and at atmospheric pressure.

Process step (VI) → (I-C) 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, diglyme, 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 (VI) → (I-C) is typically carried out in a temperature range of +20 ℃ to +100 ℃, preferably in a range of +40 ℃ to +70 ℃, optionally in a microwave oven. The conversion may be carried out at atmospheric pressure or under increased pressure, for example in the range from 0.5 to 5 bar. The reaction is generally carried out at atmospheric pressure.

Preferably, the conversion (I-B) → (VI) → (I-C) is carried out without isolation of the intermediate (VI).

The preparation described can be illustrated by the following synthetic schemes (schemes 1,2 and 3).

Scheme 1

[a):NH₃In EtOH, THF,0 ℃→ room temperature; b) PdCl₂(dppf)₂,K₂CO₃,H₂O, dioxane, microwave oven, 140 deg.C]。

Scheme 2

EtOH, refluxing; b) 1.POCl₃Room temperature; NH (NH)₃(25% strength), acetonitrile, room temperature → 50 deg.C]。

Scheme 3

Hydrazine hydrate, EtOH, room temperature; b) amino (thio) acetic acid ethyl ester, MeOH, NEt₃Refluxing; c) 1 SOCl₂Refluxing, (2) ammonia solution; ACN, room temperature; d) methanesulfonyl chloride, NEt₃Room temperature; e) chloroformate, NEt₃At room temperature]。

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

Other compounds of the invention may also optionally be prepared by converting the functional groups of the respective substituents (especially for L and R)³Groups listed) byThe compound of formula (I) obtained by the process described above is initially prepared. These transformations are carried out by the customary methods known to those skilled in the art and include, for example, nucleophilic and electrophilic substitution, oxidation, reduction, hydrogenation, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carboxamides, and the introduction and elimination of temporary protecting groups.

Compounds of formula (II) can be prepared by reacting compounds of formula (VI)

Wherein n, Q, R¹And R²Each of which has the above-mentioned meaning,

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

Wherein n, Q, R¹And R²Each of which has the above-mentioned meaning,

this compound is subsequently converted with ethyl oxoacetate in an inert solvent into a compound of formula (VII)

Wherein n, Q, R¹And R²Each of which has the above-mentioned meaning,

and the compound is reacted with thionyl chloride to give a compound of formula (II).

The following synthetic scheme (scheme 4) is used to illustrate the above described method:

scheme 4

[ a ] hydrazine hydrate, NEt₃EtOH, room temperature; b) ethyl oxoacetate and EtOH reflux; c) refluxing thionyl chloride]。

The compounds of formula (VI) are known from the literature (see, e.g., WO2010/065275, WO2011/115804 and WO2011/149921) or can be prepared analogously to methods known from the literature.

The compounds of the invention are potent elicitors of soluble guanylate cyclase, possess valuable pharmacological properties and have improved therapeutic properties, for example with respect to their in vivo properties and/or their pharmacokinetic properties. These compounds are therefore suitable for the treatment and/or prophylaxis of diseases in humans and animals.

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

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

Thus, the compounds of the invention may be used in medicaments for the following uses: for the treatment and/or prophylaxis of cardiovascular diseases, such as hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina, peripheral and cardiovascular diseases, cardiac arrhythmias, atrial and ventricular arrhythmias and impaired conduction, such as I-III atrioventricular block (AB block I-III), supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes, atrial and ventricular extrasystoles, atrioventricular junctional extrasystoles, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Wasp-Huai syndrome, Acute Coronary Syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvulitis), aortic inflammation, myocardial disease), shock such as cardiogenic shock, Septic and anaphylactic shock, aneurysm, boxer canine cardiomyopathy (premature ventricular contraction (PVC)); for the treatment and/or prophylaxis of thromboembolic disorders and ischaemias, such as myocardial ischaemia, myocardial infarction, stroke, myocardial hypertrophy, transient and ischaemic attacks, preeclampsia, inflammatory cardiovascular diseases, coronary and peripheral arterial spasms, oedema formations, such as pulmonary oedema, cerebral oedema, renal oedema or oedema caused by heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction; for the prevention of restenosis, e.g. after thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), coronary transluminal angioplasty (PTCA), heart transplantation and bypass surgery, and increased micro-and macrovascular injury (vasculitis), fibrinogen levels and Low Density Lipoprotein (LDL) levels, and increased plasminogen activator inhibitor 1(PAI-1) concentrations; and also for the treatment and/or prevention of erectile dysfunction or female sexual dysfunction.

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

In addition, the compounds of the present invention are also useful for the treatment and/or prevention of arteriosclerosis, impaired lipid metabolism, hypolipidaemia, dyslipidaemia, hypertriglyceridaemia, hyperlipidaemia, hypercholesterolaemia, betalipoproteinaemia, sitosterolemia, xanthomatosis, dangill disease, obesity (adiposity or obesy), 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, microcirculation impairment, claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic retinopathy, diabetic limb ulcers, gangrene, CREST syndrome, systemic lupus erythematosus (erythematosis), 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 disorders including neurogenic bladder overactivity symptoms (OAB) and (IC), incontinence (UI) such as mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign or malignant diseases of male or female urogenital organs.

Furthermore, the compounds of the invention are suitable for the treatment and/or prophylaxis of renal diseases, in particular acute and chronic renal insufficiency and acute and chronic renal failure. In the context of the present invention, the term renal insufficiency includes acute and chronic manifestations thereof, as well as underlying or associated renal diseases, such as hypoperfusion of the renal blood flow, dialysis-related hypotension (obstructive uropathy), glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, renal disorders (neuropathic disorders) such as primary and congenital nephropathy, nephritis, immune nephropathy such as renal graft rejection and immune complex-induced nephropathy, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be diagnostically characterized by: such as reduced creatinine and/or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium, and/or creatinine, altered activity of renal enzymes (e.g., glutamine synthetase), altered urine osmolality or urine volume, increased microalbuminuria, increased macroalbuminuria (macroalbuminuria), damage to glomeruli and arterioles, 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 prophylaxis of the sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (e.g. hyperkalemia, hyponatremia), and disorders of bone and carbohydrate metabolism.

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

The compounds described in the invention are likewise active compounds for controlling central nervous system disorders which are characterized by a disturbance of the NO/cGMP system. In particular, they are useful for improving perception, attention, learning ability or memory after cognitive deficits, such as occur in particular in connection with the following situations/diseases/symptoms: such as mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, craniocerebral injury, stroke, dementia occurring after stroke (post-stroke dementia), post-traumatic craniocerebral injury, general attention deficit, attention deficit in children with learning and memory problems, alzheimer's disease, lewy body dementia, dementia with frontal lobe degeneration including pick's syndrome, parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, Amyotrophic Lateral Sclerosis (ALS), huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or koxsackov's psychosis. They are also suitable for the treatment and/or prophylaxis of disorders of the central nervous system, such as anxiety, stress and depression states, CNS-related sexual dysfunctions and sleep disorders, and for the prevention and/or treatment of pathological disorders of the intake of food, irritants or addictive substances.

In addition, the compounds of the present invention are also useful for regulating cerebral blood flow and therefore are effective agents for preventing and treating migraine. They are also suitable for the prophylaxis and prophylaxis of the sequelae of cerebral infarction (stroke), such as apoplexy, cerebral ischaemia and craniocerebral injury. The compounds of the invention are also useful for the prevention and treatment of pain and tinnitus conditions.

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

In addition, the compounds of the present invention may also be useful in 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 diseases of internal organs, such as the lung, heart, kidney, bone marrow and in particular the liver, and fibrotic eye diseases (fibrotic eyedisorders). In the context of the present invention, the term fibrotic disease includes in particular the following terms: liver fibrosis, cirrhosis, lung fibrosis, endomyocardial fibrosis, kidney disease, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage caused by diabetes, myelofibrosis and similar fibrotic disorders, scleroderma, maculopathy, keloids, hypertrophic scars (and hypertrophic scars after surgical operations), nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (e.g. sarcoidosis).

Furthermore, the compounds of the invention are suitable for the prophylaxis and treatment of post-operative scars, for example scars resulting from glaucoma surgery.

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

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

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

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

The invention also provides the use of a compound of the invention in a method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic diseases, fibrotic diseases 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 a disease, in particular a disease as described above.

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

The present invention also provides methods for the treatment and/or prevention of diseases, in particular the above-mentioned diseases, using an effective amount of at least one compound according to the invention.

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

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

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

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

● having antithrombotic activity, such as and preferably selected from platelet aggregation inhibitors, anticoagulants or plasminogen;

● blood pressure lowering active compounds, for example and preferably 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; and/or

● active compounds which alter lipid metabolism are selected, for example and preferably, from thyroid receptor agonists, cholesterol synthesis inhibitors, such as, for example 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 preparations, polymeric bile acid adsorbents, bile acid resorption inhibitors and lipoprotein (a) antagonists.

Antithrombotic agents are preferably understood to mean compounds selected from platelet aggregation inhibitors, anticoagulants or plasminogen substances.

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

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

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban (rivaroxaban, BAY 59-7939), 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, DX 9065a, DPC 906, JTV 803, SSR-126512, or SSR-128428.

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

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

Antihypertensive agents are preferably understood to mean compounds selected from: 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 (amlodipin), 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 (carindiolol), adapalolol (cardenolol), adapalolol (celandiolol), anetholol (anetholol), or anetholol (nebiolol).

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

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 perindopril (trandopril).

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

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

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

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

Lipid metabolism regulators are preferably understood to mean compounds selected from the following: 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 (lovastatin), simvastatin (simvastatin), pravastatin (pravastatin), fluvastatin (fluvastatin), atorvastatin (atorvastatin), rosuvastatin (rosuvastatin) or pitavastatin (pitavastatin).

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

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

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

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

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe (ezetimibe), tiquinane (tiqueside) or 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, typically together with one or more inert, non-toxic, pharmaceutically suitable excipients, and the use of said medicament for the above-mentioned purposes.

The compounds of the invention may act systemically and/or locally. For this purpose, the compounds may be administered in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally or otically, or as an implant or stent.

The compounds of the present invention may be administered by administration forms suitable for the above routes of administration.

Administration forms which function according to the prior art, release the compounds of the invention in a rapid and/or modified manner and comprise the compounds of the invention in crystalline and/or amorphous and/or dissolved form, are suitable for oral administration, for example tablets (uncoated and coated tablets, for example with enteric coating or coating which dissolves in a delayed manner or is insoluble and controls the release of the compounds of the invention), tablets or films/tablets, films/lyophilisates or capsules which disintegrate rapidly in the oral cavity, for example hard or soft gelatin capsules, sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

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

For other routes of administration, suitable examples are inhalation pharmaceutical forms (including powder inhalants, sprays), nasal drops, solutions or sprays; tablets, films/slabs or capsules for lingual, sublingual or buccal administration; suppositories, otic or ocular preparations, vaginal capsules, aqueous suspensions (lotions, shakes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, sprinkles (spraying powers), implants or stents.

Oral or parenteral administration, especially oral administration, is preferred.

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

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

However, if appropriate, it may be necessary to deviate from the stated amounts, in particular depending on the body weight, the route of administration, the individual response to the active compound, the nature of the preparation and the time or interval over which the administration takes place. For example, in some cases, less than the minimum amount may be sufficient, while in other cases, the upper limit must be exceeded. In case of administration of larger amounts, it may be advisable to divide them into several individual doses during the day.

The following working examples illustrate the invention. The invention is not limited to the embodiments described.

The percentages in the following tests and examples, unless otherwise indicated, are 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：

aq. aqueous solution

calc. calculated

DCI direct chemical ionization (in mass spectrometry)

DMF dimethyl formamide

DMSO dimethyl sulfoxide

eq. equivalent

ESI electrospray ionization (in Mass Spectrometry)

Et Ethyl group

h hours

HPLC high pressure, high performance liquid chromatography

HRMS high resolution mass spectrometry

conc. concentrated

LC/MS liquid chromatography-mass spectrometry combination

LiHMDS lithium hexamethyldisilazide

Me methyl group

min for

MS Mass Spectrometry

NMR nuclear magnetic resonance spectroscopy

Pd/C on activated carbon Palladium (10%)

Ph phenyl

RT Room temperature

Rt Retention time (in HPLC)

t-Bu tert-butyl

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrum

volume ratio v/v (of solution)

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

LC/MS method：

Method 1:

The instrument comprises the following steps: waters ACQUITY SQD UPLC system; column: waters Acquity UPLC HSS T31.8 μ 50x 1 mm; mobile phase A:1l of water +0.25ml of 99% strength formic acid, mobile phase B:1l acetonitrile +0.25ml of 99% strength formic acid; gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A; column oven: 50 ℃; flow rate: 0.40 ml/min; and (4) UV detection: 208-400 nm.

Method 2:

The instrument comprises the following steps: waters ACQUITY SQD UPLC system; column: waters Acquity UPLC HSS T31.8 μ 30x 2 mm; mobile phase A:1l of water +0.25ml of 99% strength formic acid, mobile phase B:1l acetonitrile +0.25ml of 99% strength formic acid; gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A; column oven: 50 ℃; flow rate: 0.60 ml/min; and (4) UV detection: 208-400 nm.

Method 3:

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

Method 4:

The instrument is a Waters ACQUITY SQD UPLC system; column: waters Acquity UPLC HSS T31.8 μ 50x 1 mm; mobile phase A:1l of water +0.25ml of 99% strength formic acid, mobile phase B1 l of acetonitrile +0.25ml of 99% strength formic acid; gradient: 0.0min 95% A → 6.0min 5% A → 7.5min 5% A; column oven: 50 ℃; flow rate: 0.35 ml/min; and (4) UV detection: 210-400 nm.

Method 5:

The instrument is Micromass Quattro Premier with Waters UPLC Acquity; column: ThermoHypersil GOLD 1.9 μ 50 × 1 mm; mobile phase a 1l water +0.5ml 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; column oven: 50 ℃; flow rate: 0.3 ml/min; and (4) UV detection: 210 nm.

Starting materials and intermediates

Example 1A

1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamidine hydrochloride

The synthesis of this compound is described in WO03/095451, example 6A.

Example 2A

1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboximidohydrazide

50.000g (163.535mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamidine hydrochloride are dissolved in 700ml of ethanol and 66.192g (654.141mmol) of triethylamine and 10.233g (163.535mmol) of hydrazine hydrate (80% strength in water) are added at 0 ℃. The mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The residue is stirred with diethyl ether, filtered off with suction and dried under high vacuum. 46.49g (46% of theory, 68% purity) of the title compound are obtained.

LC-MS (method 5) R_t＝0.64min；MS(ESIpos):m/z＝285(M+H)⁺

Example 3A

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-ol

22.000g (68% pure, ca. 52.621mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboximidoyl hydrazide in 220ml of ethanol are initially added, 18.265(89.455mmol) of ethyl oxoacetate (50% strength in toluene) are added dropwise and the mixture is refluxed overnight. The resulting suspension was concentrated on a rotary evaporator and stirred with diethyl ether. The solid is filtered off with suction and dried under high vacuum. Further purification was carried out by chromatography on silica gel (mobile phase: dichloromethane/methanol, gradient 30:1 → 10: 1). This gives 12.07g of the expected compound (purity 69%; 49% of theory).

LC-MS (method 1) R_t＝0.80min；MS(ESIpos):m/z＝323(M+H)⁺

Example 4A

3- (5, 6-dichloro-1, 2, 4-triazin-3-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine

A solution of 12.000g (69% pure, ca. 25.690mmol) of 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-ol in 70ml of thionyl chloride was heated under reflux for 6H. The reaction mixture was concentrated on a rotary evaporator and mixed with toluene, concentrated again and dried under high vacuum. This gives 13.10g of the expected compound (purity 38%; 52% of theory).

LC-MS (method 1) R_t＝1.22min；MS(ESIpos):m/z＝375(M+H)⁺

Example 5A

6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine

A solution of 7.000g (38% pure, 7.090mmol) of 3- (5, 6-dichloro-1, 2, 4-triazin-3-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine in 200ml of anhydrous THF is initially charged. Under cooling in an ice bath 4.254ml (8.508mmol) of a 2N solution of ammonia in ethanol were added and the mixture was stirred at 0 ℃ for 1 h. Again under ice-bath cooling 4.254ml (8.508mmol) of 2N ammonia in ethanol were added and the mixture was stirred at room temperature for 1.5 h. 30ml (60.000mmol) of a 2N solution of ammonia in ethanol are added and the mixture is stirred at room temperature for 15 min. The reaction mixture is concentrated on a rotary evaporator, suspended in 100ml of dichloromethane, mixed with 50ml (100.00mmol) of a 2N solution of ammonia in ethanol and stirred at room temperature for 2 h. The mixture is concentrated on a rotary evaporator and purified by chromatography on silica gel (mobile phase: dichloromethane/methanol, gradient 20:1 → 10: 1). The product-containing fractions were concentrated and stirred with DMSO. The solid is filtered off with suction, washed with acetonitrile and dried under high vacuum. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). This gives 1.68g of the expected compound (purity 65%; 43% of theory).

LC-MS (method 1) R_t＝0.87min；MS(ESIpos):m/z＝356(M+H)⁺

Example 6A

6-amino-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-ol

A solution of 2.000g (7.035mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboximidoyl hydrazide in 50ml methanol is initially added and admixed with 0.937g (7.035mmol) of ethyl amino (thio) acetate and 1.424g (14.070mmol) of triethylamine are admixed and the mixture is heated at reflux for 5H. The reaction mixture was left overnight, the precipitate was filtered off with suction and washed with a little ethanol and dried under high vacuum. This gave 1.892g of the expected compound (purity 94%; 75% of theory).

LC-MS (method 1) R_t＝0.72min；MS(ESIpos):m/z＝338(M+H)⁺

Example 7A

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

A solution of 1.000g (67% pure, ca. 2.357mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboximidoyl hydrazide in 15ml of anhydrous ethanol is initially introduced and admixed with 1.557g (7.070mmol) of diethyl 2-fluoro-2-methyl-3-oxosuccinate (described in J.Med.chem.1966,9, 149-151). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (mobile phase: methanol/water, gradient 30:70 → 95: 5). This gives 230mg of the expected compound (95% purity; 21% of theory).

LC-MS (method 2) R_t＝1.01min；MS(ESIpos):m/z＝441(M+H)⁺

Example 8A

2- { 5-amino-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-6-yl } -2-fluoropropionamide

250mg (0.522mmol) of ethyl 2-fluoro-2- {3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5-hydroxy-1, 2, 4-triazin-6-yl } propanoate were mixed with 3ml of phosphorus oxychloride and stirred at room temperature overnight. The reaction mixture was diluted with 10ml of dry acetonitrile and stirred in 5ml of concentrated aqueous ammonia (35% strength) with cooling in an ice bath. Stirring was continued at room temperature for 2h and at 50 ℃ for 16 h. After cooling, the precipitate was filtered off with suction and dried in vacuo. Thus, 294mg (purity 95%, quantitative yield) of the target compound was obtained.

LC-MS (method 3) R_t＝0.96min；MS(ESIpos):m/z＝411(M+H)⁺

Working examples：

Example 1

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (5-fluoropyridin-3-yl) -1,2, 4-triazin-5-amine

100mg (purity 65%, 0.183mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 4ml of anhydrous dioxane under an argon atmosphere. 103mg (0.731mmol) of (5-fluoropyridin-3-yl) boronic acid and 25mg (0.183mmol) of potassium carbonate are added and argon is passed through the suspension for 10min with stirring. Subsequently, 3mg (4.020. mu. mol) [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and argon was again passed through the mixture for 1 min. The reaction mixture was stirred at 140 ℃ in a microwave for 20 min. 5mg (0.018mmol) of tricyclohexylphosphine are added and stirring is again carried out in the microwave at 140 ℃ for 20 min. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). 59mg of the expected compound (58% of theory) are obtained.

LC-MS (method 4) R_t＝4.78min；MS(ESIpos):m/z＝417(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝5.92(s,2H),7.17(t,1H),7.23-7.27(m,3H),7.35-7.41(m,1H),7.51(dd,1H),8.08(dt,1H),8.73-8.78(m,3H),8.96(dd,1H)。

Example 2

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (2-methylpyridin-3-yl) -1,2, 4-triazin-5-amine

140mg (purity 65%, 0.256mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 5ml of anhydrous dioxane under an argon atmosphere. 105mg (0.767mmol) of (2-methylpyridin-3-yl) boronic acid, 1.023ml (1.023mmol) of 1N aqueous potassium carbonate solution and 14mg (0.051mmol) of tricyclohexylphosphine are added and argon is passed through the suspension with stirring. Subsequently, 28mg (0.038mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and the reaction mixture was stirred in a microwave at 140 ℃ for 30 min. 19mg (0.026mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were again added and the reaction mixture was stirred at 150 ℃ for 40min in a microwave. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). 26mg of the expected compound (18% of theory) are obtained.

LC-MS (method 4) R_t＝4.27min；MS(ESIpos):m/z＝413(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝2.48(s,3H),5.91(s,2H),7.17(t,1H),7.22-7.27(m,2H),7.35-7.41(m,1H),7.49(dd,1H),7.68(t,1H),8.14(d,1H),8.73(dd,1H),8.77(d,1H),8.95(dd,1H)。

Example 3

6- (3, 5-dimethyl-1, 2-oxazol-4-yl) -3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine

140mg (purity 65%, 0.256mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 5ml of anhydrous dioxane under an argon atmosphere. 154mg (purity 70%, 0.767mmol) of (3, 5-dimethyl-1, 2-oxazol-4-yl) boronic acid, 1.023ml (1.023mmol) of 1N aqueous potassium carbonate solution and 14mg (0.051mmol) of tricyclohexylphosphine are added and argon is passed through the suspension for 10min with stirring. Subsequently, 28mg (0.038mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and the reaction mixture was stirred in a microwave at 140 ℃ for 30 min. The reaction mixture was then stirred at 140 ℃ in a microwave for 60 min. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). This gave 25mg of the expected compound (95% purity; 18% of theory).

LC-MS (method 4) R_t＝4.73min；MS(ESIpos):m/z＝417(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝2.22(s,3H),2.40(s,3H),5.90(s,2H),7.16(t,1H),7.21-7.27(m,2H),7.35-7.41(m,1H),7.48(dd,1H),8.72(dd,1H),8.94(dd,1H)。

Example 4

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (6-methoxypyridine-3-

1,2, 4-triazin-5-yl-amines

140mg (purity 65%, 0.256mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 5ml of anhydrous dioxane under an argon atmosphere. 117mg (0.767mmol) of (6-methoxypyridin-3-yl) boronic acid, 1.023ml (1.023mmol) of 1N aqueous potassium carbonate solution and 14mg (0.051mmol) of tricyclohexylphosphine are added and argon is passed through the suspension for 10min with stirring. Subsequently, 28mg (0.038mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and the reaction mixture was stirred in a microwave at 140 ℃ for 30 min. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). This gave 58mg of the expected compound (85% purity; 36% of theory).

LC-MS (method 4) R_t＝4.77min；MS(ESIpos):m/z＝429(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝3.96(s,3H),5.92(s,2H),7.02(d,1H),7.16(t,1H),7.21-7.27(m,2H),7.36-7.40(m,1H),7.51(dd,1H),8.03(dd,1H),8.53(d,1H),8.74(dd,1H),8.95(dd,1H)。

Example 5

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (pyridin-4-yl) -1,2, 4-triazin-5-amine

140mg (purity 65%, 0.256mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 5ml of anhydrous dioxane under an argon atmosphere. 122mg (0.767mmol) of pyridin-4-ylboronic acid hydrochloride, 1.023ml (1.023mmol) of 1N aqueous potassium carbonate solution and 14mg (0.051mmol) of tricyclohexylphosphine are added and argon is passed through the suspension for 10min with stirring. Subsequently, 28mg (0.038mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and the reaction mixture was stirred in a microwave at 140 ℃ for 30 min. The reaction mixture was then stirred at 140 ℃ in a microwave for 60 min. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). 36mg of the expected compound (33% of theory) are obtained.

LC-MS (method 4) R_t＝4.41min；MS(ESIpos):m/z＝399(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝5.90(s,2H),7.16(t,1H),7.22-7.27(m,2H),7.35-7.41(m,1H),7.48(dd,1H),7.87(d,2H),8.72(dd,1H),8.84(d,2H),8.96(dd,1H)。

Example 6

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazin-5-amine

140mg (purity 65%, 0.256mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 5ml of anhydrous dioxane under an argon atmosphere. 160mg (0.767mmol) of 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole, 1.023ml (1.023mmol) of 1N aqueous potassium carbonate solution and 14mg (0.051mmol) of tricyclohexylphosphine are added and argon is passed through the suspension for 10min with stirring. Subsequently, 28mg (0.038mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and the reaction mixture was stirred in a microwave at 140 ℃ for 30 min. The reaction mixture was then stirred at 140 ℃ in a microwave for 15 min. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). Yield 66mg of the expected compound (47% of theory).

LC-MS (method 4) R_t＝4.40min；MS(ESIpos):m/z＝402(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝3.95(s,3H),5.90(s,2H),7.16(dt,1H),7.22-7.27(m,2H),7.35-7.41(m,1H),7.49(dd,1H),8.04(s,1H),8.41(s,1H),8.73(dd,1H),8.96(dd,1H)。

Example 7

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (pyridin-3-yl) -1,2, 4-triazin-5-amine

140mg (purity 65%, 0.256mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 5ml of anhydrous dioxane under an argon atmosphere. 94mg (0.767mmol) of pyridin-3-ylboronic acid, 1.023ml (1.023mmol) of 1N aqueous potassium carbonate solution and 14mg (0.051mmol) of tricyclohexylphosphine are added and argon is passed through the suspension for 10min with stirring. Subsequently, 28mg (0.038mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and the reaction mixture was stirred in a microwave at 140 ℃ for 30 min. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). 77mg of the expected compound (65% of theory) are obtained.

LC-MS (method 4) R_t＝4.47min；MS(ESIpos):m/z＝399(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝5.92(s,2H),7.17(t,1H),7.22-7.27(m,2H),7.36-7.41(m,1H),7.51(dd,1H),7.73(dd,1H),8.27(dt,1H),8.74(dd,1H),8.82(dd,1H),8.96(dd,2H)。

Example 8

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (2-methoxypyridin-3-yl) -1,2, 4-triazin-5-amine

140mg (purity 65%, 0.256mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 5ml of anhydrous dioxane under an argon atmosphere. 117mg (0.767mmol) of (2-methoxypyridin-3-yl) boronic acid, 1.023ml (1.023mmol) of 1N aqueous potassium carbonate solution and 14mg (0.051mmol) of tricyclohexylphosphine are added and argon is passed over the suspension for 10min with stirring. Subsequently, 28mg (0.038mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and the reaction mixture was stirred in a microwave at 140 ℃ for 60 min. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). 38mg of the expected compound (27% of theory) are obtained.

LC-MS (method 4) R_t＝4.72min；MS(ESIpos):m/z＝429(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝3.32(s,2H),3.90(s,3H),5.88(s,2H),7.13-7.27(m,3H),7.34-7.40(m,1H),7.44(dd,1H),7.53-7.65(m,1H),7.87(dd,1H),8.36(dd,1H),8.69(dd,1H),8.95(dd,1H)。

Example 9

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (2-methylpyridin-4-yl) -1,2, 4-triazin-5-amine

140mg (purity 65%, 0.256mmol) of 6-chloro-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine are suspended in 5ml of anhydrous dioxane under an argon atmosphere. 105mg (0.767mmol) of (2-methylpyridin-4-yl) boronic acid, 1.023ml (1.023mmol) of 1N aqueous potassium carbonate solution and 14mg (0.051mmol) of tricyclohexylphosphine are added and argon is passed over the suspension for 10min with stirring. Subsequently, 28mg (0.038mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were added and the reaction mixture was stirred in a microwave at 140 ℃ for 30 min. 19mg (0.026mmol) of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) were again added and the reaction mixture was stirred at 150 ℃ for 40min in a microwave. After cooling, the mixture was filtered through an Extrelut filter element and washed subsequently with a dichloromethane/methanol mixture (v/v 20: 1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80 → 100: 0). This gave 53mg of the expected compound (purity 92%; 41% of theory).

LC-MS (method 4) R_t＝4.25min；MS(ESIpos):m/z＝413(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝2.72(s,3H),5.91(s,2H),7.16(t,1H),7.22-7.29(m,2H),7.35-7.41(m,1H),7.49(dd,1H),7,93(d,1H),8.01(s,1H),8.72(dd,1H),8.83(d,1H),8.96(dd,1H)。

Example 10

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazine-5, 6-diamine

3.602g (10.677mmol) 6-amino-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-ol in 45ml thionyl chloride were added and heated under reflux for 3H. The reaction mixture was diluted with 200ml of dry acetonitrile and added dropwise to 500ml of concentrated aqueous ammonia (35% strength) with cooling in an ice bath. The mixture was stirred at room temperature overnight. The acetonitrile was removed on a rotary evaporator and the precipitate was obtained by suction filtration. This gave 3.541g (purity 67%, 66% of theory) of the title compound. A small amount was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70 → 95: 5).

LC-MS (method 1) R_t＝0.71min；MS(ESIpos):m/z＝337(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝5.90(s,2H),7.13-7.18(m,1H),7.21-7.27(m,2H),7.35-7.41(m,1H),7.45-7.53(m,3H),8.53(s br,1H),8.75(dd,1H),8.84(dd,1H),9.52(s br,1H)。

Example 11

N- { 5-amino-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-6-yl } methanesulfonamide

200mg (0.595mmol) of 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazine-5, 6-diamine are mixed with 8ml of dichloromethane and cooled to 0 ℃. 545mg (4.757mmol) of methanesulfonyl chloride and 481mg (4.757mmol) of triethylamine are added and the mixture is stirred at room temperature for 72 h. The mixture was diluted with dichloromethane and filtered with suction to give a precipitate. The filtrate was partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70 → 95: 5). This gives 57mg (18% of theory) of the target compound.

LC-MS (method 2) R_t＝0.77min；MS(ESIpos):m/z＝415(M+H)⁺

¹H-NMR(400MHz,TFA-d₁):[ppm]＝3.47(s,3H),6.05(s,2H),7.08-7.14(m,1H),7.29(t,1H),7.44-7.50(m,1H),7.54-7.60(m,1H),8.09(dd,1H),9.05-9.09(m,1H),9.54(dd,1H)。

Example 12

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

200mg (purity 67%, 0.398mmol) of 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazine-5, 6-diamine are mixed with 4ml of dichloromethane and cooled to 0 ℃. 151mg (1.594mmol) of methyl chloroformate dissolved in 1ml of methylene chloride and 161mg (1.594mmol) of triethylamine were added, and the mixture was stirred at room temperature for 15 min. The precipitate is filtered off with suction and dried under high vacuum. 97mg (61% of theory) of the target compound are obtained in this way.

LC-MS (method 5) R_t＝2.09min；MS(ESIpos):m/z＝395(M+H)⁺

¹H NMR(400MHz；DMSO-d₆):[ppm]＝4.00(s,3H),5.79(s,2H),7.11-7.16(m,2H),7.20-7.25(m,1H),7.32-7.40(m,2H),8.00(d br,1H),8.56(d br,1H),8.64(dd,1H),8.75(dd,1H),9.86(s,1H)。

Example 13

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (trifluoromethyl) -1,2, 4-triazin-5-ol

A solution of 1.098g (7.035mmol) of methyl 3,3, 3-trifluoro-2-oxopropanoate in10 ml ethanol was added first and heated to reflux. Subsequently, 2.000g (7.035mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboximidoyl hydrazide suspended in 25ml of ethanol were added and the mixture was heated under reflux overnight. After cooling, the mixture was filtered off with suction, and the filter cake was washed with a little ethanol and purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, ratio 45: 55). This gives 710mg of the target compound (purity 93%; 24% of theory).

LC-MS (method 1) R_t＝0.97min；MS(ESIpos):m/z＝391(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝5.94(s,2H),7.12-7.19(m,1H),7.21-7.29(m,2H),7.33-7.42(m,1H),7.55(dd,1H),8.73(dd,1H),8.78(dd,1H)。

Example 14

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (trifluoromethyl) -1,2, 4-triazin-5-amine

690mg (1.768mmol) of 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (trifluoromethyl) -1,2, 4-triazin-5-ol are mixed with 9ml of phosphorus oxychloride and stirred at room temperature overnight. The reaction mixture was diluted with 50ml of dry acetonitrile and stirred in 123ml of concentrated aqueous ammonia (25% strength) with cooling in an ice bath. Stirring was carried out at room temperature for 48h and at 50 ℃ for 24 h. After cooling, the acetonitrile was removed on a rotary evaporator, water was added, the solid was filtered off with suction and the filter cake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70 → 95: 5). This gives 125mg (18% of theory) of the target compound.

LC-MS (method 1) R_t＝1.02min；MS(ESIpos):m/z＝390(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝5.94(s,2H),7.16(t,1H),7.22-7.27(m,2H),7.35-7.40(m,1H),7.48(dd,1H),7.79(s br,1H),8.72(dd,1H),8.78(s br,1H),8.94(dd,1H)。

Example 15

6-cyclopentyl-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-ol

A solution of 1.197g (7.035mmol) of ethyl cyclopentyl (oxo) acetate in 15ml of ethanol is initially added and heated to reflux. Subsequently, 2.000g (7.035mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboximidoyl hydrazide suspended in 20ml of ethanol was added and the mixture was heated under reflux overnight. After cooling, the mixture was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, ratio 45: 55). This gave 749mg of the expected compound (26% of theory).

LC-MS (method 2) R_t＝1.10min；MS(ESIpos):m/z＝391(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.60-1.78(m,6H),1.91-1.98(m,2H),5.90(s,2H),7.15(t,1H),7.22-7.28(m,2H),7.35-7.40(m,1H),7.48-7.51(m,1H),8.73(s,1H),8.75(dd,1H),14.25(s br,1H)。

Example 16

6-cyclopentyl-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl-1, 2, 4-triazin-amine

730mg (1.870mmol) 6-cyclopentyl-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-ol are mixed with 9ml phosphorus oxychloride and stirred at room temperature overnight. The reaction mixture is diluted with 50ml of dry acetonitrile and stirred in 130ml of concentrated aqueous ammonia (25% strength) with cooling in an ice bath. Stirring was carried out at room temperature for 48h and at 50 ℃ for 24 h. After cooling, the acetonitrile was removed on a rotary evaporator, the precipitate was filtered off with suction and the filter cake was washed with a small amount of water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70 → 95: 5). This gives 508mg (70% of theory) of the title compound.

LC-MS (method 1) R_t＝0.90min；MS(ESIpos):m/z＝390(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.62-1.88(m,6H),2.01-2.09(m,2H),3.36(qint,1H),5.92(s,2H),7.16(t,1H),7.22-7.29(m,2H),7.35-7.41(m,1H),7.54(dd,1H),8.76(dd,1H),8.90(dd,1H)。

Example 17

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6-propyl-1, 2, 4-triazin-5-ol

A solution of 0.916g (7.035mmol) methyl 2-oxopentanoate in 15ml ethanol was added first and heated to reflux. Subsequently, 2.000g (7.035mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboximidoyl hydrazide suspended in 20ml of ethanol was added and the mixture was heated under reflux overnight. After cooling, the mixture is filtered with suction and the filter cake is washed with a little ethanol and dried under high vacuum. This gives 1.75g of the expected compound (purity 92%; 63% of theory).

LC-MS (method 1) R_t＝0.96min；MS(ESIpos):m/z＝365(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝0.95(t,3H),1.66(sext,2H),2.60(t,2H),5.90(s,2H),7.15(t,1H),7.22-7.27(m,2H),7.35-7.40(m,1H),7.50(dd,1H),8.73(s,1H),8.75(dd,1H),14.27(s br,1H)。

Example 18

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6-propyl-1, 2, 4-triazin-5-amine

1.730g (4.748mmol) of 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6-propyl-1, 2, 4-triazin-5-ol are mixed with 23ml of phosphorus oxychloride and stirred at room temperature overnight. The reaction mixture is diluted with 100ml of dry acetonitrile and stirred in 330ml of concentrated aqueous ammonia (25% strength) with cooling in an ice bath. Stirring was carried out at room temperature for 48h and at 50 ℃ for 24 h. After cooling, the mixture is concentrated on a rotary evaporator, the residue is stirred with 200ml of water and filtered with suction, and the filter cake is washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70 → 95: 5). This gives 1.360g (60% of theory) of the target mixture.

LC-MS (method 1) R_t＝0.82min；MS(ESIpos):m/z＝364(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.00(t,3H),1.72(sext,2H),2.76(t,2H),5.92(s,2H),7.16(t,1H),7.22-7.28(m,2H),7.35-7.41(m,1H),7.53(dd,1H),8.76(dd,1H),8.89(dd,1H)。

Example 19

6-Ethyl-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-ol

A solution of 0.817g (7.035mmol) of methyl 2-oxobutanoate in 15ml of ethanol is initially added and heated to reflux. Subsequently, 2.000g (7.035mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboximidoyl hydrazide suspended in 20ml of ethanol was added and the mixture was heated under reflux overnight. After cooling, the mixture is filtered with suction and the filter cake is washed with a little ethanol and dried under high vacuum. This gives 1.83g of the expected mixture (74% of theory).

LC-MS (method 5) R_t＝1.98min；MS(ESIpos):m/z＝351(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.17(t,3H),2.66(q,2H),5.90(s,2H),7.15(t,1H),7.22-7.27(m,2H),7.35-7.41(m,1H),7.50(dd,1H),8.73(s,1H),8.75(d,1H),14.25(s br,1H)。

Example 20

6-Ethyl-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-amine

1.800g (5.138mmol) 6-ethyl-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-5-ol are mixed with 25ml phosphorus oxychloride and stirred at room temperature overnight. The reaction mixture is diluted with 100ml of dry acetonitrile and stirred in 375ml of concentrated aqueous ammonia (25% strength) with cooling in an ice bath. Stir at room temperature for 4 h. Concentration was performed on a rotary evaporator and the residue was partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70 → 95: 5). This gives 157mg (8% of theory) of the target compound.

LC-MS (method 1) R_t＝0.81min；MS(ESIpos):m/z＝350(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.26(t,3H),2.80(q,2H),5.92(s,2H),7.16(t,1H),7.22-7.29(m,2H),7.35-7.41(m,1H),7.54(dd,1H),8.76(dd,1H),8.89(dd,1H)。

Example 21

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6-isopropyl-1, 2, 4-triazin-5-ol

A solution of 1.014g (7.035mmol) of ethyl 3-methyl-2-oxobutanoate in 15ml of ethanol was initially added and heated to reflux. Subsequently, 2.000g (7.035mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboximidoyl hydrazide suspended in 20ml of ethanol was added and the mixture was heated under reflux overnight. After cooling, the mixture is filtered with suction and the filter cake is washed with a little ethanol and dried under high vacuum. This gives 918mg of the target compound (36% of theory).

LC-MS (method 1) R_t＝1.01min；MS(ESIpos):m/z＝365(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.20(d,6H),3.22(sept,1H),5.90(s,2H),7.15(t,1H),7.22-7.27(m,2H),7.35-7.40(m,1H),7.49-7.52(m,1H),8.73(s,1H),8.75(dd,1H),14.30(s br,1H)。

Example 22

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6-isopropyl-1, 2, 4-triazin-5-amine

900mg (5.138mmol) of 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6-isopropyl-1, 2, 4-triazin-5-ol are mixed with 12ml of phosphorus oxychloride and stirred at room temperature overnight. The reaction mixture was diluted with 50ml of dry acetonitrile and stirred in 173ml of concentrated aqueous ammonia (25% strength) with cooling in an ice bath. The reaction mixture was stirred at room temperature for 2h and at 50 ℃ for 6 h. After cooling, concentrate on a rotary evaporator. The residue was partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The residue is stirred with diethyl ether, filtered off with suction and dried under high vacuum. 266mg (purity 92%, 27% of theory) of the target compound are thus obtained.

LC-MS (method 2) R_t＝0.82min；MS(ESIpos):m/z＝364(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.28(d,6H),3.24(sept,1H),5.84(s,2H),7.12-7.26(m,3H),7.33-7.39(m,1H),7.41(dd,1H),8.66(d,1H),8.91(d,1H)。

Example 23

3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -6- (1-fluoroethyl) -1,2, 4-triazin-5-amine

290mg (purity 95%, 0.671mmol) of 2- { 5-amino-3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -1,2, 4-triazin-6-yl } -2-fluoropropanamide are initially added to 2.6ml of acetic acid and 2 drops of 1N hydrochloric acid are added. The mixture was stirred in a microwave at 100 ℃ for 30 min. After cooling, the reaction solution was mixed with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 30:70 → 95: 5). This gives 23mg (89% pure, 8% of theory) of the target compound.

LC-MS (method 1) R_t＝0.88min；MS(ESIpos):m/z＝368(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.76(dd,3H),5.86(s,2H),6.03(dq,1H),7.13-7.26(m,3H),7.34-7.40(m,1H),7.44(dd,1H),7.50(s br,1H),8.24(s br,1H),8.69(dd,1H),8.92(dd,1H)。

B.Pharmacological efficacy assessment

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

B-1.in vitro vasodilatory Effect

Rabbits were stunned by knocking the neck and exsanguinated. The aorta was removed, adherent tissue removed, and it was divided into 1.5mm wide rings. The rings were placed independently under initial tension in a 5ml organ bath containing a Krebs-Henseleit solution aerated with carbopol gas at 37 ℃ 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 measured with Statham UC2 cells, amplified and digitized with an A/D sensor (DAS-1802HC, Keithley Instruments Munich) and recorded in parallel in a linear 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 method was used to calculate the concentration (IC) required to reduce the level of the control value by 50%₅₀Value). The standard dose volume was 5. mu.l, and the DMSO content in the bath solution corresponded to 0.1%.

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

TABLE 1：

Example numbering	IC₅₀[nM]
		11	2960
12	112
		13	2630
14	52
		15	1090
16	25
		18	30
20	30
		21	916
22	27
		23	23

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

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

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

TABLE 2：

Example numbering	MEC[μM]
		1	0.1
2	0.1
		3	0.3
4	0.03
		5	0.1
6	0.1
		7	0.1
8	0.1
		9	0.1
10	0.1
		11	1.0
12	0.3
		13	3.0
14	0.03
		15	1.0
16	0.03
		17	1.0
18	0.1
		19	1.0
20	0.1
		21	0.3
22	0.1
		23	0.1

B-3.Radio telemetric measurement of blood pressure in conscious rats with spontaneous hypertension

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

The system consists of three main components:

-an implantable emitter(s) (ii)telemetry transmitter)

A receiver (a)receiver) connected to the multiplexer (DSI Data exchange matrix)

-a data acquisition computer.

The telemetry system enables continuous acquisition of blood pressure, heart rate and body movements of a conscious animal in its common habitat.

Animal material

The study was carried out in adult female rats (SHR Okamoto) weighing >200g with spontaneous hypertension. 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 F13 was handed to the national Institutes of Health (U.S.A.).

Experimental animals were housed individually in Makrolon type 3 cages after emitter implantation. They can freely ingest standard feed and water.

The day/night rhythm was altered in the test laboratory by indoor lighting at 6:00am and 7:00 pm.

Emitter implantation

The telemetry transmitter used, TA11PA-C40, was surgically implanted into experimental animals under sterile conditions at least 14 days prior to the first experimental use. Animals equipped with the apparatus described above can be reused after wound healing and transmitter incorporation.

For implantation, fasted animals were anesthetized with pentobarbital (Nembutal, Sanofi:50mg/kg i.p.) and a large area of their abdomen was shaved and disinfected. After opening the abdominal cavity along the albedo line, the fluid filled detection catheter of the system was inserted into the descending aorta in the cranial direction above the bifurcation point and fixed with tissue glue (VetBonD TM, 3M). The emitter is secured within the abdominal cavity to the abdominal wall muscles, and the wound is sutured in layers.

To prevent infection, antibiotics (Tardomyocel COMP, Bayer,1ml/kg, subcutaneous injection) were administered post-operatively.

Substances and solutions

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

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

Procedure of experiment

The ready-to-use telemetry measurement unit was configured for 24 animals. Each experiment was individually reported as the experimental group number (V years, months, days).

Each rat equipped with equipment that survived the system was assigned a separate receive antenna (1010Receiver, DSI).

The implanted transmitter may be externally activated by a built-in magnetic switch. It is switched to transmit at the start of the trial. The transmitted signal may be detected online by a data acquisition system (data request (TM) a.r.t.for WINDOWS, DSI) and processed accordingly. The data are each stored in a file created for this purpose and having the experiment number.

In the standard procedure, the following parameters 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 measurement data was repeated under computer control at 5 minute intervals. The source data obtained as absolute values are corrected in a table with the currently measured air pressure (ambient pressure reference monitor; APR-1) and stored as separate data. Further technical details are given in the manufacturer's (DSI) details.

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

Evaluation of

At the end of the experiment, the individual data collected were sorted using analytical software (DATAQUEST. TM. A.R.T.TMANALYSIS). Blank values were set 2 hours prior to dosing, so the data set selected comprised a time period from 7:00 am on the day of the experiment to 9:00am on the following day.

The data were smoothed over a predetermined time by measuring the mean (15-minute mean) and transferred to the storage medium in the form of a text file. The measurements pre-classified and compressed in this way were transferred to Excel templates and tabulated. For each day of the trial, the data obtained is stored in a designated file with the trial number. Results and experimental protocols are filed in a paper form according to numbers in a classified mode.

Literature reference

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

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

Pharmacokinetic parameters of the compounds of the invention were determined in male CD-1 mice, male Wistar rats and female beagle dogs. For mice and rats, species-specific plasma/DMSO formulations were used for intravenous administration, and for dogs, water/PEG 400/ethanol formulations were used for intravenous administration. In all species, oral administration of the dissolved substance was performed by gavage, based on a water/PEG 400/ethanol formulation. Blood removal from rats was simplified by inserting a silicone catheter into the right external jugular vein prior to administration of the substance. Surgery was performed at least one day prior to the experiment and anesthetized with isoflurane and an analgesic (atropine/ibuprofen (rimadyl) (3/1)0.1ml, administered subcutaneously). Blood was taken within a time window comprising a terminal time point of at least 24h to a maximum of 72h after administration of the substance (typically more than 10 time points). Blood was transferred to heparinized tubes. Plasma was then obtained by centrifugation; if desired, it can be stored at-20 ℃ until further processing.

Internal standards (which may also be chemically unrelated substances) are added to samples, calibration samples and standards (qualifier) of the compounds of the invention, followed by protein precipitation by excess 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.

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

Since the mass spectrometry is carried out in plasma, the blood/plasma distribution of the substance must be determined in order to be able to adjust the pharmacokinetic parameters accordingly. For this purpose, defined amounts of substances were incubated in heparinized whole blood of the species for 20min in a roller mixer (tumbling roller mixer). After 1000g centrifugation, measured (by LC-MS/MS, see above) and calculated by c_{Blood, blood-enriching agent and method for producing the same}/c_{Blood plasma}The plasma concentration is determined by the ratio of (a) to (b).

B-5.Metabolic studies

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

The compounds of the invention are incubated at a concentration of about 0.1-10. mu.M. For this purpose, acetonitrile stock solutions of the compounds of the invention at concentrations of 0.01-1mM are prepared and pipetted at 1:100 dilution into the incubation mixture. Incubating the liver microsomes and the recombinant enzyme at 37 ℃ in 50mM, pH 7.4 potassium phosphate buffer with and without an NADPH-producing system consisting of 1mM NADP⁺10mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase. Primary hepatocytes were incubated suspended in William E medium, also at 37 ℃. After incubation for 0-4h, the incubation mixture was stopped with acetonitrile (final concentration of about 30%) and the protein was centrifuged off at about 15000x g. 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 incubated sample was chromatographed using a suitable C18 reverse phase column and a variable mobile phase mixture (acetonitrile and 10mM aqueous ammonium formate or 0.05% formic acid). The UV chromatograms are combined with mass spectral data for identification, structural analysis and quantitative estimation of 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 pharmaceutical preparations as follows:

tablet formulation：

Composition of：

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

The tablets weighed 212mg, had a diameter of 8mm and a radius of curvature of 12 mm.

Preparation of：

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

Orally administrable suspensions：

Composition of：

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

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

Preparation of：

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

Orally administrable solutions：

Composition of：

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

Preparation of：

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

Solution for intravenous administration：

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 the formula (I),

wherein

Ring Q is a group of the formula

Wherein

Is and-CH₂-R²The attachment site(s) of (a),

is a site of attachment to the triazine ring,

R^1ais hydrogen or fluorine, and can be used as the active ingredient,

R^1bis hydrogen or a methyl group,

R¹is halogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₄) Alkyl, hydroxy, or hydroxy group,

Oxo or (C)₁-C₄) An alkoxy group,

n is a number 0, 1 or 2,

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

and is

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

and is

R⁴is a hydroxyl group or an amino group,

and salts thereof.

2. A process for the preparation of a compound of formula (I) as defined in claim 1, characterized in that

[A] A compound of formula (II)

Wherein n, Q, R¹And R²Each having the meaning specified in claim 1,

Wherein

R^3AIs phenyl, pyrazolyl, oxazolyl or pyridyl,

and is

T¹Is hydrogen or (C)₁-C₄) Alkyl, or two T¹The radicals together forming-C (CH)₃)₂-C(CH₃)₂-a bridge for connecting the bridge to the ground,

to give a compound of the formula (I-A)

Wherein n, Q, R¹、R²And R^3AEach having the meaning as specified above, are,

or

[B] A compound of formula (IV)

Wherein n, Q, R¹And R²Each having the meaning specified in claim 1,

with a compound of formula (V) in an inert solvent

Wherein R is^3BIs difluoromethyl, trifluoromethyl, (C)₁-C₆) Alkyl, cyclopropyl, cyclobutyl or cyclopentyl,

and is

T²Is (C)₁-C₄) An alkyl group, a carboxyl group,

to give a compound of the formula (I-B)

Wherein n, Q, R¹、R²And R^3BEach having the meaning as specified above, are,

or

[C] Converting the compound of formula (I-B) to the compound of formula (VI) with phosphorus oxychloride

Wherein n, Q, R¹、R²And R^3BEach having the meaning as specified above, are,

directly reacting the compound with ammonia to obtain the compound of formula (I-C)

Wherein n, Q, R¹、R²And R^3BEach having the meaning as specified above, are,

and the resulting compounds of the formulae (I-A), (I-B) and (I-C) are converted, if appropriate with the appropriate (ii) acid or base, into their salts.

3. Use of a compound of formula (I) as defined in claim 1 for the preparation of a medicament for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, ischemia, vascular diseases, renal insufficiency and fibrotic diseases.

4. The use according to claim 3, wherein the compound is used for the preparation of a medicament for the treatment and/or prophylaxis of thromboembolic disorders, arteriosclerosis.

5. The use according to claim 3, wherein the compound is used for the preparation of a medicament for the treatment and/or prevention of pulmonary hypertension.

6. A medicament comprising a compound of formula (I) as defined in claim 1, together with inert, non-toxic pharmaceutically suitable excipients.

7. A medicament comprising a compound of formula (I) as defined in claim 1, and a further active compound selected from NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modulators.

8. The medicament of claim 7, wherein the further active compound is selected from organic nitrates.

9. The medicament according to any one of claims 6 to 8 for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, ischemia, vascular diseases, renal insufficiency and fibrotic diseases.

10. The medicament according to claim 9, which is used for the treatment and/or prevention of thromboembolic diseases, arteriosclerosis.

11. The medicament according to claim 9 for the treatment and/or prophylaxis of pulmonary hypertension.